miladalsh/processed_scinews_dataset · Datasets at Hugging Face

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Temozolomide (TMZ) is an oral alkylating agent used for the treatment of glioblastoma and is now becoming a chemotherapeutic option in patients diagnosed with high-risk low-grade gliomas. The O-6-methylguanine-DNA methyltransferase (MGMT) is responsible for the direct repair of the main TMZ-induced toxic DNA adduct, the O6-Methylguanine lesion. MGMT promoter hypermethylation is currently the only known biomarker for TMZ response in glioblastoma patients. Here we show that a subset of recurrent gliomas carries MGMT genomic rearrangements that lead to MGMT overexpression, independently from changes in its promoter methylation. By leveraging the CRISPR/Cas9 technology we generated some of these MGMT rearrangements in glioma cells and demonstrated that the MGMT genomic rearrangements contribute to TMZ resistance both in vitro and in vivo. Lastly, we showed that such fusions can be detected in tumor-derived exosomes and could potentially represent an early detection marker of tumor recurrence in a subset of patients treated with TMZ. Introduction The therapeutic benefits of TMZ depend on its ability to methylate DNA, which takes place at the N-7 and O6 positions of guanine and N-3 position of adenine. Although the minor product O6-methylguanine (O6-meG) accounts for <10% of total alkylation, it exerts the greatest potential for apoptosis induction 1 . O6-meG pairs with thymine as opposed to cytosine during DNA replication. The O6-meG:thymine mismatch can be recognized by the post-replication mismatch repair (MMR) system and, according to the futile repair hypothesis, ultimately induces DNA double-strand breaks, cell-cycle arrest, and cell death 2 . The O6-methylguanine-DNA methyltransferase (MGMT) is responsible for the direct repair of O6-meG lesion by transferring the alkyl group from guanine to a cysteine residue. Epigenetic silencing, due to promoter methylation, of the MGMT gene prevents the synthesis of this enzyme, and as a consequence increases the tumors sensitivity to the cytotoxic effects induced by TMZ and other alkylating compounds 3 , 4 . As today, MGMT promoter hypermethylation is the only known biomarker for TMZ response 4 . However, the discordance between promoter methylation and protein expression detected in a subset of patients limits the prognostic value of methylation assessment 5 , 6 . Moreover, while MGMT methylation at diagnosis predicts longer survival, this is not the case at recurrence 7 . These evidence would suggest that other mechanisms, in addition to promoter methylation, could contribute to MGMT upregulation in the recurrent tumors 5 , 7 . According to the 2016 WHO classification, that integrates both histological and molecular features, diffuse gliomas can be divided in IDH -wildtype or IDH -mutant, by the presence of mutations in the isocitrate dehydrogenase 1 and 2 ( IDH1/2 ) genes 8 . TMZ is the standard chemotherapeutic approach in IDH -wildtype gliomas, such as glioblastomas, and, more recently in high-risk IDH -mutant gliomas 9 . By analyzing a large cohort of IDH -wildtype and mutant recurrent gliomas treated with TMZ, we have discovered that a subset of patients carries distinct MGMT genomic rearrangements. These MGMT alterations lead to MGMT overexpression, independently from changes in its promoter methylation, and contribute to TMZ resistance both in vitro and in vivo. Results Identification of MGMT gene fusions in recurrent gliomas To reveal the landscape of TMZ resistance in glioma patients, we analyzed RNA-sequencing data of 252 TMZ-treated recurrent gliomas, among which 105 (42%) were newly collected (Supplementary Fig. 1a, b and Supplementary Data 1 ). We then integrated clinical information and performed bioinformatics analysis to determine the mutational status of several key alterations (“Methods”). Overall, we found IDH1 mutation in 38.4% (94 out of 245) patients, 1p/19q co-deletion in 9.4% (23 out of 245) patients, MGMT promoter hypomethylation in 38% (52 out of 136) patients, and DNA hypermutation in 10.7% (27 out of 252) patients (Fig. 1a ). By analyzing the RNA-seq data of 252 recurrent gliomas, we identified eight different MGMT fusions in seven patients (~3% of all patients, 95% CI, 1.1–5.6%) (Supplementary Data 1 and Supplementary Table 1 ). Of note, among the seven patients who harbor MGMT fusions, six are females, which is significantly higher than expected ( P = 0.015, Fisher exact test, Supplementary Fig. 1c ). Importantly, there was significant mutual-exclusiveness between MGMT hypomethylation, DNA hypermutation and MGMT fusion as revealed by a bootstrapping method ( P < 10 −4 , see “Methods”), suggesting these alterations were carrying out alternative roles during cancer progression. Fig. 1: Multiple MGMT fusions in TMZ-treated recurrent gliomas. a Landscape of MGMT hypomethylation, MGMT fusions, DNA hypermutation. b Circos plot showing the identified MGMT fusions. c Structure of the MGMT fusion proteins. Each partner gene is indicated by color, and the narrow bars in SAR1A-MGMT, RPH3A-MGMT, and CTBP2-MGMT mean 5′UTR. d , e Validation of the MGMT fusion genes in positive samples by PCR and Sanger sequencing. The bands in the left panel were validated by Sanger sequencing in the right panel. Limited by specimen availability the validation was performed once. f The genomic rearrangement generating FAM175B-MGMT fusion. WGS whole-genome sequencing. Source data are provided as a Source Data file. Full size image Gliomas with MGMT fusions or hypomethylated MGMT promoter had significantly higher MGMT expression, while the DNA hypermutated patients showed the lowest MGMT expression, even lower than the MGMT-methylated tumors (Supplementary Fig. 1d , P -values calculated by Wilcoxon rank-sum test). Interestingly, we found that in IDH -wild-type glioma patients, high MGMT expression indicates worse survival ( P = 0.02, log-rank test, Supplementary Fig. 1e ), while it is associated to a trend of better survival in IDH -mutant patients ( P = 0.04, log-rank test, Supplementary Fig. 1f ). We next performed an in-depth investigation of the eight different MGMT rearrangements: BTRC - MGMT , CAPZB - MGMT , GLRX3 - MGMT , NFYC - MGMT , RPH3A - MGMT , and SAR1A - MGMT in HGG, and CTBP2 - MGMT and FAM175B - MGMT in LGG (Fig. 1b ). Five of the eight partner genes located on chromosome 10q, mostly close to MGMT (Fig. 1b ). Interestingly, although the left partners of the MGMT fusions were different,", "role": "user" }, { "content": "A team led by Massimo Squatrito, Head of the Seve Ballesteros Foundation Brain Tumor Group at the Spanish National Cancer Research Centre (CNIO), has made important findings of how some gliomas can acquire chemoresistance. Carried out together with the laboratory of Jiguang Wang from the Hong Kong University of Science and Technology (HKUST) and a clinical team led by Tao Jiang from Beijing Neurological Institute, and published in Nature Communications, the study provides new clues on how to monitor the efficacy of therapy. At present, the main, and virtually only, treatment for glioma—a very common type of tumor originating in the brain—is a combination of radiotherapy and the chemotherapy agent temozolomide. This type of treatment can improve patients' survival rates by up to 30%. Similar to most of the chemotherapy drugs, temozolomide induces DNA damage in cancer cells. Gliomas can progress by repairing this damage through an enzyme encoded by the MGMT gene. In patients whose MGMT activity is blocked because of a modification of its promoter called 'hypermethylation', cancer cells cannot repair the temozolomide-induced damage and collapse. Unfortunately, up to 40-50% of patients are intrinsically resistant to temozolomide. These patients express high levels of MGMT and the tumor continue growing under treatment. Now, the recent study carried out by the CNIO and the HKUST team shows that a subset of patients acquires a specific genetic alteration that can evade the combined therapy. Control changes hands \"Translocation of the MGMT gene was observed in a group of patients,\" says Massimo Squatrito. \"These genomic rearrangements involve the fusion of MGMT with other genes, which means that MGMT is now regulated by the promoters it is fused with, that contributes to its overexpression. When this type of rearrangements take place, the temozolomide-induced DNA damage is very efficiently repaired and the glioma continues growing even under treatment.\" The team at the HKUST validated the presence of the genetic rearrangement in a subset of a large cohort of recurrent tumors, coming from different hospitals, mainly from Beijing Tiantan Hospital. Using the CRISPR-Cas9 genomic editing tool, the team at CNIO replicated some of these translocations in different cell and animal models and confirmed that they can confer resistance to temozolomide. \"It appears that the translocations are not present in the original tumor, only in recurrent ones, that are, tumors that emerge after the original cancer is treated,\" Squatrito says. \"This indicates that the resistance may occur as a consequence to the treatment itself.\" The findings may lead to changes in the methods to monitor therapy efficacy: \"Currently, the only known therapeutic biomarker in gliomas is the analysis of MGMT promoter status. When methylated, the MGMT gene is silenced and the patient is predicted to respond to temozolomide. The study shows this method is no longer valid when there has been a genetic translocation. The promoter might still be blocked, but the gene is being overactivated by other promoters and hence could contribute to tumor recurrence.\" Another relevant finding from animal models is that the MGMT translocations are present in exosomes—extracellular vesicles released by glioma cells into the bloodstream. \"If this finding is validated in patients, it could become a useful tool for early resistance detection. A liquid biopsy, that is, a simple test using blood samples, could tell us when patients are developing resistance to temozolomide, and they could be advised to switch to other therapeutic options when they will become available.\" The next step will be identifying novel treatment intervention for the temozolomide resistant patients. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Temozolomide (TMZ) is an oral alkylating agent used for the treatment of glioblastoma and is now becoming a chemotherapeutic option in patients diagnosed with high-risk low-grade gliomas. The O-6-methylguanine-DNA methyltransferase (MGMT) is responsible for the direct repair of the main TMZ-induced toxic DNA adduct, the O6-Methylguanine lesion. MGMT promoter hypermethylation is currently the only known biomarker for TMZ response in glioblastoma patients. Here we show that a subset of recurrent gliomas carries MGMT genomic rearrangements that lead to MGMT overexpression, independently from changes in its promoter methylation. By leveraging the CRISPR/Cas9 technology we generated some of these MGMT rearrangements in glioma cells and demonstrated that the MGMT genomic rearrangements contribute to TMZ resistance both in vitro and in vivo. Lastly, we showed that such fusions can be detected in tumor-derived exosomes and could potentially represent an early detection marker of tumor recurrence in a subset of patients treated with TMZ. Introduction The therapeutic benefits of TMZ depend on its ability to methylate DNA, which takes place at the N-7 and O6 positions of guanine and N-3 position of adenine. Although the minor product O6-methylguanine (O6-meG) accounts for <10% of total alkylation, it exerts the greatest potential for apoptosis induction 1 . O6-meG pairs with thymine as opposed to cytosine during DNA replication. The O6-meG:thymine mismatch can be recognized by the post-replication mismatch repair (MMR) system and, according to the futile repair hypothesis, ultimately induces DNA double-strand breaks, cell-cycle arrest, and cell death 2 . The O6-methylguanine-DNA methyltransferase (MGMT) is responsible for the direct repair of O6-meG lesion by transferring the alkyl group from guanine to a cysteine residue. Epigenetic silencing, due to promoter methylation, of the MGMT gene prevents the synthesis of this enzyme, and as a consequence increases the tumors sensitivity to the cytotoxic effects induced by TMZ and other alkylating compounds 3 , 4 . As today, MGMT promoter hypermethylation is the only known biomarker for TMZ response 4 . However, the discordance between promoter methylation and protein expression detected in a subset of patients limits the prognostic value of methylation assessment 5 , 6 . Moreover, while MGMT methylation at diagnosis predicts longer survival, this is not the case at recurrence 7 . These evidence would suggest that other mechanisms, in addition to promoter methylation, could contribute to MGMT upregulation in the recurrent tumors 5 , 7 . According to the 2016 WHO classification, that integrates both histological and molecular features, diffuse gliomas can be divided in IDH -wildtype or IDH -mutant, by the presence of mutations in the isocitrate dehydrogenase 1 and 2 ( IDH1/2 ) genes 8 . TMZ is the standard chemotherapeutic approach in IDH -wildtype gliomas, such as glioblastomas, and, more recently in high-risk IDH -mutant gliomas 9 . By analyzing a large cohort of IDH -wildtype and mutant recurrent gliomas treated with TMZ, we have discovered that a subset of patients carries distinct MGMT genomic rearrangements. These MGMT alterations lead to MGMT overexpression, independently from changes in its promoter methylation, and contribute to TMZ resistance both in vitro and in vivo. Results Identification of MGMT gene fusions in recurrent gliomas To reveal the landscape of TMZ resistance in glioma patients, we analyzed RNA-sequencing data of 252 TMZ-treated recurrent gliomas, among which 105 (42%) were newly collected (Supplementary Fig. 1a, b and Supplementary Data 1 ). We then integrated clinical information and performed bioinformatics analysis to determine the mutational status of several key alterations (“Methods”). Overall, we found IDH1 mutation in 38.4% (94 out of 245) patients, 1p/19q co-deletion in 9.4% (23 out of 245) patients, MGMT promoter hypomethylation in 38% (52 out of 136) patients, and DNA hypermutation in 10.7% (27 out of 252) patients (Fig. 1a ). By analyzing the RNA-seq data of 252 recurrent gliomas, we identified eight different MGMT fusions in seven patients (~3% of all patients, 95% CI, 1.1–5.6%) (Supplementary Data 1 and Supplementary Table 1 ). Of note, among the seven patients who harbor MGMT fusions, six are females, which is significantly higher than expected ( P = 0.015, Fisher exact test, Supplementary Fig. 1c ). Importantly, there was significant mutual-exclusiveness between MGMT hypomethylation, DNA hypermutation and MGMT fusion as revealed by a bootstrapping method ( P < 10 −4 , see “Methods”), suggesting these alterations were carrying out alternative roles during cancer progression. Fig. 1: Multiple MGMT fusions in TMZ-treated recurrent gliomas. a Landscape of MGMT hypomethylation, MGMT fusions, DNA hypermutation. b Circos plot showing the identified MGMT fusions. c Structure of the MGMT fusion proteins. Each partner gene is indicated by color, and the narrow bars in SAR1A-MGMT, RPH3A-MGMT, and CTBP2-MGMT mean 5′UTR. d , e Validation of the MGMT fusion genes in positive samples by PCR and Sanger sequencing. The bands in the left panel were validated by Sanger sequencing in the right panel. Limited by specimen availability the validation was performed once. f The genomic rearrangement generating FAM175B-MGMT fusion. WGS whole-genome sequencing. Source data are provided as a Source Data file. Full size image Gliomas with MGMT fusions or hypomethylated MGMT promoter had significantly higher MGMT expression, while the DNA hypermutated patients showed the lowest MGMT expression, even lower than the MGMT-methylated tumors (Supplementary Fig. 1d , P -values calculated by Wilcoxon rank-sum test). Interestingly, we found that in IDH -wild-type glioma patients, high MGMT expression indicates worse survival ( P = 0.02, log-rank test, Supplementary Fig. 1e ), while it is associated to a trend of better survival in IDH -mutant patients ( P = 0.04, log-rank test, Supplementary Fig. 1f ). We next performed an in-depth investigation of the eight different MGMT rearrangements: BTRC - MGMT , CAPZB - MGMT , GLRX3 - MGMT , NFYC - MGMT , RPH3A - MGMT , and SAR1A - MGMT in HGG, and CTBP2 - MGMT and FAM175B - MGMT in LGG (Fig. 1b ). Five of the eight partner genes located on chromosome 10q, mostly close to MGMT (Fig. 1b ). Interestingly, although the left partners of the MGMT fusions were different,<|im_end|> <|im_start|>assistant A team led by Massimo Squatrito, Head of the Seve Ballesteros Foundation Brain Tumor Group at the Spanish National Cancer Research Centre (CNIO), has made important findings of how some gliomas can acquire chemoresistance. Carried out together with the laboratory of Jiguang Wang from the Hong Kong University of Science and Technology (HKUST) and a clinical team led by Tao Jiang from Beijing Neurological Institute, and published in Nature Communications, the study provides new clues on how to monitor the efficacy of therapy. At present, the main, and virtually only, treatment for glioma—a very common type of tumor originating in the brain—is a combination of radiotherapy and the chemotherapy agent temozolomide. This type of treatment can improve patients' survival rates by up to 30%. Similar to most of the chemotherapy drugs, temozolomide induces DNA damage in cancer cells. Gliomas can progress by repairing this damage through an enzyme encoded by the MGMT gene. In patients whose MGMT activity is blocked because of a modification of its promoter called 'hypermethylation', cancer cells cannot repair the temozolomide-induced damage and collapse. Unfortunately, up to 40-50% of patients are intrinsically resistant to temozolomide. These patients express high levels of MGMT and the tumor continue growing under treatment. Now, the recent study carried out by the CNIO and the HKUST team shows that a subset of patients acquires a specific genetic alteration that can evade the combined therapy. Control changes hands "Translocation of the MGMT gene was observed in a group of patients," says Massimo Squatrito. "These genomic rearrangements involve the fusion of MGMT with other genes, which means that MGMT is now regulated by the promoters it is fused with, that contributes to its overexpression. When this type of rearrangements take place, the temozolomide-induced DNA damage is very efficiently repaired and the glioma continues growing even under treatment." The team at the HKUST validated the presence of the genetic rearrangement in a subset of a large cohort of recurrent tumors, coming from different hospitals, mainly from Beijing Tiantan Hospital. Using the CRISPR-Cas9 genomic editing tool, the team at CNIO replicated some of these translocations in different cell and animal models and confirmed that they can confer resistance to temozolomide. "It appears that the translocations are not present in the original tumor, only in recurrent ones, that are, tumors that emerge after the original cancer is treated," Squatrito says. "This indicates that the resistance may occur as a consequence to the treatment itself." The findings may lead to changes in the methods to monitor therapy efficacy: "Currently, the only known therapeutic biomarker in gliomas is the analysis of MGMT promoter status. When methylated, the MGMT gene is silenced and the patient is predicted to respond to temozolomide. The study shows this method is no longer valid when there has been a genetic translocation. The promoter might still be blocked, but the gene is being overactivated by other promoters and hence could contribute to tumor recurrence." Another relevant finding from animal models is that the MGMT translocations are present in exosomes—extracellular vesicles released by glioma cells into the bloodstream. "If this finding is validated in patients, it could become a useful tool for early resistance detection. A liquid biopsy, that is, a simple test using blood samples, could tell us when patients are developing resistance to temozolomide, and they could be advised to switch to other therapeutic options when they will become available." The next step will be identifying novel treatment intervention for the temozolomide resistant patients. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Research has found that the appearance of women’s apparel helps increase their attractiveness as rated by men and that men care more about physical features in potential opposite-sex mates. However, the effect of sartorial appearance has received little interest from scientists. In a series of studies, the length of women’s shoe heels was examined. A woman confederate wearing black shoes with 0, 5, or 9 cm heels asked men for help in various circumstances. In Study 1, she asked men to respond to a short survey on gender equality. In Study 2, the confederate asked men and women to participate in a survey on local food habit consumption. In Study 3, men and women in the street were observed while walking in back of the female confederate who dropped a glove apparently unaware of her loss. It was found that men’s helping behavior increased as soon as heel length increased. However, heel length had no effect on women’s helping behavior. It was also found that men spontaneously approached women more quickly when they wore high-heeled shoes (Study 4). Change in gait, foot-size judgment, and misattribution of sexiness and sexual intent were used as possible explanations. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Introduction Research has found that across all cultures men care more about physical features in potential opposite-sex mates while women care more about resource features (Buss, 1989 ; Kenrick, Groth, Trost, & Sadalla, 1993 ; Shackelford, Schmitt, & Buss, 2005 ). In sex differences in human mate preferences conducted in 37 cultures, Buss ( 1989 ) reported that males value physical attractiveness in potential mates more than females do in 34 cultures (mean Cohen’s d = 0.59). Women’s physical attractiveness is important and men can therefore be influenced by various aspects of their appearance. Women’s Physical Appearance and Men’s Behavior Prior studies have indicated that different morphological features of women are associated with varied levels of attractiveness in the eyes of men. Furnham, Lavancy, and McClelland ( 2001 ), Henss ( 2000 ), Singh ( 1993 ), and Singh and Luis ( 1995 ) reported that a lower waist-to-hip ratio of women was associated with greater physical attractiveness when evaluated by men. Another important morphological factor associated with female attractiveness is breast size. Beck, Ward-Hull, and McLear ( 1976 ) found that males from the United States rated a female figure with larger than average-sized breasts more favorably than others. Wildman and Wildman ( 1976 ) found that the bust was the most sexually stimulating female body part for males and that those men preferred busts larger than what women possess on average. In a field study, Guéguen ( 2007a ) reported that men but not women drivers were more likely to stop to offer a ride to a female hitchhiker as soon as her breast size increased. In Western cultures, several studies have reported that women’s hair color influenced male behavior and judgments. Men were more likely to approach women with blond hair for a date. Swami and Barrett ( 2011 ) and Guéguen ( 2012a ) reported that the same female confederate was approached more frequently in a bar or nightclub setting as a blond than as a redhead or brunette. Lynn ( 2009 ) observed in a survey that higher waitressing tips from men were associated with having blond hair. It has also been found that men are sensitive to other female physical cues not related to morphological appearance. Sometimes slight modifications in women’s physical appearance are associated with variation in men’s reactions. Some studies have reported that women with apparent tattoos are perceived to be more sexually promiscuous by men (Swami & Furnham, 2007 ). Guéguen ( 2013 ) reported that a female confederate with a temporary tattoo placed on her lower back was more favorably approached by men and perceived as more probable to have sex on the first date. Research has shown that men’s behavior and evaluation are also affected by women’s cosmetics. Graham and Jouhar ( 1981 ) reported that photographs of female targets wearing make-up compared with the same photographs of female targets with no make-up were rated by men as being tidier, more feminine, and physically attractive, as well as being more secure, sociable, interesting, poised, confident, organized, and popular. Cox and Glick ( 1986 ) examined how average-looking women were perceived after a professional make-over compared to being cosmetics free and found that cosmetics were positively associated with femininity and sexiness. Workman and Johnson ( 1991 ) instructed participants to view one of three colored photographs of a professional model wearing either heavy, moderate, or no cosmetics. They found that cosmetics significantly enhanced the impression of attractiveness and femininity. Cash, Dawson, Davis, Bowen, and Galumbeck ( 1989 ) conducted an experiment in which American college students were photographed while wearing their typical facial cosmetics and again following the removal of their makeup. Participants rated the physical attractiveness of the women. It was found that male judgments were more favorable when the women were photographed with cosmetics than when they were without cosmetics. Female judgments, on the other hand, were not affected by the presence versus absence of make-up. Women’s Clothing Appearance and Men’s Behavior Research has also found that men react differently toward women based on their clothing appearance. Abbey ( 1987 ) found that males were more likely than females to interpret a low-cut top, shorts, tight jeans, or no bra as an indication of sexual receptiveness. Abbey, Cozzarelli, Mclaughlin, and Harnish ( 1987 ) found that female targets who wore revealing clothing were rated by men as sexier as and more seductive than those wearing non-revealing clothing. This effect was confirmed in a study by Koukounas and Letch ( 2001 ) who found that an actress wearing revealing clothing was more often perceived by male than by female observers as having greater sexual intent. Research has also reported that the color of women’s clothing was associated with", "role": "user" }, { "content": "If it's help a woman needs, maybe she should wear high heels. That's the message from Nicolas Guéguen of the Université de Bretagne-Sud in France, after he observed how helpful men are towards women in high heels versus those wearing flat, sensible shoes. The study, published in Springer's journal Archives of Sexual Behavior, is the first ever to investigate how the height of a woman's shoe heel influences how men behave towards her. Research across various cultures has shown at length how important physical features, such as body size and the style and color of a woman's clothing, influence a man's behavior towards and judgment of a woman. Even though a link between high-heeled shoes and sexiness is implied by the many models wearing such shoes in magazines and adult films, only one previous study has tested the effect of women's shoe heels on men's judgment. Guéguen therefore set out to conduct field experiments to test the influence of different shoe styles on men's helping behavior. He watched what happened when a woman in flat shoes asked people to complete a survey, and whether or not they complied more readily when she was wearing high heels. He also tested whether or not people's spontaneous urge to help changed when the same woman - again wearing shoes with different heel sizes - dropped a glove. The findings show that men's helpfulness increased along with the height of the heels a woman was wearing. However, heel height had no influence on other women's willingness to help. In the final experiment, Guéguen found that men in a bar were quicker to start chatting with a woman wearing heels than when she was wearing flat shoes. \"Women's shoe heel size exerts a powerful effect on men's behavior,\" summarizes Guéguen, who argues that the results of these studies once again reveal how men focus on women's physical attributes when judging and interacting with members of the opposite sex. He believes that more research must be done to examine whether this effect depends on a woman's shoe heel size and on any change of gait due to wearing high heels. He speculates that, because sexy female models often wear such shoes in the media, men have started to associate the wearers of high-heeled shoes with those having sexual intent. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Research has found that the appearance of women’s apparel helps increase their attractiveness as rated by men and that men care more about physical features in potential opposite-sex mates. However, the effect of sartorial appearance has received little interest from scientists. In a series of studies, the length of women’s shoe heels was examined. A woman confederate wearing black shoes with 0, 5, or 9 cm heels asked men for help in various circumstances. In Study 1, she asked men to respond to a short survey on gender equality. In Study 2, the confederate asked men and women to participate in a survey on local food habit consumption. In Study 3, men and women in the street were observed while walking in back of the female confederate who dropped a glove apparently unaware of her loss. It was found that men’s helping behavior increased as soon as heel length increased. However, heel length had no effect on women’s helping behavior. It was also found that men spontaneously approached women more quickly when they wore high-heeled shoes (Study 4). Change in gait, foot-size judgment, and misattribution of sexiness and sexual intent were used as possible explanations. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Introduction Research has found that across all cultures men care more about physical features in potential opposite-sex mates while women care more about resource features (Buss, 1989 ; Kenrick, Groth, Trost, & Sadalla, 1993 ; Shackelford, Schmitt, & Buss, 2005 ). In sex differences in human mate preferences conducted in 37 cultures, Buss ( 1989 ) reported that males value physical attractiveness in potential mates more than females do in 34 cultures (mean Cohen’s d = 0.59). Women’s physical attractiveness is important and men can therefore be influenced by various aspects of their appearance. Women’s Physical Appearance and Men’s Behavior Prior studies have indicated that different morphological features of women are associated with varied levels of attractiveness in the eyes of men. Furnham, Lavancy, and McClelland ( 2001 ), Henss ( 2000 ), Singh ( 1993 ), and Singh and Luis ( 1995 ) reported that a lower waist-to-hip ratio of women was associated with greater physical attractiveness when evaluated by men. Another important morphological factor associated with female attractiveness is breast size. Beck, Ward-Hull, and McLear ( 1976 ) found that males from the United States rated a female figure with larger than average-sized breasts more favorably than others. Wildman and Wildman ( 1976 ) found that the bust was the most sexually stimulating female body part for males and that those men preferred busts larger than what women possess on average. In a field study, Guéguen ( 2007a ) reported that men but not women drivers were more likely to stop to offer a ride to a female hitchhiker as soon as her breast size increased. In Western cultures, several studies have reported that women’s hair color influenced male behavior and judgments. Men were more likely to approach women with blond hair for a date. Swami and Barrett ( 2011 ) and Guéguen ( 2012a ) reported that the same female confederate was approached more frequently in a bar or nightclub setting as a blond than as a redhead or brunette. Lynn ( 2009 ) observed in a survey that higher waitressing tips from men were associated with having blond hair. It has also been found that men are sensitive to other female physical cues not related to morphological appearance. Sometimes slight modifications in women’s physical appearance are associated with variation in men’s reactions. Some studies have reported that women with apparent tattoos are perceived to be more sexually promiscuous by men (Swami & Furnham, 2007 ). Guéguen ( 2013 ) reported that a female confederate with a temporary tattoo placed on her lower back was more favorably approached by men and perceived as more probable to have sex on the first date. Research has shown that men’s behavior and evaluation are also affected by women’s cosmetics. Graham and Jouhar ( 1981 ) reported that photographs of female targets wearing make-up compared with the same photographs of female targets with no make-up were rated by men as being tidier, more feminine, and physically attractive, as well as being more secure, sociable, interesting, poised, confident, organized, and popular. Cox and Glick ( 1986 ) examined how average-looking women were perceived after a professional make-over compared to being cosmetics free and found that cosmetics were positively associated with femininity and sexiness. Workman and Johnson ( 1991 ) instructed participants to view one of three colored photographs of a professional model wearing either heavy, moderate, or no cosmetics. They found that cosmetics significantly enhanced the impression of attractiveness and femininity. Cash, Dawson, Davis, Bowen, and Galumbeck ( 1989 ) conducted an experiment in which American college students were photographed while wearing their typical facial cosmetics and again following the removal of their makeup. Participants rated the physical attractiveness of the women. It was found that male judgments were more favorable when the women were photographed with cosmetics than when they were without cosmetics. Female judgments, on the other hand, were not affected by the presence versus absence of make-up. Women’s Clothing Appearance and Men’s Behavior Research has also found that men react differently toward women based on their clothing appearance. Abbey ( 1987 ) found that males were more likely than females to interpret a low-cut top, shorts, tight jeans, or no bra as an indication of sexual receptiveness. Abbey, Cozzarelli, Mclaughlin, and Harnish ( 1987 ) found that female targets who wore revealing clothing were rated by men as sexier as and more seductive than those wearing non-revealing clothing. This effect was confirmed in a study by Koukounas and Letch ( 2001 ) who found that an actress wearing revealing clothing was more often perceived by male than by female observers as having greater sexual intent. Research has also reported that the color of women’s clothing was associated with<|im_end|> <|im_start|>assistant If it's help a woman needs, maybe she should wear high heels. That's the message from Nicolas Guéguen of the Université de Bretagne-Sud in France, after he observed how helpful men are towards women in high heels versus those wearing flat, sensible shoes. The study, published in Springer's journal Archives of Sexual Behavior, is the first ever to investigate how the height of a woman's shoe heel influences how men behave towards her. Research across various cultures has shown at length how important physical features, such as body size and the style and color of a woman's clothing, influence a man's behavior towards and judgment of a woman. Even though a link between high-heeled shoes and sexiness is implied by the many models wearing such shoes in magazines and adult films, only one previous study has tested the effect of women's shoe heels on men's judgment. Guéguen therefore set out to conduct field experiments to test the influence of different shoe styles on men's helping behavior. He watched what happened when a woman in flat shoes asked people to complete a survey, and whether or not they complied more readily when she was wearing high heels. He also tested whether or not people's spontaneous urge to help changed when the same woman - again wearing shoes with different heel sizes - dropped a glove. The findings show that men's helpfulness increased along with the height of the heels a woman was wearing. However, heel height had no influence on other women's willingness to help. In the final experiment, Guéguen found that men in a bar were quicker to start chatting with a woman wearing heels than when she was wearing flat shoes. "Women's shoe heel size exerts a powerful effect on men's behavior," summarizes Guéguen, who argues that the results of these studies once again reveal how men focus on women's physical attributes when judging and interacting with members of the opposite sex. He believes that more research must be done to examine whether this effect depends on a woman's shoe heel size and on any change of gait due to wearing high heels. He speculates that, because sexy female models often wear such shoes in the media, men have started to associate the wearers of high-heeled shoes with those having sexual intent. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Coral gardening plays an important role in the recovery of depleted populations of threatened Acropora cervicornis in the Caribbean. Over the past decade, high survival coupled with fast growth of in situ nursery corals have allowed practitioners to create healthy and genotypically diverse nursery stocks. Currently, thousands of corals are propagated and outplanted onto degraded reefs on a yearly basis, representing a substantial increase in the abundance, biomass, and overall footprint of A. cervicornis . Here, we combined an extensive dataset collected by restoration practitioners to document early (1–2 yr) restoration success metrics in Florida and Puerto Rico, USA. By reporting region-specific data on the impacts of fragment collection on donor colonies, survivorship and productivity of nursery corals, and survivorship and productivity of outplanted corals during normal conditions, we provide the basis for a stop-light indicator framework for new or existing restoration programs to evaluate their performance. We show that current restoration methods are very effective, that no excess damage is caused to donor colonies, and that once outplanted, corals behave just as wild colonies. We also provide science-based benchmarks that can be used by programs to evaluate successes and challenges of their efforts, and to make modifications where needed. We propose that up to 10% of the biomass can be collected from healthy, large A. cervicornis donor colonies for nursery propagation. We also propose the following benchmarks for the first year of activities for A. cervicornis restoration: (1) >75% live tissue cover on donor colonies; (2) >80% survivorship of nursery corals; and (3) >70% survivorship of outplanted corals. Finally, we report productivity means of 4.4 cm yr −1 for nursery corals and 4.8 cm yr −1 for outplants as a frame of reference for ranking performance within programs. Such benchmarks, and potential subsequent adaptive actions, are needed to fully assess the long-term success of coral restoration and species recovery programs. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Introduction In the last 20 yr, active restoration to mitigate declines in coral cover has increased worldwide and coral propagation for restoration is now considered an essential component of coral conservation and management plans (Rinkevich 2005 ; Precht 2006 ; Edwards and Gomez 2007 ; Lirman and Schopmeyer 2016 ). In 2012, over 60 restoration projects focusing on the threatened coral genus Acropora were identified in the Caribbean (Young et al. 2012 ). Once one of the Caribbean’s predominant reef-building coral genera, Acropora has suffered significant degradation from both biological and anthropogenic stressors (Jaap et al. 1988 ; Porter and Meier 1992 ) and is now listed as threatened under the Endangered Species Act (NMFS 2006 , 2014 ). The decline of acroporids leads to the loss of reef function and structural complexity, both of which are critical for reef growth, fisheries habitat, coastal protection, and overall reef biodiversity (Bruckner 2002 ; Alvarez-Filip et al. 2009 ). Adapted from terrestrial silviculture, “coral gardening” is one of the most commonly used coral propagation and restoration methods (Rinkevich 1995 ; Bowden-Kerby 2001 ; Epstein et al. 2003 ; Shafir et al. 2006 ; Shafir and Rinkevich 2008 ; Shaish et al. 2008 ). This method involves removing a limited amount of tissue and skeleton (from a few polyps to small branches) from healthy wild coral populations and propagating an initial stock within ex situ or, more commonly, in situ coral nurseries. Throughout the Caribbean, in situ coral nurseries are used to propagate a renewable source of the threatened staghorn coral, Acropora cervicornis for restoration and species recovery (Johnson et al. 2011 ). Nursery-reared corals are “outplanted” from nurseries to reef restoration sites to bridge spatial gaps between existing populations (Griffin et al. 2012 , 2015 ), enhance A. cervicornis abundance, supplement genetic and genotypic diversity (Lirman and Schopmeyer 2016 ), and promote natural recovery through the creation of sexually reproductive populations (Baums 2008 ). Acropora cervicornis is considered a good candidate for use in restoration projects due to its high growth rates, natural use of fragmentation for asexual reproduction, ability to heal wounds, and high survivorship of fragments compared to other coral species (Gladfelter et al. 1978 ; Tunnicliffe 1981 ; Bak and Criens 1982 ; Highsmith 1982 ; Lirman et al. 2010 , 2014a ). The ability of coral propagation and restoration programs to create renewable sources of corals for use in restoration using low-cost, science-based methods has been well documented (Soong and Chen 2003 ; Lirman et al. 2010 , 2014a ; Rinkevich 2014 ). While long-term monitoring is required by permitting agencies for many, if not all, restoration projects, few studies have published the impacts of collection on existing wild populations used to populate coral nurseries (Epstein et al. 2001 ; Shafir et al. 2006 ; Lirman et al. 2010 ), or the success of restoration projects over the course of more than a few months (Bruckner and Bruckner 2001 ; Griffin et al. 2015 ) especially in the Caribbean where coral gardening activities generally began more recently than in the Red Sea and the Pacific. This information is needed to evaluate the performance of restoration efforts. These knowledge gaps within the literature can lead to criticism of restoration or population enhancement programs and questions the ability of such programs to successfully create functioning populations (Rinkevich 2014 ). In this study, we address these gaps by evaluating the effects of fragment collection on donor colonies, documenting the success of coral propagation within in situ coral nurseries, and tracking the survival and productivity of nursery-reared corals for up to 2 yr after outplanting in Florida and Puerto Rico, USA. Based on our analyses, which combine information from thousands of staghorn corals during “normal” conditions (i.e., no disease or thermal stress) from >120 distinct genotypes from six geographical regions, we propose coral propagation and outplanting benchmarks that may be used by existing and new restoration programs to assess performance and progress towards restoration goals. Materials and methods Beginning in 2009, funding was received as", "role": "user" }, { "content": "A new study found that Caribbean staghorn corals (Acropora cervicornis) are benefiting from \"coral gardening,\" the process of restoring coral populations by planting laboratory-raised coral fragments on reefs. The research, led by scientists at the University of Miami (UM) Rosenstiel School of Marine and Atmospheric Science and partners, has important implications for the long-term survival of coral reefs worldwide, which have been in worldwide decline from multiple stressors such as climate change and ocean pollution. \"Our study showed that current restoration methods are very effective,\" said UM Rosenstiel school coral biologist Stephanie Schopmeyer, the lead author of the study. \"Healthy coral reefs are essential to our everyday life and successful coral restoration has been proven as a recovery tool for lost coastal resources.\" In the study, the researchers set out to document restoration success during their initial two years at several coral restoration sites in Florida and Puerto Rico. Their findings showed that current restoration methods are not causing excess damage to donor colonies as a result of removing coral tissue to propagate new coral in the lab, and that once outplanted, corals behave just as wild colonies do. Staghorn coral populations have declined as much as 90% in the Caribbean since the 1980s. As a result, the species was listed as threatened under the U.S. Endangered Species Act in 2006 to help protect and conserve these species that form the foundation of the biologically rich coral reef habitats. The findings, published in the of the journal Coral Reefs, offers a guide for successful restoration and recovery efforts of the threatened species worldwide. Thousands of corals are raised in laboratories and planted onto degraded reefs each year. This study is the first to collect baseline coral restoration survival and productivity data at regional scales including data from 1,000s of individual A. cervicornis colonies, more than 120 distinct genotypes within six geographical regions to develop benchmarks to fully assess the progress and impacts of the region's coral and reef restoration efforts. Coral reefs provide many goods and services including fisheries habitat, food for humans and other ocean species, and protection against natural hazards such as hurricanes. As a result, coral restoration is viewed as an effective and cost-efficient strategy to buffer coastlines from the effects of storm surge and sea-level rise. \"Coral reefs are declining at an alarming rate and coral restoration programs are now considered an essential component to coral conservation and management plan,\" said Diego Lirman, UM Rosenstiel School professor of marine biology and ecology and a coauthor of the study. \"Our findings provide the necessary scientific benchmarks to evaluate restoration progress moving forward.\" The study was conducted in collaboration with U.S. Acropora Recovery Program partners: Nova Southeastern University, University of Miami, Florida Fish and Wildlife Conservation Commission, Mote Marine Laboratory, The Nature Conservancy, and the National Oceanic and Atmospheric Administration (NOAA). The public can get involved in restoration through the UM Rescue-a-Reef program, where citizen scientists help plant nursery-grown corals onto depleted reefs alongside scientists. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Coral gardening plays an important role in the recovery of depleted populations of threatened Acropora cervicornis in the Caribbean. Over the past decade, high survival coupled with fast growth of in situ nursery corals have allowed practitioners to create healthy and genotypically diverse nursery stocks. Currently, thousands of corals are propagated and outplanted onto degraded reefs on a yearly basis, representing a substantial increase in the abundance, biomass, and overall footprint of A. cervicornis . Here, we combined an extensive dataset collected by restoration practitioners to document early (1–2 yr) restoration success metrics in Florida and Puerto Rico, USA. By reporting region-specific data on the impacts of fragment collection on donor colonies, survivorship and productivity of nursery corals, and survivorship and productivity of outplanted corals during normal conditions, we provide the basis for a stop-light indicator framework for new or existing restoration programs to evaluate their performance. We show that current restoration methods are very effective, that no excess damage is caused to donor colonies, and that once outplanted, corals behave just as wild colonies. We also provide science-based benchmarks that can be used by programs to evaluate successes and challenges of their efforts, and to make modifications where needed. We propose that up to 10% of the biomass can be collected from healthy, large A. cervicornis donor colonies for nursery propagation. We also propose the following benchmarks for the first year of activities for A. cervicornis restoration: (1) >75% live tissue cover on donor colonies; (2) >80% survivorship of nursery corals; and (3) >70% survivorship of outplanted corals. Finally, we report productivity means of 4.4 cm yr −1 for nursery corals and 4.8 cm yr −1 for outplants as a frame of reference for ranking performance within programs. Such benchmarks, and potential subsequent adaptive actions, are needed to fully assess the long-term success of coral restoration and species recovery programs. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Introduction In the last 20 yr, active restoration to mitigate declines in coral cover has increased worldwide and coral propagation for restoration is now considered an essential component of coral conservation and management plans (Rinkevich 2005 ; Precht 2006 ; Edwards and Gomez 2007 ; Lirman and Schopmeyer 2016 ). In 2012, over 60 restoration projects focusing on the threatened coral genus Acropora were identified in the Caribbean (Young et al. 2012 ). Once one of the Caribbean’s predominant reef-building coral genera, Acropora has suffered significant degradation from both biological and anthropogenic stressors (Jaap et al. 1988 ; Porter and Meier 1992 ) and is now listed as threatened under the Endangered Species Act (NMFS 2006 , 2014 ). The decline of acroporids leads to the loss of reef function and structural complexity, both of which are critical for reef growth, fisheries habitat, coastal protection, and overall reef biodiversity (Bruckner 2002 ; Alvarez-Filip et al. 2009 ). Adapted from terrestrial silviculture, “coral gardening” is one of the most commonly used coral propagation and restoration methods (Rinkevich 1995 ; Bowden-Kerby 2001 ; Epstein et al. 2003 ; Shafir et al. 2006 ; Shafir and Rinkevich 2008 ; Shaish et al. 2008 ). This method involves removing a limited amount of tissue and skeleton (from a few polyps to small branches) from healthy wild coral populations and propagating an initial stock within ex situ or, more commonly, in situ coral nurseries. Throughout the Caribbean, in situ coral nurseries are used to propagate a renewable source of the threatened staghorn coral, Acropora cervicornis for restoration and species recovery (Johnson et al. 2011 ). Nursery-reared corals are “outplanted” from nurseries to reef restoration sites to bridge spatial gaps between existing populations (Griffin et al. 2012 , 2015 ), enhance A. cervicornis abundance, supplement genetic and genotypic diversity (Lirman and Schopmeyer 2016 ), and promote natural recovery through the creation of sexually reproductive populations (Baums 2008 ). Acropora cervicornis is considered a good candidate for use in restoration projects due to its high growth rates, natural use of fragmentation for asexual reproduction, ability to heal wounds, and high survivorship of fragments compared to other coral species (Gladfelter et al. 1978 ; Tunnicliffe 1981 ; Bak and Criens 1982 ; Highsmith 1982 ; Lirman et al. 2010 , 2014a ). The ability of coral propagation and restoration programs to create renewable sources of corals for use in restoration using low-cost, science-based methods has been well documented (Soong and Chen 2003 ; Lirman et al. 2010 , 2014a ; Rinkevich 2014 ). While long-term monitoring is required by permitting agencies for many, if not all, restoration projects, few studies have published the impacts of collection on existing wild populations used to populate coral nurseries (Epstein et al. 2001 ; Shafir et al. 2006 ; Lirman et al. 2010 ), or the success of restoration projects over the course of more than a few months (Bruckner and Bruckner 2001 ; Griffin et al. 2015 ) especially in the Caribbean where coral gardening activities generally began more recently than in the Red Sea and the Pacific. This information is needed to evaluate the performance of restoration efforts. These knowledge gaps within the literature can lead to criticism of restoration or population enhancement programs and questions the ability of such programs to successfully create functioning populations (Rinkevich 2014 ). In this study, we address these gaps by evaluating the effects of fragment collection on donor colonies, documenting the success of coral propagation within in situ coral nurseries, and tracking the survival and productivity of nursery-reared corals for up to 2 yr after outplanting in Florida and Puerto Rico, USA. Based on our analyses, which combine information from thousands of staghorn corals during “normal” conditions (i.e., no disease or thermal stress) from >120 distinct genotypes from six geographical regions, we propose coral propagation and outplanting benchmarks that may be used by existing and new restoration programs to assess performance and progress towards restoration goals. Materials and methods Beginning in 2009, funding was received as<|im_end|> <|im_start|>assistant A new study found that Caribbean staghorn corals (Acropora cervicornis) are benefiting from "coral gardening," the process of restoring coral populations by planting laboratory-raised coral fragments on reefs. The research, led by scientists at the University of Miami (UM) Rosenstiel School of Marine and Atmospheric Science and partners, has important implications for the long-term survival of coral reefs worldwide, which have been in worldwide decline from multiple stressors such as climate change and ocean pollution. "Our study showed that current restoration methods are very effective," said UM Rosenstiel school coral biologist Stephanie Schopmeyer, the lead author of the study. "Healthy coral reefs are essential to our everyday life and successful coral restoration has been proven as a recovery tool for lost coastal resources." In the study, the researchers set out to document restoration success during their initial two years at several coral restoration sites in Florida and Puerto Rico. Their findings showed that current restoration methods are not causing excess damage to donor colonies as a result of removing coral tissue to propagate new coral in the lab, and that once outplanted, corals behave just as wild colonies do. Staghorn coral populations have declined as much as 90% in the Caribbean since the 1980s. As a result, the species was listed as threatened under the U.S. Endangered Species Act in 2006 to help protect and conserve these species that form the foundation of the biologically rich coral reef habitats. The findings, published in the of the journal Coral Reefs, offers a guide for successful restoration and recovery efforts of the threatened species worldwide. Thousands of corals are raised in laboratories and planted onto degraded reefs each year. This study is the first to collect baseline coral restoration survival and productivity data at regional scales including data from 1,000s of individual A. cervicornis colonies, more than 120 distinct genotypes within six geographical regions to develop benchmarks to fully assess the progress and impacts of the region's coral and reef restoration efforts. Coral reefs provide many goods and services including fisheries habitat, food for humans and other ocean species, and protection against natural hazards such as hurricanes. As a result, coral restoration is viewed as an effective and cost-efficient strategy to buffer coastlines from the effects of storm surge and sea-level rise. "Coral reefs are declining at an alarming rate and coral restoration programs are now considered an essential component to coral conservation and management plan," said Diego Lirman, UM Rosenstiel School professor of marine biology and ecology and a coauthor of the study. "Our findings provide the necessary scientific benchmarks to evaluate restoration progress moving forward." The study was conducted in collaboration with U.S. Acropora Recovery Program partners: Nova Southeastern University, University of Miami, Florida Fish and Wildlife Conservation Commission, Mote Marine Laboratory, The Nature Conservancy, and the National Oceanic and Atmospheric Administration (NOAA). The public can get involved in restoration through the UM Rescue-a-Reef program, where citizen scientists help plant nursery-grown corals onto depleted reefs alongside scientists. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Guidelines Hypothesis Interesting Images Letter New Book Received Obituary Opinion Perspective Proceeding Paper Project Report Protocol Registered Report Reply Retraction Short Note Study Protocol Systematic Review Technical Note Tutorial Viewpoint All Article Types Advanced Search Section All Sections Air, Climate Change and Sustainability Bioeconomy of Sustainability Development Goals towards Sustainability Economic and Business Aspects of Sustainability Energy Sustainability Environmental Sustainability and Applications Green Building Hazards and Sustainability Health, Well-Being and Sustainability Pollution Prevention, Mitigation and Sustainability Psychology of Sustainability and Sustainable Development Resources and Sustainable Utilization Social Ecology and Sustainability Soil Conservation and Sustainability Sustainability in Geographic Science Sustainability, Biodiversity and Conservation Sustainable Agriculture Sustainable Chemical Engineering and Technology Sustainable Education and Approaches Sustainable Engineering and Science Sustainable Food Sustainable Forestry Sustainable Management Sustainable Materials Sustainable Oceans Sustainable Products and Services Sustainable Transportation Sustainable Urban and Rural Development Sustainable Water Management Tourism, Culture, and Heritage Waste and Recycling All Sections Special Issue All Special Issues (In)Corporate Sustainability: A Systemic Shift towards Sustainability 10th Anniversary of Sustainability—Recent Advances in Sustainability Studies 14th CIRIAF National Congress - Energy, Environment and Sustainable Development 15th CIRIAF National Congress – Environmental Footprint and Sustainable Development 16th CIRIAF National Congress – Sustainable Development, Environment and Human Health Protection 17th CIRIAF National Congress—Energy–Environmental Sustainability and Seismic Retrofit of Built Heritage 3D Printed Object or Molds for Educational Use: Design and Validation 3D Printing Applications and Sustainable Construction 3D Printing Influence in Engineering 3D Technology for Sustainable Education, Culture and Divulgation 40th Anniversary of 'The Limits to Growth' 4th Industrial Revolution and New Trends in Service Industry 5G, Energy Efficiency and Sustainability 5G: Smart Technology for Environment and Sustainable Development 5th World Sustainability Forum - Selected Papers 6th World Sustainability Forum - Selected Papers 7th World Sustainability Forum—Selected Papers 8th World Sustainability Forum—Selected Papers A Contextual and Dynamic Understanding of Sustainable Urbanisation A Decision-Making Model on the Impact of Vehicle Use on Urban Safety A Multidisciplinary Approach to Sustainability A Promising Approach: Nanotechnology A Research Agenda for Ecological Economics A Sustainable Revolution: Let's Go Sustainable to Get our Globe Cleaner A Systemic Perspective on Urban Food Supply: Assessing Different Types of Urban Agriculture Academic Contributions to the UNESCO 2019 Forum on Education for Sustainable Development and Global Citizenship Accounting, Financing and Governing Global Sustainability for Businesses and Societies Achieving a Just Transition in the Pursuit of Global Sustainability Achieving Sustainable Development Goals (SDGs) among Walking and Talking Achieving Sustainable Development Goals in COVID-19 Pandemic Times Achieving Sustainable Development of Enterprises through Digital Transformation Achieving Sustainable Public Transportation System: Travel Behaviors, New Technologies and Their Equity, Accessibility and Planning Implications Achieving Sustainable Village Development though Traditional and Innovative Approaches Achieving Zero Carbon Strategy: Towards What Direction Should Supply Chain Focus On? Adaptation or Extinction Adapting to Climate Change: The Interplay between International and Domestic Institutions in the Context of Climate Finance Adaptive Components for Building Performance Control Adaptive Reuse Processes: Bridging the Gap between Memory and New Values Additive Manufacturing and Sustainability in the Digital Age: People, Factories and Businesses of the Future Addressing Sustainability at a Community Scale Addressing Sustainable Development in the Digital Construction Age Advanced Analysis of Energy Economics and Sustainable Development in China in the Context of Carbon Neutrality Advanced Application of Green and Sustainable Computing Advanced Cutting-Edge Research on Applied Research on Human-Computer Interaction Advanced Forum for Sustainable Development Advanced IT based Future Sustainable Computing Advanced IT based Future Sustainable Computing Advanced Methodologies for Sustainability Assessment: Theory and Practice Advanced Science and Technology of Sustainable Development for Cities, Infrastructures, Living Spaces and Natural Environment: Including Collections from the Latest Papers of KRIS 2023 Advanced Technologies Applied to Renewable Energy Advanced Technology for Sustainable Development in Arid and Semi-Arid Regions Advanced Theory and Practice in Sustainable Sport Management Advances and Challenges of Green Chemistry and Engineering Advances and Challenges of Sustainability in/by Software Engineering Advances in Architectures, Big Data, and Machine Learning Techniques for Complex Internet of Things Systems Advances in Artificial Intelligence in Sustainable Business Management Advances in Corporate Governance Mechanisms and Corporate Social Responsibility Advances in Decision Making and Data Analysis for Sustainable Operations and Supply Chain Management in the Industry 4.0 Era Advances in Food and Non-Food Biomass Production, Processing and Use in Sub-Saharan Africa: Towards a Basis for a Regional Bioeconomy Advances in Gas Separation Technologies for Green Process Engineering Advances in Green Infrastructure Planning Advances in Hydrological Modelling, Quantitative Analysis and Prediction for a Changing Environment Advances in Industrial Risk Analysis and Management Advances in Machine Learning Technology in Information and Cyber Security Advances in Multiple Criteria Decision Making for Sustainability: Modeling and Applications Advances in Post Occupancy Evaluation Advances in Research and Sustainable Applications of Energy—Related Occupant Behavior in Buildings Advances in Rural and Aquatic Sustainability Advances in Sports Science and Physical Activity: New Methodological Perspectives Advances in Sustainability Oriented Innovations Advances in Sustainability Research at the University of Malta Advances in Sustainability Research from Poznan University of Technology Advances in Sustainability Research from the University of Oradea Advances in Sustainability: Selected Papers from 1st World Sustainability Forum Advances in Sustainability: Selected Papers from the Second World Sustainability Forum (2012) Advances in Sustainable Development: Selected Papers from 2016 Energy and Environment Knowledge Week Advances in Sustainable Drainage Systems and Stormwater Control Measures Advances in Sustainable Energy Systems and Environmental Remediation Technologies Advances in Sustainable Nanocomposites Advances in Sustainable Technology: The Lean 6S Methodology Advances in Sustainable Tourism and Responsible Travel Advances in the Sustainability and Resilience Interface at the Urban and Regional Levels: Sciences, Plans, Policies, and Actions for the Next Challenging Decades Advances of Digital Transformation in the Education Domain Advances of Sustainability Research: A Canadian Perspective Advances on Building Performance and Sustainability Advancing a Sustainable Future: Automation, Data Analysis, Modelling, and Simulations Advancing Sustainability through Well-Being Advancing Urban Sustainability through a Diverse Social-Ecological System Research Agenda Aerosol Pollution and Severe Weather Affordable Housing Planning for Sustainability After the Anthropocene: Time and Mobility Agricultural and Food Systems Sustainability: The Complex Challenge of Losses and Waste Agricultural Development", "role": "user" }, { "content": "Curtin University research has found deep listening or Autonomous Sensory Meridian Response (ASMR) could be used as an effective tool to encourage pro-environmental behavior and create social bonding among young people. ASMR is a spontaneous, calming, positive feeling that occurs in response to certain stimuli including whispering and brushing sounds. This exploratory study used similar stimuli in a purpose-made video to promote positive climate change messages to high school students, and then gaged their opinions on whether the approach could be effective. Lead researcher, Curtin Adjunct Postdoctoral Fellow and University of Sydney researcher and Manager of the Center for Advanced Food Enginomics (CAFE) Diana Bogueva, who undertook the study while at Curtin University Sustainability Policy (CUSP) Institute said the study was focused on whether ASMR can be used to communicate positively about climate change with young people. \"Young people are consistently bombarded with gloomy messages on climate change and the environment, including devastating pictures of bushfires and other extreme weather events. So we asked whether there were other, more optimistic ways, to talk about the issue to evoke positive feelings and empower young people to take action,\" Dr. Bogueva said. \"To do this, we employed the relatively new and unexplored concept of ASMR. We made a video featuring an anonymous 16-year-old girl talking about what positive climate change actions can be taken in everyday life. Her performance was based on the traditional soft whispering voice used for ASMR, with some sound effects, including tapping and noises, to grab the attention of the viewers. The majority (65 percent) of high school students who participated in the study found the video would be effective to communicate positively about climate change. Importantly, some of the participants who felt overwhelmed by climate change prior to watching the video, reported feeling 'confident' and 'encouraged' to act, after the viewing.\" Co-author Professor Dora Marinova at the Curtin University Sustainability Policy Institute said the findings from the exploratory study could now lead to a larger-scale survey on the impact of using ASMR with young people. \"Our study is just the beginning. We've shown that Generation Z is willing to be experimental, experience-focused and socially active in responding to climate change challenges, now more needs to be done on both ASMR (which is relatively untested) and the use of positive messaging, instead of focussing on the negative,\" Professor Marinova said. \"We know climate change is a major concern for young people in Australia and around the world, and causes a range of negative feelings including anger, pessimism, stress and despair, as well as mental health issues—so any methods we can use to change the narrative, could also change lives.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Guidelines Hypothesis Interesting Images Letter New Book Received Obituary Opinion Perspective Proceeding Paper Project Report Protocol Registered Report Reply Retraction Short Note Study Protocol Systematic Review Technical Note Tutorial Viewpoint All Article Types Advanced Search Section All Sections Air, Climate Change and Sustainability Bioeconomy of Sustainability Development Goals towards Sustainability Economic and Business Aspects of Sustainability Energy Sustainability Environmental Sustainability and Applications Green Building Hazards and Sustainability Health, Well-Being and Sustainability Pollution Prevention, Mitigation and Sustainability Psychology of Sustainability and Sustainable Development Resources and Sustainable Utilization Social Ecology and Sustainability Soil Conservation and Sustainability Sustainability in Geographic Science Sustainability, Biodiversity and Conservation Sustainable Agriculture Sustainable Chemical Engineering and Technology Sustainable Education and Approaches Sustainable Engineering and Science Sustainable Food Sustainable Forestry Sustainable Management Sustainable Materials Sustainable Oceans Sustainable Products and Services Sustainable Transportation Sustainable Urban and Rural Development Sustainable Water Management Tourism, Culture, and Heritage Waste and Recycling All Sections Special Issue All Special Issues (In)Corporate Sustainability: A Systemic Shift towards Sustainability 10th Anniversary of Sustainability—Recent Advances in Sustainability Studies 14th CIRIAF National Congress - Energy, Environment and Sustainable Development 15th CIRIAF National Congress – Environmental Footprint and Sustainable Development 16th CIRIAF National Congress – Sustainable Development, Environment and Human Health Protection 17th CIRIAF National Congress—Energy–Environmental Sustainability and Seismic Retrofit of Built Heritage 3D Printed Object or Molds for Educational Use: Design and Validation 3D Printing Applications and Sustainable Construction 3D Printing Influence in Engineering 3D Technology for Sustainable Education, Culture and Divulgation 40th Anniversary of 'The Limits to Growth' 4th Industrial Revolution and New Trends in Service Industry 5G, Energy Efficiency and Sustainability 5G: Smart Technology for Environment and Sustainable Development 5th World Sustainability Forum - Selected Papers 6th World Sustainability Forum - Selected Papers 7th World Sustainability Forum—Selected Papers 8th World Sustainability Forum—Selected Papers A Contextual and Dynamic Understanding of Sustainable Urbanisation A Decision-Making Model on the Impact of Vehicle Use on Urban Safety A Multidisciplinary Approach to Sustainability A Promising Approach: Nanotechnology A Research Agenda for Ecological Economics A Sustainable Revolution: Let's Go Sustainable to Get our Globe Cleaner A Systemic Perspective on Urban Food Supply: Assessing Different Types of Urban Agriculture Academic Contributions to the UNESCO 2019 Forum on Education for Sustainable Development and Global Citizenship Accounting, Financing and Governing Global Sustainability for Businesses and Societies Achieving a Just Transition in the Pursuit of Global Sustainability Achieving Sustainable Development Goals (SDGs) among Walking and Talking Achieving Sustainable Development Goals in COVID-19 Pandemic Times Achieving Sustainable Development of Enterprises through Digital Transformation Achieving Sustainable Public Transportation System: Travel Behaviors, New Technologies and Their Equity, Accessibility and Planning Implications Achieving Sustainable Village Development though Traditional and Innovative Approaches Achieving Zero Carbon Strategy: Towards What Direction Should Supply Chain Focus On? Adaptation or Extinction Adapting to Climate Change: The Interplay between International and Domestic Institutions in the Context of Climate Finance Adaptive Components for Building Performance Control Adaptive Reuse Processes: Bridging the Gap between Memory and New Values Additive Manufacturing and Sustainability in the Digital Age: People, Factories and Businesses of the Future Addressing Sustainability at a Community Scale Addressing Sustainable Development in the Digital Construction Age Advanced Analysis of Energy Economics and Sustainable Development in China in the Context of Carbon Neutrality Advanced Application of Green and Sustainable Computing Advanced Cutting-Edge Research on Applied Research on Human-Computer Interaction Advanced Forum for Sustainable Development Advanced IT based Future Sustainable Computing Advanced IT based Future Sustainable Computing Advanced Methodologies for Sustainability Assessment: Theory and Practice Advanced Science and Technology of Sustainable Development for Cities, Infrastructures, Living Spaces and Natural Environment: Including Collections from the Latest Papers of KRIS 2023 Advanced Technologies Applied to Renewable Energy Advanced Technology for Sustainable Development in Arid and Semi-Arid Regions Advanced Theory and Practice in Sustainable Sport Management Advances and Challenges of Green Chemistry and Engineering Advances and Challenges of Sustainability in/by Software Engineering Advances in Architectures, Big Data, and Machine Learning Techniques for Complex Internet of Things Systems Advances in Artificial Intelligence in Sustainable Business Management Advances in Corporate Governance Mechanisms and Corporate Social Responsibility Advances in Decision Making and Data Analysis for Sustainable Operations and Supply Chain Management in the Industry 4.0 Era Advances in Food and Non-Food Biomass Production, Processing and Use in Sub-Saharan Africa: Towards a Basis for a Regional Bioeconomy Advances in Gas Separation Technologies for Green Process Engineering Advances in Green Infrastructure Planning Advances in Hydrological Modelling, Quantitative Analysis and Prediction for a Changing Environment Advances in Industrial Risk Analysis and Management Advances in Machine Learning Technology in Information and Cyber Security Advances in Multiple Criteria Decision Making for Sustainability: Modeling and Applications Advances in Post Occupancy Evaluation Advances in Research and Sustainable Applications of Energy—Related Occupant Behavior in Buildings Advances in Rural and Aquatic Sustainability Advances in Sports Science and Physical Activity: New Methodological Perspectives Advances in Sustainability Oriented Innovations Advances in Sustainability Research at the University of Malta Advances in Sustainability Research from Poznan University of Technology Advances in Sustainability Research from the University of Oradea Advances in Sustainability: Selected Papers from 1st World Sustainability Forum Advances in Sustainability: Selected Papers from the Second World Sustainability Forum (2012) Advances in Sustainable Development: Selected Papers from 2016 Energy and Environment Knowledge Week Advances in Sustainable Drainage Systems and Stormwater Control Measures Advances in Sustainable Energy Systems and Environmental Remediation Technologies Advances in Sustainable Nanocomposites Advances in Sustainable Technology: The Lean 6S Methodology Advances in Sustainable Tourism and Responsible Travel Advances in the Sustainability and Resilience Interface at the Urban and Regional Levels: Sciences, Plans, Policies, and Actions for the Next Challenging Decades Advances of Digital Transformation in the Education Domain Advances of Sustainability Research: A Canadian Perspective Advances on Building Performance and Sustainability Advancing a Sustainable Future: Automation, Data Analysis, Modelling, and Simulations Advancing Sustainability through Well-Being Advancing Urban Sustainability through a Diverse Social-Ecological System Research Agenda Aerosol Pollution and Severe Weather Affordable Housing Planning for Sustainability After the Anthropocene: Time and Mobility Agricultural and Food Systems Sustainability: The Complex Challenge of Losses and Waste Agricultural Development<|im_end|> <|im_start|>assistant Curtin University research has found deep listening or Autonomous Sensory Meridian Response (ASMR) could be used as an effective tool to encourage pro-environmental behavior and create social bonding among young people. ASMR is a spontaneous, calming, positive feeling that occurs in response to certain stimuli including whispering and brushing sounds. This exploratory study used similar stimuli in a purpose-made video to promote positive climate change messages to high school students, and then gaged their opinions on whether the approach could be effective. Lead researcher, Curtin Adjunct Postdoctoral Fellow and University of Sydney researcher and Manager of the Center for Advanced Food Enginomics (CAFE) Diana Bogueva, who undertook the study while at Curtin University Sustainability Policy (CUSP) Institute said the study was focused on whether ASMR can be used to communicate positively about climate change with young people. "Young people are consistently bombarded with gloomy messages on climate change and the environment, including devastating pictures of bushfires and other extreme weather events. So we asked whether there were other, more optimistic ways, to talk about the issue to evoke positive feelings and empower young people to take action," Dr. Bogueva said. "To do this, we employed the relatively new and unexplored concept of ASMR. We made a video featuring an anonymous 16-year-old girl talking about what positive climate change actions can be taken in everyday life. Her performance was based on the traditional soft whispering voice used for ASMR, with some sound effects, including tapping and noises, to grab the attention of the viewers. The majority (65 percent) of high school students who participated in the study found the video would be effective to communicate positively about climate change. Importantly, some of the participants who felt overwhelmed by climate change prior to watching the video, reported feeling 'confident' and 'encouraged' to act, after the viewing." Co-author Professor Dora Marinova at the Curtin University Sustainability Policy Institute said the findings from the exploratory study could now lead to a larger-scale survey on the impact of using ASMR with young people. "Our study is just the beginning. We've shown that Generation Z is willing to be experimental, experience-focused and socially active in responding to climate change challenges, now more needs to be done on both ASMR (which is relatively untested) and the use of positive messaging, instead of focussing on the negative," Professor Marinova said. "We know climate change is a major concern for young people in Australia and around the world, and causes a range of negative feelings including anger, pessimism, stress and despair, as well as mental health issues—so any methods we can use to change the narrative, could also change lives." <|im_end|>

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1,872

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Co-infections are common in host-parasite interactions, but studies about their impact on the virulence of parasites/diseases are still scarce. The present study compared mortality induced by a fatal bacterial pathogen, Flavobacterium columnare between brown trout infected with glochidia from the endangered freshwater pearl mussel, Margaritifera margaritifera , and uninfected control fish during the parasitic period and after the parasitic period (i.e. glochidia detached) in a laboratory experiment. We hypothesised that glochidial infection would increase host susceptibility to and/or pathogenicity of the bacterial infection. We found that the highly virulent strain of F. columnare caused an intense disease outbreak, with mortality reaching 100% within 29 h. Opposite to the study hypothesis, both fresh ongoing and past infection (14 months post-infection) with glochidia prolonged the fish host’s survival statistically significantly by 1 h compared to the control fish (two-way ANOVA: fresh-infection, F 1, 82 = 7.144, p = 0.009 and post-infection, F 1, 51 = 4.227, p = 0.044). Furthermore, fish survival time increased with glochidia abundance (MLR: post-infection, t = 2.103, p = 0.045). The mechanism could be connected to an enhanced non-specific immunity or changed gill structure of the fish, as F. columnare enters the fish body mainly via the gills, which is also the glochidia’s attachment site. The results increase current knowledge about the interactions between freshwater mussels and their (commercially important) fish hosts and fish pathogens and also emphasise the importance of (unknown) ecosystem services (e.g., protection against pathogens) potentially associated with imperilled freshwater mussels. Working on a manuscript? Avoid the common mistakes Introduction Free-living individuals are likely to be infected by several parasitic species and pathogens, although most studies on the subject focus on a one host–one parasite interaction (Rigaud et al. 2010 ). A parasitic infection can either directly or indirectly influence any subsequent infections (Cox 2001 ; Johnson et al. 2015 ; Vaumourin et al. 2015 ; Kotob et al. 2016 ; Gopko et al. 2018 ). This influence can be positive, negative or neutral (Vaumourin et al. 2015 ; Chowdhury et al. 2017 ; Klemme and Karvonen 2017 ). In fishes, parasitic infections increase the host’s risk of secondary infections and can act as a vehicle for the transmission of bacteria to fish (Kotob et al. 2016 ). For instance, the monogenean parasite Dactylogyrus intermedius increases the susceptibility of goldfish, or Carassius auratus , to Flavobacterium columnare , resulting in higher mortality when compared to non-parasitised fish (Zhang et al. 2015 ). Similarly, rainbow trout co-infected with Diplostomum pseudospathaceum experienced higher host mortality when exposed to bacteria compared with single infections (Louhi et al. 2015 ). Flavobacterium columnare causes columnaris disease (warm water disease) in fish, including salmonids. This pathogen can cause remarkable economic losses in fish farming due to the high mortality associated with the disease (Wagner et al. 2002 ; Pulkkinen et al. 2010 ). Flavobacterium columnare is an opportunistic fish pathogen that can also grow outside of the fish host (Kunttu et al. 2012 ). Flavobacterium columnare strains differ in their virulence (Suomalainen et al. 2006 ; Pulkkinen et al. 2018 ) and are capable of causing up to 100% mortality in juvenile salmonids (Suomalainen et al. 2005 ). Since there is no effective vaccination available for young salmonids (Sundell et al. 2014 ), the only treatment against F. columnare is antibiotics (Rach et al. 2008 ). Freshwater mussels, including the freshwater pearl mussel Margaritifera margaritifera , are critically endangered in Europe IUCN ( 2019 ). They have declined worldwide due to habitat destruction, loss of fish hosts, siltation, pollution, invasive species and over-exploitation (Bauer 1986 ; Lopes-Lima et al. 2017 ). The life cycle of M. margaritifera in Europe includes an obligatory host-specific parasitic period in the gills of the Atlantic salmon Salmo salar or the brown trout S. trutta (Salonen et al. 2016 , 2017 ) that lasts for 9–11 months (Salonen and Taskinen 2017 ). Therefore, the success of restoration of the endangered M. margaritifera is entirely dependent on the success of glochidium larvae in salmonid fish host. When matured and metamorphosed, the glochidia detach from the fish host and drop to the bottom of the river as juvenile mussels, where they begin their benthic life, which lasts up to 200 years (Helama and Valovirta 2008 ). Freshwater mussels are involved in many ecosystem functions and services such as biofiltration, nutrient cycling and storage, food web dynamics and bottom quality modification, leading to improved water quality, habitat structure and biodiversity, in addition of direct provision of food, tools and jewellery (Vaughn & Hakenkamp 2001 ; Strayer 2014 ; Vaughn et al. 2008 ; Haag 2012 ; Vaughn 2018 ). Furthermore, filtration by unionid mussel ( Anodonta anatina ) reduced the density of the cercarial larvae of the harmful fish parasite Diplostomum (Gopko et al. 2017b ). Therefore, the decline of M. margaritifera can potentially induce changes in ecological interactions and services in aquatic ecosystems. Infection by M. margaritifera glochidia has many adverse effects on the fish host such as hyperplasia and gill filament fusion, reduced swimming capability, increased mortality, altered thermoregulation, reduced foraging, decreased activity, lowered growth rate and social dominance and increased metabolic rate (Treasurer and Turnbull 2000 ; Taeubert and Geist 2013 ; Österling et al. 2014 ; Thomas et al. 2014 ; Filipsson et al. 2016 , 2017 , Chowdhury et al. 2019 ; Horký et al. 2019 . Furthermore, brown trout infected with M. margaritifera glochidia had an increased susceptibility to subsequent infection with the trematode parasite D. pseudospathaceum (Gopko et al. 2018 ). Hence, it can be expected that exposing fish to F. columnare — and the pathogenicity and virulence of F. columnare during the disease outbreak — would be higher in glochidia-infected individuals than in uninfected fish, as gills are the leading and first site of infection by F. columnare (Declercq et al. 2013 , 2015 ). In contrast, Ziuganov ( 2005 ) proposed that M. margaritifera infection could stimulate healing of the fish host Salmo salar , e.g. from hook", "role": "user" }, { "content": "Researchers from the University of Jyväskylä found brown trout better survived a Flavobacterium disease outbreak if the fish had larvae of freshwater pearl mussel in their gills. In another study, duck mussels were observed to filter and remove Flavobacterium from the water. Flavobacteria are a severe problem for fish farming and cause substantial economic losses. The \"warm water disease\" caused by Flavobacterium columnare is especially problematic since a functional vaccine against the bacterium is not available. The skin and gill damage in diseased individuals can cause high mortality in young salmonids. Larvae of the freshwater pearl mussel can give protection against bacterial infection Glochidium larvae of the freshwater pearl mussel attach to salmon or trout gills, where they develop and grow for 9 to 11 months until they detach and sink to the river bottom, starting their life as mussels. Glochidium larva is a parasite in the gills of fish. Therefore, it was assumed that glochidia-infested fish would be more prone to bacterial infection. Against expectations, brown trout infested with pearl mussel larvae better survived an outbreak of Flavobacterium columnare. Moreover, the protective effect of glochidia infestation against bacterial disease sustained several months after the larvae had dropped off from the gills of fish. The higher the number of pearl mussel larvae in the gills was, the better the trout survived. Colonies of Flavobacterium columnare on a plate. Credit: Katja Pulkkinen / University of Jyväskylä Mussels can remove flavobacteria from water Freshwater mussel are filter-feeders. They remove suspended materials efficiently, cleaning tens of liters of water a day. Thus, their ability to filter and remove harmful F. columnare bacteria from water was tested. The result was clear: in aquaria, one mussel individual could halve the density of bacteria within two days. Freshwater pearl mussels. Credit: Mikko Ranta Species diversity loss will cause loss of important ecosystem services The freshwater pearl mussel is an endangered species which has disappeared from a large part of its original distribution area. The present results indicate that with the extirpation of species we may lose important and valuable ecosystem services. \"Filtering freshwater mussels could be potentially utilized in water treatment applications,\" says Head of Konnevesi Research Station and LIFE Revives project, professor Jouni Taskinen. \"As species disappear, we may lose ecosystem services the species provide—probably before we have even found them.\" The research was published in Parasitology Research and Hydrobiologia. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Co-infections are common in host-parasite interactions, but studies about their impact on the virulence of parasites/diseases are still scarce. The present study compared mortality induced by a fatal bacterial pathogen, Flavobacterium columnare between brown trout infected with glochidia from the endangered freshwater pearl mussel, Margaritifera margaritifera , and uninfected control fish during the parasitic period and after the parasitic period (i.e. glochidia detached) in a laboratory experiment. We hypothesised that glochidial infection would increase host susceptibility to and/or pathogenicity of the bacterial infection. We found that the highly virulent strain of F. columnare caused an intense disease outbreak, with mortality reaching 100% within 29 h. Opposite to the study hypothesis, both fresh ongoing and past infection (14 months post-infection) with glochidia prolonged the fish host’s survival statistically significantly by 1 h compared to the control fish (two-way ANOVA: fresh-infection, F 1, 82 = 7.144, p = 0.009 and post-infection, F 1, 51 = 4.227, p = 0.044). Furthermore, fish survival time increased with glochidia abundance (MLR: post-infection, t = 2.103, p = 0.045). The mechanism could be connected to an enhanced non-specific immunity or changed gill structure of the fish, as F. columnare enters the fish body mainly via the gills, which is also the glochidia’s attachment site. The results increase current knowledge about the interactions between freshwater mussels and their (commercially important) fish hosts and fish pathogens and also emphasise the importance of (unknown) ecosystem services (e.g., protection against pathogens) potentially associated with imperilled freshwater mussels. Working on a manuscript? Avoid the common mistakes Introduction Free-living individuals are likely to be infected by several parasitic species and pathogens, although most studies on the subject focus on a one host–one parasite interaction (Rigaud et al. 2010 ). A parasitic infection can either directly or indirectly influence any subsequent infections (Cox 2001 ; Johnson et al. 2015 ; Vaumourin et al. 2015 ; Kotob et al. 2016 ; Gopko et al. 2018 ). This influence can be positive, negative or neutral (Vaumourin et al. 2015 ; Chowdhury et al. 2017 ; Klemme and Karvonen 2017 ). In fishes, parasitic infections increase the host’s risk of secondary infections and can act as a vehicle for the transmission of bacteria to fish (Kotob et al. 2016 ). For instance, the monogenean parasite Dactylogyrus intermedius increases the susceptibility of goldfish, or Carassius auratus , to Flavobacterium columnare , resulting in higher mortality when compared to non-parasitised fish (Zhang et al. 2015 ). Similarly, rainbow trout co-infected with Diplostomum pseudospathaceum experienced higher host mortality when exposed to bacteria compared with single infections (Louhi et al. 2015 ). Flavobacterium columnare causes columnaris disease (warm water disease) in fish, including salmonids. This pathogen can cause remarkable economic losses in fish farming due to the high mortality associated with the disease (Wagner et al. 2002 ; Pulkkinen et al. 2010 ). Flavobacterium columnare is an opportunistic fish pathogen that can also grow outside of the fish host (Kunttu et al. 2012 ). Flavobacterium columnare strains differ in their virulence (Suomalainen et al. 2006 ; Pulkkinen et al. 2018 ) and are capable of causing up to 100% mortality in juvenile salmonids (Suomalainen et al. 2005 ). Since there is no effective vaccination available for young salmonids (Sundell et al. 2014 ), the only treatment against F. columnare is antibiotics (Rach et al. 2008 ). Freshwater mussels, including the freshwater pearl mussel Margaritifera margaritifera , are critically endangered in Europe IUCN ( 2019 ). They have declined worldwide due to habitat destruction, loss of fish hosts, siltation, pollution, invasive species and over-exploitation (Bauer 1986 ; Lopes-Lima et al. 2017 ). The life cycle of M. margaritifera in Europe includes an obligatory host-specific parasitic period in the gills of the Atlantic salmon Salmo salar or the brown trout S. trutta (Salonen et al. 2016 , 2017 ) that lasts for 9–11 months (Salonen and Taskinen 2017 ). Therefore, the success of restoration of the endangered M. margaritifera is entirely dependent on the success of glochidium larvae in salmonid fish host. When matured and metamorphosed, the glochidia detach from the fish host and drop to the bottom of the river as juvenile mussels, where they begin their benthic life, which lasts up to 200 years (Helama and Valovirta 2008 ). Freshwater mussels are involved in many ecosystem functions and services such as biofiltration, nutrient cycling and storage, food web dynamics and bottom quality modification, leading to improved water quality, habitat structure and biodiversity, in addition of direct provision of food, tools and jewellery (Vaughn & Hakenkamp 2001 ; Strayer 2014 ; Vaughn et al. 2008 ; Haag 2012 ; Vaughn 2018 ). Furthermore, filtration by unionid mussel ( Anodonta anatina ) reduced the density of the cercarial larvae of the harmful fish parasite Diplostomum (Gopko et al. 2017b ). Therefore, the decline of M. margaritifera can potentially induce changes in ecological interactions and services in aquatic ecosystems. Infection by M. margaritifera glochidia has many adverse effects on the fish host such as hyperplasia and gill filament fusion, reduced swimming capability, increased mortality, altered thermoregulation, reduced foraging, decreased activity, lowered growth rate and social dominance and increased metabolic rate (Treasurer and Turnbull 2000 ; Taeubert and Geist 2013 ; Österling et al. 2014 ; Thomas et al. 2014 ; Filipsson et al. 2016 , 2017 , Chowdhury et al. 2019 ; Horký et al. 2019 . Furthermore, brown trout infected with M. margaritifera glochidia had an increased susceptibility to subsequent infection with the trematode parasite D. pseudospathaceum (Gopko et al. 2018 ). Hence, it can be expected that exposing fish to F. columnare — and the pathogenicity and virulence of F. columnare during the disease outbreak — would be higher in glochidia-infected individuals than in uninfected fish, as gills are the leading and first site of infection by F. columnare (Declercq et al. 2013 , 2015 ). In contrast, Ziuganov ( 2005 ) proposed that M. margaritifera infection could stimulate healing of the fish host Salmo salar , e.g. from hook<|im_end|> <|im_start|>assistant Researchers from the University of Jyväskylä found brown trout better survived a Flavobacterium disease outbreak if the fish had larvae of freshwater pearl mussel in their gills. In another study, duck mussels were observed to filter and remove Flavobacterium from the water. Flavobacteria are a severe problem for fish farming and cause substantial economic losses. The "warm water disease" caused by Flavobacterium columnare is especially problematic since a functional vaccine against the bacterium is not available. The skin and gill damage in diseased individuals can cause high mortality in young salmonids. Larvae of the freshwater pearl mussel can give protection against bacterial infection Glochidium larvae of the freshwater pearl mussel attach to salmon or trout gills, where they develop and grow for 9 to 11 months until they detach and sink to the river bottom, starting their life as mussels. Glochidium larva is a parasite in the gills of fish. Therefore, it was assumed that glochidia-infested fish would be more prone to bacterial infection. Against expectations, brown trout infested with pearl mussel larvae better survived an outbreak of Flavobacterium columnare. Moreover, the protective effect of glochidia infestation against bacterial disease sustained several months after the larvae had dropped off from the gills of fish. The higher the number of pearl mussel larvae in the gills was, the better the trout survived. Colonies of Flavobacterium columnare on a plate. Credit: Katja Pulkkinen / University of Jyväskylä Mussels can remove flavobacteria from water Freshwater mussel are filter-feeders. They remove suspended materials efficiently, cleaning tens of liters of water a day. Thus, their ability to filter and remove harmful F. columnare bacteria from water was tested. The result was clear: in aquaria, one mussel individual could halve the density of bacteria within two days. Freshwater pearl mussels. Credit: Mikko Ranta Species diversity loss will cause loss of important ecosystem services The freshwater pearl mussel is an endangered species which has disappeared from a large part of its original distribution area. The present results indicate that with the extirpation of species we may lose important and valuable ecosystem services. "Filtering freshwater mussels could be potentially utilized in water treatment applications," says Head of Konnevesi Research Station and LIFE Revives project, professor Jouni Taskinen. "As species disappear, we may lose ecosystem services the species provide—probably before we have even found them." The research was published in Parasitology Research and Hydrobiologia. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Chronic cytomegalovirus (CMV) infection leads to long-term maintenance of extraordinarily large CMV-specific T cell populations. The magnitude of this so-called ‘memory inflation’ is thought to mainly depend on antigenic stimulation during the chronic phase of infection. However, by mapping the long-term development of CD8 + T cell families derived from single naive precursors, we find that fate decisions made during the acute phase of murine CMV infection can alter the level of memory inflation by more than 1,000-fold. Counterintuitively, a T cell family’s capacity for memory inflation is not determined by its initial expansion. Instead, those rare T cell families that dominate the chronic phase of infection show an early transcriptomic signature akin to that of established T central memory cells. Accordingly, a T cell family’s long-term dominance is best predicted by its early content of T central memory precursors, which later serve as a stem-cell-like source for memory inflation. Main Inflationary T cell memory is a specific form of immunological memory 1 , 2 that critically depends on presentation of defined viral antigens throughout the chronic phase of cytomegalovirus (CMV) infection 3 , 4 . It is characterized by continued maintenance of large antigen-specific CD8 + T cell populations 5 , which circulate in the blood, home to peripheral tissues and show immediate cytolytic effector function 6 . These unique features of inflationary T cells have spurred great interest in utilizing CMV as a vaccine vector. Indeed, recombinant CMV, engineered to express defined vaccine antigens 7 , has shown immense promise for induction of protective cytotoxic T cell immunity, directed against simian immunodeficiency virus (SIV) 8 , 9 , 10 or Mycobacterium tuberculosis 11 . Importantly, not all CD8 + T cells that recognize epitopes presented during CMV latency strongly contribute to memory inflation. Instead, inflationary T cell populations become increasingly oligoclonal throughout the course of chronic CMV persistence 1 , 12 , 13 —a feature shared by other chronic infections 14 , 15 . The clonality of these responses indicates that they originate from one or few naive T cells harboring the same T cell receptor (TCR). Starting out from these rare naive precursors, the development of clonal dominance is thought to be predetermined by defined cellular features, such as TCR specificity and affinity 16 , 17 , 18 , 19 , 20 , 21 , 22 . However, in the context of acutely resolving infections, single-cell fate mapping has shown that even T cells expressing identical TCRs display massive variation of clonal expansion, with only some strongly dominating the acute response to infection 23 , 24 , 25 , 26 . The extent to which this fundamental, early variation that emerges from TCR-identical single cells also shapes T cell immunity against chronically persisting infections remains unknown. One option is that early single-cell-derived variation is erased by the effects of long-term TCR re-stimulation during chronic infection. Alternatively, such early variation in the life histories of single-cell-derived ‘T cell families’ may leave a lasting imprint on their long-term capacity for memory inflation and immunodominance. To resolve which of these two scenarios is true, we monitored, in vivo, the long-term development of T cell families derived from single naive precursors harboring identical TCRs specific to a vaccine antigen expressed by recombinant murine CMV (MCMV). We utilized blood sampling or hemisplenectomy to gauge a T cell family’s initial clonal expansion, monitored its differentiation state via RNA sequencing and flow cytometry and then tracked its long-term inflationary output throughout the chronic phase of MCMV infection. In addition, we utilized single-cell RNA sequencing (scRNA-seq) and RNA velocity analyses 27 to decipher the differentiation dynamics within an established inflationary T cell population. By integrating these approaches, we find that a T cell family’s initial clonal expansion does not predict its capacity for memory inflation. Instead, we identify a fundamental single-cell-derived variation in the amount of T central memory precursors (CMPs) generated during the acute phase of chronic viral infection. This variation defines a set point for the magnitude of memory inflation and imprints lasting hierarchies of immunodominance upon TCR-identical cells. We anticipate that measuring and altering this early CMP-related set point will be of critical relevance in the design of future vaccination strategies and immunotherapeutic approaches. Results Single-cell-derived memory inflation is highly variable and not predicted by acute clonal expansion Clonal expansion and phenotypic differentiation derived from single naive T cells has been found to vary massively upon acute infection 23 , 24 , 25 , 28 , 29 . Due to ‘response averaging’ this fundamental variation goes unnoticed when monitoring the expansion and differentiation of epitope-specific T cell populations 26 . Here, we aimed to evaluate the long-term consequences of such discrepant initial T cell behavior in the context of chronic infection. To achieve this, we made use of a recombinant MCMV vector into which a sequence encoding the SIINFEKL peptide of chicken ovalbumin (OVA) had been inserted at the 3′ end of the immediate early 2 (ie2) gene 30 (Extended Data Fig. 1a ). The promoter of ie2 remains active during chronic MCMV latency and, thereby, guarantees lasting expression of the engineered epitope 31 . We found that infection with MCMV- ie2 -SIINFEKL reliably induced memory inflation of endogenous SIINFEKL-specific CD8 + T cells (Fig. 1a ) and of adoptively transferred monoclonal populations of OT-1 T cells, whose transgenic TCR binds with high affinity to SIINFEKL in the context of H2-K b (Fig. 1b and Extended Data Fig. 1b ). Next, we adoptively transferred single naive CD8 + T cells and mapped their acute expansion and long-term memory inflation in response to MCMV- ie2- SIINFEKL. As done previously 23 , 25 , 32 , 33 , 34 , we increased our capacity for parallel fate mapping by collecting single naive T cells from OT-1 Rag-1 −/− donors expressing distinct combinations of the congenic markers CD45.1, CD45.2, CD90.1 and CD90.2. Upon adoptive transfer, we found that both acute and long-term expansion derived from these single naive T cells varied massively, with only", "role": "user" }, { "content": "For a person to acquire immunity to a disease, T cells must develop into memory cells after contact with the pathogen. Until now, the number of cells that do this was believed to depend above all on the magnitude of the initial immune response. A team of researchers at the Technical University of Munich (TUM) has now called this into question. When a virus enters the body, it is picked up by certain cells of the immune system. They transport the virus to the lymph nodes where they present its fragments, known as antigens, to CD8+ T cells responsible control of viral infections. Each of these cells carries a unique T cell receptor on the surface that can recognize certain antigens. However, only very few T cell receptors match a given viral the antigen. To bring the infection under control and maximize the defenses against the virus, these few antigen-specific T cells start dividing rapidly and develop into effector T cells. These kill virus-infected host cells and then die off themselves once the infection is cleared. Some of these short-lived effector cells—according to the generally accepted theory—turn into memory T cells, which persist in the organism long term. In case the same pathogen enters the body again, memory T cells are already present and ready to fight the invader more swiftly and effectively than during the first encounter. Memory cells and their origin \"Prevailing scientific opinion says that activated T cells first become effector cells and only then gradually develop into memory cells,\" says Dr. Veit Buchholz, a specialist in microbiology and working group leader at the Institute for Medical Microbiology, Immunology and Hygiene at TUM. \"In our view, however, that isn't the case. It would mean that the more effector cells are formed after contact with the pathogen, the more numerous the memory cells would become.\" However, Buchholz and his colleagues observed a different course of events and have now published their results in the journal Nature Immunology. \"We investigated the antiviral immune responses resulting from individual activated T cells in mice and traced the lineage of the ensuing memory cells using single-cell fate mapping,\" reports first author Dr. Simon Grassmann. \"Based on these experiments, we were able to show that certain 'T cell families' descended from individual cells form up to 1000 times more 'memory' than others. However, these long-term dominating T cell families only contributed little to the magnitude of the initial immune response, which was dominated by effector cells derived from other shorter-lived T cell families.\" At the level of individual cells, it therefore became evident that development of effector and memory cells segregates at a much earlier stage than previously believed: \"Already in the first week after the confrontation with the pathogen, we saw major differences in the transcriptomes of the detected T cell families,\" says Lorenz Mihatsch, also a first author of the study. \"Normally at this time of the immune response CD8+ T cells are enriched in molecules that help to kill virus infected cells. However, we found no indication of these cytolytic molecules in the long-term dominating T cell families. Instead, they were already geared exclusively towards memory development at this early stage.\" Optimization of vaccines These results could help to improve vaccine development in the future, says Veit Buchholz: \"To generate an optimal immune response through vaccination, the body needs to produce as many memory cells as possible. For that purpose, it is important to have a precise understanding of how individual T cells are programmed.\" Buchholz's study might also prove useful in helping to recognize sooner whether a new vaccine is effective. \"To determine the long-term strength of an immune response, it could be helpful to measure the number of memory precursors within a few days of administering a vaccine,\" says Buchholz. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Chronic cytomegalovirus (CMV) infection leads to long-term maintenance of extraordinarily large CMV-specific T cell populations. The magnitude of this so-called ‘memory inflation’ is thought to mainly depend on antigenic stimulation during the chronic phase of infection. However, by mapping the long-term development of CD8 + T cell families derived from single naive precursors, we find that fate decisions made during the acute phase of murine CMV infection can alter the level of memory inflation by more than 1,000-fold. Counterintuitively, a T cell family’s capacity for memory inflation is not determined by its initial expansion. Instead, those rare T cell families that dominate the chronic phase of infection show an early transcriptomic signature akin to that of established T central memory cells. Accordingly, a T cell family’s long-term dominance is best predicted by its early content of T central memory precursors, which later serve as a stem-cell-like source for memory inflation. Main Inflationary T cell memory is a specific form of immunological memory 1 , 2 that critically depends on presentation of defined viral antigens throughout the chronic phase of cytomegalovirus (CMV) infection 3 , 4 . It is characterized by continued maintenance of large antigen-specific CD8 + T cell populations 5 , which circulate in the blood, home to peripheral tissues and show immediate cytolytic effector function 6 . These unique features of inflationary T cells have spurred great interest in utilizing CMV as a vaccine vector. Indeed, recombinant CMV, engineered to express defined vaccine antigens 7 , has shown immense promise for induction of protective cytotoxic T cell immunity, directed against simian immunodeficiency virus (SIV) 8 , 9 , 10 or Mycobacterium tuberculosis 11 . Importantly, not all CD8 + T cells that recognize epitopes presented during CMV latency strongly contribute to memory inflation. Instead, inflationary T cell populations become increasingly oligoclonal throughout the course of chronic CMV persistence 1 , 12 , 13 —a feature shared by other chronic infections 14 , 15 . The clonality of these responses indicates that they originate from one or few naive T cells harboring the same T cell receptor (TCR). Starting out from these rare naive precursors, the development of clonal dominance is thought to be predetermined by defined cellular features, such as TCR specificity and affinity 16 , 17 , 18 , 19 , 20 , 21 , 22 . However, in the context of acutely resolving infections, single-cell fate mapping has shown that even T cells expressing identical TCRs display massive variation of clonal expansion, with only some strongly dominating the acute response to infection 23 , 24 , 25 , 26 . The extent to which this fundamental, early variation that emerges from TCR-identical single cells also shapes T cell immunity against chronically persisting infections remains unknown. One option is that early single-cell-derived variation is erased by the effects of long-term TCR re-stimulation during chronic infection. Alternatively, such early variation in the life histories of single-cell-derived ‘T cell families’ may leave a lasting imprint on their long-term capacity for memory inflation and immunodominance. To resolve which of these two scenarios is true, we monitored, in vivo, the long-term development of T cell families derived from single naive precursors harboring identical TCRs specific to a vaccine antigen expressed by recombinant murine CMV (MCMV). We utilized blood sampling or hemisplenectomy to gauge a T cell family’s initial clonal expansion, monitored its differentiation state via RNA sequencing and flow cytometry and then tracked its long-term inflationary output throughout the chronic phase of MCMV infection. In addition, we utilized single-cell RNA sequencing (scRNA-seq) and RNA velocity analyses 27 to decipher the differentiation dynamics within an established inflationary T cell population. By integrating these approaches, we find that a T cell family’s initial clonal expansion does not predict its capacity for memory inflation. Instead, we identify a fundamental single-cell-derived variation in the amount of T central memory precursors (CMPs) generated during the acute phase of chronic viral infection. This variation defines a set point for the magnitude of memory inflation and imprints lasting hierarchies of immunodominance upon TCR-identical cells. We anticipate that measuring and altering this early CMP-related set point will be of critical relevance in the design of future vaccination strategies and immunotherapeutic approaches. Results Single-cell-derived memory inflation is highly variable and not predicted by acute clonal expansion Clonal expansion and phenotypic differentiation derived from single naive T cells has been found to vary massively upon acute infection 23 , 24 , 25 , 28 , 29 . Due to ‘response averaging’ this fundamental variation goes unnoticed when monitoring the expansion and differentiation of epitope-specific T cell populations 26 . Here, we aimed to evaluate the long-term consequences of such discrepant initial T cell behavior in the context of chronic infection. To achieve this, we made use of a recombinant MCMV vector into which a sequence encoding the SIINFEKL peptide of chicken ovalbumin (OVA) had been inserted at the 3′ end of the immediate early 2 (ie2) gene 30 (Extended Data Fig. 1a ). The promoter of ie2 remains active during chronic MCMV latency and, thereby, guarantees lasting expression of the engineered epitope 31 . We found that infection with MCMV- ie2 -SIINFEKL reliably induced memory inflation of endogenous SIINFEKL-specific CD8 + T cells (Fig. 1a ) and of adoptively transferred monoclonal populations of OT-1 T cells, whose transgenic TCR binds with high affinity to SIINFEKL in the context of H2-K b (Fig. 1b and Extended Data Fig. 1b ). Next, we adoptively transferred single naive CD8 + T cells and mapped their acute expansion and long-term memory inflation in response to MCMV- ie2- SIINFEKL. As done previously 23 , 25 , 32 , 33 , 34 , we increased our capacity for parallel fate mapping by collecting single naive T cells from OT-1 Rag-1 −/− donors expressing distinct combinations of the congenic markers CD45.1, CD45.2, CD90.1 and CD90.2. Upon adoptive transfer, we found that both acute and long-term expansion derived from these single naive T cells varied massively, with only<|im_end|> <|im_start|>assistant For a person to acquire immunity to a disease, T cells must develop into memory cells after contact with the pathogen. Until now, the number of cells that do this was believed to depend above all on the magnitude of the initial immune response. A team of researchers at the Technical University of Munich (TUM) has now called this into question. When a virus enters the body, it is picked up by certain cells of the immune system. They transport the virus to the lymph nodes where they present its fragments, known as antigens, to CD8+ T cells responsible control of viral infections. Each of these cells carries a unique T cell receptor on the surface that can recognize certain antigens. However, only very few T cell receptors match a given viral the antigen. To bring the infection under control and maximize the defenses against the virus, these few antigen-specific T cells start dividing rapidly and develop into effector T cells. These kill virus-infected host cells and then die off themselves once the infection is cleared. Some of these short-lived effector cells—according to the generally accepted theory—turn into memory T cells, which persist in the organism long term. In case the same pathogen enters the body again, memory T cells are already present and ready to fight the invader more swiftly and effectively than during the first encounter. Memory cells and their origin "Prevailing scientific opinion says that activated T cells first become effector cells and only then gradually develop into memory cells," says Dr. Veit Buchholz, a specialist in microbiology and working group leader at the Institute for Medical Microbiology, Immunology and Hygiene at TUM. "In our view, however, that isn't the case. It would mean that the more effector cells are formed after contact with the pathogen, the more numerous the memory cells would become." However, Buchholz and his colleagues observed a different course of events and have now published their results in the journal Nature Immunology. "We investigated the antiviral immune responses resulting from individual activated T cells in mice and traced the lineage of the ensuing memory cells using single-cell fate mapping," reports first author Dr. Simon Grassmann. "Based on these experiments, we were able to show that certain 'T cell families' descended from individual cells form up to 1000 times more 'memory' than others. However, these long-term dominating T cell families only contributed little to the magnitude of the initial immune response, which was dominated by effector cells derived from other shorter-lived T cell families." At the level of individual cells, it therefore became evident that development of effector and memory cells segregates at a much earlier stage than previously believed: "Already in the first week after the confrontation with the pathogen, we saw major differences in the transcriptomes of the detected T cell families," says Lorenz Mihatsch, also a first author of the study. "Normally at this time of the immune response CD8+ T cells are enriched in molecules that help to kill virus infected cells. However, we found no indication of these cytolytic molecules in the long-term dominating T cell families. Instead, they were already geared exclusively towards memory development at this early stage." Optimization of vaccines These results could help to improve vaccine development in the future, says Veit Buchholz: "To generate an optimal immune response through vaccination, the body needs to produce as many memory cells as possible. For that purpose, it is important to have a precise understanding of how individual T cells are programmed." Buchholz's study might also prove useful in helping to recognize sooner whether a new vaccine is effective. "To determine the long-term strength of an immune response, it could be helpful to measure the number of memory precursors within a few days of administering a vaccine," says Buchholz. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract RAS mutations are the most common oncogenic drivers across human cancers, but there remains a paucity of clinically-validated pharmacological inhibitors of RAS, as druggable pockets have proven difficult to identify. Here, we identify two RAS-binding Affimer proteins, K3 and K6, that inhibit nucleotide exchange and downstream signaling pathways with distinct isoform and mutant profiles. Affimer K6 binds in the SI/SII pocket, whilst Affimer K3 is a non-covalent inhibitor of the SII region that reveals a conformer of wild-type RAS with a large, druggable SII/α3 pocket. Competitive NanoBRET between the RAS-binding Affimers and known RAS binding small-molecules demonstrates the potential to use Affimers as tools to identify pharmacophores. This work highlights the potential of using biologics with small interface surfaces to select unseen, druggable conformations in conjunction with pharmacophore identification for hard-to-drug proteins. Introduction The RAS family of small GTPases consists of four members, KRAS4A, KRAS4B, HRAS, and NRAS, which act as bi-directional molecular switches that cycle between an inactive GDP-bound form, and an active GTP-bound form 1 . Mutations in RAS are the most common oncogenic drivers, with KRAS being the most frequently affected member; especially in pancreatic, lung, and colon cancer 1 . This makes RAS a strong therapeutic target, but despite having been identified as a drug target for over 30 years, only recently have compounds been developed that show promise in pre-clinical trials 2 . This paucity of agents has been caused by the lack of clearly druggable pockets on the surface of RAS. However, recent work has identified two pockets that may be amenable for drug binding 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 . The first of these, the SI/II-pocket, exists between the Switch I and Switch II regions of RAS in an area involved in the binding of the nucleotide exchange factor, Son of Sevenless (SOS). Several groups have independently developed compounds that bind this pocket with varying affinities and efficacies, predominately in the micromolar range 5 , 6 , 7 , 8 , except for BI-2852 which has nanomolar binding affinity and efficacy 11 . The second, the SII-pocket, is located under the Switch II loop and was identified using a tethered warhead approach relying on the reactive nature of the cysteine in the G12C mutant 9 , 10 . This pocket is not fully formed in published KRAS structures in the absence of the inhibitor; however, a groove is evident in some structures and it has been identified as a potential allosteric site computationally 3 , 4 . The development of tethered compounds targeting this pocket has led to the only series of RAS inhibitors currently in clinical trials 12 , 13 . This compound series is limited to cancers harboring G12C mutations, however, a cyclic peptide, KRpep-2d with a preference for G12D mutations has been identified that binds in a similar pocket 14 , 15 showing that biologics can also probe pockets in KRAS. It would be interesting to determine whether this pocket can be non-covalently exploited in other RAS isoforms and mutants, giving wider application to RAS-driven cancers. Targeting of RAS has also been explored using scaffold-based biologics, besides the cyclic peptide KRpep-2d. Antibodies and their alternatives have been developed that bind RAS with nanomolar affinities, inhibiting nucleotide exchange, interactions with RAF, and activation of downstream pathways concurrent with negative impacts on RAS-induced cell growth and transformation 16 , 17 , 18 , 19 , 20 , 21 . Amongst others, these include scFvs, DARPins, and monobodies 16 , 17 , 19 , 21 , 22 . Although to date some of these have been used to assist the identification of small molecules 5 , 7 , 23 , none have directly probed druggable pockets on RAS, as the majority of these scaffold-based biologics tend to bind over large protein interfaces 16 , 17 , 19 , 22 that are difficult to mimic with small molecules 24 . As some scaffold-based biologics form smaller interfaces 21 , 25 , 26 there emerges the tantalizing prospect that biologics could be used as tools to identify druggable pockets and novel conformers, and could also have the potential to act as pharmacophore templates for in silico-informed drug discovery. Here, we explore the possibility of using Affimer proteins, an established biologic with a small probe surface formed by two variable regions 26 known to bind at protein interaction ‘hotspots’ 25 , 27 , 28 , to probe RAS for druggable pockets and conformers that might be amenable to small-molecule inhibition. Such a direct approach utilizing small probe surfaces has not previously been used with scaffold-based biologics and could revolutionize drug discovery, by exemplifying a pipeline for small molecule design that has the potential to unlock the currently ‘undruggable’ proteins. Here, we demonstrate the use of Affimer proteins, a scaffold-based biologic, to identify and directly probe two druggable pockets on wild-type KRAS associated with inhibition of nucleotide exchange and effector molecule binding. The Affimer that binds to the SI/SII pocket actually mimics the current small molecule inhibitors that target the pocket as seen in a competitive NanoBRET assay, providing a proof-of-principle for using Affimer-target interfaces as pharmacophore templates. The Affimer that binds the SII region selects a previously unseen conformer of the pocket present in wild-type KRAS. The Switch II region adopts a more open position, demonstrating that selecting and targeting this site via non-covalent binding is possible. Our work supports two important concepts in the use of biologics: firstly, they can be used to select for, and stabilize, conformations that are only present as a small fraction of the conformations of the target protein in solution, particularly those that may not be present in extant crystal structures; and secondly, scaffold-based biologics can act as drug discovery tools and/or pharmacophore templates for identification and development of small-molecule inhibitors. This approach is likely to be applicable to other important therapeutic targets and presents the exciting potential for an alternative pipeline for drug discovery. Results Identification", "role": "user" }, { "content": "A new way to target a mutant protein which can cause the deadliest of cancers in humans has been uncovered by scientists at the University of Leeds.The mutated form of the RAS protein has been referred to as the \"Death Star\" because of its ability to resist treatments and is found in 96% of pancreatic cancers and 54% of colorectal cancers. RAS is a protein important for health but in its mutated form it can be switched on for longer, leading to the growth of tumors. One drug has already been approved for treatment but it can only tackle a small subset of the total number of cancers driven by RAS. Now a team from the University of Leeds' School of Molecular and Cellular Biology has gone further and found a new way to target the protein to pave the way for a greater range of treatments for more patients. Lead author of the report, Dr. Darren Tomlinson, of the Astbury Centre for Structural and Molecular Biology, said: \"The RAS protein has been referred to as the Death Star with good reason and that's because it's spherical and impenetrable, essentially preventing drugs binding and inhibiting it. We've identified a further chink in the Death Star that can be used to develop new drugs beyond the ones already in development.\" The researchers used the School of Molecular and Cellular Biology's own patented Affimer biotechnology platform to pinpoint druggable \"pockets\" on the protein to allow effective treatment to take place. The study was funded by the Wellcome Trust, the Medical Research Council, the Technology Strategy Board and Avacta and is published today (30 June 2021) in the journal, Nature Communications. Dr. Tomlinson added: \"This work opens up the door for the hundreds of other disease targets. We could effectively probe any protein involved in any disease for druggable pockets in the future.\" Co-first author of the report and Ph.D. student, Amy Turner, from the School of Molecular and Cellular Biology, said: \"Because it causes 20-30% of all known cancers, RAS really is the Holy Grail of therapeutic targets. The fact that it has previously been termed 'undruggable' has allowed us to demonstrate the huge impact that our Affimer technology can have when it comes to treating challenging pathologies. We have already identified small molecules that bind to RAS, so it will be very exciting to be involved in developing these over the next few years.\" The researchers say work on expanding more ways to target RAS is still in its early stages but they believe their discovery could lead to new treatments, putting Leeds at the forefront of the fight against cancer. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract RAS mutations are the most common oncogenic drivers across human cancers, but there remains a paucity of clinically-validated pharmacological inhibitors of RAS, as druggable pockets have proven difficult to identify. Here, we identify two RAS-binding Affimer proteins, K3 and K6, that inhibit nucleotide exchange and downstream signaling pathways with distinct isoform and mutant profiles. Affimer K6 binds in the SI/SII pocket, whilst Affimer K3 is a non-covalent inhibitor of the SII region that reveals a conformer of wild-type RAS with a large, druggable SII/α3 pocket. Competitive NanoBRET between the RAS-binding Affimers and known RAS binding small-molecules demonstrates the potential to use Affimers as tools to identify pharmacophores. This work highlights the potential of using biologics with small interface surfaces to select unseen, druggable conformations in conjunction with pharmacophore identification for hard-to-drug proteins. Introduction The RAS family of small GTPases consists of four members, KRAS4A, KRAS4B, HRAS, and NRAS, which act as bi-directional molecular switches that cycle between an inactive GDP-bound form, and an active GTP-bound form 1 . Mutations in RAS are the most common oncogenic drivers, with KRAS being the most frequently affected member; especially in pancreatic, lung, and colon cancer 1 . This makes RAS a strong therapeutic target, but despite having been identified as a drug target for over 30 years, only recently have compounds been developed that show promise in pre-clinical trials 2 . This paucity of agents has been caused by the lack of clearly druggable pockets on the surface of RAS. However, recent work has identified two pockets that may be amenable for drug binding 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 . The first of these, the SI/II-pocket, exists between the Switch I and Switch II regions of RAS in an area involved in the binding of the nucleotide exchange factor, Son of Sevenless (SOS). Several groups have independently developed compounds that bind this pocket with varying affinities and efficacies, predominately in the micromolar range 5 , 6 , 7 , 8 , except for BI-2852 which has nanomolar binding affinity and efficacy 11 . The second, the SII-pocket, is located under the Switch II loop and was identified using a tethered warhead approach relying on the reactive nature of the cysteine in the G12C mutant 9 , 10 . This pocket is not fully formed in published KRAS structures in the absence of the inhibitor; however, a groove is evident in some structures and it has been identified as a potential allosteric site computationally 3 , 4 . The development of tethered compounds targeting this pocket has led to the only series of RAS inhibitors currently in clinical trials 12 , 13 . This compound series is limited to cancers harboring G12C mutations, however, a cyclic peptide, KRpep-2d with a preference for G12D mutations has been identified that binds in a similar pocket 14 , 15 showing that biologics can also probe pockets in KRAS. It would be interesting to determine whether this pocket can be non-covalently exploited in other RAS isoforms and mutants, giving wider application to RAS-driven cancers. Targeting of RAS has also been explored using scaffold-based biologics, besides the cyclic peptide KRpep-2d. Antibodies and their alternatives have been developed that bind RAS with nanomolar affinities, inhibiting nucleotide exchange, interactions with RAF, and activation of downstream pathways concurrent with negative impacts on RAS-induced cell growth and transformation 16 , 17 , 18 , 19 , 20 , 21 . Amongst others, these include scFvs, DARPins, and monobodies 16 , 17 , 19 , 21 , 22 . Although to date some of these have been used to assist the identification of small molecules 5 , 7 , 23 , none have directly probed druggable pockets on RAS, as the majority of these scaffold-based biologics tend to bind over large protein interfaces 16 , 17 , 19 , 22 that are difficult to mimic with small molecules 24 . As some scaffold-based biologics form smaller interfaces 21 , 25 , 26 there emerges the tantalizing prospect that biologics could be used as tools to identify druggable pockets and novel conformers, and could also have the potential to act as pharmacophore templates for in silico-informed drug discovery. Here, we explore the possibility of using Affimer proteins, an established biologic with a small probe surface formed by two variable regions 26 known to bind at protein interaction ‘hotspots’ 25 , 27 , 28 , to probe RAS for druggable pockets and conformers that might be amenable to small-molecule inhibition. Such a direct approach utilizing small probe surfaces has not previously been used with scaffold-based biologics and could revolutionize drug discovery, by exemplifying a pipeline for small molecule design that has the potential to unlock the currently ‘undruggable’ proteins. Here, we demonstrate the use of Affimer proteins, a scaffold-based biologic, to identify and directly probe two druggable pockets on wild-type KRAS associated with inhibition of nucleotide exchange and effector molecule binding. The Affimer that binds to the SI/SII pocket actually mimics the current small molecule inhibitors that target the pocket as seen in a competitive NanoBRET assay, providing a proof-of-principle for using Affimer-target interfaces as pharmacophore templates. The Affimer that binds the SII region selects a previously unseen conformer of the pocket present in wild-type KRAS. The Switch II region adopts a more open position, demonstrating that selecting and targeting this site via non-covalent binding is possible. Our work supports two important concepts in the use of biologics: firstly, they can be used to select for, and stabilize, conformations that are only present as a small fraction of the conformations of the target protein in solution, particularly those that may not be present in extant crystal structures; and secondly, scaffold-based biologics can act as drug discovery tools and/or pharmacophore templates for identification and development of small-molecule inhibitors. This approach is likely to be applicable to other important therapeutic targets and presents the exciting potential for an alternative pipeline for drug discovery. Results Identification<|im_end|> <|im_start|>assistant A new way to target a mutant protein which can cause the deadliest of cancers in humans has been uncovered by scientists at the University of Leeds.The mutated form of the RAS protein has been referred to as the "Death Star" because of its ability to resist treatments and is found in 96% of pancreatic cancers and 54% of colorectal cancers. RAS is a protein important for health but in its mutated form it can be switched on for longer, leading to the growth of tumors. One drug has already been approved for treatment but it can only tackle a small subset of the total number of cancers driven by RAS. Now a team from the University of Leeds' School of Molecular and Cellular Biology has gone further and found a new way to target the protein to pave the way for a greater range of treatments for more patients. Lead author of the report, Dr. Darren Tomlinson, of the Astbury Centre for Structural and Molecular Biology, said: "The RAS protein has been referred to as the Death Star with good reason and that's because it's spherical and impenetrable, essentially preventing drugs binding and inhibiting it. We've identified a further chink in the Death Star that can be used to develop new drugs beyond the ones already in development." The researchers used the School of Molecular and Cellular Biology's own patented Affimer biotechnology platform to pinpoint druggable "pockets" on the protein to allow effective treatment to take place. The study was funded by the Wellcome Trust, the Medical Research Council, the Technology Strategy Board and Avacta and is published today (30 June 2021) in the journal, Nature Communications. Dr. Tomlinson added: "This work opens up the door for the hundreds of other disease targets. We could effectively probe any protein involved in any disease for druggable pockets in the future." Co-first author of the report and Ph.D. student, Amy Turner, from the School of Molecular and Cellular Biology, said: "Because it causes 20-30% of all known cancers, RAS really is the Holy Grail of therapeutic targets. The fact that it has previously been termed 'undruggable' has allowed us to demonstrate the huge impact that our Affimer technology can have when it comes to treating challenging pathologies. We have already identified small molecules that bind to RAS, so it will be very exciting to be involved in developing these over the next few years." The researchers say work on expanding more ways to target RAS is still in its early stages but they believe their discovery could lead to new treatments, putting Leeds at the forefront of the fight against cancer. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Cooperatively nesting birds are vulnerable to social parasites that lay their eggs in host nests but provide no parental care 1 , 2 , 3 , 4 . Most previous research has focused on the co-evolutionary arms race between host defences and the parasites that attempt to circumvent them 5 , 6 , 7 , 8 , 9 , but it remains unclear why females sometimes cooperate and sometimes parasitize, and how parasitic tactics arise in cooperative systems 10 , 11 , 12 . Here we show that cooperative and parasitic reproductive strategies result in approximately equal fitness pay-offs in the greater ani ( Crotophaga major ), a long-lived tropical cuckoo, using an 11-year dataset and comprehensive genetic data that enable comparisons of the life-histories of individual females. We found that most females in the population nested cooperatively at the beginning of the breeding season; however, of those birds that had their first nests destroyed, a minority subsequently acted as reproductive parasites. The tendency to parasitize was highly repeatable, which indicates individual specialization. Across years, the fitness pay-offs of the two strategies were approximately equal: females who never parasitized (a ‘pure cooperative’ strategy) laid larger clutches and fledged more young from their own nests than did birds that both nested and parasitized (a ‘mixed’ strategy). Our results suggest that the success of parasites is constrained by reproductive trade-offs as well as by host defences, and illustrate how cooperative and parasitic tactics can coexist stably in the same population. Main Conspecific brood parasitism—in which a female lays her egg in the nest of another female of the same species, but provides no parental care—is a widespread reproductive tactic that has been documented in over 250 species of birds 13 and many insects 14 . This form of social parasitism has been the subject of much research over the past thirty years, which has primarily focused on quantifying the costs suffered by hosts 15 , 16 and the benefits gained by parasites 2 , 17 , 18 , 19 . In some species, the co-evolutionary arms race between brood parasites and hosts has resulted in an array of specialized adaptations, including distinctive egg and juvenile phenotypes 6 , 7 and the cognitive abilities to detect parasitic offspring by offspring number, phenotype or timing of laying 3 , 8 , 20 , 21 . However, a major unresolved question is why some females care for their own offspring whereas other females in the same population act as parasites 5 , 12 . Three hypotheses have previously been proposed to explain the coexistence of independent nesting and conspecific brood parasitism 22 . First, parasitism may be a ‘best-of-a-bad-job’ tactic: females lay parasitically when they are unable to reproduce independently (owing to poor environmental conditions or individual quality), or after their own nest is destroyed during laying. This hypothesis predicts that parasitism should be a conditional tactic, which yields lower fitness benefits than independent nesting but higher benefits than failing to reproduce entirely. Second, parasitism may be a discrete behavioural polymorphism, such that some females act as specialized parasites throughout their lives. This hypothesis predicts that the frequencies of hosts and parasites in the population should be maintained in a mixed evolutionarily stable state by negative-frequency-dependent selection, and that hosts and parasites should have equal fitness at equilibrium. Third, parasitism may be an opportunistic tactic to increase total fecundity, in which females nest independently but lay additional eggs in host nests if possible. This hypothesis predicts that the fitness benefits of adopting both tactics are greater than either parasitism or independent nesting, but that the opportunities for parasitism are limited (either by female body condition or by host availability 14 ). There is currently no empirical evidence to support the hypothesis that parasitism is a discrete behavioural polymorphism, whereas there is limited support for the best-of-a-bad-job and opportunistic hypotheses 12 , 14 , 15 , 16 , 17 , 18 , 19 , 23 , 24 . Even with the recent development of molecular techniques to genotype eggs, it is difficult to identify parasitic eggs in host clutches, trace these eggs to the parasites that laid them and track the reproductive behaviours of these females across years. As a result, there is a critical lack of empirical data on the long-term fitness costs and benefits of alternative tactics, on the individual life-histories of parasitic females and on whether these females consistently adopt the same tactics over time. Here we address these questions in a long-term study of a tropical cuckoo, the greater ani ( C. major ), in Panama. The cooperative breeding system of anis provides a rare opportunity to examine the selective pressures that maintain alternative reproductive tactics: nesting groups typically consist of two or three genetically unrelated pairs that together build a single nest, lay approximately equal numbers of eggs and share parental care of the mixed clutch 25 . Previous studies have found that cooperative nesting reduces the probability of nest predation: reproductive success increases with group size and lone nesting is extremely rare 25 , 26 . Conspecific parasitism—in which extra-group females lay their eggs into host nests but provide no parental care—affects between 10% and 30% of nests each year 3 . Female anis therefore have three options for reproduction: (1) nesting cooperatively to share parental care; (2) acting as a parasite and laying eggs in another nest; or (3) nesting both cooperatively and parasitically. Here we show that although ‘pure’ parasites do not occur in this population, some females consistently lay parasitically if their first clutch is destroyed by predators (a mixed strategy) whereas others never lay parasitically (a pure cooperative strategy). Females that practiced the latter strategy laid larger clutches and fledged more young from their own nests than did females that practiced the former strategy, such that the two strategies yielded approximately equal fitness returns across years. We used 12 polymorphic microsatellite loci 27 to genotype 1,776 eggs laid by 210 females in 240 clutches from", "role": "user" }, { "content": "In the tropical jungle of Central America where predators abound, a species of cuckoo has found safety in numbers by building communal nests guarded by two or three breeding pairs. Why then do these agreeable avians sometimes ditch the collaborative lifestyle and instead deposit eggs into nests outside the communal group, acting like social parasites, in the hopes that other females will raise the chicks as their own? In a paper published online in the journal Nature, Princeton researchers show that the cuckoos, known as greater anis (Crotophaga major), act collectively for the most part but can become social parasites after their communal nest is destroyed. They start the breeding season placing all their eggs in one basket, but if predators intervene, the birds switch to a strategy of spreading the eggs around in other nests. \"When different females in a population pursue different reproductive tactics, like cooperative and parasitic nesting, this poses an evolutionary puzzle. We wondered why some females lay their eggs into other groups' nests, whereas other females never do,\" said Christina Riehl, assistant professor of ecology and evolutionary biology. She and co-author Meghan Strong, a research specialist in the Department of Ecology and Evolutionary Biology, conducted the study with help from undergraduates, graduate students and interns, including several from the Princeton Environmental Institute (PEI). \"We found the parasitic strategy is more of a second-line option,\" Riehl said. \"It's as if the birds say, 'If our cooperative attempt fails, let's go to Option B.'\" The team concluded that the two reproductive strategies can coexist in the population because the mixed strategy of first cooperating and then parasitizing yields about the same number of offspring as the pure cooperative strategy does. If one or the other were clearly better, then all the birds would most likely adopt the most successful strategy. The greater ani is one of the few bird species in which unrelated females come together to raise their young communally. In contrast, social parasitism is quite common, found in over 250 bird species. To find out why the normally collaborative anis resort to parasitism, the scientists observed the birds and their nesting behaviors over an 11-year period at Barro Colorado Nature Monument in Panama. The birds build the nests in branches that overhang the Panama Canal, requiring the researchers to reach the nests by boat. Under constant threat from predators such as snakes and monkeys, nearly all of the anis start the breeding season in communal groups, the researchers found. However, social parasitism is also widespread, the researchers found, with about 25 percent of the nests being parasitized by a female who was not a member of the group. Communal nest of Greater Anis containing nestlings from two breeding pairs. Barro Colorado Island, Panama. Credit: Christina Riehl The team found that females whose nests were destroyed by predators early in the nesting cycle were most likely to lay parasitically, typically in nests close to their own failed nest. The researchers also asked whether switching mid-season from collective nesting to social parasitism might actually lead to more offspring. Although laying as many eggs as possible sounds like a good strategy, social parasitism has drawbacks. The eggs tend to be slightly smaller and thus less likely to thrive. And due to the risk of being found out, these eggs have a lower chance of survival to the stage where the chicks leave the nest. In contrast, the cooperative females lay fewer eggs but they put more effort into tending them, so more chicks survive to leave the nest. The take-away: Both of the reproductive strategies—communal breeding only versus the mixed approach of starting as communal breeders and switching to parasitism—are viable reproductive strategies. Mark Hauber is an ornithologist and behavioral ecologist of the University of Illinois at Urbana-Champaign who was not involved in the study. \"The study explains why cooperative breeding is maintained evolutionarily in this species—solitary breeding or parasitism alone are simply not productive enough,\" Hauber said. \"But either cooperative breeding with large clutches or failed cooperative breeding followed by parasitism are equivalent strategies fitness-wise. Thus parasitism continues to be present in the population and so is cooperative breeding.\" The team also found that the same females turned to parasitism after the failure of their nests year after year. \"Previously in my own work on captive zebra finches I found that some individuals are more likely to become brood parasites than others,\" Hauber said. \"This is now demonstrated and confirmed firmly in a wild population of free-living tropical birds.\" The ongoing study monitors roughly 40 to 60 nests per year. Overall, for the current finding, the team studied genetic data from 1,776 eggs laid by 210 females in 240 nests from 2007-17. Each year the team begins the breeding season in June by searching for nests in the vegetation along the shoreline. The researchers check the nests daily, swabbing each new egg to collect cells and blood left on the egg with the goal of using genetics to identify each egg's mother. They weigh and measure every egg, and collect blood from the chicks to confirm their parentage. \"Getting into the nest is actually often the trickiest part of collecting measurements,\" said Luke Carabbia, Class of 2019, who conducted field work as a PEI intern. \"While some groups of birds cooperate with us very well and nest right at an accessible chest height, others build their nests all the way at the top of their trees or in flimsy reeds deep in grass, and the birds often have a real knack for picking spots that are either incredibly thorny or right next to a nest of angry wasps.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Cooperatively nesting birds are vulnerable to social parasites that lay their eggs in host nests but provide no parental care 1 , 2 , 3 , 4 . Most previous research has focused on the co-evolutionary arms race between host defences and the parasites that attempt to circumvent them 5 , 6 , 7 , 8 , 9 , but it remains unclear why females sometimes cooperate and sometimes parasitize, and how parasitic tactics arise in cooperative systems 10 , 11 , 12 . Here we show that cooperative and parasitic reproductive strategies result in approximately equal fitness pay-offs in the greater ani ( Crotophaga major ), a long-lived tropical cuckoo, using an 11-year dataset and comprehensive genetic data that enable comparisons of the life-histories of individual females. We found that most females in the population nested cooperatively at the beginning of the breeding season; however, of those birds that had their first nests destroyed, a minority subsequently acted as reproductive parasites. The tendency to parasitize was highly repeatable, which indicates individual specialization. Across years, the fitness pay-offs of the two strategies were approximately equal: females who never parasitized (a ‘pure cooperative’ strategy) laid larger clutches and fledged more young from their own nests than did birds that both nested and parasitized (a ‘mixed’ strategy). Our results suggest that the success of parasites is constrained by reproductive trade-offs as well as by host defences, and illustrate how cooperative and parasitic tactics can coexist stably in the same population. Main Conspecific brood parasitism—in which a female lays her egg in the nest of another female of the same species, but provides no parental care—is a widespread reproductive tactic that has been documented in over 250 species of birds 13 and many insects 14 . This form of social parasitism has been the subject of much research over the past thirty years, which has primarily focused on quantifying the costs suffered by hosts 15 , 16 and the benefits gained by parasites 2 , 17 , 18 , 19 . In some species, the co-evolutionary arms race between brood parasites and hosts has resulted in an array of specialized adaptations, including distinctive egg and juvenile phenotypes 6 , 7 and the cognitive abilities to detect parasitic offspring by offspring number, phenotype or timing of laying 3 , 8 , 20 , 21 . However, a major unresolved question is why some females care for their own offspring whereas other females in the same population act as parasites 5 , 12 . Three hypotheses have previously been proposed to explain the coexistence of independent nesting and conspecific brood parasitism 22 . First, parasitism may be a ‘best-of-a-bad-job’ tactic: females lay parasitically when they are unable to reproduce independently (owing to poor environmental conditions or individual quality), or after their own nest is destroyed during laying. This hypothesis predicts that parasitism should be a conditional tactic, which yields lower fitness benefits than independent nesting but higher benefits than failing to reproduce entirely. Second, parasitism may be a discrete behavioural polymorphism, such that some females act as specialized parasites throughout their lives. This hypothesis predicts that the frequencies of hosts and parasites in the population should be maintained in a mixed evolutionarily stable state by negative-frequency-dependent selection, and that hosts and parasites should have equal fitness at equilibrium. Third, parasitism may be an opportunistic tactic to increase total fecundity, in which females nest independently but lay additional eggs in host nests if possible. This hypothesis predicts that the fitness benefits of adopting both tactics are greater than either parasitism or independent nesting, but that the opportunities for parasitism are limited (either by female body condition or by host availability 14 ). There is currently no empirical evidence to support the hypothesis that parasitism is a discrete behavioural polymorphism, whereas there is limited support for the best-of-a-bad-job and opportunistic hypotheses 12 , 14 , 15 , 16 , 17 , 18 , 19 , 23 , 24 . Even with the recent development of molecular techniques to genotype eggs, it is difficult to identify parasitic eggs in host clutches, trace these eggs to the parasites that laid them and track the reproductive behaviours of these females across years. As a result, there is a critical lack of empirical data on the long-term fitness costs and benefits of alternative tactics, on the individual life-histories of parasitic females and on whether these females consistently adopt the same tactics over time. Here we address these questions in a long-term study of a tropical cuckoo, the greater ani ( C. major ), in Panama. The cooperative breeding system of anis provides a rare opportunity to examine the selective pressures that maintain alternative reproductive tactics: nesting groups typically consist of two or three genetically unrelated pairs that together build a single nest, lay approximately equal numbers of eggs and share parental care of the mixed clutch 25 . Previous studies have found that cooperative nesting reduces the probability of nest predation: reproductive success increases with group size and lone nesting is extremely rare 25 , 26 . Conspecific parasitism—in which extra-group females lay their eggs into host nests but provide no parental care—affects between 10% and 30% of nests each year 3 . Female anis therefore have three options for reproduction: (1) nesting cooperatively to share parental care; (2) acting as a parasite and laying eggs in another nest; or (3) nesting both cooperatively and parasitically. Here we show that although ‘pure’ parasites do not occur in this population, some females consistently lay parasitically if their first clutch is destroyed by predators (a mixed strategy) whereas others never lay parasitically (a pure cooperative strategy). Females that practiced the latter strategy laid larger clutches and fledged more young from their own nests than did females that practiced the former strategy, such that the two strategies yielded approximately equal fitness returns across years. We used 12 polymorphic microsatellite loci 27 to genotype 1,776 eggs laid by 210 females in 240 clutches from<|im_end|> <|im_start|>assistant In the tropical jungle of Central America where predators abound, a species of cuckoo has found safety in numbers by building communal nests guarded by two or three breeding pairs. Why then do these agreeable avians sometimes ditch the collaborative lifestyle and instead deposit eggs into nests outside the communal group, acting like social parasites, in the hopes that other females will raise the chicks as their own? In a paper published online in the journal Nature, Princeton researchers show that the cuckoos, known as greater anis (Crotophaga major), act collectively for the most part but can become social parasites after their communal nest is destroyed. They start the breeding season placing all their eggs in one basket, but if predators intervene, the birds switch to a strategy of spreading the eggs around in other nests. "When different females in a population pursue different reproductive tactics, like cooperative and parasitic nesting, this poses an evolutionary puzzle. We wondered why some females lay their eggs into other groups' nests, whereas other females never do," said Christina Riehl, assistant professor of ecology and evolutionary biology. She and co-author Meghan Strong, a research specialist in the Department of Ecology and Evolutionary Biology, conducted the study with help from undergraduates, graduate students and interns, including several from the Princeton Environmental Institute (PEI). "We found the parasitic strategy is more of a second-line option," Riehl said. "It's as if the birds say, 'If our cooperative attempt fails, let's go to Option B.'" The team concluded that the two reproductive strategies can coexist in the population because the mixed strategy of first cooperating and then parasitizing yields about the same number of offspring as the pure cooperative strategy does. If one or the other were clearly better, then all the birds would most likely adopt the most successful strategy. The greater ani is one of the few bird species in which unrelated females come together to raise their young communally. In contrast, social parasitism is quite common, found in over 250 bird species. To find out why the normally collaborative anis resort to parasitism, the scientists observed the birds and their nesting behaviors over an 11-year period at Barro Colorado Nature Monument in Panama. The birds build the nests in branches that overhang the Panama Canal, requiring the researchers to reach the nests by boat. Under constant threat from predators such as snakes and monkeys, nearly all of the anis start the breeding season in communal groups, the researchers found. However, social parasitism is also widespread, the researchers found, with about 25 percent of the nests being parasitized by a female who was not a member of the group. Communal nest of Greater Anis containing nestlings from two breeding pairs. Barro Colorado Island, Panama. Credit: Christina Riehl The team found that females whose nests were destroyed by predators early in the nesting cycle were most likely to lay parasitically, typically in nests close to their own failed nest. The researchers also asked whether switching mid-season from collective nesting to social parasitism might actually lead to more offspring. Although laying as many eggs as possible sounds like a good strategy, social parasitism has drawbacks. The eggs tend to be slightly smaller and thus less likely to thrive. And due to the risk of being found out, these eggs have a lower chance of survival to the stage where the chicks leave the nest. In contrast, the cooperative females lay fewer eggs but they put more effort into tending them, so more chicks survive to leave the nest. The take-away: Both of the reproductive strategies—communal breeding only versus the mixed approach of starting as communal breeders and switching to parasitism—are viable reproductive strategies. Mark Hauber is an ornithologist and behavioral ecologist of the University of Illinois at Urbana-Champaign who was not involved in the study. "The study explains why cooperative breeding is maintained evolutionarily in this species—solitary breeding or parasitism alone are simply not productive enough," Hauber said. "But either cooperative breeding with large clutches or failed cooperative breeding followed by parasitism are equivalent strategies fitness-wise. Thus parasitism continues to be present in the population and so is cooperative breeding." The team also found that the same females turned to parasitism after the failure of their nests year after year. "Previously in my own work on captive zebra finches I found that some individuals are more likely to become brood parasites than others," Hauber said. "This is now demonstrated and confirmed firmly in a wild population of free-living tropical birds." The ongoing study monitors roughly 40 to 60 nests per year. Overall, for the current finding, the team studied genetic data from 1,776 eggs laid by 210 females in 240 nests from 2007-17. Each year the team begins the breeding season in June by searching for nests in the vegetation along the shoreline. The researchers check the nests daily, swabbing each new egg to collect cells and blood left on the egg with the goal of using genetics to identify each egg's mother. They weigh and measure every egg, and collect blood from the chicks to confirm their parentage. "Getting into the nest is actually often the trickiest part of collecting measurements," said Luke Carabbia, Class of 2019, who conducted field work as a PEI intern. "While some groups of birds cooperate with us very well and nest right at an accessible chest height, others build their nests all the way at the top of their trees or in flimsy reeds deep in grass, and the birds often have a real knack for picking spots that are either incredibly thorny or right next to a nest of angry wasps." <|im_end|>

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275, 2740, 320, 64, 10748, 48566, 8446, 570, 35295, 3916, 430, 44664, 279, 15629, 8446, 17551, 8294, 1206, 88449, 323, 30010, 3640, 810, 3995, 505, 872, 1866, 96221, 1109, 1550, 28585, 430, 44664, 279, 4846, 8446, 11, 1778, 430, 279, 1403, 15174, 58487, 13489, 6273, 17479, 4780, 4028, 1667, 13, 1226, 1511, 220, 717, 46033, 41969, 8162, 37568, 18652, 1353, 72, 220, 1544, 311, 80285, 220, 16, 11, 23823, 19335, 17551, 555, 220, 8848, 28585, 304, 220, 8273, 1206, 88449, 505, 128257, 198, 128256, 78191, 198, 644, 279, 35148, 45520, 315, 10913, 5270, 1405, 56217, 87690, 11, 264, 9606, 315, 63279, 2689, 706, 1766, 7296, 304, 5219, 555, 4857, 57937, 96221, 64263, 555, 1403, 477, 2380, 40308, 13840, 13, 8595, 1243, 656, 1521, 7655, 481, 1860, 5493, 7170, 50104, 279, 40806, 19433, 323, 4619, 16946, 19335, 1139, 96221, 4994, 279, 57937, 1912, 11, 15718, 1093, 3674, 79383, 11, 304, 279, 16388, 430, 1023, 28585, 690, 4933, 279, 69089, 439, 872, 1866, 30, 763, 264, 5684, 4756, 2930, 304, 279, 8486, 22037, 11, 50421, 12074, 1501, 430, 279, 63279, 78, 437, 11, 3967, 439, 7191, 459, 285, 320, 96141, 3565, 71, 12748, 3682, 705, 1180, 45925, 369, 279, 1455, 961, 719, 649, 3719, 3674, 79383, 1306, 872, 57937, 23634, 374, 14763, 13, 2435, 1212, 279, 40308, 3280, 25012, 682, 872, 19335, 304, 832, 14351, 11, 719, 422, 56217, 55579, 11, 279, 20229, 3480, 311, 264, 8446, 315, 31135, 279, 19335, 2212, 304, 1023, 96221, 13, 330, 4599, 2204, 28585, 304, 264, 7187, 23564, 2204, 42889, 26411, 11, 1093, 48566, 323, 33403, 49086, 67810, 11, 420, 34103, 459, 41993, 25649, 13, 1226, 31156, 3249, 1063, 28585, 11203, 872, 19335, 1139, 1023, 5315, 6, 96221, 11, 20444, 1023, 28585, 2646, 656, 1359, 1071, 60771, 432, 648, 18442, 11, 18328, 14561, 315, 72546, 323, 41993, 34458, 13, 3005, 323, 1080, 43802, 80134, 27191, 11, 264, 3495, 24687, 304, 279, 6011, 315, 78375, 323, 38321, 661, 40023, 11, 13375, 279, 4007, 449, 1520, 505, 86172, 52085, 11, 19560, 4236, 323, 99934, 11, 2737, 3892, 505, 279, 50421, 25027, 10181, 320, 1777, 40, 570, 330, 1687, 1766, 279, 33403, 49086, 8446, 374, 810, 315, 264, 2132, 8614, 3072, 1359, 432, 648, 18442, 1071, 13, 330, 2181, 596, 439, 422, 279, 20229, 2019, 11, 364, 2746, 1057, 48566, 4879, 14865, 11, 1095, 596, 733, 311, 7104, 426, 30251, 578, 2128, 20536, 430, 279, 1403, 42889, 15174, 649, 1080, 29675, 304, 279, 7187, 1606, 279, 9709, 8446, 315, 1176, 82589, 323, 1243, 33403, 275, 4954, 36508, 922, 279, 1890, 1396, 315, 46471, 439, 279, 10748, 48566, 8446, 1587, 13, 1442, 832, 477, 279, 1023, 1051, 9539, 2731, 11, 1243, 682, 279, 20229, 1053, 1455, 4461, 11142, 279, 1455, 6992, 8446, 13, 578, 7191, 53088, 374, 832, 315, 279, 2478, 12224, 9606, 304, 902, 46305, 28585, 2586, 3871, 311, 4933, 872, 3995, 34561, 750, 13, 763, 13168, 11, 3674, 33403, 275, 2191, 374, 5115, 4279, 11, 1766, 304, 927, 220, 5154, 12224, 9606, 13, 2057, 1505, 704, 3249, 279, 14614, 40806, 459, 285, 22541, 311, 33403, 275, 2191, 11, 279, 14248, 13468, 279, 20229, 323, 872, 67810, 28198, 927, 459, 220, 806, 4771, 4261, 520, 4821, 299, 15745, 22037, 72377, 304, 49136, 13, 578, 20229, 1977, 279, 96221, 304, 23962, 430, 927, 21313, 279, 49136, 53748, 11, 23537, 279, 12074, 311, 5662, 279, 96221, 555, 15688, 13, 9636, 6926, 6023, 505, 56217, 1778, 439, 57196, 323, 61820, 11, 7154, 682, 315, 279, 459, 285, 1212, 279, 40308, 3280, 304, 57937, 5315, 11, 279, 12074, 1766, 13, 4452, 11, 3674, 33403, 275, 2191, 374, 1101, 24716, 11, 279, 12074, 1766, 11, 449, 922, 220, 914, 3346, 315, 279, 96221, 1694, 33403, 84543, 555, 264, 8954, 889, 574, 539, 264, 4562, 315, 279, 1912, 13, 6947, 26663, 23634, 315, 33381, 1556, 285, 8649, 23634, 19342, 505, 1403, 40308, 13840, 13, 4821, 299, 15745, 10951, 11, 49136, 13, 16666, 25, 60771, 432, 648, 18442, 578, 2128, 1766, 430, 28585, 6832, 96221, 1051, 14763, 555, 56217, 4216, 304, 279, 67810, 11008, 1051, 1455, 4461, 311, 11203, 33403, 275, 2740, 11, 11383, 304, 96221, 3345, 311, 872, 1866, 4745, 23634, 13, 578, 12074, 1101, 4691, 3508, 28865, 5209, 31300, 505, 22498, 67810, 311, 3674, 33403, 275, 2191, 2643, 3604, 3063, 311, 810, 46471, 13, 10541, 35744, 439, 1690, 19335, 439, 3284, 10578, 1093, 264, 1695, 8446, 11, 3674, 33403, 275, 2191, 706, 89173, 13, 578, 19335, 8541, 311, 387, 10284, 9333, 323, 8617, 2753, 4461, 311, 41972, 13, 1628, 4245, 311, 279, 5326, 315, 1694, 1766, 704, 11, 1521, 19335, 617, 264, 4827, 6140, 315, 20237, 311, 279, 6566, 1405, 279, 69089, 5387, 279, 23634, 13, 763, 13168, 11, 279, 48566, 28585, 11203, 17162, 19335, 719, 814, 2231, 810, 5149, 1139, 259, 2518, 1124, 11, 779, 810, 69089, 18167, 311, 5387, 279, 23634, 13, 578, 1935, 90724, 25, 11995, 315, 279, 42889, 15174, 2345, 3705, 26663, 40308, 1193, 19579, 279, 9709, 5603, 315, 6041, 439, 57937, 28875, 388, 323, 28865, 311, 33403, 275, 2191, 83872, 31528, 42889, 15174, 13, 4488, 14433, 30970, 374, 459, 40545, 411, 16549, 323, 36695, 12208, 16549, 315, 279, 3907, 315, 19174, 520, 72313, 3444, 30653, 18666, 889, 574, 539, 6532, 304, 279, 4007, 13, 330, 791, 4007, 15100, 3249, 48566, 40308, 374, 18908, 15740, 6751, 304, 420, 9606, 2345, 39298, 45906, 40308, 477, 33403, 275, 2191, 7636, 527, 5042, 539, 27331, 3403, 1359, 14433, 30970, 1071, 13, 330, 4071, 3060, 48566, 40308, 449, 3544, 1206, 88449, 477, 4745, 48566, 40308, 8272, 555, 33403, 275, 2191, 527, 13890, 15174, 17479, 45539, 13, 14636, 33403, 275, 2191, 9731, 311, 387, 3118, 304, 279, 7187, 323, 779, 374, 48566, 40308, 1210, 578, 2128, 1101, 1766, 430, 279, 1890, 28585, 6656, 311, 33403, 275, 2191, 1306, 279, 8060, 315, 872, 96221, 1060, 1306, 1060, 13, 330, 83039, 304, 856, 1866, 990, 389, 60951, 1167, 51313, 1913, 8696, 358, 1766, 430, 1063, 7931, 527, 810, 4461, 311, 3719, 2967, 347, 79383, 1109, 3885, 1359, 14433, 30970, 1071, 13, 330, 2028, 374, 1457, 21091, 323, 11007, 32620, 304, 264, 8545, 7187, 315, 1949, 2922, 2299, 35148, 20229, 1210, 578, 14529, 4007, 37577, 17715, 220, 1272, 311, 220, 1399, 96221, 824, 1060, 13, 28993, 11, 369, 279, 1510, 9455, 11, 279, 2128, 20041, 19465, 828, 505, 220, 16, 11, 23823, 19335, 17551, 555, 220, 8848, 28585, 304, 220, 8273, 96221, 505, 220, 1049, 22, 12, 1114, 13, 9062, 1060, 279, 2128, 12302, 279, 40308, 3280, 304, 5651, 555, 15389, 369, 96221, 304, 279, 54832, 3235, 279, 99164, 13, 578, 12074, 1817, 279, 96221, 7446, 11, 2064, 370, 7278, 1855, 502, 19151, 311, 6667, 7917, 323, 6680, 2163, 389, 279, 19151, 449, 279, 5915, 315, 1701, 56104, 311, 10765, 1855, 19151, 596, 6691, 13, 2435, 17988, 323, 6767, 1475, 19151, 11, 323, 6667, 6680, 505, 279, 69089, 311, 7838, 872, 2748, 425, 13, 330, 29755, 1139, 279, 23634, 374, 3604, 3629, 279, 14397, 13744, 961, 315, 26984, 22323, 1359, 1071, 25459, 3341, 12806, 689, 11, 3308, 315, 220, 679, 24, 11, 889, 13375, 2115, 990, 439, 264, 22557, 40, 2655, 13, 330, 8142, 1063, 5315, 315, 20229, 47903, 449, 603, 1633, 1664, 323, 23634, 1314, 520, 459, 15987, 15489, 2673, 11, 3885, 1977, 872, 96221, 682, 279, 1648, 520, 279, 1948, 315, 872, 12690, 477, 304, 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2,457

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Genomic analyses have revealed mutational footprints associated with DNA maintenance gone awry, or with mutagen exposures. Because cancer therapeutics often target DNA synthesis or repair, we asked if mutational signatures make useful markers of drug sensitivity. We detect mutational signatures in cancer cell line exomes (where matched healthy tissues are not available) by adjusting for the confounding germline mutation spectra across ancestries. We identify robust associations between various mutational signatures and drug activity across cancer cell lines; these are as numerous as associations with established genetic markers such as driver gene alterations. Signatures of prior exposures to DNA damaging agents – including chemotherapy – tend to associate with drug resistance, while signatures of deficiencies in DNA repair tend to predict sensitivity towards particular therapeutics. Replication analyses across independent drug and CRISPR genetic screening data sets reveal hundreds of robust associations, which are provided as a resource for drug repurposing guided by mutational signature markers. Introduction Cancer precision medicine draws on the presence of somatically acquired changes in the tumor, which serve as predictive markers of response to drugs and other therapies. Commonly these markers are individual genetic changes, such as driver mutations affecting oncogenes or tumor suppressor genes, or copy-number alterations thereof. Many commonly employed cancer drugs act by interfering with DNA synthesis or maintenance or by damaging DNA. Therefore, the altered capacity of cancer cells to repair and/or replicate DNA is the basis of many classical therapies, such as platinum-based agents, and also recently introduced or upcoming therapies, such as PARP inhibitors or ATR inhibitors (reviewed in refs. 1 , 2 , 3 ). It is paramount to identify predictive markers that are associated with failures of DNA maintenance in cancer cells. However, while DNA repair is often deficient in tumors, many DNA repair genes such as MLH1 , MGMT , BRCA1, or ATM do not commonly bear somatic mutations. Instead, they are commonly inactivated epigenetically 4 , 5 , 6 , or by alterations in trans-acting factors 7 , and so their deficiencies are difficult to predict from the gene sequence. Additionally, germline cancer-predisposing variants commonly affect DNA repair genes 8 , 9 , 10 , however, pathogenicity of such variants is often challenging to predict. Because of the above, other types of molecular markers may be more useful to infer about failed DNA repair. This is exemplified in ”BRCAness” – a gene expression signature that suggests a deficient homologous recombination (HR) pathway, even in the absence of deleterious genetic variants in the BRCA1/2 genes. In addition to gene expression, mutational signatures–readouts of genome instability–can characterize DNA repair deficiencies. One common type of signature describes relative frequencies of somatic single-nucleotide variants (SNV) across different trinucleotide contexts. Certain mutational signatures were found to be associated with failures in DNA mismatch repair (MMR) and HR pathways 11 as well as DNA polymerase proofreading 12 , 13 and base excision repair (BER) 14 , 15 , 16 and nucleotide excision repair (NER) 17 failures. Inducing DNA repair deficiencies in cancer cell lines is able to reproduce some of these signatures 18 , 19 , 20 , 21 . Other types of mutation signatures based on small insertions and deletions (indels) 9 and on structural variants 22 are also starting to be introduced. Because mutational signatures describe the state of the DNA repair machinery of a cancer cell, they may be able to serve as a drug sensitivity marker. This is exemplified by a mutational signature associated with pathogenic variants in BRCA1 and BRCA2 genes 11 , 23 , thus identifying HR deficient tumors. The signature is common in ovarian and breast cancers, but genomic analyses have detected it across other cancer types 24 , 25 , suggesting the potential for broad use of drugs that target HR-deficient cells, such as PARP inhibitors. To this end, genomics-based predictors that draw on mutational signatures of HR deficiency have been developed 26 , 27 . We propose that this principle may extend to other types of mutational processes, potentially revealing tumor vulnerabilities. Human cancer cell line panels provide an experimental model for the diversity in tumor biology that is amenable to scaling-up. Drug screens and genetic screens on large cell line panels 28 , 29 have identified correlations between the sensitivity to a drug (or to a genetic perturbation), and the genetic, epigenetic, or transcriptomic markers in the cell lines. Encouragingly, genetic markers known to have clinical utility (e.g. BRAF mutations for vemurafenib, EGFR mutations for gefitinib, BCR-ABL fusion for imatinib sensitivity) are also evident in cell line panel data analyses 30 , suggesting potential for discovery of further useful genomic markers. Here, we used large-scale cell line data to investigate the hypothesis that mutational signatures in cancer genomes constitute markers of drug sensitivity. Quantifying somatic mutational signatures in cell line genomes is however difficult, because a matched normal tissue from the same individual is typically not available and thus cannot be used to remove the abundant germline variation. After filtering the known germline variants listed in population genomic databases 31 , 32 , somatic mutations are still greatly outnumbered by the residual germline variants (Fig. 1a, b ), which may confound downstream analyses such as the inference of mutational signatures. We introduce a method to infer somatic mutational spectra from cancer genomes without a matched control sample, while adjusting for the residual germline variation. We apply this to infer trinucleotide mutation signatures in cancer cell line exomes, and identify associations with sensitivity to drugs and to genetic perturbation across cell line panels. Replication analyses across independent data sets indicated that mutational signatures are broadly applicable markers of drug sensitivity, matching or exceeding common genomic markers such as oncogenic driver mutations or copy number alterations. Fig. 1: Evaluation of the ancestry-matching method to infer somatic mutation spectra on exomes without a matched normal control. a , b Germline variants greatly outnumber somatic mutations in exomes of various tumor types ( n = 52 BRCA, 33 KIRC, 53 GBM, 19 BLCA, 15 LUSC, and", "role": "user" }, { "content": "As an approach to personalized medicine, a new Nature Communications study proposes that \"mutational footprints\" of DNA repair are a promising predictive genetic marker for determining which tumors will respond to certain therapies. Cancer therapy increasingly relies on a personalized approach, where genetic changes in an individual tumor can be used to determine the best therapeutic strategy. In many cases thus far, these genetic changes included a so-called driver mutation that would predict response to a drug. For instance, mutations in the BRAF gene in melanoma predict response to BRAF inhibitor drugs, and amplifications in the ERBB2 gene in breast cancer predict response to ERBB inhibitor drugs. However, these examples of successful drug markers are still quite rare. For many mutated driver genes, specific drugs to target them are not available. Moreover, tumors of different patients show high variability in response to drugs and such variability is often not linked to driver gene mutations. Researchers at IRB Barcelona, led by Dr. Fran Supek, ICREA researcher and head of the Genome Data Science lab, have found that so-called mutational signatures can accurately predict the activity of various drugs applied to cancer cells originating from many types of tumors. These mutational signatures do not originate from driver genes; instead, they reflect a collection of mutations found across the entire genome of a tumor. The mutational signatures can reflect, for example, that the tumor has difficulties in copying or repairing DNA, which may make it more amenable to therapy. \"We have performed statistical analysis using machine-learning methods, considering jointly cancer cell genomes, their response to various drugs, and their response to gene editing experiments. Surprisingly, our analysis revealed that the 'classical' genetic markers such as driver gene mutations or copy-number changes are often less powerful than the mutational signature genetic markers in predicting drug response,\" explains Dr. Supek. DNA repair deficiencies make cancer cells easier to target by many drugs This study found many statistical predictions linking an observed mutational signature with the response (or lack of) towards a cancer drug. It was previously known that a certain type of deficiency in so-called BRCA genes—which can cause breast, ovarian and prostate cancers—predicts response to drugs targeting BRCA deficiency. This deficiency also leaves a mutational signature in the genome of certain types of deletions (removed DNA), which can signal that the tumor is treatable by drugs targeting BRCA deficiency. In the current study, IRB Barcelona researchers, headed by the Marie Curie postdoctoral fellow Dr. Jurica Levatić, now a postdoctoral researcher in the Jozef Stefan Institute in Slovenia, have shown that this is only one example of many: various types of DNA repair deficiency, such as defects in the \"genomic spellchecker\" (DNA mismatch repair), can predispose cancer cells to sensitivity to certain drugs. Given that tumors have impaired DNA repair mechanisms, these predicted therapies would have a greater capacity to kill cancer cells and spare healthy ones. Prior exposure to mutagenic chemicals, including drugs, may confer cancer cells resistance to future therapies The statistical and machine-learning analyses in this work, jointly implemented by Marina Salvadores, a Ph.D. student at the Genome Data Science lab, can connect databases from prior experiments in which many drugs had been tested on cancer cells growing in vitro (in the lab). Moreover, this study also integrated gene editing experimental data, where CRISPR was used to switch off various drug target genes in the same types of cancer cells. This approach allowed the researchers to link drug target genes to drug treatments, thus adding confidence to their main finding that mutational signatures predict drug activity in cancer. Interestingly, the cancer cells that bear genomic \"scars\" (mutational signatures) of previous exposure to mutagenic chemicals tended to be resistant to diverse chemotherapeutic drugs. One possible explanation for this is based on the known mechanism by which, for example, brain cancer cells can switch off their DNA repair systems during treatment with the mutagenic drug TMZ, which could permanently covert them into hardy, hypermutating cells resistant to a range of future treatments. The study suggests that this sort of adaptation may be common in cancer. This has potential implications as tumors caused by mutagen exposure (e.g., lung exposure to tobacco or skin exposure to UV light) may be more difficult to treat, since the cells may harbor a long-term memory of dealing with DNA damage. The algorithms used to identify the mutational signatures and link them to drug vulnerabilities are open access. Future work by the lab will focus on testing these prediction algorithms on patients' data, thereby overcoming the challenge of the scarcity of public genomic data for patients that correlate with randomized clinical trials. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Genomic analyses have revealed mutational footprints associated with DNA maintenance gone awry, or with mutagen exposures. Because cancer therapeutics often target DNA synthesis or repair, we asked if mutational signatures make useful markers of drug sensitivity. We detect mutational signatures in cancer cell line exomes (where matched healthy tissues are not available) by adjusting for the confounding germline mutation spectra across ancestries. We identify robust associations between various mutational signatures and drug activity across cancer cell lines; these are as numerous as associations with established genetic markers such as driver gene alterations. Signatures of prior exposures to DNA damaging agents – including chemotherapy – tend to associate with drug resistance, while signatures of deficiencies in DNA repair tend to predict sensitivity towards particular therapeutics. Replication analyses across independent drug and CRISPR genetic screening data sets reveal hundreds of robust associations, which are provided as a resource for drug repurposing guided by mutational signature markers. Introduction Cancer precision medicine draws on the presence of somatically acquired changes in the tumor, which serve as predictive markers of response to drugs and other therapies. Commonly these markers are individual genetic changes, such as driver mutations affecting oncogenes or tumor suppressor genes, or copy-number alterations thereof. Many commonly employed cancer drugs act by interfering with DNA synthesis or maintenance or by damaging DNA. Therefore, the altered capacity of cancer cells to repair and/or replicate DNA is the basis of many classical therapies, such as platinum-based agents, and also recently introduced or upcoming therapies, such as PARP inhibitors or ATR inhibitors (reviewed in refs. 1 , 2 , 3 ). It is paramount to identify predictive markers that are associated with failures of DNA maintenance in cancer cells. However, while DNA repair is often deficient in tumors, many DNA repair genes such as MLH1 , MGMT , BRCA1, or ATM do not commonly bear somatic mutations. Instead, they are commonly inactivated epigenetically 4 , 5 , 6 , or by alterations in trans-acting factors 7 , and so their deficiencies are difficult to predict from the gene sequence. Additionally, germline cancer-predisposing variants commonly affect DNA repair genes 8 , 9 , 10 , however, pathogenicity of such variants is often challenging to predict. Because of the above, other types of molecular markers may be more useful to infer about failed DNA repair. This is exemplified in ”BRCAness” – a gene expression signature that suggests a deficient homologous recombination (HR) pathway, even in the absence of deleterious genetic variants in the BRCA1/2 genes. In addition to gene expression, mutational signatures–readouts of genome instability–can characterize DNA repair deficiencies. One common type of signature describes relative frequencies of somatic single-nucleotide variants (SNV) across different trinucleotide contexts. Certain mutational signatures were found to be associated with failures in DNA mismatch repair (MMR) and HR pathways 11 as well as DNA polymerase proofreading 12 , 13 and base excision repair (BER) 14 , 15 , 16 and nucleotide excision repair (NER) 17 failures. Inducing DNA repair deficiencies in cancer cell lines is able to reproduce some of these signatures 18 , 19 , 20 , 21 . Other types of mutation signatures based on small insertions and deletions (indels) 9 and on structural variants 22 are also starting to be introduced. Because mutational signatures describe the state of the DNA repair machinery of a cancer cell, they may be able to serve as a drug sensitivity marker. This is exemplified by a mutational signature associated with pathogenic variants in BRCA1 and BRCA2 genes 11 , 23 , thus identifying HR deficient tumors. The signature is common in ovarian and breast cancers, but genomic analyses have detected it across other cancer types 24 , 25 , suggesting the potential for broad use of drugs that target HR-deficient cells, such as PARP inhibitors. To this end, genomics-based predictors that draw on mutational signatures of HR deficiency have been developed 26 , 27 . We propose that this principle may extend to other types of mutational processes, potentially revealing tumor vulnerabilities. Human cancer cell line panels provide an experimental model for the diversity in tumor biology that is amenable to scaling-up. Drug screens and genetic screens on large cell line panels 28 , 29 have identified correlations between the sensitivity to a drug (or to a genetic perturbation), and the genetic, epigenetic, or transcriptomic markers in the cell lines. Encouragingly, genetic markers known to have clinical utility (e.g. BRAF mutations for vemurafenib, EGFR mutations for gefitinib, BCR-ABL fusion for imatinib sensitivity) are also evident in cell line panel data analyses 30 , suggesting potential for discovery of further useful genomic markers. Here, we used large-scale cell line data to investigate the hypothesis that mutational signatures in cancer genomes constitute markers of drug sensitivity. Quantifying somatic mutational signatures in cell line genomes is however difficult, because a matched normal tissue from the same individual is typically not available and thus cannot be used to remove the abundant germline variation. After filtering the known germline variants listed in population genomic databases 31 , 32 , somatic mutations are still greatly outnumbered by the residual germline variants (Fig. 1a, b ), which may confound downstream analyses such as the inference of mutational signatures. We introduce a method to infer somatic mutational spectra from cancer genomes without a matched control sample, while adjusting for the residual germline variation. We apply this to infer trinucleotide mutation signatures in cancer cell line exomes, and identify associations with sensitivity to drugs and to genetic perturbation across cell line panels. Replication analyses across independent data sets indicated that mutational signatures are broadly applicable markers of drug sensitivity, matching or exceeding common genomic markers such as oncogenic driver mutations or copy number alterations. Fig. 1: Evaluation of the ancestry-matching method to infer somatic mutation spectra on exomes without a matched normal control. a , b Germline variants greatly outnumber somatic mutations in exomes of various tumor types ( n = 52 BRCA, 33 KIRC, 53 GBM, 19 BLCA, 15 LUSC, and<|im_end|> <|im_start|>assistant As an approach to personalized medicine, a new Nature Communications study proposes that "mutational footprints" of DNA repair are a promising predictive genetic marker for determining which tumors will respond to certain therapies. Cancer therapy increasingly relies on a personalized approach, where genetic changes in an individual tumor can be used to determine the best therapeutic strategy. In many cases thus far, these genetic changes included a so-called driver mutation that would predict response to a drug. For instance, mutations in the BRAF gene in melanoma predict response to BRAF inhibitor drugs, and amplifications in the ERBB2 gene in breast cancer predict response to ERBB inhibitor drugs. However, these examples of successful drug markers are still quite rare. For many mutated driver genes, specific drugs to target them are not available. Moreover, tumors of different patients show high variability in response to drugs and such variability is often not linked to driver gene mutations. Researchers at IRB Barcelona, led by Dr. Fran Supek, ICREA researcher and head of the Genome Data Science lab, have found that so-called mutational signatures can accurately predict the activity of various drugs applied to cancer cells originating from many types of tumors. These mutational signatures do not originate from driver genes; instead, they reflect a collection of mutations found across the entire genome of a tumor. The mutational signatures can reflect, for example, that the tumor has difficulties in copying or repairing DNA, which may make it more amenable to therapy. "We have performed statistical analysis using machine-learning methods, considering jointly cancer cell genomes, their response to various drugs, and their response to gene editing experiments. Surprisingly, our analysis revealed that the 'classical' genetic markers such as driver gene mutations or copy-number changes are often less powerful than the mutational signature genetic markers in predicting drug response," explains Dr. Supek. DNA repair deficiencies make cancer cells easier to target by many drugs This study found many statistical predictions linking an observed mutational signature with the response (or lack of) towards a cancer drug. It was previously known that a certain type of deficiency in so-called BRCA genes—which can cause breast, ovarian and prostate cancers—predicts response to drugs targeting BRCA deficiency. This deficiency also leaves a mutational signature in the genome of certain types of deletions (removed DNA), which can signal that the tumor is treatable by drugs targeting BRCA deficiency. In the current study, IRB Barcelona researchers, headed by the Marie Curie postdoctoral fellow Dr. Jurica Levatić, now a postdoctoral researcher in the Jozef Stefan Institute in Slovenia, have shown that this is only one example of many: various types of DNA repair deficiency, such as defects in the "genomic spellchecker" (DNA mismatch repair), can predispose cancer cells to sensitivity to certain drugs. Given that tumors have impaired DNA repair mechanisms, these predicted therapies would have a greater capacity to kill cancer cells and spare healthy ones. Prior exposure to mutagenic chemicals, including drugs, may confer cancer cells resistance to future therapies The statistical and machine-learning analyses in this work, jointly implemented by Marina Salvadores, a Ph.D. student at the Genome Data Science lab, can connect databases from prior experiments in which many drugs had been tested on cancer cells growing in vitro (in the lab). Moreover, this study also integrated gene editing experimental data, where CRISPR was used to switch off various drug target genes in the same types of cancer cells. This approach allowed the researchers to link drug target genes to drug treatments, thus adding confidence to their main finding that mutational signatures predict drug activity in cancer. Interestingly, the cancer cells that bear genomic "scars" (mutational signatures) of previous exposure to mutagenic chemicals tended to be resistant to diverse chemotherapeutic drugs. One possible explanation for this is based on the known mechanism by which, for example, brain cancer cells can switch off their DNA repair systems during treatment with the mutagenic drug TMZ, which could permanently covert them into hardy, hypermutating cells resistant to a range of future treatments. The study suggests that this sort of adaptation may be common in cancer. This has potential implications as tumors caused by mutagen exposure (e.g., lung exposure to tobacco or skin exposure to UV light) may be more difficult to treat, since the cells may harbor a long-term memory of dealing with DNA damage. The algorithms used to identify the mutational signatures and link them to drug vulnerabilities are open access. Future work by the lab will focus on testing these prediction algorithms on patients' data, thereby overcoming the challenge of the scarcity of public genomic data for patients that correlate with randomized clinical trials. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Controlled formation of non-equilibrium crystal structures is one of the most important challenges in crystal growth. Catalytically grown nanowires are ideal systems for studying the fundamental physics of phase selection, and could lead to new electronic applications based on the engineering of crystal phases. Here we image gallium arsenide (GaAs) nanowires during growth as they switch between phases as a result of varying growth conditions. We find clear differences between the growth dynamics of the phases, including differences in interface morphology, step flow and catalyst geometry. We explain these differences, and the phase selection, using a model that relates the catalyst volume, the contact angle at the trijunction (the point at which solid, liquid and vapour meet) and the nucleation site of each new layer of GaAs. This model allows us to predict the conditions under which each phase should be observed, and use these predictions to design GaAs heterostructures. These results could apply to phase selection in other nanowire systems. Main Many materials can grow in multiple (meta)stable crystal structures, and phase selection is one of the most fundamental problems in materials science. However, the selection process is difficult to access experimentally; for example, many metastable phases are obtained only by rapid quenching of a liquid into a polycrystalline multiphase solid. By contrast, nanowires provide an ideal system for studying phase selection. Typical zinc-blende (ZB)-structure III-V semiconductors form nanowires in the wurtzite (WZ) structure as well as the ZB 1 , 2 , 3 , 4 , 5 . Nanowires can easily be switched between these phases by varying the temperature, source-material flux or impurities 3 , 4 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ; and their small diameter guarantees that they are single crystals, with phase switching occurring along the growth axis where it is easily observed. ZB and WZ semiconductors have different band structures 15 , which creates opportunities for designing modulated nanowire structures with new electronic properties. Crystal phase heterostructures are particularly interesting because they can access the electronic properties of heterostructure quantum dots for photonics and single-electron-transistor applications, but without the challenge of achieving compositional control 16 , 17 , 18 , 19 . To take full advantage of the possibilities offered by crystal structure control, a detailed understanding of the physics behind crystal phase selection is required. On the basis of post-growth observations, different models have been proposed for phase selection. These models emphasize the role of supersaturation, catalyst geometry and interfacial energies 20 , 21 , 22 , 23 , 24 , 25 . Experimental results are typically interpreted in terms of the dominant role of one of these factors 6 , 7 , 8 , 10 , 12 , 20 , 26 , 27 , 28 . Here, we directly observe the dynamic processes that take place during nanowire growth for each crystal phase, and during the switch between phases, using in situ transmission electron microscopy. We find surprising differences in the structure and dynamics during growth of ZB and WZ nanowires. The switching process itself, and the associated changes in geometry, provide clues that allow us to develop a new model identifying the underlying mechanism driving crystal phase selection. In this model, droplet geometry is the key parameter in determining structure, but in an indirect way, via its effect on the nanowire edge morphology. This understanding allows us to form crystal phase quantum dots with atomic layer precision. Imaging interface and catalyst geometry We observed the two GaAs nanowire crystal phases during growth in situ using a Hitachi H-9000 ultra-high vacuum transmission electron microscope (UHVTEM) 29 , 30 . Si substrates were first covered with pre-grown GaAs nanowires using standard metal–organic vapour phase epitaxy (MOVPE) and Au aerosol particles with diameters of 30 nm, 50 nm and 70 nm. Such samples were loaded into the TEM and heated resistively, using a pyrometer to calibrate the temperature at each heating current (see Methods). Pure trimethylgallium (TMGa) and arsine (AsH 3 ) were used as precursor gases, and were introduced close to the substrate using separate capillary tubes to a maximum total pressure during imaging of 2 × 10 −5 Torr. Details of how the growth parameters in situ compare to conventional MOVPE are provided in Methods. On heating to temperatures of about 550 °C, a liquid AuGa droplet formed at the nanowire tips and growth took place at the droplet/nanowire interface. Growth was recorded at 30 images per second. Dark-field imaging conditions, as used in Fig. 1 , allow the crystal structure to be distinguished, that is, the WZ phase and the two twin variants of the ZB phase ( Extended Data Fig. 1 ). Bright-field imaging conditions, as used in Fig. 2 , allow a more accurate determination of the dimensions of the droplet and the nanowire. Figure 1: Interface dynamics during WZ and ZB growth of GaAs. a , Images extracted from a dark-field movie recorded during WZ GaAs growth. A step flows across the top facet of a nanowire that has a diameter of 60 nm; the position of the step is indicated by the arrows. See also Supplementary Video 1 . Growth conditions: 550 °C, AsH 3 pressure of 1 × 10 −5 Torr, TMGa pressure of 3.5 × 10 −8 Torr. The narrow stripes show previously grown ZB segments: ZB can occur in two twinned orientations, one appearing bright and the other dark in this imaging condition. b , Images extracted from a dark-field movie recorded during ZB GaAs growth. The truncation slowly fills then jumps back to its maximum size (the simultaneous rapid step flow across the growth interface is not visible). See also Supplementary Video 2 . Growth conditions (not steady-state for this example): 550 °C, AsH 3 pressure increased from 10 −7 Torr to 1.4 × 10 −5 Torr a few seconds before the first image was recorded, TMGa pressure of 2.0 × 10 −8 Torr. ZB phases appear bright and", "role": "user" }, { "content": "(Phys.org)—A team of researchers with members from Sweden, the U.K. and the U.S. has used a transmission electron microscope to discover the secrets behind how nanowires used to make semiconductors grow. In their paper published in the journal Nature, the team describes their microscopic study of gallium arsenide nanowires during their growth phase and what they learned about the process. Anna Fontcuberta i Morral with École Polytechnique Fédérale de Lausanne in Switzerland offers a News & Views Perspective piece on the work done by the team in the same journal issue outlining the process used and explaining what the results will mean for advances in electronics, photonics and quantum information research efforts. Scientists have discovered many useful properties of crystals leading to the development of many modern products, such as computers and photonic devices. Such devices depend on an ability to grow crystals in ways that suit particular needs. But, as Fontcuberta i Morral notes, a complete understanding of what occurs during the initial stages of crystal growth is holding back the development of a wider range of products. In this new effort, the researchers sought to learn more about polytypism—where a compound has the ability to exist as various crystal forms with differences only in their bilayer structure—by taking a very close look at the initial stages of gallium arsenide nanowire formation during the vapor–liquid–solid method. They report that their observations revealed that new bilayers formed at the triple-phase line, resulting in a flat layer at the top, but when the liquid-metal droplet used as a catalyst grew to a certain size, an edge appeared which altered the growth of the crystal—bilayers suddenly formed faster and the edge began to oscillate. The researchers suggest that their observations revealed that droplet size directly impacted the contact angle and the morphology of the liquid-solid interface. They noted also that angles close to 90° typically resulted in nucleation of bilayers, whereas smaller angles typically led to suppression of nucleation of bilayers allowing for the formation of zinc-blende structures. Fontcuberta i Morral suggests the findings by the team provide a new pathway towards crystal-phase design, allowing for engineers to select the crystal phase they desire for particular applications. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Controlled formation of non-equilibrium crystal structures is one of the most important challenges in crystal growth. Catalytically grown nanowires are ideal systems for studying the fundamental physics of phase selection, and could lead to new electronic applications based on the engineering of crystal phases. Here we image gallium arsenide (GaAs) nanowires during growth as they switch between phases as a result of varying growth conditions. We find clear differences between the growth dynamics of the phases, including differences in interface morphology, step flow and catalyst geometry. We explain these differences, and the phase selection, using a model that relates the catalyst volume, the contact angle at the trijunction (the point at which solid, liquid and vapour meet) and the nucleation site of each new layer of GaAs. This model allows us to predict the conditions under which each phase should be observed, and use these predictions to design GaAs heterostructures. These results could apply to phase selection in other nanowire systems. Main Many materials can grow in multiple (meta)stable crystal structures, and phase selection is one of the most fundamental problems in materials science. However, the selection process is difficult to access experimentally; for example, many metastable phases are obtained only by rapid quenching of a liquid into a polycrystalline multiphase solid. By contrast, nanowires provide an ideal system for studying phase selection. Typical zinc-blende (ZB)-structure III-V semiconductors form nanowires in the wurtzite (WZ) structure as well as the ZB 1 , 2 , 3 , 4 , 5 . Nanowires can easily be switched between these phases by varying the temperature, source-material flux or impurities 3 , 4 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ; and their small diameter guarantees that they are single crystals, with phase switching occurring along the growth axis where it is easily observed. ZB and WZ semiconductors have different band structures 15 , which creates opportunities for designing modulated nanowire structures with new electronic properties. Crystal phase heterostructures are particularly interesting because they can access the electronic properties of heterostructure quantum dots for photonics and single-electron-transistor applications, but without the challenge of achieving compositional control 16 , 17 , 18 , 19 . To take full advantage of the possibilities offered by crystal structure control, a detailed understanding of the physics behind crystal phase selection is required. On the basis of post-growth observations, different models have been proposed for phase selection. These models emphasize the role of supersaturation, catalyst geometry and interfacial energies 20 , 21 , 22 , 23 , 24 , 25 . Experimental results are typically interpreted in terms of the dominant role of one of these factors 6 , 7 , 8 , 10 , 12 , 20 , 26 , 27 , 28 . Here, we directly observe the dynamic processes that take place during nanowire growth for each crystal phase, and during the switch between phases, using in situ transmission electron microscopy. We find surprising differences in the structure and dynamics during growth of ZB and WZ nanowires. The switching process itself, and the associated changes in geometry, provide clues that allow us to develop a new model identifying the underlying mechanism driving crystal phase selection. In this model, droplet geometry is the key parameter in determining structure, but in an indirect way, via its effect on the nanowire edge morphology. This understanding allows us to form crystal phase quantum dots with atomic layer precision. Imaging interface and catalyst geometry We observed the two GaAs nanowire crystal phases during growth in situ using a Hitachi H-9000 ultra-high vacuum transmission electron microscope (UHVTEM) 29 , 30 . Si substrates were first covered with pre-grown GaAs nanowires using standard metal–organic vapour phase epitaxy (MOVPE) and Au aerosol particles with diameters of 30 nm, 50 nm and 70 nm. Such samples were loaded into the TEM and heated resistively, using a pyrometer to calibrate the temperature at each heating current (see Methods). Pure trimethylgallium (TMGa) and arsine (AsH 3 ) were used as precursor gases, and were introduced close to the substrate using separate capillary tubes to a maximum total pressure during imaging of 2 × 10 −5 Torr. Details of how the growth parameters in situ compare to conventional MOVPE are provided in Methods. On heating to temperatures of about 550 °C, a liquid AuGa droplet formed at the nanowire tips and growth took place at the droplet/nanowire interface. Growth was recorded at 30 images per second. Dark-field imaging conditions, as used in Fig. 1 , allow the crystal structure to be distinguished, that is, the WZ phase and the two twin variants of the ZB phase ( Extended Data Fig. 1 ). Bright-field imaging conditions, as used in Fig. 2 , allow a more accurate determination of the dimensions of the droplet and the nanowire. Figure 1: Interface dynamics during WZ and ZB growth of GaAs. a , Images extracted from a dark-field movie recorded during WZ GaAs growth. A step flows across the top facet of a nanowire that has a diameter of 60 nm; the position of the step is indicated by the arrows. See also Supplementary Video 1 . Growth conditions: 550 °C, AsH 3 pressure of 1 × 10 −5 Torr, TMGa pressure of 3.5 × 10 −8 Torr. The narrow stripes show previously grown ZB segments: ZB can occur in two twinned orientations, one appearing bright and the other dark in this imaging condition. b , Images extracted from a dark-field movie recorded during ZB GaAs growth. The truncation slowly fills then jumps back to its maximum size (the simultaneous rapid step flow across the growth interface is not visible). See also Supplementary Video 2 . Growth conditions (not steady-state for this example): 550 °C, AsH 3 pressure increased from 10 −7 Torr to 1.4 × 10 −5 Torr a few seconds before the first image was recorded, TMGa pressure of 2.0 × 10 −8 Torr. ZB phases appear bright and<|im_end|> <|im_start|>assistant (Phys.org)—A team of researchers with members from Sweden, the U.K. and the U.S. has used a transmission electron microscope to discover the secrets behind how nanowires used to make semiconductors grow. In their paper published in the journal Nature, the team describes their microscopic study of gallium arsenide nanowires during their growth phase and what they learned about the process. Anna Fontcuberta i Morral with École Polytechnique Fédérale de Lausanne in Switzerland offers a News & Views Perspective piece on the work done by the team in the same journal issue outlining the process used and explaining what the results will mean for advances in electronics, photonics and quantum information research efforts. Scientists have discovered many useful properties of crystals leading to the development of many modern products, such as computers and photonic devices. Such devices depend on an ability to grow crystals in ways that suit particular needs. But, as Fontcuberta i Morral notes, a complete understanding of what occurs during the initial stages of crystal growth is holding back the development of a wider range of products. In this new effort, the researchers sought to learn more about polytypism—where a compound has the ability to exist as various crystal forms with differences only in their bilayer structure—by taking a very close look at the initial stages of gallium arsenide nanowire formation during the vapor–liquid–solid method. They report that their observations revealed that new bilayers formed at the triple-phase line, resulting in a flat layer at the top, but when the liquid-metal droplet used as a catalyst grew to a certain size, an edge appeared which altered the growth of the crystal—bilayers suddenly formed faster and the edge began to oscillate. The researchers suggest that their observations revealed that droplet size directly impacted the contact angle and the morphology of the liquid-solid interface. They noted also that angles close to 90° typically resulted in nucleation of bilayers, whereas smaller angles typically led to suppression of nucleation of bilayers allowing for the formation of zinc-blende structures. Fontcuberta i Morral suggests the findings by the team provide a new pathway towards crystal-phase design, allowing for engineers to select the crystal phase they desire for particular applications. <|im_end|>

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1,850

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract T cells are important in tumour immunity but a better understanding is needed of the differentiation of antigen-specific T cells in human cancer 1 , 2 . Here we studied CD8 T cells in patients with human papillomavirus (HPV)-positive head and neck cancer and identified several epitopes derived from HPV E2, E5 and E6 proteins that allowed us to analyse virus-specific CD8 T cells using major histocompatibility complex (MHC) class I tetramers. HPV-specific CD8 T cells expressed PD-1 and were detectable in the tumour at levels that ranged from 0.1% to 10% of tumour-infiltrating CD8 T lymphocytes (TILs) for a given epitope. Single-cell RNA-sequencing analyses of tetramer-sorted HPV-specific PD-1 + CD8 TILs revealed three transcriptionally distinct subsets. One subset expressed TCF7 and other genes associated with PD-1 + stem-like CD8 T cells that are critical for maintaining T cell responses in conditions of antigen persistence. The second subset expressed more effector molecules, representing a transitory cell population, and the third subset was characterized by a terminally differentiated gene signature. T cell receptor clonotypes were shared between the three subsets and pseudotime analysis suggested a hypothetical differentiation trajectory from stem-like to transitory to terminally differentiated cells. More notably, HPV-specific PD-1 + TCF-1 + stem-like TILs proliferated and differentiated into more effector-like cells after in vitro stimulation with the cognate HPV peptide, whereas the more terminally differentiated cells did not proliferate. The presence of functional HPV-specific PD-1 + TCF-1 + CD45RO + stem-like CD8 T cells with proliferative capacity shows that the cellular machinery to respond to PD-1 blockade exists in HPV-positive head and neck cancer, supporting the further investigation of PD-1 targeted therapies in this malignancy. Furthermore, HPV therapeutic vaccination efforts have focused on E6 and E7 proteins; our results suggest that E2 and E5 should also be considered for inclusion as vaccine antigens to elicit tumour-reactive CD8 T cell responses of maximal breadth. Main Chronic viral infections and cancer result in compromised CD8 T cell function characterized by the expression of several inhibitory receptors including PD-1 1 , 2 , 3 , 4 , 5 . Blockade of the PD-1 inhibitory pathway enhances T cell function and is an effective treatment for several cancers 1 , 2 , 5 . Preclinical studies have characterized a unique PD-1 + TCF-1 + stem-like subset of CD8 T cells that maintains the CD8 T cell response during chronic infection and provides the proliferative burst after PD-1 directed immunotherapy 6 , 7 , 8 , 9 , 10 , 11 . Similar PD-1 + TCF-1 + CD8 T cells have been found in human tumours 12 , 13 , 14 . However, a better definition of their antigen specificity and their lineage relationship with other CD8 T cell subsets in the tumour is needed for understanding T cell differentiation pathways in human cancer and to optimize immunotherapeutic approaches. Here we address these questions by analysing HPV-specific CD8 T cells in head and neck squamous cell carcinoma (HNSCC). Characterization of CD8 TILs in HNSCC To investigate the CD8 T cell response to HNSCC, we characterized TILs from six primary tumours and eight metastatic lymph nodes of twelve patients from our treatment-naive HPV-positive HNSCC cohort. CD8 T cells comprised around 30% of TILs by flow cytometry (Extended Data Fig. 1a ). The majority of CD8 TILs expressed high levels of PD-1 and all of the PD-1 + cells were CD45RA-negative (Fig. 1a ). These PD-1 + CD45RA − CD8 T cells included distinct populations that expressed either TCF-1 or TIM-3 (Fig. 1b ), markers that are commonly used to distinguish stem-like (TCF-1 + TIM-3 − ) and terminally differentiated (TIM-3 + TCF-1 − ) PD-1 + CD8 T cells 6 , 7 , 8 , 14 . Although ranging widely between patients, on average 45% of PD-1 + cells exhibited a terminally differentiated phenotype. Stem-like PD-1 + TCF-1 + CD8 T cells were present in all patients and expressed significantly lower levels of granzyme B, Ki-67 and CD39 compared to TIM-3 + cells (Fig. 1b , Extended Data Fig. 1b, c ). Both subsets expressed TOX (Extended Data Fig. 1d ), a key transcription factor for CD8 T cell differentiation during chronic viral infections and cancer 15 . We next examined the anatomical location of these PD-1 + CD8 T cell subsets in primary tumours and metastatic lymph nodes using multiplex immunohistochemistry. CD8 + and PD-1 + cells were diffusely present in the cytokeratin-positive tumour parenchyma as well as in the stroma within and around the tumour bed (Fig. 1c , Extended Data Fig. 1e, f ). Notably, PD-1 + TCF-1 + cells were predominantly found in the stromal areas and were rarely present in the tumour parenchyma (Fig. 1d, e ), whereas the more differentiated cells were diffusely dispersed in the tumour microenvironment (TME) (Extended Data Fig. 1g, h ), suggesting that the stem-like cells reside in distinct niches within the TME and stay away from the tumour itself. Fig. 1: Intratumoral PD-1 + CD8 T cells are made up of distinct subsets with PD-1 + TCF-1 + stem-like cells residing in lymphoid-like stromal areas. a , Frequency of PD-1 + cells among CD8 + TILs. Flow plot is gated on CD8 T cells. b , Frequency of TCF-1 + TIM-3 − and TIM-3 + TCF-1 − subsets in PD-1 + CD8 TILs, with mean and s.d. Two-sided Wilcoxon matched-pairs rank test. Flow plot is gated on PD-1 + CD8 T cells. c , Representative multiplex immunohistochemistry staining of one of five primary HPV-positive HNSCC tumours with orange dashed lines highlighting parenchyma (cytokeratin + ) and stromal borders. Scale bars, 100 μm. d , e , Frequency ( d ) and density ( e ) of PD-1 + TCF-1 + CD8 TILs in the tumour parenchyma and stroma, with mean and s.d. n = 7 (five primary tumours (pink) and two metastatic lymph nodes (grey)). Two-sided paired t -tests. Full size image Identification of HPV-specific CD8 TILs HPV-positive HNSCC offers the opportunity to identify", "role": "user" }, { "content": "A new study from scientists at Emory Vaccine Center and Winship Cancer Institute of Emory University reports that the immune cells that are the major targets of immune checkpoint inhibitors are present in tumors from head and neck cancer patients. The study focuses on head and neck tumors that are positive for human papillomavirus (HPV), which is becoming one of most common types of head and neck cancers treated in the Western world. The results are scheduled for publication in Nature. It suggests checkpoint inhibitors, which have transformed the treatment of several types of cancer, could be uniquely effective against this type of head and neck cancer. The results also indicate that the experimental approach of therapeutic vaccination for HPV+ cancer could be broadened to include more elements of the virus, to potentially trigger a broader and stronger immune response. Researchers from Rafi Ahmed's lab at Emory Vaccine Center collaborated with the co-directors of the Winship Head and Neck Cancers working group, oncologists Nabil Saba, MD and Mihir Patel, MD, to obtain samples from patients with head and neck tumors early in the course of treatment. \"About five years ago, we began to have an influx of patients that sought out our center for surgical treatment,\" Patel says. \"We often heard some variation of a similar story: I was sick with cold-like symptoms and once that resolved this I noticed swelling in a lymph node on the side of my neck. Stories like this made us think about how the immune system might play a unique role, different than typical smoking-related head and neck cancers.\" The team wanted to learn more about the different kinds of CD8 or \"killer\" T cells present within the cancers; CD8 T cells are specialized immune cells capable of detecting and killing virus-infected or tumor cells, if they are not constrained by regulatory signals. The inhibitory receptor PD-1 is highly expressed on exhausted CD8 T cells in chronic viral infections and cancer, and stem-like PD-1+ CD8 T cells are crucial for maintaining tumor-specific CD8 T cell responses. The majority of currently available checkpoint inhibitors, such as pembrolizumab and nivolumab, block the PD-1 signaling pathway. \"Our results show that a subset of HPV-specific CD8 T cells in the tumor exhibits a striking resemblance to the stem-like CD8 T cells our lab has previously defined in mouse models as proliferating in response to PD-1 blockade,\" says Andreas Wieland, Ph.D., co-lead author of the paper and an instructor in Ahmed's lab. \"It is reasonable to assume that these cells would similarly provide a proliferative burst in response to PD-1 blockade in these patients. However, this remains to be formally tested.\" HPV-positive tumors do have a relatively good response to conventional forms of treatment such as radiation and chemotherapy, Wieland adds. The group of patients studied at Winship was treatment-naïve when tumor samples were obtained; how radiation and chemotherapy affect the number and phenotype of T cells in the tumor needs additional investigation. \"These findings greatly enhance our understanding of CD8 T cell responses in the tumor micro-environment in HPV-related oropharynx cancers, and likely other virally mediated tumors,\" Saba says. \"It confirms the existence of the different lineages necessary for an effective T cell specific anti-tumor response. Taking advantage of the local immune-response by avoiding its possible early elimination by traditional therapeutic modalities may pave the way to an improved clinical outcome for patients. It may have implications for how best to incorporate immunotherapy in the treatment of other virally mediated tumors.\" \"We now have an inclination that incorporating immune therapy with PD-1 blockade prior to surgery or radiation may benefit patients,\" Patel says. \"We are actively in the process of developing 'window of opportunity' studies to understand this. Looking at both primary tumors and metastatic lymph nodes, the researchers were able to detect both tumor-specific stem-like CD8 T cells, which can proliferate in response to HPV peptides, and more terminally differentiated cells that do not proliferate. In contrast to significant numbers of tumor-specific CD8 T cells in the tumors, tumor-specific cells appeared at a very low abundance in patients' blood, suggesting that they preferentially reside in tumors. The team also found that the different CD8 T cell subsets in the tumor microenvironment differ in their localization, with stem-like cells residing in distinct niches within the stroma and away from the tumor cells themselves. Concentrating on HPV-positive tumors in this study facilitated the study of tumor-specific T cells with defined specificities across several patients as the virus is providing a defined set of tumor-associated antigens, whereas in other types of cancer the antigens caused by mutations will vary from individual to individual. Co-first authors of the paper are Haydn Kissick, Ph.D., assistant professor of urology and microbiology and immunology, and Christiane Eberhardt, MD, a former postdoctoral fellow in Ahmed's lab who is now at the University of Geneva. Patel is also associate professor of otolaryngology at Emory University School of Medicine. Saba is professor and Vice Chair in the Department of Hematology and Medical Oncology. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract T cells are important in tumour immunity but a better understanding is needed of the differentiation of antigen-specific T cells in human cancer 1 , 2 . Here we studied CD8 T cells in patients with human papillomavirus (HPV)-positive head and neck cancer and identified several epitopes derived from HPV E2, E5 and E6 proteins that allowed us to analyse virus-specific CD8 T cells using major histocompatibility complex (MHC) class I tetramers. HPV-specific CD8 T cells expressed PD-1 and were detectable in the tumour at levels that ranged from 0.1% to 10% of tumour-infiltrating CD8 T lymphocytes (TILs) for a given epitope. Single-cell RNA-sequencing analyses of tetramer-sorted HPV-specific PD-1 + CD8 TILs revealed three transcriptionally distinct subsets. One subset expressed TCF7 and other genes associated with PD-1 + stem-like CD8 T cells that are critical for maintaining T cell responses in conditions of antigen persistence. The second subset expressed more effector molecules, representing a transitory cell population, and the third subset was characterized by a terminally differentiated gene signature. T cell receptor clonotypes were shared between the three subsets and pseudotime analysis suggested a hypothetical differentiation trajectory from stem-like to transitory to terminally differentiated cells. More notably, HPV-specific PD-1 + TCF-1 + stem-like TILs proliferated and differentiated into more effector-like cells after in vitro stimulation with the cognate HPV peptide, whereas the more terminally differentiated cells did not proliferate. The presence of functional HPV-specific PD-1 + TCF-1 + CD45RO + stem-like CD8 T cells with proliferative capacity shows that the cellular machinery to respond to PD-1 blockade exists in HPV-positive head and neck cancer, supporting the further investigation of PD-1 targeted therapies in this malignancy. Furthermore, HPV therapeutic vaccination efforts have focused on E6 and E7 proteins; our results suggest that E2 and E5 should also be considered for inclusion as vaccine antigens to elicit tumour-reactive CD8 T cell responses of maximal breadth. Main Chronic viral infections and cancer result in compromised CD8 T cell function characterized by the expression of several inhibitory receptors including PD-1 1 , 2 , 3 , 4 , 5 . Blockade of the PD-1 inhibitory pathway enhances T cell function and is an effective treatment for several cancers 1 , 2 , 5 . Preclinical studies have characterized a unique PD-1 + TCF-1 + stem-like subset of CD8 T cells that maintains the CD8 T cell response during chronic infection and provides the proliferative burst after PD-1 directed immunotherapy 6 , 7 , 8 , 9 , 10 , 11 . Similar PD-1 + TCF-1 + CD8 T cells have been found in human tumours 12 , 13 , 14 . However, a better definition of their antigen specificity and their lineage relationship with other CD8 T cell subsets in the tumour is needed for understanding T cell differentiation pathways in human cancer and to optimize immunotherapeutic approaches. Here we address these questions by analysing HPV-specific CD8 T cells in head and neck squamous cell carcinoma (HNSCC). Characterization of CD8 TILs in HNSCC To investigate the CD8 T cell response to HNSCC, we characterized TILs from six primary tumours and eight metastatic lymph nodes of twelve patients from our treatment-naive HPV-positive HNSCC cohort. CD8 T cells comprised around 30% of TILs by flow cytometry (Extended Data Fig. 1a ). The majority of CD8 TILs expressed high levels of PD-1 and all of the PD-1 + cells were CD45RA-negative (Fig. 1a ). These PD-1 + CD45RA − CD8 T cells included distinct populations that expressed either TCF-1 or TIM-3 (Fig. 1b ), markers that are commonly used to distinguish stem-like (TCF-1 + TIM-3 − ) and terminally differentiated (TIM-3 + TCF-1 − ) PD-1 + CD8 T cells 6 , 7 , 8 , 14 . Although ranging widely between patients, on average 45% of PD-1 + cells exhibited a terminally differentiated phenotype. Stem-like PD-1 + TCF-1 + CD8 T cells were present in all patients and expressed significantly lower levels of granzyme B, Ki-67 and CD39 compared to TIM-3 + cells (Fig. 1b , Extended Data Fig. 1b, c ). Both subsets expressed TOX (Extended Data Fig. 1d ), a key transcription factor for CD8 T cell differentiation during chronic viral infections and cancer 15 . We next examined the anatomical location of these PD-1 + CD8 T cell subsets in primary tumours and metastatic lymph nodes using multiplex immunohistochemistry. CD8 + and PD-1 + cells were diffusely present in the cytokeratin-positive tumour parenchyma as well as in the stroma within and around the tumour bed (Fig. 1c , Extended Data Fig. 1e, f ). Notably, PD-1 + TCF-1 + cells were predominantly found in the stromal areas and were rarely present in the tumour parenchyma (Fig. 1d, e ), whereas the more differentiated cells were diffusely dispersed in the tumour microenvironment (TME) (Extended Data Fig. 1g, h ), suggesting that the stem-like cells reside in distinct niches within the TME and stay away from the tumour itself. Fig. 1: Intratumoral PD-1 + CD8 T cells are made up of distinct subsets with PD-1 + TCF-1 + stem-like cells residing in lymphoid-like stromal areas. a , Frequency of PD-1 + cells among CD8 + TILs. Flow plot is gated on CD8 T cells. b , Frequency of TCF-1 + TIM-3 − and TIM-3 + TCF-1 − subsets in PD-1 + CD8 TILs, with mean and s.d. Two-sided Wilcoxon matched-pairs rank test. Flow plot is gated on PD-1 + CD8 T cells. c , Representative multiplex immunohistochemistry staining of one of five primary HPV-positive HNSCC tumours with orange dashed lines highlighting parenchyma (cytokeratin + ) and stromal borders. Scale bars, 100 μm. d , e , Frequency ( d ) and density ( e ) of PD-1 + TCF-1 + CD8 TILs in the tumour parenchyma and stroma, with mean and s.d. n = 7 (five primary tumours (pink) and two metastatic lymph nodes (grey)). Two-sided paired t -tests. Full size image Identification of HPV-specific CD8 TILs HPV-positive HNSCC offers the opportunity to identify<|im_end|> <|im_start|>assistant A new study from scientists at Emory Vaccine Center and Winship Cancer Institute of Emory University reports that the immune cells that are the major targets of immune checkpoint inhibitors are present in tumors from head and neck cancer patients. The study focuses on head and neck tumors that are positive for human papillomavirus (HPV), which is becoming one of most common types of head and neck cancers treated in the Western world. The results are scheduled for publication in Nature. It suggests checkpoint inhibitors, which have transformed the treatment of several types of cancer, could be uniquely effective against this type of head and neck cancer. The results also indicate that the experimental approach of therapeutic vaccination for HPV+ cancer could be broadened to include more elements of the virus, to potentially trigger a broader and stronger immune response. Researchers from Rafi Ahmed's lab at Emory Vaccine Center collaborated with the co-directors of the Winship Head and Neck Cancers working group, oncologists Nabil Saba, MD and Mihir Patel, MD, to obtain samples from patients with head and neck tumors early in the course of treatment. "About five years ago, we began to have an influx of patients that sought out our center for surgical treatment," Patel says. "We often heard some variation of a similar story: I was sick with cold-like symptoms and once that resolved this I noticed swelling in a lymph node on the side of my neck. Stories like this made us think about how the immune system might play a unique role, different than typical smoking-related head and neck cancers." The team wanted to learn more about the different kinds of CD8 or "killer" T cells present within the cancers; CD8 T cells are specialized immune cells capable of detecting and killing virus-infected or tumor cells, if they are not constrained by regulatory signals. The inhibitory receptor PD-1 is highly expressed on exhausted CD8 T cells in chronic viral infections and cancer, and stem-like PD-1+ CD8 T cells are crucial for maintaining tumor-specific CD8 T cell responses. The majority of currently available checkpoint inhibitors, such as pembrolizumab and nivolumab, block the PD-1 signaling pathway. "Our results show that a subset of HPV-specific CD8 T cells in the tumor exhibits a striking resemblance to the stem-like CD8 T cells our lab has previously defined in mouse models as proliferating in response to PD-1 blockade," says Andreas Wieland, Ph.D., co-lead author of the paper and an instructor in Ahmed's lab. "It is reasonable to assume that these cells would similarly provide a proliferative burst in response to PD-1 blockade in these patients. However, this remains to be formally tested." HPV-positive tumors do have a relatively good response to conventional forms of treatment such as radiation and chemotherapy, Wieland adds. The group of patients studied at Winship was treatment-naïve when tumor samples were obtained; how radiation and chemotherapy affect the number and phenotype of T cells in the tumor needs additional investigation. "These findings greatly enhance our understanding of CD8 T cell responses in the tumor micro-environment in HPV-related oropharynx cancers, and likely other virally mediated tumors," Saba says. "It confirms the existence of the different lineages necessary for an effective T cell specific anti-tumor response. Taking advantage of the local immune-response by avoiding its possible early elimination by traditional therapeutic modalities may pave the way to an improved clinical outcome for patients. It may have implications for how best to incorporate immunotherapy in the treatment of other virally mediated tumors." "We now have an inclination that incorporating immune therapy with PD-1 blockade prior to surgery or radiation may benefit patients," Patel says. "We are actively in the process of developing 'window of opportunity' studies to understand this. Looking at both primary tumors and metastatic lymph nodes, the researchers were able to detect both tumor-specific stem-like CD8 T cells, which can proliferate in response to HPV peptides, and more terminally differentiated cells that do not proliferate. In contrast to significant numbers of tumor-specific CD8 T cells in the tumors, tumor-specific cells appeared at a very low abundance in patients' blood, suggesting that they preferentially reside in tumors. The team also found that the different CD8 T cell subsets in the tumor microenvironment differ in their localization, with stem-like cells residing in distinct niches within the stroma and away from the tumor cells themselves. Concentrating on HPV-positive tumors in this study facilitated the study of tumor-specific T cells with defined specificities across several patients as the virus is providing a defined set of tumor-associated antigens, whereas in other types of cancer the antigens caused by mutations will vary from individual to individual. Co-first authors of the paper are Haydn Kissick, Ph.D., assistant professor of urology and microbiology and immunology, and Christiane Eberhardt, MD, a former postdoctoral fellow in Ahmed's lab who is now at the University of Geneva. Patel is also associate professor of otolaryngology at Emory University School of Medicine. Saba is professor and Vice Chair in the Department of Hematology and Medical Oncology. <|im_end|>

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6156, 15756, 2530, 323, 68370, 780, 43745, 7954, 1701, 12842, 2635, 33119, 2319, 26407, 52755, 13, 11325, 23, 489, 323, 27572, 12, 16, 489, 7917, 1051, 3722, 355, 989, 3118, 304, 279, 79909, 10668, 15111, 69788, 15756, 414, 39040, 331, 1631, 64, 439, 1664, 439, 304, 279, 357, 58084, 2949, 323, 2212, 279, 15756, 414, 4950, 320, 30035, 13, 220, 16, 66, 1174, 41665, 2956, 23966, 13, 220, 16, 68, 11, 282, 7609, 2876, 2915, 11, 27572, 12, 16, 489, 350, 9847, 12, 16, 489, 7917, 1051, 47904, 1766, 304, 279, 120004, 278, 5789, 323, 1051, 19029, 3118, 304, 279, 15756, 414, 39040, 331, 1631, 64, 320, 30035, 13, 220, 16, 67, 11, 384, 7026, 20444, 279, 810, 89142, 7917, 1051, 3722, 355, 989, 77810, 304, 279, 15756, 414, 8162, 24175, 320, 51, 7614, 8, 320, 54290, 2956, 23966, 13, 220, 16, 70, 11, 305, 7026, 23377, 430, 279, 19646, 12970, 7917, 48383, 304, 12742, 58971, 288, 2949, 279, 350, 7614, 323, 4822, 3201, 505, 279, 15756, 414, 5196, 13, 23966, 13, 220, 16, 25, 61894, 27349, 10020, 27572, 12, 16, 489, 11325, 23, 350, 7917, 527, 1903, 709, 315, 12742, 75605, 449, 27572, 12, 16, 489, 350, 9847, 12, 16, 489, 19646, 12970, 7917, 67512, 304, 43745, 590, 12970, 120004, 278, 5789, 13, 264, 1174, 43480, 315, 27572, 12, 16, 489, 7917, 4315, 11325, 23, 489, 350, 1750, 82, 13, 23260, 7234, 374, 85811, 389, 11325, 23, 350, 7917, 13, 293, 1174, 43480, 315, 350, 9847, 12, 16, 489, 18214, 12, 18, 25173, 323, 18214, 12, 18, 489, 350, 9847, 12, 16, 25173, 75605, 304, 27572, 12, 16, 489, 11325, 23, 350, 1750, 82, 11, 449, 3152, 323, 274, 962, 13, 9220, 50858, 10785, 1030, 62585, 18545, 2320, 4825, 7222, 1296, 13, 23260, 7234, 374, 85811, 389, 27572, 12, 16, 489, 11325, 23, 350, 7917, 13, 272, 1174, 38366, 12842, 2635, 33119, 2319, 26407, 52755, 88896, 315, 832, 315, 4330, 6156, 74469, 69788, 473, 2507, 3791, 15756, 2530, 449, 19087, 67822, 5238, 39686, 39040, 331, 1631, 64, 320, 11377, 83, 10668, 15111, 489, 883, 323, 120004, 278, 24743, 13, 25635, 16283, 11, 220, 1041, 33983, 76, 13, 294, 1174, 384, 1174, 43480, 320, 294, 883, 323, 17915, 320, 384, 883, 315, 27572, 12, 16, 489, 350, 9847, 12, 16, 489, 11325, 23, 350, 1750, 82, 304, 279, 15756, 414, 39040, 331, 1631, 64, 323, 357, 58084, 11, 449, 3152, 323, 274, 962, 13, 308, 284, 220, 22, 320, 53770, 6156, 15756, 2530, 320, 64349, 8, 323, 1403, 68370, 780, 43745, 7954, 320, 35671, 4682, 9220, 50858, 35526, 259, 482, 24781, 13, 8797, 1404, 2217, 59776, 315, 74469, 19440, 11325, 23, 350, 1750, 82, 74469, 69788, 473, 2507, 3791, 6209, 279, 6776, 311, 10765, 128257, 198, 128256, 78191, 198, 32, 502, 4007, 505, 14248, 520, 5867, 683, 100058, 5955, 323, 12468, 5383, 26211, 10181, 315, 5867, 683, 3907, 6821, 430, 279, 22852, 7917, 430, 527, 279, 3682, 11811, 315, 22852, 30395, 68642, 527, 3118, 304, 56071, 505, 2010, 323, 13272, 9572, 6978, 13, 578, 4007, 24400, 389, 2010, 323, 13272, 56071, 430, 527, 6928, 369, 3823, 26365, 484, 316, 24713, 320, 6748, 53, 705, 902, 374, 10671, 832, 315, 1455, 4279, 4595, 315, 2010, 323, 13272, 51423, 12020, 304, 279, 11104, 1917, 13, 578, 3135, 527, 13847, 369, 17009, 304, 22037, 13, 1102, 13533, 30395, 68642, 11, 902, 617, 24411, 279, 6514, 315, 3892, 4595, 315, 9572, 11, 1436, 387, 42329, 7524, 2403, 420, 955, 315, 2010, 323, 13272, 9572, 13, 578, 3135, 1101, 13519, 430, 279, 22772, 5603, 315, 37471, 47165, 369, 74469, 10, 9572, 1436, 387, 7353, 6901, 311, 2997, 810, 5540, 315, 279, 17188, 11, 311, 13893, 8346, 264, 27927, 323, 16643, 22852, 2077, 13, 59250, 505, 40677, 72, 41769, 596, 10278, 520, 5867, 683, 100058, 5955, 78174, 449, 279, 1080, 44624, 1105, 315, 279, 12468, 5383, 11452, 323, 44055, 356, 32842, 3318, 1912, 11, 78970, 22012, 452, 13052, 328, 12273, 11, 14306, 323, 386, 7141, 404, 63855, 11, 14306, 11, 311, 6994, 10688, 505, 6978, 449, 2010, 323, 13272, 56071, 4216, 304, 279, 3388, 315, 6514, 13, 330, 10714, 4330, 1667, 4227, 11, 584, 6137, 311, 617, 459, 53952, 315, 6978, 430, 16495, 704, 1057, 4219, 369, 34933, 6514, 1359, 63855, 2795, 13, 330, 1687, 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279, 1396, 323, 82423, 315, 350, 7917, 304, 279, 36254, 3966, 5217, 8990, 13, 330, 9673, 14955, 19407, 18885, 1057, 8830, 315, 11325, 23, 350, 2849, 14847, 304, 279, 36254, 8162, 21430, 3182, 304, 74469, 14228, 477, 5237, 661, 24244, 51423, 11, 323, 4461, 1023, 9043, 750, 78926, 56071, 1359, 328, 12273, 2795, 13, 330, 2181, 43496, 279, 14209, 315, 279, 2204, 1584, 1154, 5995, 369, 459, 7524, 350, 2849, 3230, 7294, 2442, 69361, 2077, 13, 36925, 9610, 315, 279, 2254, 22852, 59569, 555, 31526, 1202, 3284, 4216, 44032, 555, 8776, 37471, 13531, 1385, 1253, 94123, 279, 1648, 311, 459, 13241, 14830, 15632, 369, 6978, 13, 1102, 1253, 617, 25127, 369, 1268, 1888, 311, 33435, 33119, 42811, 304, 279, 6514, 315, 1023, 9043, 750, 78926, 56071, 1210, 330, 1687, 1457, 617, 459, 77004, 430, 52913, 22852, 15419, 449, 27572, 12, 16, 77237, 4972, 311, 15173, 477, 25407, 1253, 8935, 6978, 1359, 63855, 2795, 13, 330, 1687, 527, 22815, 304, 279, 1920, 315, 11469, 364, 5624, 315, 6776, 6, 7978, 311, 3619, 420, 13, 21815, 520, 2225, 6156, 56071, 323, 68370, 780, 43745, 7954, 11, 279, 12074, 1051, 3025, 311, 11388, 2225, 36254, 19440, 19646, 12970, 11325, 23, 350, 7917, 11, 902, 649, 43036, 349, 304, 2077, 311, 74469, 96434, 11, 323, 810, 10415, 750, 89142, 7917, 430, 656, 539, 43036, 349, 13, 763, 13168, 311, 5199, 5219, 315, 36254, 19440, 11325, 23, 350, 7917, 304, 279, 56071, 11, 36254, 19440, 7917, 9922, 520, 264, 1633, 3428, 37492, 304, 6978, 6, 6680, 11, 23377, 430, 814, 10932, 31668, 48383, 304, 56071, 13, 578, 2128, 1101, 1766, 430, 279, 2204, 11325, 23, 350, 2849, 75605, 304, 279, 36254, 8162, 24175, 1782, 304, 872, 53404, 11, 449, 19646, 12970, 7917, 67512, 304, 12742, 58971, 288, 2949, 279, 357, 58084, 323, 3201, 505, 279, 36254, 7917, 5694, 13, 62261, 22696, 389, 74469, 69788, 56071, 304, 420, 4007, 72849, 279, 4007, 315, 36254, 19440, 350, 7917, 449, 4613, 3230, 1385, 4028, 3892, 6978, 439, 279, 17188, 374, 8405, 264, 4613, 743, 315, 36254, 75968, 68937, 729, 11, 20444, 304, 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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract In the face of the biodiversity crisis, it is argued that we should prioritize species in order to capture high functional diversity (FD). Because species traits often reflect shared evolutionary history, many researchers have assumed that maximizing phylogenetic diversity (PD) should indirectly capture FD, a hypothesis that we name the “phylogenetic gambit”. Here, we empirically test this gambit using data on ecologically relevant traits from >15,000 vertebrate species. Specifically, we estimate a measure of surrogacy of PD for FD. We find that maximizing PD results in an average gain of 18% of FD relative to random choice. However, this average gain obscures the fact that in over one-third of the comparisons, maximum PD sets contain less FD than randomly chosen sets of species. These results suggest that, while maximizing PD protection can help to protect FD, it represents a risky conservation strategy. Introduction We are in the midst of a period of heightened biological extinction, with rates several orders of magnitude higher than background rates estimated from the fossil record 1 , 2 , 3 . In addition to having potentially widespread consequences for the functioning of ecosystems and the provisioning of valuable ecosystem services, this situation poses an immense moral challenge 4 , 5 , 6 , 7 , 8 . Since the extent that resources for conservation actions remain limited, agonizing choices as to which species most warrant attention become necessary 9 , 10 . To keep humanity’s options open, and our common legacy as rich as possible, it is widely argued that we should seek to maximize the biological diversity of form and function in conservation strategies 6 , 7 , 8 , 9 , 10 , 11 , 12 . The biological diversity of form and function can be measured as functional diversity (FD) (see Methods). However, in practice, it is challenging to prioritize species on the basis of FD: we have imperfect knowledge about which, and how many traits and functions are important in a given context, how these traits and functions vary among species and across space, and how the importance of traits may change in the future 13 . Many researchers have therefore advocated for a hypothesis that we name the ‘phylogenetic gambit’; that is, if species traits reflect their shared evolutionary history, then the pattern of that evolutionary history—their phylogeny—should serve as a useful stand-in for unmeasured and unmeasurable traits 9 , 14 , 15 . The phylogenetic gambit implies that maximizing phylogenetic diversity (PD), i.e., the breadth of evolutionary history, will ensure that a wide variety of forms and functions are present within a species set 14 , 15 , 16 , 17 . Following this logic, phylogenetic diversity has formed the basis of global conservation schemes, notably the EDGE of existence program 18 has been used by restoration biologists 19 and has been widely embraced by researchers across the biodiversity sciences 20 , 21 , 22 , 23 . Despite this enthusiasm, the critical question of whether maximizing PD will actually capture more FD than prioritization schemes that ignore phylogeny has, to our knowledge, never been empirically tested 16 . Some studies have discussed 24 , 25 and documented the relationship between FD and PD, both at regional 26 and global scales 20 , 22 , and many of these studies have shown that maximizing PD does not maximize FD. However, such studies do not test the fundamental phylogenetic gambit at the heart of all PD-based conservation strategies: maximizing PD captures more FD than randomly choosing species. No one would dispute that the best way to maximize FD is to prioritize FD, but phylogenetic diversity has emerged as prioritization tool because we rarely have sufficient trait data to calculate FD. Here we test whether PD-based conservation passes a much less stringent, but ultimately more fundamental, test: is conserving on the basis of PD better than conserving at random? Worryingly, a recent theoretical study has demonstrated that PD could be a poor surrogate for FD and, in some scenarios, prioritizing species on the basis of PD could actually capture less FD than if species were simply selected at random 16 . This recent work points to the need for empirical tests of the phylogenetic gambit, i.e., whether—within a given species pool—sets of species selected to maximize PD actually contain more FD than sets of species selected without regard to evolutionary relatedness. We clarify what our goals are in testing the utility of PD to capture FD. First, we take as given that maximizing PD is not the overarching goal per se of PD-maximization schemes, but rather that a PD maximization strategy is valued for its ability to capture more FD compared to a strategy that ignores phylogeny. Second, it is important to note that we are selecting species sets to maximize PD or FD within a region. While this is a simplification, as conservation actions often aim to select sets of areas (e.g., in reserve design), the only global phylogenetically informed conservation initiative is species-centered 18 (EDGE). Critically, the question we raise has been shown to be distinct from asking whether traits have phylogenetic signal (whether closely related species tend to share similar sets of traits), since PD can be a poor surrogate for FD even if traits exhibit phylogenetic signal 16 . Here, we test the phylogenetic gambit using data on ecologically-relevant traits from >15,000 vertebrate species. We find that maximizing PD results in an average gain of 18% of FD relative to random choice. However, this average gain obscures the fact that in over one third of the comparisons, maximum PD sets contain less FD than randomly chosen sets of species. These results suggest that, while maximizing PD protection can help to protect FD, it represents a risky conservation strategy. Results Approach We evaluate the PD–FD relationship for different species pools (taxonomic families and geographical assemblages, i.e., sets of species co-occurring at a given scale) using a large global dataset including trait, phylogenetic, and geographic range data for", "role": "user" }, { "content": "Conservation biologists recognize a sobering reality. \"We're losing species left, right and center,\" says Utah State University scientist Will Pearse. 'We call it the 'Noah's Ark Problem,' and we have to pick species to save. We can't save them all.\" The biblical mariner seemed capable of building a vessel to accommodate mating pairs of all the world's creatures. The metaphor, today, however, would portray the harried Noah bailing water and valiantly trying to prioritize saving animals most beneficial for the future, as his boat rapidly sank. Pearse, with colleagues Florent Mazel, Arne Mooers and Caroline Tucker of Simon Fraser University and the University of British Columbia, Marc Cadotte of the University of Toronto, Sandra Diaz of Argentina's National University of Cordoba, Giulio Valentino Dalla Riva of the University of British Columbia, Richard Grenyer of the University of Oxford, Fabien Leprieur of the University of Montpellier and David Mouillot of James Cook University, explore phylogenetic diversity as a metric of conservation prioritization in the July 23, 2018, issue of Nature Communications. \"Our paper tests a fundamental component of conservation biology we refer to as the 'phylogenetic gambit,'\" says Pearse, assistant professor in USU's Department of Biology and the USU Ecology Center. \"That is, conservation biologists often use species' evolutionary history – their phylogeny – to identify groups of species to save.\" This idea is based on the assumption that preserving phylogenetic diversity among species preserves more functional diversity than selecting species to preserve by chance. Functional diversity is important, Pearse says, because it drives ecosystem health and productivity. \"Yet measuring the effectiveness of functional diversity is difficult,\" he says. \"So using phylogenetic diversity as a surrogate for functional diversity has made conservation biology much easier and more effective.\" In global datasets of mammals, birds and tropical fishes, the team demonstrates that, for the most part, the phylogenetic gambit holds. Preserving phylogenetic diversity preserves 18 percent more functional diversity than would be expected if species to save were selected at random. \"Worryingly, though, we found in some parts of the world, and in some groups of species, preserving phylogenetic diversity did worse or just the same as random chance,\" Pearse says. \"Luckily, we identified the areas and reasons this was happening, which still makes this selection technique valid and valuable for conservation biologists.\" The team's efforts, organized through an international working group initiated by Tucker and Mooers, were funded by sDIV, the Synthesis Center for Biodiversity Sciences based in Leipzig, Germany. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract In the face of the biodiversity crisis, it is argued that we should prioritize species in order to capture high functional diversity (FD). Because species traits often reflect shared evolutionary history, many researchers have assumed that maximizing phylogenetic diversity (PD) should indirectly capture FD, a hypothesis that we name the “phylogenetic gambit”. Here, we empirically test this gambit using data on ecologically relevant traits from >15,000 vertebrate species. Specifically, we estimate a measure of surrogacy of PD for FD. We find that maximizing PD results in an average gain of 18% of FD relative to random choice. However, this average gain obscures the fact that in over one-third of the comparisons, maximum PD sets contain less FD than randomly chosen sets of species. These results suggest that, while maximizing PD protection can help to protect FD, it represents a risky conservation strategy. Introduction We are in the midst of a period of heightened biological extinction, with rates several orders of magnitude higher than background rates estimated from the fossil record 1 , 2 , 3 . In addition to having potentially widespread consequences for the functioning of ecosystems and the provisioning of valuable ecosystem services, this situation poses an immense moral challenge 4 , 5 , 6 , 7 , 8 . Since the extent that resources for conservation actions remain limited, agonizing choices as to which species most warrant attention become necessary 9 , 10 . To keep humanity’s options open, and our common legacy as rich as possible, it is widely argued that we should seek to maximize the biological diversity of form and function in conservation strategies 6 , 7 , 8 , 9 , 10 , 11 , 12 . The biological diversity of form and function can be measured as functional diversity (FD) (see Methods). However, in practice, it is challenging to prioritize species on the basis of FD: we have imperfect knowledge about which, and how many traits and functions are important in a given context, how these traits and functions vary among species and across space, and how the importance of traits may change in the future 13 . Many researchers have therefore advocated for a hypothesis that we name the ‘phylogenetic gambit’; that is, if species traits reflect their shared evolutionary history, then the pattern of that evolutionary history—their phylogeny—should serve as a useful stand-in for unmeasured and unmeasurable traits 9 , 14 , 15 . The phylogenetic gambit implies that maximizing phylogenetic diversity (PD), i.e., the breadth of evolutionary history, will ensure that a wide variety of forms and functions are present within a species set 14 , 15 , 16 , 17 . Following this logic, phylogenetic diversity has formed the basis of global conservation schemes, notably the EDGE of existence program 18 has been used by restoration biologists 19 and has been widely embraced by researchers across the biodiversity sciences 20 , 21 , 22 , 23 . Despite this enthusiasm, the critical question of whether maximizing PD will actually capture more FD than prioritization schemes that ignore phylogeny has, to our knowledge, never been empirically tested 16 . Some studies have discussed 24 , 25 and documented the relationship between FD and PD, both at regional 26 and global scales 20 , 22 , and many of these studies have shown that maximizing PD does not maximize FD. However, such studies do not test the fundamental phylogenetic gambit at the heart of all PD-based conservation strategies: maximizing PD captures more FD than randomly choosing species. No one would dispute that the best way to maximize FD is to prioritize FD, but phylogenetic diversity has emerged as prioritization tool because we rarely have sufficient trait data to calculate FD. Here we test whether PD-based conservation passes a much less stringent, but ultimately more fundamental, test: is conserving on the basis of PD better than conserving at random? Worryingly, a recent theoretical study has demonstrated that PD could be a poor surrogate for FD and, in some scenarios, prioritizing species on the basis of PD could actually capture less FD than if species were simply selected at random 16 . This recent work points to the need for empirical tests of the phylogenetic gambit, i.e., whether—within a given species pool—sets of species selected to maximize PD actually contain more FD than sets of species selected without regard to evolutionary relatedness. We clarify what our goals are in testing the utility of PD to capture FD. First, we take as given that maximizing PD is not the overarching goal per se of PD-maximization schemes, but rather that a PD maximization strategy is valued for its ability to capture more FD compared to a strategy that ignores phylogeny. Second, it is important to note that we are selecting species sets to maximize PD or FD within a region. While this is a simplification, as conservation actions often aim to select sets of areas (e.g., in reserve design), the only global phylogenetically informed conservation initiative is species-centered 18 (EDGE). Critically, the question we raise has been shown to be distinct from asking whether traits have phylogenetic signal (whether closely related species tend to share similar sets of traits), since PD can be a poor surrogate for FD even if traits exhibit phylogenetic signal 16 . Here, we test the phylogenetic gambit using data on ecologically-relevant traits from >15,000 vertebrate species. We find that maximizing PD results in an average gain of 18% of FD relative to random choice. However, this average gain obscures the fact that in over one third of the comparisons, maximum PD sets contain less FD than randomly chosen sets of species. These results suggest that, while maximizing PD protection can help to protect FD, it represents a risky conservation strategy. Results Approach We evaluate the PD–FD relationship for different species pools (taxonomic families and geographical assemblages, i.e., sets of species co-occurring at a given scale) using a large global dataset including trait, phylogenetic, and geographic range data for<|im_end|> <|im_start|>assistant Conservation biologists recognize a sobering reality. "We're losing species left, right and center," says Utah State University scientist Will Pearse. 'We call it the 'Noah's Ark Problem,' and we have to pick species to save. We can't save them all." The biblical mariner seemed capable of building a vessel to accommodate mating pairs of all the world's creatures. The metaphor, today, however, would portray the harried Noah bailing water and valiantly trying to prioritize saving animals most beneficial for the future, as his boat rapidly sank. Pearse, with colleagues Florent Mazel, Arne Mooers and Caroline Tucker of Simon Fraser University and the University of British Columbia, Marc Cadotte of the University of Toronto, Sandra Diaz of Argentina's National University of Cordoba, Giulio Valentino Dalla Riva of the University of British Columbia, Richard Grenyer of the University of Oxford, Fabien Leprieur of the University of Montpellier and David Mouillot of James Cook University, explore phylogenetic diversity as a metric of conservation prioritization in the July 23, 2018, issue of Nature Communications. "Our paper tests a fundamental component of conservation biology we refer to as the 'phylogenetic gambit,'" says Pearse, assistant professor in USU's Department of Biology and the USU Ecology Center. "That is, conservation biologists often use species' evolutionary history – their phylogeny – to identify groups of species to save." This idea is based on the assumption that preserving phylogenetic diversity among species preserves more functional diversity than selecting species to preserve by chance. Functional diversity is important, Pearse says, because it drives ecosystem health and productivity. "Yet measuring the effectiveness of functional diversity is difficult," he says. "So using phylogenetic diversity as a surrogate for functional diversity has made conservation biology much easier and more effective." In global datasets of mammals, birds and tropical fishes, the team demonstrates that, for the most part, the phylogenetic gambit holds. Preserving phylogenetic diversity preserves 18 percent more functional diversity than would be expected if species to save were selected at random. "Worryingly, though, we found in some parts of the world, and in some groups of species, preserving phylogenetic diversity did worse or just the same as random chance," Pearse says. "Luckily, we identified the areas and reasons this was happening, which still makes this selection technique valid and valuable for conservation biologists." The team's efforts, organized through an international working group initiated by Tucker and Mooers, were funded by sDIV, the Synthesis Center for Biodiversity Sciences based in Leipzig, Germany. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract In Saccharomyces cerevisiae , deletion of large ribosomal subunit protein-encoding genes increases the replicative lifespan in a Gcn4-dependent manner. However, how Gcn4, a key transcriptional activator of amino acid biosynthesis genes, increases lifespan, is unknown. Here we show that Gcn4 acts as a repressor of protein synthesis. By analyzing the messenger RNA and protein abundance, ribosome occupancy and protein synthesis rate in various yeast strains, we demonstrate that Gcn4 is sufficient to reduce protein synthesis and increase yeast lifespan. Chromatin immunoprecipitation reveals Gcn4 binding not only at genes that are activated, but also at genes, some encoding ribosomal proteins, that are repressed upon Gcn4 overexpression. The promoters of repressed genes contain Rap1 binding motifs. Our data suggest that Gcn4 is a central regulator of protein synthesis under multiple perturbations, including ribosomal protein gene deletions, calorie restriction, and rapamycin treatment, and provide an explanation for its role in longevity and stress response. Introduction The discovery that individual genes can significantly and reproducibly modulate the lifespan of eukaryotic organisms 1 opened the process of aging to investigation by geneticists and molecular biologists. The ease of its genetic manipulation has made the yeast Saccharomyces cerevisiae an important experimental model for aging studies. The number of divisions that a mother yeast cell undergoes before it enters senescence is used as a measure of lifespan, also called replicative lifespan 2 . Genetic studies have linked nutrient sensing pathways to aging (extensively reviewed in refs. 3 , 4 ) and consistently, caloric restriction improved the functionality and increased the lifespan of many model organisms (reviewed in ref. 5 ). Although the molecular mechanisms underlying changes in lifespan are still debated 4 , modulation of protein synthesis by the target of rapamycin (TOR) serine/threonine kinase seems to play an important role 6 , 7 . Reducing TOR activity increased lifespan in yeast, worms, flies, and mammals 8 . Furthermore, deletion of translation-related genes such as SCH9 , TIF1 , and TIF2 , increased the yeast replicative lifespan 9 , 10 , 11 , and inhibition of translation in the worm Caenorhabditis elegans promoted longevity 12 , 13 , 14 . These observations indicate that reducing cellular translation is a conserved mechanism of lifespan extension 15 . Translation of messenger RNA (mRNAs) into proteins is carried out by the ribosome, a molecular machine that in S. cerevisiae is composed of four ribosomal RNAs and 78 ribosomal proteins (RPs). The yeast genome contains 137 RP-encoding genes, 59 of which are paralogs 16 . Screening studies have found that deletion of RPL31A , RPL6B and other RPs increased replicative lifespan 9 , 10 , 17 , and a systematic survey of 107 RP gene deletion strains comprehensively showed that the specific reduction of the 60S ribosome subunit significantly extends replicative lifespan 18 . The fact that RPs are downstream targets of TOR signaling reinforces the link between nutrient sensing pathways, protein synthesis, and aging 18 , 19 , 20 . Lifespan extension in large ribosomal subunit protein (RPL) deletion strains depends on the upregulation of Gcn4 18 . This protein is the key transcriptional activator of amino acid biosynthesis genes in yeast, being translationally upregulated in various stress conditions 21 , 22 , 23 , 24 , 25 , as well as upon deletion of RPL genes 18 , 26 , 27 . Other modulators of aging such as the tRNA transporter Los1 and mitochondrial AAA protease gene Afg3 are also thought to exert their lifespan-increasing effects through Gcn4 11 , 28 . The GCN4 mRNA provides one of the best well characterized models of translational control 29 . When sufficient nutrients are available, most ribosomes are sequestered at four upstream open reading frames (uORFs) present in the 5′ UTR, resulting in low Gcn4 abundance. Upon amino acid starvation, the Gcn2 kinase phosphorylates the translation initiation factor eIF2α, leading to reduced levels of GTP-bound eIF2 and depletion of the ternary translation initiation complex. This allows the scanning of 40S ribosomes past the uORF4, resulting in increased initiation at the main ORF and higher production of Gcn4. However, in spite of Gcn4’s central role in yeast longevity, it is difficult to link mechanistically its activity of transcriptional activator of amino acid biosynthesis genes to lifespan extension. Characterizing the gene expression of RP deletion (RPKO) strains with mRNA sequencing (m RNA-seq), ribosome profiling and proteomics we found that reduced protein synthesis, impaired ribosome assembly and general uORF skipping leading to Gcn4 expression are hallmarks of RPKO strains with increased replicative lifespan. Consistently, we show that Gcn4 is necessary for the translation repression observed not only in long-lived RPKO strains, but also under glucose starvation and rapamycin treatment conditions, and that overexpression of Gcn4 is sufficient to promote longevity and reduce protein biosynthesis. Our results thus suggest that the reduction in protein synthesis capacity contributes to the Gcn4-mediated lifespan extension. Results Long and short-lived RPKO strains differ in gene expression To understand the molecular mechanisms behind the increased lifespan of RPKO strains, we compared gene expression of the wild-type strain with that of two RPKO strains with increased ( Δrpl7a and Δrpl9a ) and three with decreased ( Δrpl6a , Δrpl15b , and Δrps27b ) lifespan 18 . For each strain we determined transcript levels by mRNA-seq, ribosome occupancy by ribosome footprint sequencing (Ribo-seq), and protein levels by shotgun proteomics (Supplementary Data 1 ). Interestingly, all but one RPKO strain (Δ rpl15b ) showed an increased expression of the paralog of the deleted RP (Supplementary Fig. 1a, b ), suggesting that yeast cells can compensate for the lack of individual RP genes. Beyond the expected upregulation of amino acid biosynthesis genes in the large subunit RPKO (RPLKO) strains 26 , 27 , we found that RPLKO strains with increased replicative lifespan showed the strongest upregulation of these pathways, both at mRNA and protein levels (Fig. 1a ; Supplementary Data 2 for the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways that are significantly altered in these strains). Unexpectedly, genes from the biosynthetic", "role": "user" }, { "content": "To understand and control aging is the aspiration of many scientists. Researchers at the Biozentrum of the University of Basel have now discovered that the protein Gcn4 decreases protein synthesis and extends the life of yeast cells. Understanding how individual genes affect lifespan opens new ways to control the aging process and the occurrence of aging-related diseases. The results of this study have recently been published in Nature Communications. For about one hundred years it has been known that nutrient restriction and moderate stress can significantly prolong life. The researchers led by Prof. Mihaela Zavolan and Prof. Anne Spang, both at the Biozentrum of the University of Basel, have discovered how the transcription factor Gcn4, a protein that regulates the expression of many genes, extends the life of baker's yeast Saccharomyces cerevisiae. In various stress situations, the cells stimulate Gcn4 production which leads to reduced biosynthesis of new proteins and increased yeast lifespan. Transcription factor represses protein synthesis It has long been known that protein synthesis – also known as translation – plays an important role in aging. Inhibition of protein synthesis, caused for example by reduced nutrient intake, can have a positive effect on the life expectancy of diverse organisms such as yeast, flies, worms or fish. Reducing the ribosomes, the protein factories of the cell, can also considerably extend the lifespan of yeast cells. What these cellular stresses have in common is that they activate the production of Gcn4. However, how this protein promotes longevity has remained unclear. In their study, the team working with Zavolan exposed yeast cells to different stress conditions, measured their lifespan, protein synthesis rates and Gcn4 expression. \"We observed that the level of the Gcn4 protein was positively correlated with the longevity of yeast cells,\" says Mihaela Zavolan, Professor of Computational and Systems Biology. \"However, we wanted to understand why. We have now shown for the first time that it is the transcriptional suppression of genes that are important for cellular protein synthesis by Gcn4 that seems to account for its lifespan extension effect. As the translation machinery is limiting, the energy-intensive production of new proteins is overall dampened.\" From the yeast cell's point of view, this is an advantage: This enables them to live about 40 percent longer than usual. The transcription factor Gcn4 is conserved in over 50 different organisms, including mammals, and it likely play a significant role in the aging of these organisms as well. Zavolan's group will now investigate whether the mammalian homolog similarly slows aging and extends lifespan by regulating protein synthesis genes in response to nutrients and stress. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract In Saccharomyces cerevisiae , deletion of large ribosomal subunit protein-encoding genes increases the replicative lifespan in a Gcn4-dependent manner. However, how Gcn4, a key transcriptional activator of amino acid biosynthesis genes, increases lifespan, is unknown. Here we show that Gcn4 acts as a repressor of protein synthesis. By analyzing the messenger RNA and protein abundance, ribosome occupancy and protein synthesis rate in various yeast strains, we demonstrate that Gcn4 is sufficient to reduce protein synthesis and increase yeast lifespan. Chromatin immunoprecipitation reveals Gcn4 binding not only at genes that are activated, but also at genes, some encoding ribosomal proteins, that are repressed upon Gcn4 overexpression. The promoters of repressed genes contain Rap1 binding motifs. Our data suggest that Gcn4 is a central regulator of protein synthesis under multiple perturbations, including ribosomal protein gene deletions, calorie restriction, and rapamycin treatment, and provide an explanation for its role in longevity and stress response. Introduction The discovery that individual genes can significantly and reproducibly modulate the lifespan of eukaryotic organisms 1 opened the process of aging to investigation by geneticists and molecular biologists. The ease of its genetic manipulation has made the yeast Saccharomyces cerevisiae an important experimental model for aging studies. The number of divisions that a mother yeast cell undergoes before it enters senescence is used as a measure of lifespan, also called replicative lifespan 2 . Genetic studies have linked nutrient sensing pathways to aging (extensively reviewed in refs. 3 , 4 ) and consistently, caloric restriction improved the functionality and increased the lifespan of many model organisms (reviewed in ref. 5 ). Although the molecular mechanisms underlying changes in lifespan are still debated 4 , modulation of protein synthesis by the target of rapamycin (TOR) serine/threonine kinase seems to play an important role 6 , 7 . Reducing TOR activity increased lifespan in yeast, worms, flies, and mammals 8 . Furthermore, deletion of translation-related genes such as SCH9 , TIF1 , and TIF2 , increased the yeast replicative lifespan 9 , 10 , 11 , and inhibition of translation in the worm Caenorhabditis elegans promoted longevity 12 , 13 , 14 . These observations indicate that reducing cellular translation is a conserved mechanism of lifespan extension 15 . Translation of messenger RNA (mRNAs) into proteins is carried out by the ribosome, a molecular machine that in S. cerevisiae is composed of four ribosomal RNAs and 78 ribosomal proteins (RPs). The yeast genome contains 137 RP-encoding genes, 59 of which are paralogs 16 . Screening studies have found that deletion of RPL31A , RPL6B and other RPs increased replicative lifespan 9 , 10 , 17 , and a systematic survey of 107 RP gene deletion strains comprehensively showed that the specific reduction of the 60S ribosome subunit significantly extends replicative lifespan 18 . The fact that RPs are downstream targets of TOR signaling reinforces the link between nutrient sensing pathways, protein synthesis, and aging 18 , 19 , 20 . Lifespan extension in large ribosomal subunit protein (RPL) deletion strains depends on the upregulation of Gcn4 18 . This protein is the key transcriptional activator of amino acid biosynthesis genes in yeast, being translationally upregulated in various stress conditions 21 , 22 , 23 , 24 , 25 , as well as upon deletion of RPL genes 18 , 26 , 27 . Other modulators of aging such as the tRNA transporter Los1 and mitochondrial AAA protease gene Afg3 are also thought to exert their lifespan-increasing effects through Gcn4 11 , 28 . The GCN4 mRNA provides one of the best well characterized models of translational control 29 . When sufficient nutrients are available, most ribosomes are sequestered at four upstream open reading frames (uORFs) present in the 5′ UTR, resulting in low Gcn4 abundance. Upon amino acid starvation, the Gcn2 kinase phosphorylates the translation initiation factor eIF2α, leading to reduced levels of GTP-bound eIF2 and depletion of the ternary translation initiation complex. This allows the scanning of 40S ribosomes past the uORF4, resulting in increased initiation at the main ORF and higher production of Gcn4. However, in spite of Gcn4’s central role in yeast longevity, it is difficult to link mechanistically its activity of transcriptional activator of amino acid biosynthesis genes to lifespan extension. Characterizing the gene expression of RP deletion (RPKO) strains with mRNA sequencing (m RNA-seq), ribosome profiling and proteomics we found that reduced protein synthesis, impaired ribosome assembly and general uORF skipping leading to Gcn4 expression are hallmarks of RPKO strains with increased replicative lifespan. Consistently, we show that Gcn4 is necessary for the translation repression observed not only in long-lived RPKO strains, but also under glucose starvation and rapamycin treatment conditions, and that overexpression of Gcn4 is sufficient to promote longevity and reduce protein biosynthesis. Our results thus suggest that the reduction in protein synthesis capacity contributes to the Gcn4-mediated lifespan extension. Results Long and short-lived RPKO strains differ in gene expression To understand the molecular mechanisms behind the increased lifespan of RPKO strains, we compared gene expression of the wild-type strain with that of two RPKO strains with increased ( Δrpl7a and Δrpl9a ) and three with decreased ( Δrpl6a , Δrpl15b , and Δrps27b ) lifespan 18 . For each strain we determined transcript levels by mRNA-seq, ribosome occupancy by ribosome footprint sequencing (Ribo-seq), and protein levels by shotgun proteomics (Supplementary Data 1 ). Interestingly, all but one RPKO strain (Δ rpl15b ) showed an increased expression of the paralog of the deleted RP (Supplementary Fig. 1a, b ), suggesting that yeast cells can compensate for the lack of individual RP genes. Beyond the expected upregulation of amino acid biosynthesis genes in the large subunit RPKO (RPLKO) strains 26 , 27 , we found that RPLKO strains with increased replicative lifespan showed the strongest upregulation of these pathways, both at mRNA and protein levels (Fig. 1a ; Supplementary Data 2 for the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways that are significantly altered in these strains). Unexpectedly, genes from the biosynthetic<|im_end|> <|im_start|>assistant To understand and control aging is the aspiration of many scientists. Researchers at the Biozentrum of the University of Basel have now discovered that the protein Gcn4 decreases protein synthesis and extends the life of yeast cells. Understanding how individual genes affect lifespan opens new ways to control the aging process and the occurrence of aging-related diseases. The results of this study have recently been published in Nature Communications. For about one hundred years it has been known that nutrient restriction and moderate stress can significantly prolong life. The researchers led by Prof. Mihaela Zavolan and Prof. Anne Spang, both at the Biozentrum of the University of Basel, have discovered how the transcription factor Gcn4, a protein that regulates the expression of many genes, extends the life of baker's yeast Saccharomyces cerevisiae. In various stress situations, the cells stimulate Gcn4 production which leads to reduced biosynthesis of new proteins and increased yeast lifespan. Transcription factor represses protein synthesis It has long been known that protein synthesis – also known as translation – plays an important role in aging. Inhibition of protein synthesis, caused for example by reduced nutrient intake, can have a positive effect on the life expectancy of diverse organisms such as yeast, flies, worms or fish. Reducing the ribosomes, the protein factories of the cell, can also considerably extend the lifespan of yeast cells. What these cellular stresses have in common is that they activate the production of Gcn4. However, how this protein promotes longevity has remained unclear. In their study, the team working with Zavolan exposed yeast cells to different stress conditions, measured their lifespan, protein synthesis rates and Gcn4 expression. "We observed that the level of the Gcn4 protein was positively correlated with the longevity of yeast cells," says Mihaela Zavolan, Professor of Computational and Systems Biology. "However, we wanted to understand why. We have now shown for the first time that it is the transcriptional suppression of genes that are important for cellular protein synthesis by Gcn4 that seems to account for its lifespan extension effect. As the translation machinery is limiting, the energy-intensive production of new proteins is overall dampened." From the yeast cell's point of view, this is an advantage: This enables them to live about 40 percent longer than usual. The transcription factor Gcn4 is conserved in over 50 different organisms, including mammals, and it likely play a significant role in the aging of these organisms as well. Zavolan's group will now investigate whether the mammalian homolog similarly slows aging and extends lifespan by regulating protein synthesis genes in response to nutrients and stress. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract For more than one century, photochemical [2+2]-cycloadditions have been used by synthetic chemists to make cyclobutanes, four-membered carbon-based rings. In this reaction, typically two olefin subunits (two π -electrons per olefin) cyclize to form two new C–C σ -bonds. Although the development of photochemical [2+2]-cycloadditions has made enormous progress within the last century, research has been focused on such [2 π +2 π ]-systems, in which two π -bonds are converted into two new σ -bonds 1 , 2 . Here we report an intermolecular [2+2]-photocycloaddition that uses bicyclo[1.1.0]butanes as 2 σ -electron reactants 3 , 4 , 5 , 6 , 7 . This strain-release-driven [2 π +2 σ ]-photocycloaddition reaction was realized by visible-light-mediated triplet energy transfer catalysis 8 , 9 . A simple, modular and diastereoselective synthesis of bicyclo[2.1.1]hexanes from heterocyclic olefin coupling partners, namely coumarins, flavones and indoles, is disclosed. Given the increasing importance of bicyclo[2.1.1]hexanes as bioisosteres—groups that convey similar biological properties to those they replace—in pharmaceutical research and considering their limited access 10 , 11 , there remains a need for new synthetic methodologies. Applying this strategy enabled us to extend the intermolecular [2+2]-photocycloadditions to σ -bonds and provides previously inaccessible structural motifs. Main [2+2]-Photocycloadditions belong to the most fundamental organic transformations and are an established tool for the straightforward synthesis of strained cyclobutane rings 1 , 2 . The formation of two new C–C σ -bonds and up to four stereogenic centres in a single step with perfect atom economy renders these processes highly attractive 12 . The first reported photochemical [2+2]-cycloaddition—a solid-state photodimerization of thymoquinone mediated by exposure to sunlight—was published by Liebermann as early as 1877 (ref. 13 ). Additional selected milestones in the history of photochemical [2+2]-cycloadditions including intramolecular and diastereoselective variants are depicted in Fig. 1a (refs. 14 , 15 , 16 , 17 ). In particular, the development of cross-selective intermolecular protocols has gained tremendous attention 2 , 18 . In contrast to intramolecular or dimerization approaches, these transformations allow modular variation of the olefin components and provide rapid access to molecular complexity. The general concept of cross-selective photochemical [2+2]-cycloadditions consists of selective activation of olefin A , which is then able to react with olefin B (Fig. 1b ). From a mechanistic perspective, the most relevant strategy in this regard is the excitation of one substrate into its triplet state (T 1 ). This mainly stems from the comparably long lifetime of such triplet excited states, leading to an increased probability for productive intermolecular interaction 1 . The triplet state of a substrate can be reached either by direct excitation and subsequent intersystem crossing from the excited singlet state (S 1 ) or by indirect population, mediated by triplet–triplet energy transfer (ENT) from a suitable photosensitizer 8 . A major drawback of direct excitation is that most organic substrates require harsh, ionizing ultraviolet (UV) light irradiation, which often results in undesired and competitive side reactions. Therefore, the synthetic community has recently focused on the use of milder visible light to enable ENT processes to overcome these selectivity and activation issues 19 , 20 , 21 , 22 . Fig. 1: Background and motivation of the present work. a , Selected milestones in the history of photochemical [2+2]-cycloadditions. b , Mechanistic outline of stepwise [2+2]-photocycloadditions by triplet excited state olefins and general selectivity issues. c , Intramolecular [2 π +2 σ ]-valence isomerization of strained tricyclic systems, seminal reports by Prinzbach in the 1960s. d , Synthesis of bicyclo[2.1.1]hexanes enabled by ENT-mediated intermolecular [2 π +2 σ ]-photocycloaddition undertaken in this work. ISC, intersystem crossing. Full size image Inspired by seminal reports by Prinzbach and coworkers from the 1960s about intramolecular valence [2 π +2 σ ]-photoisomerization of tricyclic systems (Fig. 1c ) 23 , 24 , 25 , we questioned whether a strain-release approach 26 , 27 could enable an intermolecular [2 π +2 σ ]-photocycloaddition in which an excited π -bond in its triplet state reacts with a σ -bond to form two new C–C σ -bonds (Fig. 1d ). We envisioned that bicyclo[1.1.0]butanes (BCBs) 4 , 5 , 6 would be ideally suited for our proposed [2 π +2 σ ]-photocycloaddition as they would enable the construction of bicyclo[2.1.1]hexane (BCH) products by simple reaction with an olefin component 28 , 29 . Three-dimensional architectures with conformationally restricted C( sp 3 )-rich skeletons such as BCHs are becoming increasingly relevant in bioisosterism 30 , 31 , and are thus extremely valuable for medicinal chemistry. However, the lack of practical synthetic access to these frameworks, especially for highly substituted examples 10 , 11 , inherently limits their application in drug discovery. Consequently, the development of new methodologies towards their simple and modular synthesis is of highest interest to the synthetic community. With this in mind, we initiated our investigations by evaluating a suitable olefin coupling partner (for unsuccessful olefin coupling partners see Supplementary Table 2 ) in combination with dibenzyl amide-substituted BCB 2a in the presence of iridium-based triplet sensitizer [Ir(dF(CF 3 )ppy) 2 (dtbbpy)]PF 6 ( Ir-F , triplet excited state energy E T = 61.8 kcal mol –1 ) 8 under visible light irradiation with blue light-emitting diodes (LEDs) in MeCN. Fortunately, when using coumarin ( 1a , E T = 62.1 kcal mol –1 ) 32 as a coupling partner the desired [2 π +2 σ ]-cycloaddition product 3a was formed. Intrigued by this finding, we began with the optimization studies ( Supplementary Table 1 ). The use of simple thioxanthone triplet sensitizer ( TXT , E T = 65.5 kcal mol –1 ) 33 not only improved the yield but also allowed us to perform the reaction metal-free. In control experiments no product formation was observed in the absence of photocatalyst or light. Note that during the optimization and substrate scope analysis only formation of the cis -diastereomer was observed. Having established the optimized reaction conditions, we proceeded with the investigation of the substrate scope (Fig. 2 ), starting with an array", "role": "user" }, { "content": "In synthetic organic chemistry, so-called cycloadditions are a particularly important class of reactions. With this type of reaction, ring-shaped molecules can be constructed simply and efficiently by joining (\"adding\") two compounds that each contain double bonds. A team led by Prof. Dr. Frank Glorius from the University of Münster has now succeeded in performing an unconventional cycloaddition in which a carbon-carbon double bond reacts with a carbon-carbon single bond. In double bonds, atoms are connected by two pairs of electrons; in single bonds, only one pair of electrons is involved. The key to success was the use of particularly \"strained\" single bonds. To enable mild reaction conditions, the chemists used a photosensitizer, a catalyst that drives the reaction using light energy. The study has now been published in the journal Nature. \"In addition to its conceptual and mechanistic importance, this method also has a synthetic benefit,\" explains lead author Roman Kleinmans. \"This is because we can use it to build polycyclic, three-dimensional carbon scaffolds that have been difficult or impossible to access. Such three-dimensional architectures are fascinating and play an increasingly important role in medicinal chemistry.\" The chemistry in detail For more than a century, so-called [2+2] photocycloadditions have been studied and developed. Research has focused specifically on [2π+2π]-systems in which, for example, two double bonds react to form two new single bonds giving a four-membered ring product. The team from Münster has now achieved a breakthrough by realizing this type of reaction using a single bond (\"2π+2σ\"). The team used a class of compounds with \"strained\" single bonds: so-called bicyclo[1.1.0]butanes (BCBs). These carbon compounds have a butterfly-like shape, with two linked triangles on the single bond that look like wings. The internal wing angles (60 degrees each) deviate greatly from the ideal unstrained angles (109 degrees each). The opening of the central single bond releases strain energy—thermodynamically favoring the reaction with the carbon-carbon double bond. Using this strategy, the researchers also succeeded in incorporating a nitrogen atom into the carbon skeleton of the product. The visible light driven \"triplet-triplet energy transfer catalysis\" allows the reaction to be carried out as mildly as possible, so that irradiation of the reaction with harsh UV light, which is commonly used in chemistry of this type, was not needed. In this mechanism, the catalyst absorbs energy from the irradiated light and transfers it to a suitable substrate. The catalyst returns to the ground state (it is regenerated), and the corresponding molecule is left in an energetically excited state (triplet state). The excited molecule is then able to react with the single bond. \"We used a simple organic photosensitizer for this, namely thioxanthone, dispensing with rare and expensive transition metal-based catalysts,\" emphasizes Frank Glorius. To further understand the molecular mechanism of the reaction in more detail, the chemists carried out computational calculations using \"density functional theory.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract For more than one century, photochemical [2+2]-cycloadditions have been used by synthetic chemists to make cyclobutanes, four-membered carbon-based rings. In this reaction, typically two olefin subunits (two π -electrons per olefin) cyclize to form two new C–C σ -bonds. Although the development of photochemical [2+2]-cycloadditions has made enormous progress within the last century, research has been focused on such [2 π +2 π ]-systems, in which two π -bonds are converted into two new σ -bonds 1 , 2 . Here we report an intermolecular [2+2]-photocycloaddition that uses bicyclo[1.1.0]butanes as 2 σ -electron reactants 3 , 4 , 5 , 6 , 7 . This strain-release-driven [2 π +2 σ ]-photocycloaddition reaction was realized by visible-light-mediated triplet energy transfer catalysis 8 , 9 . A simple, modular and diastereoselective synthesis of bicyclo[2.1.1]hexanes from heterocyclic olefin coupling partners, namely coumarins, flavones and indoles, is disclosed. Given the increasing importance of bicyclo[2.1.1]hexanes as bioisosteres—groups that convey similar biological properties to those they replace—in pharmaceutical research and considering their limited access 10 , 11 , there remains a need for new synthetic methodologies. Applying this strategy enabled us to extend the intermolecular [2+2]-photocycloadditions to σ -bonds and provides previously inaccessible structural motifs. Main [2+2]-Photocycloadditions belong to the most fundamental organic transformations and are an established tool for the straightforward synthesis of strained cyclobutane rings 1 , 2 . The formation of two new C–C σ -bonds and up to four stereogenic centres in a single step with perfect atom economy renders these processes highly attractive 12 . The first reported photochemical [2+2]-cycloaddition—a solid-state photodimerization of thymoquinone mediated by exposure to sunlight—was published by Liebermann as early as 1877 (ref. 13 ). Additional selected milestones in the history of photochemical [2+2]-cycloadditions including intramolecular and diastereoselective variants are depicted in Fig. 1a (refs. 14 , 15 , 16 , 17 ). In particular, the development of cross-selective intermolecular protocols has gained tremendous attention 2 , 18 . In contrast to intramolecular or dimerization approaches, these transformations allow modular variation of the olefin components and provide rapid access to molecular complexity. The general concept of cross-selective photochemical [2+2]-cycloadditions consists of selective activation of olefin A , which is then able to react with olefin B (Fig. 1b ). From a mechanistic perspective, the most relevant strategy in this regard is the excitation of one substrate into its triplet state (T 1 ). This mainly stems from the comparably long lifetime of such triplet excited states, leading to an increased probability for productive intermolecular interaction 1 . The triplet state of a substrate can be reached either by direct excitation and subsequent intersystem crossing from the excited singlet state (S 1 ) or by indirect population, mediated by triplet–triplet energy transfer (ENT) from a suitable photosensitizer 8 . A major drawback of direct excitation is that most organic substrates require harsh, ionizing ultraviolet (UV) light irradiation, which often results in undesired and competitive side reactions. Therefore, the synthetic community has recently focused on the use of milder visible light to enable ENT processes to overcome these selectivity and activation issues 19 , 20 , 21 , 22 . Fig. 1: Background and motivation of the present work. a , Selected milestones in the history of photochemical [2+2]-cycloadditions. b , Mechanistic outline of stepwise [2+2]-photocycloadditions by triplet excited state olefins and general selectivity issues. c , Intramolecular [2 π +2 σ ]-valence isomerization of strained tricyclic systems, seminal reports by Prinzbach in the 1960s. d , Synthesis of bicyclo[2.1.1]hexanes enabled by ENT-mediated intermolecular [2 π +2 σ ]-photocycloaddition undertaken in this work. ISC, intersystem crossing. Full size image Inspired by seminal reports by Prinzbach and coworkers from the 1960s about intramolecular valence [2 π +2 σ ]-photoisomerization of tricyclic systems (Fig. 1c ) 23 , 24 , 25 , we questioned whether a strain-release approach 26 , 27 could enable an intermolecular [2 π +2 σ ]-photocycloaddition in which an excited π -bond in its triplet state reacts with a σ -bond to form two new C–C σ -bonds (Fig. 1d ). We envisioned that bicyclo[1.1.0]butanes (BCBs) 4 , 5 , 6 would be ideally suited for our proposed [2 π +2 σ ]-photocycloaddition as they would enable the construction of bicyclo[2.1.1]hexane (BCH) products by simple reaction with an olefin component 28 , 29 . Three-dimensional architectures with conformationally restricted C( sp 3 )-rich skeletons such as BCHs are becoming increasingly relevant in bioisosterism 30 , 31 , and are thus extremely valuable for medicinal chemistry. However, the lack of practical synthetic access to these frameworks, especially for highly substituted examples 10 , 11 , inherently limits their application in drug discovery. Consequently, the development of new methodologies towards their simple and modular synthesis is of highest interest to the synthetic community. With this in mind, we initiated our investigations by evaluating a suitable olefin coupling partner (for unsuccessful olefin coupling partners see Supplementary Table 2 ) in combination with dibenzyl amide-substituted BCB 2a in the presence of iridium-based triplet sensitizer [Ir(dF(CF 3 )ppy) 2 (dtbbpy)]PF 6 ( Ir-F , triplet excited state energy E T = 61.8 kcal mol –1 ) 8 under visible light irradiation with blue light-emitting diodes (LEDs) in MeCN. Fortunately, when using coumarin ( 1a , E T = 62.1 kcal mol –1 ) 32 as a coupling partner the desired [2 π +2 σ ]-cycloaddition product 3a was formed. Intrigued by this finding, we began with the optimization studies ( Supplementary Table 1 ). The use of simple thioxanthone triplet sensitizer ( TXT , E T = 65.5 kcal mol –1 ) 33 not only improved the yield but also allowed us to perform the reaction metal-free. In control experiments no product formation was observed in the absence of photocatalyst or light. Note that during the optimization and substrate scope analysis only formation of the cis -diastereomer was observed. Having established the optimized reaction conditions, we proceeded with the investigation of the substrate scope (Fig. 2 ), starting with an array<|im_end|> <|im_start|>assistant In synthetic organic chemistry, so-called cycloadditions are a particularly important class of reactions. With this type of reaction, ring-shaped molecules can be constructed simply and efficiently by joining ("adding") two compounds that each contain double bonds. A team led by Prof. Dr. Frank Glorius from the University of Münster has now succeeded in performing an unconventional cycloaddition in which a carbon-carbon double bond reacts with a carbon-carbon single bond. In double bonds, atoms are connected by two pairs of electrons; in single bonds, only one pair of electrons is involved. The key to success was the use of particularly "strained" single bonds. To enable mild reaction conditions, the chemists used a photosensitizer, a catalyst that drives the reaction using light energy. The study has now been published in the journal Nature. "In addition to its conceptual and mechanistic importance, this method also has a synthetic benefit," explains lead author Roman Kleinmans. "This is because we can use it to build polycyclic, three-dimensional carbon scaffolds that have been difficult or impossible to access. Such three-dimensional architectures are fascinating and play an increasingly important role in medicinal chemistry." The chemistry in detail For more than a century, so-called [2+2] photocycloadditions have been studied and developed. Research has focused specifically on [2π+2π]-systems in which, for example, two double bonds react to form two new single bonds giving a four-membered ring product. The team from Münster has now achieved a breakthrough by realizing this type of reaction using a single bond ("2π+2σ"). The team used a class of compounds with "strained" single bonds: so-called bicyclo[1.1.0]butanes (BCBs). These carbon compounds have a butterfly-like shape, with two linked triangles on the single bond that look like wings. The internal wing angles (60 degrees each) deviate greatly from the ideal unstrained angles (109 degrees each). The opening of the central single bond releases strain energy—thermodynamically favoring the reaction with the carbon-carbon double bond. Using this strategy, the researchers also succeeded in incorporating a nitrogen atom into the carbon skeleton of the product. The visible light driven "triplet-triplet energy transfer catalysis" allows the reaction to be carried out as mildly as possible, so that irradiation of the reaction with harsh UV light, which is commonly used in chemistry of this type, was not needed. In this mechanism, the catalyst absorbs energy from the irradiated light and transfers it to a suitable substrate. The catalyst returns to the ground state (it is regenerated), and the corresponding molecule is left in an energetically excited state (triplet state). The excited molecule is then able to react with the single bond. "We used a simple organic photosensitizer for this, namely thioxanthone, dispensing with rare and expensive transition metal-based catalysts," emphasizes Frank Glorius. To further understand the molecular mechanism of the reaction in more detail, the chemists carried out computational calculations using "density functional theory." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The standard density functional theory (DFT) based first-principles approach has been widely used for modeling nanoscale electronic devices. A recent experiment, however, reported surprising transport properties of thiol-terminated silane junctions that cannot be understood using the standard DFT approach, presenting a severe challenge for the current computational understanding of electron transport at the nanoscale. Using the recently proposed steady-state DFT (SS-DFT) for nonequilibrium quantum systems, we found that in silane junctions, underlying the puzzling experimental observations is a novel type of intriguing nonequilibrium effect that is beyond the framework of the standard DFT approach. Our calculations show that the standard DFT approach is a good approximation of SS-DFT when silane junctions are near equilibrium, but the aforementioned nonequilibrium effects could drive the thiol-terminated silanes far away from equilibrium even at low biases of around 0.2 V. Further analysis suggests that these nonequilibrium effects could generally exist in nanoscale devices in which there are conducting channels mainly residing at the source contact and close to the bias window. These findings significantly broaden our fundamental understanding of electron transport at the nanoscale. This article is part of the themed collection: Nanoscale Horizons 2022 Lunar New Year Collection New concepts Understanding bias-induced nonequilibrium effects on the transport properties of nanoscale electronic devices is one of the biggest challenges in computational nanoscience. In this work, with the recently proposed steady-state density functional theory (SS-DFT) for nonequilibrium quantum systems, we predict a novel type of nonequilibrium effect (named ‘nonequilibrium pulling’ in the paper) that could exist in nanoscale devices even at low biases well within the expected linear-response regime. The effects lead to surprising transport phenomena that are beyond the framework of conventional DFT-based methods, which result in the puzzling transport properties of silane junctions reported in a recent experiment. Further analysis points out that the ‘nonequilibrium pulling’ originates from the ‘two-dimensional’ nature of the theory: in SS-DFT, the transport state is a functional of two densities, the total electron density and the current-carrying electron density. When conducting channels exist near the bias window that mainly reside in the source contact, the dimension of the current-carrying electron density can be significant, causing ‘nonequilibrium pulling’ and the failure of the conventional ‘one-dimensional’ DFT method. Similar nonequilibrium effects could also exist in other bias-driven processes under scanning tunnelling microscopes and electrochemical systems. Introduction Nanoscale electronic devices that often contain a molecular scale center have become one of the most promising candidates for the next generation of electronic devices. In the past two decades, numerous nanoscale devices with various functions, such as transistors, 1,2 switches, 3–5 diodes, 6–8 spintronic devices, 9–11 and many others 12–14 have been proposed theoretically and/or experimentally. The density functional theory (DFT) based first-principles approach that combines the DFT and nonequilibrium Green's function (NEGF) techniques 15–17 has been widely used in qualitatively understanding experiments by linking the measured transport properties of a device to the tunnelling of electrons through orbitals of the molecular scale device center. A recent experiment, 18 however, reported surprising transport phenomena through silane junctions that cannot be understood using the standard DFT based method. Therein the low-bias conductance of various silane molecules with different linker groups (amine or thiol) bridging different metal electrodes (Au or Ag) were measured. It was found that with the amine linker, the Au electrode generates a much higher conductance than that of Ag, while with the thiol linker, the trend reverses and the Ag electrode is significantly more conducting than the Au electrode. In contrast, DFT-based transport calculations predict that Au electrodes are always more conducting than Ag regardless of linkers. 18 This contradiction between theory and experiment presents the community of computational nanoscience with a severe challenge. To address this challenge, we theoretically study the transport properties of silane junctions using both the standard DFT-based approach and the steady-state DFT (SS-DFT) we recently proposed. 19 Several widely used implementations of the DFT-based approach, i.e. , TranSIESTA, 16 SMEAGOL, 17 and ATK, 20 which only differ from each other in the detail of the numerical procedures, were used in this study. Unlike the DFT-based method, SS-DFT considers nonequilibrium effects in full by employing Hershfield's nonequilibrium quantum statistics. 21 In SS-DFT, the nonequilibrium quantum device is mapped to an effective equilibrium system using Hershfield's statistics and then the desired nonequilibrium steady state of the device can be obtained by minimizing the effective energy of the mapped equilibrium, Ẽ [ ρ t , ρ n ], which is a functional of both the total electron density, ρ t , and the current-carrying electron density, ρ n . The effective energy is calculated by subtracting a bias-dependent term from the energy of the steady state, E SS [ ρ t , ρ n ], as shown in eqn (1) below. (1) Hereinafter the bias-dependent term in eqn (1) is referred to as nonequilibrium energy E n [ ρ n ] that measures how far the system is away from equilibrium. Note that E SS [ ρ t , ρ n ] is the same as the conventional DFT energy except for the two-density dependence (see the Methods section). The minus sign in eqn (1) is the reason why minimizing Ẽ drives the system out of equilibrium. It has been proven that as the bias voltage, V b , approaches zero, E SS [ ρ t , ρ n ] goes to the conventional DFT energy functional E DFT [ ρ t ], and SS-DFT reduces to DFT. 20 In the next section, we present our calculations from all these DFT and SS-DFT computational packages for the transport properties of silane junctions. We show that the competition between two energies, E SS and E n , yields a novel type of nonequilibrium effect in the thiol-terminated silanes that is beyond the framework of the standard DFT-based method, which results in the experimentally observed dramatic trend reversal of conductance. Results and discussions Herein, the transport properties of a series of methylamine- and methylthiol-terminated permethyloligosilanes (denoted Si n – NH", "role": "user" }, { "content": "NUS scientists have predicted a new type of nonequilibrium effects that could generally exist in nanoscale electronic devices, and successfully explained a recent puzzling experiment using the effects. Understanding bias-induced nonequilibrium effects on electron transport properties of nanoscale junctions is the central issue in computational nanoscience. The standard density functional theory (DFT)-based first-principles method that combines DFT and nonequilibrium Green's functions' techniques has been widely used in modeling nonequilibrium nanoscale devices. This provides qualitative understanding of experiments by relating the measured conductance to tunneling of electrons through \"molecular\" orbitals of the devices. A recent experiment, however, reported surprising transport phenomena through silane junctions that cannot be understood by the standard DFT method. The conductance for various silane molecules connected with two different linker groups (amine or thiol) to either gold (Au) or silver (Ag) metal electrodes were measured. It was found that, when using the amine linker, the Au electrode generates a much higher conductance when compared to an Ag electrode. With the thiol linker, this trend reverses and the Ag electrode is significantly more conducting than the Au electrode. In contrast, DFT-based calculations predict that the Au electrode is always more conducting than the Ag electrode regardless of the type of linkers. This contradiction between theoretical and experimental results presents the community of computational nanoscience with an exciting challenge. To address this challenge, the research group led by Prof Zhang Chun from the Department of Physics and the Department of Chemistry, National University of Singapore, studied the theoretical transport properties of silane junctions building on the steady-state DFT technique that was proposed by Prof Zhang himself back in 2015. The steady-state DFT considers nonequilibrium effects in full by employing nonequilibrium quantum statistics. They found that underlying the puzzling experimental observations is a novel type of nonequilibrium effects (named \"nonequilibrium pulling\" in their work) that exist in silane junctions having thiol linkers. Their theoretical calculations show that, when the junction is near equilibrium, the standard DFT method is an excellent approximation of steady state conditions. However, at low biases around the region of 0.2 volts, the \"nonequilibrium pulling\" effect drives the thiol-terminated silanes far away from equilibrium, thus resulting in the reversal of conductance values observed in experiments. Prof Zhang says that \"further analysis suggests that these nonequilibrium effects could generally exist in nanoscale devices in which there are conducting channels mainly residing at the source contact and located close to the bias window. These findings significantly broaden our fundamental understanding of electron transport at the nanoscale.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The standard density functional theory (DFT) based first-principles approach has been widely used for modeling nanoscale electronic devices. A recent experiment, however, reported surprising transport properties of thiol-terminated silane junctions that cannot be understood using the standard DFT approach, presenting a severe challenge for the current computational understanding of electron transport at the nanoscale. Using the recently proposed steady-state DFT (SS-DFT) for nonequilibrium quantum systems, we found that in silane junctions, underlying the puzzling experimental observations is a novel type of intriguing nonequilibrium effect that is beyond the framework of the standard DFT approach. Our calculations show that the standard DFT approach is a good approximation of SS-DFT when silane junctions are near equilibrium, but the aforementioned nonequilibrium effects could drive the thiol-terminated silanes far away from equilibrium even at low biases of around 0.2 V. Further analysis suggests that these nonequilibrium effects could generally exist in nanoscale devices in which there are conducting channels mainly residing at the source contact and close to the bias window. These findings significantly broaden our fundamental understanding of electron transport at the nanoscale. This article is part of the themed collection: Nanoscale Horizons 2022 Lunar New Year Collection New concepts Understanding bias-induced nonequilibrium effects on the transport properties of nanoscale electronic devices is one of the biggest challenges in computational nanoscience. In this work, with the recently proposed steady-state density functional theory (SS-DFT) for nonequilibrium quantum systems, we predict a novel type of nonequilibrium effect (named ‘nonequilibrium pulling’ in the paper) that could exist in nanoscale devices even at low biases well within the expected linear-response regime. The effects lead to surprising transport phenomena that are beyond the framework of conventional DFT-based methods, which result in the puzzling transport properties of silane junctions reported in a recent experiment. Further analysis points out that the ‘nonequilibrium pulling’ originates from the ‘two-dimensional’ nature of the theory: in SS-DFT, the transport state is a functional of two densities, the total electron density and the current-carrying electron density. When conducting channels exist near the bias window that mainly reside in the source contact, the dimension of the current-carrying electron density can be significant, causing ‘nonequilibrium pulling’ and the failure of the conventional ‘one-dimensional’ DFT method. Similar nonequilibrium effects could also exist in other bias-driven processes under scanning tunnelling microscopes and electrochemical systems. Introduction Nanoscale electronic devices that often contain a molecular scale center have become one of the most promising candidates for the next generation of electronic devices. In the past two decades, numerous nanoscale devices with various functions, such as transistors, 1,2 switches, 3–5 diodes, 6–8 spintronic devices, 9–11 and many others 12–14 have been proposed theoretically and/or experimentally. The density functional theory (DFT) based first-principles approach that combines the DFT and nonequilibrium Green's function (NEGF) techniques 15–17 has been widely used in qualitatively understanding experiments by linking the measured transport properties of a device to the tunnelling of electrons through orbitals of the molecular scale device center. A recent experiment, 18 however, reported surprising transport phenomena through silane junctions that cannot be understood using the standard DFT based method. Therein the low-bias conductance of various silane molecules with different linker groups (amine or thiol) bridging different metal electrodes (Au or Ag) were measured. It was found that with the amine linker, the Au electrode generates a much higher conductance than that of Ag, while with the thiol linker, the trend reverses and the Ag electrode is significantly more conducting than the Au electrode. In contrast, DFT-based transport calculations predict that Au electrodes are always more conducting than Ag regardless of linkers. 18 This contradiction between theory and experiment presents the community of computational nanoscience with a severe challenge. To address this challenge, we theoretically study the transport properties of silane junctions using both the standard DFT-based approach and the steady-state DFT (SS-DFT) we recently proposed. 19 Several widely used implementations of the DFT-based approach, i.e. , TranSIESTA, 16 SMEAGOL, 17 and ATK, 20 which only differ from each other in the detail of the numerical procedures, were used in this study. Unlike the DFT-based method, SS-DFT considers nonequilibrium effects in full by employing Hershfield's nonequilibrium quantum statistics. 21 In SS-DFT, the nonequilibrium quantum device is mapped to an effective equilibrium system using Hershfield's statistics and then the desired nonequilibrium steady state of the device can be obtained by minimizing the effective energy of the mapped equilibrium, Ẽ [ ρ t , ρ n ], which is a functional of both the total electron density, ρ t , and the current-carrying electron density, ρ n . The effective energy is calculated by subtracting a bias-dependent term from the energy of the steady state, E SS [ ρ t , ρ n ], as shown in eqn (1) below. (1) Hereinafter the bias-dependent term in eqn (1) is referred to as nonequilibrium energy E n [ ρ n ] that measures how far the system is away from equilibrium. Note that E SS [ ρ t , ρ n ] is the same as the conventional DFT energy except for the two-density dependence (see the Methods section). The minus sign in eqn (1) is the reason why minimizing Ẽ drives the system out of equilibrium. It has been proven that as the bias voltage, V b , approaches zero, E SS [ ρ t , ρ n ] goes to the conventional DFT energy functional E DFT [ ρ t ], and SS-DFT reduces to DFT. 20 In the next section, we present our calculations from all these DFT and SS-DFT computational packages for the transport properties of silane junctions. We show that the competition between two energies, E SS and E n , yields a novel type of nonequilibrium effect in the thiol-terminated silanes that is beyond the framework of the standard DFT-based method, which results in the experimentally observed dramatic trend reversal of conductance. Results and discussions Herein, the transport properties of a series of methylamine- and methylthiol-terminated permethyloligosilanes (denoted Si n – NH<|im_end|> <|im_start|>assistant NUS scientists have predicted a new type of nonequilibrium effects that could generally exist in nanoscale electronic devices, and successfully explained a recent puzzling experiment using the effects. Understanding bias-induced nonequilibrium effects on electron transport properties of nanoscale junctions is the central issue in computational nanoscience. The standard density functional theory (DFT)-based first-principles method that combines DFT and nonequilibrium Green's functions' techniques has been widely used in modeling nonequilibrium nanoscale devices. This provides qualitative understanding of experiments by relating the measured conductance to tunneling of electrons through "molecular" orbitals of the devices. A recent experiment, however, reported surprising transport phenomena through silane junctions that cannot be understood by the standard DFT method. The conductance for various silane molecules connected with two different linker groups (amine or thiol) to either gold (Au) or silver (Ag) metal electrodes were measured. It was found that, when using the amine linker, the Au electrode generates a much higher conductance when compared to an Ag electrode. With the thiol linker, this trend reverses and the Ag electrode is significantly more conducting than the Au electrode. In contrast, DFT-based calculations predict that the Au electrode is always more conducting than the Ag electrode regardless of the type of linkers. This contradiction between theoretical and experimental results presents the community of computational nanoscience with an exciting challenge. To address this challenge, the research group led by Prof Zhang Chun from the Department of Physics and the Department of Chemistry, National University of Singapore, studied the theoretical transport properties of silane junctions building on the steady-state DFT technique that was proposed by Prof Zhang himself back in 2015. The steady-state DFT considers nonequilibrium effects in full by employing nonequilibrium quantum statistics. They found that underlying the puzzling experimental observations is a novel type of nonequilibrium effects (named "nonequilibrium pulling" in their work) that exist in silane junctions having thiol linkers. Their theoretical calculations show that, when the junction is near equilibrium, the standard DFT method is an excellent approximation of steady state conditions. However, at low biases around the region of 0.2 volts, the "nonequilibrium pulling" effect drives the thiol-terminated silanes far away from equilibrium, thus resulting in the reversal of conductance values observed in experiments. Prof Zhang says that "further analysis suggests that these nonequilibrium effects could generally exist in nanoscale devices in which there are conducting channels mainly residing at the source contact and located close to the bias window. These findings significantly broaden our fundamental understanding of electron transport at the nanoscale." <|im_end|>

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1,972

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Restoration of channelized streams by returning coarse sediment from stream edges to the wetted channel has become a common practice in Sweden. Yet, restoration activities do not always result in the return of desired biota. This study evaluated a restoration project in the Vindel River in northern Sweden in which practitioners further increased channel complexity of previously restored stream reaches by placing very large boulders (>1 m), trees (>8 m), and salmonid spawning gravel from adjacent upland areas into the channels. One reach restored with basic methods and another with enhanced methods were selected in each of ten different tributaries to the main channel. Geomorphic and hydraulic complexity was enhanced but the chemical composition of riparian soils and the communities of riparian plants and fish did not exhibit any clear responses to the enhanced restoration measures during the first 5 years compared to reaches restored with basic restoration methods. The variation in the collected data was among streams instead of between types of restored reaches. We conclude that restoration is a disturbance in itself, that immigration potential varies across landscapes, and that biotic recovery processes in boreal river systems are slow. We suggest that enhanced restoration has to apply a catchment-scale approach accounting for connectivity and availability of source populations, and that low-intensity monitoring has to be performed over several decades to evaluate restoration outcomes. Working on a manuscript? Avoid the common mistakes Introduction Restoration of deteriorated streams and rivers aims to improve biodiversity, recreation, and mitigation of impacts from direct anthropogenic alterations and climate change. The development of restoration methods is currently getting a boost, as it is supported by national and international directives (Bullock and others 2011 ; Aronson and Alexander 2013 ; Pander and Geist 2013 ). Recent findings, that stream restoration is economically profitable (Acuna and others 2013 ), may further contribute to its development. The increase in different ways to restore streams and rivers is also clearly reflected in a steadily increasing number of scientific papers reporting on their results. For example, a recent (27 April 2016) search for ‘(stream* OR river*) AND restoration’ in the Core Collection of Web of Science generated 9134 hits and the number of papers quadrupled between years 2000 and 2014. Although most stream restoration projects are completed without or with very little evaluation of the outcome (Kondolf and Micheli 1995 ; Bernhardt and others 2005 ; Suding 2011 ), the growing body of literature and initiatives such as RiverWiki ( 2014 ) have expanded the knowledge about how restoration measures should be designed to be effective (for example, Alexander and Allan 2007 ; Kail and others 2007 ; Jähnig and others 2010 ; Palmer and others 2010 ; Fryirs and others 2013 ; Nilsson and others 2015 ; Wohl and others 2015 ). Streams can now be restored more effectively than just a few decades ago, but there is certainly room for further improvements. Hitherto, most restoration projects have been one-time-events, irrespective of the nature of results achieved in any follow-up studies. At best, new restoration projects have applied knowledge gained from previous studies and applied a modified design. For that to happen, however, close engagement with managers is required rather than publication of scientific papers (Bernhardt and others 2007 ; Wohl and others 2015 ). There are also examples of when restoration practices have been redesigned because of changing climatic conditions, that is, “adaptive restoration” in response to a moving target (Zedler 2010 ; Nungesser and others 2015 ). Another strategy would be “additional restoration,” which can mean: (1) increasing the area of restored habitat to improve the responses of the originally restored area (for example, Krause and Culmsee 2013 ; Conlisk and others 2014 ), (2) connecting the restored site to other restored sites (Aviron and others 2011 ; Crouzeilles and others 2014 ), or (3) returning to the restored site before it has fully recovered to make further adjustments based on new knowledge of the design and outcomes of monitoring (for example, Harms and Hiebert 2006 ; van Dijk and others 2007 ; Jiménez and others 2015 ). This paper will deal with the third of these strategies. Over more than a century, streams and rivers in many boreal regions have been successively straightened and simplified and even dammed to facilitate the floating of logs—a procedure summarized as channelization (Törnlund and Östlund 2002 ). In a stream restoration project that started in northern Sweden in 2002, practitioners restored streams that were previously channelized for timber-floating, while scientists described the previously used floatway structures and their geomorphic impacts, predicted environmental outcomes of restoration, and studied the biotic effects of this and even earlier restoration projects (Nilsson and others 2005a ). The return of coarse sediment formerly extracted from the channel, reopening of closed side channels and removal of splash dams made the restored reaches more complex with wider channels and increased floodplain connectivity (Polvi and others 2014 ). Follow-up studies of in-stream organisms 3–8 years after restoration, however, showed only very modest recovery of macroinvertebrates and fish (Lepori and others 2005 , 2006 ). Recent studies have shown that for riparian vegetation it can take at least 25 years until its status even resembles that of channelized reaches, where restoration is a disturbance that vegetation has to recover from (Hasselquist and others 2015 ), although there are local exceptions where riparian plants respond faster (Helfield and others 2007 ). The slow or absent biotic response to restoration measures fostered the idea that the physical modifications were not strong enough and that further addition of spawning gravel, big boulders, and large wood would improve the biotic recovery (Palm and others 2007 ; Rosenfeld and others 2011 ). This idea was based on the hypothesis that habitat heterogeneity favors biodiversity (Ward and Tockner 2001 ; Tews and others 2004 ; Elosegi and others 2010 ). A more recent stream restoration project in northern Sweden which began in 2010 ( ) gave practitioners an opportunity to apply such enhanced", "role": "user" }, { "content": "A common way to restore Swedish streams previously used for timber-floating has been to return rocks. A group of researchers at Umeå University has studied the effects of improved methods that also add large boulders and trees. Creating complex channels and watercourses is easy, but reintroducing plants and aquatic animals is a challenge, according to Umeå researchers. The results have been published in Ecosystems. \"Restoration is in itself a disturbance that watercourses need to recover from. We've seen that the ability for various species to re-enter varies depending on landscape and happens at a much slower pace in northern streams,\" says Christer Nilsson, professor in landscape ecology at Umeå University. Over more than a century beginning in the 19th century, human kind cleared, straightened, channelized and dammed Swedish watercourses to simplify for timber-floating. When timber-floating was discontinued in the 1970s, the work of restoring watercourses was introduced. So far most restoration projects have been single activities without further evaluation. Conservationists have only in a few cases been able to improve their own methods based on learnings from former studies. The novel method in this project, named Vindel River LIFE and funded by the EU Life Foundation, was to collect very large boulders and trees from the adjacent upland areas to place in the water as well as adding gravel to spawning beds in reaches of tributaries that have previously been restored using more basic methods. In that way, the restored reaches became more complex, which ought to improve biodiversity. Researchers later compared the more restored river reaches with reaches where only basic restoration had been made. \"It was obvious that the shape of the reach and its hydraulics showed an increased variation. Riparian soil chemistry, riparian vegetation and fish fauna, however, showed no evident reaction to the restoration in the first five years when the two types of river reaches were compared. The variation was greater between the various tributaries than between the different types of restoration,\" says Christer Nilsson. However, vegetation along river reaches where only basic restoration had been done showed improvements in comparison to river reaches that had never been restored. The expectation was therefore for the new restoration to yield an even better result. \"The fact that it takes a long time for plants to establish can depend on the lack of seeds in the vicinity,\" says Christer Nilsson. When it comes to fish, it is possible that part restorations of reaches are not sufficient in order to gain clear results. As we know, many fish move across large areas. It can also be due to prey not having recovered or on anchor ice, i.e. ice anchored to the bottom, killing spawn and small fish. \"To increase the chances of successful restorations, we recommend restoring entire river basins. Furthermore, follow-up studies are required for decades to be able to follow the result. The slow recovery of ecosystems after restorations in northern streams is also an important reason to protect them from future harm,\" concludes Christer Nilsson. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Restoration of channelized streams by returning coarse sediment from stream edges to the wetted channel has become a common practice in Sweden. Yet, restoration activities do not always result in the return of desired biota. This study evaluated a restoration project in the Vindel River in northern Sweden in which practitioners further increased channel complexity of previously restored stream reaches by placing very large boulders (>1 m), trees (>8 m), and salmonid spawning gravel from adjacent upland areas into the channels. One reach restored with basic methods and another with enhanced methods were selected in each of ten different tributaries to the main channel. Geomorphic and hydraulic complexity was enhanced but the chemical composition of riparian soils and the communities of riparian plants and fish did not exhibit any clear responses to the enhanced restoration measures during the first 5 years compared to reaches restored with basic restoration methods. The variation in the collected data was among streams instead of between types of restored reaches. We conclude that restoration is a disturbance in itself, that immigration potential varies across landscapes, and that biotic recovery processes in boreal river systems are slow. We suggest that enhanced restoration has to apply a catchment-scale approach accounting for connectivity and availability of source populations, and that low-intensity monitoring has to be performed over several decades to evaluate restoration outcomes. Working on a manuscript? Avoid the common mistakes Introduction Restoration of deteriorated streams and rivers aims to improve biodiversity, recreation, and mitigation of impacts from direct anthropogenic alterations and climate change. The development of restoration methods is currently getting a boost, as it is supported by national and international directives (Bullock and others 2011 ; Aronson and Alexander 2013 ; Pander and Geist 2013 ). Recent findings, that stream restoration is economically profitable (Acuna and others 2013 ), may further contribute to its development. The increase in different ways to restore streams and rivers is also clearly reflected in a steadily increasing number of scientific papers reporting on their results. For example, a recent (27 April 2016) search for ‘(stream* OR river*) AND restoration’ in the Core Collection of Web of Science generated 9134 hits and the number of papers quadrupled between years 2000 and 2014. Although most stream restoration projects are completed without or with very little evaluation of the outcome (Kondolf and Micheli 1995 ; Bernhardt and others 2005 ; Suding 2011 ), the growing body of literature and initiatives such as RiverWiki ( 2014 ) have expanded the knowledge about how restoration measures should be designed to be effective (for example, Alexander and Allan 2007 ; Kail and others 2007 ; Jähnig and others 2010 ; Palmer and others 2010 ; Fryirs and others 2013 ; Nilsson and others 2015 ; Wohl and others 2015 ). Streams can now be restored more effectively than just a few decades ago, but there is certainly room for further improvements. Hitherto, most restoration projects have been one-time-events, irrespective of the nature of results achieved in any follow-up studies. At best, new restoration projects have applied knowledge gained from previous studies and applied a modified design. For that to happen, however, close engagement with managers is required rather than publication of scientific papers (Bernhardt and others 2007 ; Wohl and others 2015 ). There are also examples of when restoration practices have been redesigned because of changing climatic conditions, that is, “adaptive restoration” in response to a moving target (Zedler 2010 ; Nungesser and others 2015 ). Another strategy would be “additional restoration,” which can mean: (1) increasing the area of restored habitat to improve the responses of the originally restored area (for example, Krause and Culmsee 2013 ; Conlisk and others 2014 ), (2) connecting the restored site to other restored sites (Aviron and others 2011 ; Crouzeilles and others 2014 ), or (3) returning to the restored site before it has fully recovered to make further adjustments based on new knowledge of the design and outcomes of monitoring (for example, Harms and Hiebert 2006 ; van Dijk and others 2007 ; Jiménez and others 2015 ). This paper will deal with the third of these strategies. Over more than a century, streams and rivers in many boreal regions have been successively straightened and simplified and even dammed to facilitate the floating of logs—a procedure summarized as channelization (Törnlund and Östlund 2002 ). In a stream restoration project that started in northern Sweden in 2002, practitioners restored streams that were previously channelized for timber-floating, while scientists described the previously used floatway structures and their geomorphic impacts, predicted environmental outcomes of restoration, and studied the biotic effects of this and even earlier restoration projects (Nilsson and others 2005a ). The return of coarse sediment formerly extracted from the channel, reopening of closed side channels and removal of splash dams made the restored reaches more complex with wider channels and increased floodplain connectivity (Polvi and others 2014 ). Follow-up studies of in-stream organisms 3–8 years after restoration, however, showed only very modest recovery of macroinvertebrates and fish (Lepori and others 2005 , 2006 ). Recent studies have shown that for riparian vegetation it can take at least 25 years until its status even resembles that of channelized reaches, where restoration is a disturbance that vegetation has to recover from (Hasselquist and others 2015 ), although there are local exceptions where riparian plants respond faster (Helfield and others 2007 ). The slow or absent biotic response to restoration measures fostered the idea that the physical modifications were not strong enough and that further addition of spawning gravel, big boulders, and large wood would improve the biotic recovery (Palm and others 2007 ; Rosenfeld and others 2011 ). This idea was based on the hypothesis that habitat heterogeneity favors biodiversity (Ward and Tockner 2001 ; Tews and others 2004 ; Elosegi and others 2010 ). A more recent stream restoration project in northern Sweden which began in 2010 ( ) gave practitioners an opportunity to apply such enhanced<|im_end|> <|im_start|>assistant A common way to restore Swedish streams previously used for timber-floating has been to return rocks. A group of researchers at Umeå University has studied the effects of improved methods that also add large boulders and trees. Creating complex channels and watercourses is easy, but reintroducing plants and aquatic animals is a challenge, according to Umeå researchers. The results have been published in Ecosystems. "Restoration is in itself a disturbance that watercourses need to recover from. We've seen that the ability for various species to re-enter varies depending on landscape and happens at a much slower pace in northern streams," says Christer Nilsson, professor in landscape ecology at Umeå University. Over more than a century beginning in the 19th century, human kind cleared, straightened, channelized and dammed Swedish watercourses to simplify for timber-floating. When timber-floating was discontinued in the 1970s, the work of restoring watercourses was introduced. So far most restoration projects have been single activities without further evaluation. Conservationists have only in a few cases been able to improve their own methods based on learnings from former studies. The novel method in this project, named Vindel River LIFE and funded by the EU Life Foundation, was to collect very large boulders and trees from the adjacent upland areas to place in the water as well as adding gravel to spawning beds in reaches of tributaries that have previously been restored using more basic methods. In that way, the restored reaches became more complex, which ought to improve biodiversity. Researchers later compared the more restored river reaches with reaches where only basic restoration had been made. "It was obvious that the shape of the reach and its hydraulics showed an increased variation. Riparian soil chemistry, riparian vegetation and fish fauna, however, showed no evident reaction to the restoration in the first five years when the two types of river reaches were compared. The variation was greater between the various tributaries than between the different types of restoration," says Christer Nilsson. However, vegetation along river reaches where only basic restoration had been done showed improvements in comparison to river reaches that had never been restored. The expectation was therefore for the new restoration to yield an even better result. "The fact that it takes a long time for plants to establish can depend on the lack of seeds in the vicinity," says Christer Nilsson. When it comes to fish, it is possible that part restorations of reaches are not sufficient in order to gain clear results. As we know, many fish move across large areas. It can also be due to prey not having recovered or on anchor ice, i.e. ice anchored to the bottom, killing spawn and small fish. "To increase the chances of successful restorations, we recommend restoring entire river basins. Furthermore, follow-up studies are required for decades to be able to follow the result. The slow recovery of ecosystems after restorations in northern streams is also an important reason to protect them from future harm," concludes Christer Nilsson. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Shape-morphing structures are at the core of future applications in aeronautics 1 , minimally invasive surgery 2 , tissue engineering 3 and smart materials 4 . However, current engineering technologies, based on inhomogeneous actuation across the thickness of slender structures, are intrinsically limited to one-directional bending 5 . Here, we describe a strategy where mesostructured elastomer plates undergo fast, controllable and complex shape transformations under applied pressure. Similar to pioneering techniques based on soft hydrogel swelling 6 , 7 , 8 , 9 , 10 , these pneumatic shape-morphing elastomers, termed here as ‘baromorphs’, are inspired by the morphogenesis of biological structures 11 , 12 , 13 , 14 , 15 . Geometric restrictions are overcome by controlling precisely the local growth rate and direction through a specific network of airways embedded inside the rubber plate. We show how arbitrary three-dimensional shapes can be programmed using an analytic theoretical model, propose a direct geometric solution to the inverse problem, and illustrate the versatility of the technique with a collection of configurations. Main Morphing a thin plate into a programmed shape is a challenging problem, as highlighted by Gauss: if the distances along the surface are not modified, the Gaussian curvature cannot be changed, and only a limited family of three-dimensional (3D) surfaces is achievable, as commonly observed with bilayer sheets 16 , 17 . However, nature overflows with examples of geometrically complex thin objects, such as leaves or organ epithelia 11 . For instance, differential growth induces the elegant shape of flower petals 12 , or may crinkle an initially flat leave when the growth rate is deregulated 13 . While the growth process may be spatially homogeneous, the orientations of cellulose fibres may also induce anisotropic growth, which leads to the hygroscopic actuation of wheat awns 14 or to the chiral shape of some seed pods 15 . Inspired by biological morphogenesis, pioneering experiments have been carried out with hydrogel plates where inhomogeneous isotropic 6 , 7 , 18 or anisotropic 9 , 10 swelling properties are spatially distributed to obtain various 3D shapes after being immersed in a bath of hot water. Nevertheless, the experimental realizations developed so far involve slow diffusive swelling processes and very soft objects that generally cannot sustain their own weight. In contrast, pneumatic actuation presents strong advantages, such as large work load, reversibility, controllability and fast actuation, which have led to the recent development of multiple soft robotics actuators for twisting, contracting, expanding or bending motions 19 . However, such actuators generally rely on bilayers 5 or are limited to surface texturing effects 20 ; this imposes strong constraints on the achievable states. Our approach bridges these two emerging fields—bio-inspired shape-morphing and pneumatic soft robotics—with a new easy-to-build, easy-to-control object, referred to as a baromorph. Baromorphs consist of elastomer plates embedding a network of airways (see Methods for fabrication details), which give rise to a programmed family of shapes under air inflation or suction. Such structures can be viewed as pneumatic metamaterials 21 . When the inner pressure is increased (or decreased), the elongated channels tend to inflate (or deflate) anisotropically 22 . The length of an inflated channel remains almost unchanged, while its width increases (Fig. 1a ). This anisotropy results in a controllable modification of the effective rest lengths of the baromorph, mimicking the anisotropic growth of a biological tissue, with a magnitude that depends on the geometry of the inner channels and on the applied pressure. The plate deforms according to the new target metric imposed by the network of airways, and may buckle out of plane to reach an equilibrium 3D shape that minimizes the total elastic energy (the sum of stretching and bending energies). Fig. 1: Principle of pressure-actuated baromorph plate. a , Schematic of actuation: the pressure inside the airways induces anisotropic inflation of the plate (higher strain normal to the airways than along the channels). b , 3D printed mould used to cast the baromorph illustrated in c . c , Actuation of the plate: suction (left) tends to contract the plate in the azimuthal direction, leading to a bowl (positive Gaussian curvature), while inflation (right) leads to an excess angle and a transformation into a saddle shape (negative Gaussian curvature). Scale bars, 1 cm. d , Evolution of the cap of an Acetabularia alga from a bowl to a saddle shape due to preferential growth in the azimuthal direction. Adapted from ref. 23 ,Springer ( d ). Full size image Figure 1c presents the deformation of a baromorph plate with radial channels obtained by casting the 3D printed template shown in Fig. 1b : the target expansion is mainly circumferential. Following suction and consequent azimuthal contraction, the plate adopts a bowl shape (with positive Gaussian curvature). Conversely, inflation induces an azimuthal expansion and leads to an excess angle in the plate, which destabilizes into a surface of negative Gaussian curvature. These transformations are reminiscent of the morphing evolution of Acetabularia (Fig. 1d ) 11 , 23 . After initiation, the cap of this unicellular alga evolves from a bowl to a flat configuration, and eventually to a saddle shape, essentially for the same reason as our baromorph: biological growth in the cap is stronger in the circumferential direction than along the radius. A first step in understanding and programming a baromorph is to predict the local deformation of airways in the absence of external geometrical constraints, that is, the target in-plane strains orthogonal ε t ⊥ and parallel ε t ∥ to the airway direction. The channel geometry (Fig. 2a ) can be reduced to two relevant parameters in our minimal model: the relative channel height with respect to the total thickness of the sheet Ψ = h /( h + 2 e ) and the in-plane channel density Φ = d /( d + d w ), where h , e , d and d w are geometrical parameters of the structure (Fig. 2b ). Balancing stresses and making simplifying assumptions (for details", "role": "user" }, { "content": "A small team of researchers at ESPCI Paris has come up with a way to combine pneumatics with a hydrogel to create a baromorph for soft robotics applications—a baromorph is a soft material that self-configures when inflated. In their paper published in the journal Nature Materials, the group describes their research and their geometric creations. Efi Efrati with the Weizmann Institute of Science has written a News and Views piece on the work done by the team in the same journal issue. In the never-ending quest to create robots that are ever more capable, roboticists have often been inspired by creatures that nature has designed. Attempting to mimic humans is a popular research area, as is copying four-legged creatures. Efrati notes that most such animals have one thing in common—stiff parts of their anatomy working against other stiff parts produce motion—bones in joints, for example. But as Efrati also notes, there is another area of research focused on the development of softer components that are manipulated without stiffer components—like jellyfish, for example, or flowers. Unfortunately, progress in this area has been rather slow—soft machines tend to respond slowly due to actuation issues. And they also tend to have limited degrees of motion and wear out quickly. In this new effort, the researchers have come up with a novel approach to creating soft machines—combining the bendability of hydrogels with the power of air pressure. They call their creations baromorphs, and they have demonstrated that they can be used to create soft-machines in wide variety of shapes. Each baromorph is essentially a sheet of hydrogel with channels inside of it. In its initial relaxed state, it is typically flat. When air is pumped in, it is routed through the channels in such a way as to inflate the baromoph into a desired shape. The channels are designed using a computer program, which also handles the formation of the resultant product. To prove the viability of their method, the researchers created baromorphs that were shaped like bowls, a saddle and even a human face. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Shape-morphing structures are at the core of future applications in aeronautics 1 , minimally invasive surgery 2 , tissue engineering 3 and smart materials 4 . However, current engineering technologies, based on inhomogeneous actuation across the thickness of slender structures, are intrinsically limited to one-directional bending 5 . Here, we describe a strategy where mesostructured elastomer plates undergo fast, controllable and complex shape transformations under applied pressure. Similar to pioneering techniques based on soft hydrogel swelling 6 , 7 , 8 , 9 , 10 , these pneumatic shape-morphing elastomers, termed here as ‘baromorphs’, are inspired by the morphogenesis of biological structures 11 , 12 , 13 , 14 , 15 . Geometric restrictions are overcome by controlling precisely the local growth rate and direction through a specific network of airways embedded inside the rubber plate. We show how arbitrary three-dimensional shapes can be programmed using an analytic theoretical model, propose a direct geometric solution to the inverse problem, and illustrate the versatility of the technique with a collection of configurations. Main Morphing a thin plate into a programmed shape is a challenging problem, as highlighted by Gauss: if the distances along the surface are not modified, the Gaussian curvature cannot be changed, and only a limited family of three-dimensional (3D) surfaces is achievable, as commonly observed with bilayer sheets 16 , 17 . However, nature overflows with examples of geometrically complex thin objects, such as leaves or organ epithelia 11 . For instance, differential growth induces the elegant shape of flower petals 12 , or may crinkle an initially flat leave when the growth rate is deregulated 13 . While the growth process may be spatially homogeneous, the orientations of cellulose fibres may also induce anisotropic growth, which leads to the hygroscopic actuation of wheat awns 14 or to the chiral shape of some seed pods 15 . Inspired by biological morphogenesis, pioneering experiments have been carried out with hydrogel plates where inhomogeneous isotropic 6 , 7 , 18 or anisotropic 9 , 10 swelling properties are spatially distributed to obtain various 3D shapes after being immersed in a bath of hot water. Nevertheless, the experimental realizations developed so far involve slow diffusive swelling processes and very soft objects that generally cannot sustain their own weight. In contrast, pneumatic actuation presents strong advantages, such as large work load, reversibility, controllability and fast actuation, which have led to the recent development of multiple soft robotics actuators for twisting, contracting, expanding or bending motions 19 . However, such actuators generally rely on bilayers 5 or are limited to surface texturing effects 20 ; this imposes strong constraints on the achievable states. Our approach bridges these two emerging fields—bio-inspired shape-morphing and pneumatic soft robotics—with a new easy-to-build, easy-to-control object, referred to as a baromorph. Baromorphs consist of elastomer plates embedding a network of airways (see Methods for fabrication details), which give rise to a programmed family of shapes under air inflation or suction. Such structures can be viewed as pneumatic metamaterials 21 . When the inner pressure is increased (or decreased), the elongated channels tend to inflate (or deflate) anisotropically 22 . The length of an inflated channel remains almost unchanged, while its width increases (Fig. 1a ). This anisotropy results in a controllable modification of the effective rest lengths of the baromorph, mimicking the anisotropic growth of a biological tissue, with a magnitude that depends on the geometry of the inner channels and on the applied pressure. The plate deforms according to the new target metric imposed by the network of airways, and may buckle out of plane to reach an equilibrium 3D shape that minimizes the total elastic energy (the sum of stretching and bending energies). Fig. 1: Principle of pressure-actuated baromorph plate. a , Schematic of actuation: the pressure inside the airways induces anisotropic inflation of the plate (higher strain normal to the airways than along the channels). b , 3D printed mould used to cast the baromorph illustrated in c . c , Actuation of the plate: suction (left) tends to contract the plate in the azimuthal direction, leading to a bowl (positive Gaussian curvature), while inflation (right) leads to an excess angle and a transformation into a saddle shape (negative Gaussian curvature). Scale bars, 1 cm. d , Evolution of the cap of an Acetabularia alga from a bowl to a saddle shape due to preferential growth in the azimuthal direction. Adapted from ref. 23 ,Springer ( d ). Full size image Figure 1c presents the deformation of a baromorph plate with radial channels obtained by casting the 3D printed template shown in Fig. 1b : the target expansion is mainly circumferential. Following suction and consequent azimuthal contraction, the plate adopts a bowl shape (with positive Gaussian curvature). Conversely, inflation induces an azimuthal expansion and leads to an excess angle in the plate, which destabilizes into a surface of negative Gaussian curvature. These transformations are reminiscent of the morphing evolution of Acetabularia (Fig. 1d ) 11 , 23 . After initiation, the cap of this unicellular alga evolves from a bowl to a flat configuration, and eventually to a saddle shape, essentially for the same reason as our baromorph: biological growth in the cap is stronger in the circumferential direction than along the radius. A first step in understanding and programming a baromorph is to predict the local deformation of airways in the absence of external geometrical constraints, that is, the target in-plane strains orthogonal ε t ⊥ and parallel ε t ∥ to the airway direction. The channel geometry (Fig. 2a ) can be reduced to two relevant parameters in our minimal model: the relative channel height with respect to the total thickness of the sheet Ψ = h /( h + 2 e ) and the in-plane channel density Φ = d /( d + d w ), where h , e , d and d w are geometrical parameters of the structure (Fig. 2b ). Balancing stresses and making simplifying assumptions (for details<|im_end|> <|im_start|>assistant A small team of researchers at ESPCI Paris has come up with a way to combine pneumatics with a hydrogel to create a baromorph for soft robotics applications—a baromorph is a soft material that self-configures when inflated. In their paper published in the journal Nature Materials, the group describes their research and their geometric creations. Efi Efrati with the Weizmann Institute of Science has written a News and Views piece on the work done by the team in the same journal issue. In the never-ending quest to create robots that are ever more capable, roboticists have often been inspired by creatures that nature has designed. Attempting to mimic humans is a popular research area, as is copying four-legged creatures. Efrati notes that most such animals have one thing in common—stiff parts of their anatomy working against other stiff parts produce motion—bones in joints, for example. But as Efrati also notes, there is another area of research focused on the development of softer components that are manipulated without stiffer components—like jellyfish, for example, or flowers. Unfortunately, progress in this area has been rather slow—soft machines tend to respond slowly due to actuation issues. And they also tend to have limited degrees of motion and wear out quickly. In this new effort, the researchers have come up with a novel approach to creating soft machines—combining the bendability of hydrogels with the power of air pressure. They call their creations baromorphs, and they have demonstrated that they can be used to create soft-machines in wide variety of shapes. Each baromorph is essentially a sheet of hydrogel with channels inside of it. In its initial relaxed state, it is typically flat. When air is pumped in, it is routed through the channels in such a way as to inflate the baromoph into a desired shape. The channels are designed using a computer program, which also handles the formation of the resultant product. To prove the viability of their method, the researchers created baromorphs that were shaped like bowls, a saddle and even a human face. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Crystallization is a fundamental and ubiquitous process much studied over the centuries. But although the crystallization of atoms is fairly well understood 1 , 2 , it remains challenging to predict reliably the outcome of molecular crystallization processes that are complicated by various molecular interactions and solvent involvement. This difficulty also applies to nanoparticles: high-quality three-dimensional crystals 3 , 4 , 5 , 6 are mostly produced using drying and sedimentation techniques that are often impossible to rationalize and control to give a desired crystal symmetry, lattice spacing and habit (crystal shape). In principle, DNA-mediated assembly of nanoparticles offers an ideal opportunity for studying nanoparticle crystallization 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 : a well-defined set of rules have been developed to target desired lattice symmetries and lattice constants 8 , 9 , 18 , and the occurrence of features such as grain boundaries and twinning in DNA superlattices and traditional crystals comprised of molecular or atomic building blocks suggests that similar principles govern their crystallization. But the presence of charged biomolecules, interparticle spacings of tens of nanometres, and the realization so far of only polycrystalline DNA-interconnected nanoparticle superlattices, all suggest that DNA-guided crystallization may differ from traditional crystal growth. Here we show that very slow cooling, over several days, of solutions of complementary-DNA-modified nanoparticles through the melting temperature of the system gives the thermodynamic product with a specific and uniform crystal habit. We find that our nanoparticle assemblies have the Wulff equilibrium crystal structure that is predicted from theoretical considerations and molecular dynamics simulations, thus establishing that DNA hybridization can direct nanoparticle assembly along a pathway that mimics atomic crystallization. Main The crystallization of nanoparticles mediated by DNA typically involves initial assembly of a disordered aggregate, which upon thermal annealing slightly below its melting temperature transforms into an ordered superlattice ( Fig. 1a , blue arrows) 12 . Transmission electron microscopy (TEM) images and the presence of rings in the small-angle X-ray scattering (SAXS) data show that all superlattices formed using this approach thus far are polycrystalline, with ordered micrometre-sized domains randomly oriented with respect to one another 9 , 19 . Considering that traditional crystallization techniques for atoms and molecules typically rely on slow cooling through the melting temperature 20 , we hypothesized that such a slow cooling approach applied to DNA-based assembly strategies might yield faceted crystals. DNA-functionalized nanoparticle solutions were therefore heated to above the melting temperature of the DNA links designed to connect particles and then slowly cooled to room temperature ( Fig. 1a , red arrows), in a process which typically took two to three days to complete. A key parameter known to the researcher before doing the experiments is the aggregate melting temperature, which is well defined and directly correlated with the nucleic acid sequences used for assembly 12 . Figure 1: Superlattices formed by the slow-cooling method. a , Two approaches for DNA-mediated nanoparticle crystallization are designated by arrows on a thermal melting curve of a DNA-linked gold nanoparticle aggregate. The traditional method (blue arrow), in which the aggregate is annealed a few degrees below the melting temperature, produces polycrystalline superlattices with no defined shape. The slow-cooling method (red arrow), in which the aggregate is heated above its melting temperature and cooled at a rate of 0.01 °C min −1 , produced well-defined, faceted microcrystals in each of the dozens of experiments conducted using these conditions. Extinction wavelength measured from the ultraviolet–visible spectrum, 520 nm (a.u.). b , Representative one-dimensional (top) and two-dimensional (bottom) SAXS data for b.c.c. (i) and CsCl (ii) superlattices synthesized from the slow-cooling technique. In the one-dimensional data, the red trace is the experimentally obtained scattering pattern and the black trace is the predicted scattering pattern for a perfect lattice. SAXS data are shown as plots of superlattice structure factor ( S ( q ), in arbitrary units) versus scattering vector ( q , in units of Å −1 ). c , TEM images of shape-controlled b.c.c. (i)–(ii) and CsCl (iii)–(iv) microcrystals. Scale bars are 1.5 µm for (i), 1.0 µm for (ii), 0.5 µm for (iii) and 0.5 µm for (iv). d , SEM image of a representative b.c.c. microcrystal with visible faceting where constituent nanoparticles can readily be seen (20-nm gold nanoparticles shown; scale bar is 1 µm). The inset shows a high-magnification (×52,500) view of the crystal facet with labelled surface defects. PowerPoint slide Full size image The slow cooling of the combination of two sets of gold nanoparticles functionalized with complementary DNA linker strands 9 produces superlattices with the expected body-centred cubic (b.c.c.) packing when using 20-nm gold nanoparticles and CsCl packing when using 20-nm and 15-nm gold nanoparticles, as confirmed by the radially averaged one-dimensional SAXS data ( Fig. 1b , (i) and (ii)). To enable direct visualization, the superlattices were also stabilized by embedding in silica 19 . TEM images of these structures reveal uniform crystals with square- and hexagonal-shaped domains for both the b.c.c. ( Fig. 1c , (i) and (ii)) and the CsCl ( Fig. 1c , (iii) and (iv)) particle packing symmetries, whereas scanning electron microscopy (SEM) allows us to observe surface features and the overall crystal habit ( Fig. 1d ). Evidently, the slow-cooling process enables DNA-driven assembly and crystallization that favours faceted rhombic dodecahedron microcrystals over the polycrystalline assemblies obtained by annealing below the melting temperature. Although single-crystal formation by annealing below the melting temperature may in principle be possible, the kinetics of reorganization from an irregularly shaped crystal into a well-defined microcrystal are likely to be too slow to be observed experimentally. SEM images of the microcrystals in different orientations on the substrate are all consistent with rhombic dodecahedron formation ( Fig. 2a ). Closer inspection of one of the crystals ( Fig. 2a , bottom) reveals extraordinarily well ordered nanoparticles at the surface, as well as the presence of common surface defects including ‘particle adatoms’ (a surface defect in", "role": "user" }, { "content": "Nature builds flawless diamonds, sapphires and other gems. Now a Northwestern University research team is the first to build near-perfect single crystals out of nanoparticles and DNA, using the same structure favored by nature. \"Single crystals are the backbone of many things we rely on—diamonds for beauty as well as industrial applications, sapphires for lasers and silicon for electronics,\" said nanoscientist Chad A. Mirkin. \"The precise placement of atoms within a well-defined lattice defines these high-quality crystals. \"Now we can do the same with nanomaterials and DNA, the blueprint of life,\" Mirkin said. \"Our method could lead to novel technologies and even enable new industries, much as the ability to grow silicon in perfect crystalline arrangements made possible the multibillion-dollar semiconductor industry.\" His research group developed the \"recipe\" for using nanomaterials as atoms, DNA as bonds and a little heat to form tiny crystals. This single-crystal recipe builds on superlattice techniques Mirkin's lab has been developing for nearly two decades. In this recent work, Mirkin, an experimentalist, teamed up with Monica Olvera de la Cruz, a theoretician, to evaluate the new technique and develop an understanding of it. Given a set of nanoparticles and a specific type of DNA, Olvera de la Cruz showed they can accurately predict the 3-D structure, or crystal shape, into which the disordered components will self-assemble. Mirkin is the George B. Rathmann Professor of Chemistry in the Weinberg College of Arts and Sciences. Olvera de la Cruz is a Lawyer Taylor Professor and professor of materials science and engineering in the McCormick School of Engineering and Applied Science. The two are senior co-authors of the study. The results will be published Nov. 27 in the journal Nature. The general set of instructions gives researchers unprecedented control over the type and shape of crystals they can build. The Northwestern team worked with gold nanoparticles, but the recipe can be applied to a variety of materials, with potential applications in the fields of materials science, photonics, electronics and catalysis. DNA is used as both the blueprint and the basic building block for the construction of well-defined crystals. Through the use of programmed DNA interactions, nanoparticles are assembled into ordered lattices which form the structural components that make up three-dimensional crystals with a well-defined shape. Credit: Evelyn Auyeung/Ting Li/Chad A. Mirkin/Monica Olvera de la Cruz A single crystal has order: its crystal lattice is continuous and unbroken throughout. The absence of defects in the material can give these crystals unique mechanical, optical and electrical properties, making them very desirable. In the Northwestern study, strands of complementary DNA act as bonds between disordered gold nanoparticles, transforming them into an orderly crystal. The researchers determined that the ratio of the DNA linker's length to the size of the nanoparticle is critical. \"If you get the right ratio it makes a perfect crystal—isn't that fun?\" said Olvera de la Cruz, who also is a professor of chemistry in the Weinberg College of Arts and Sciences. \"That's the fascinating thing, that you have to have the right ratio. We are learning so many rules for calculating things that other people cannot compute in atoms, in atomic crystals.\" The ratio affects the energy of the faces of the crystals, which determines the final crystal shape. Ratios that don't follow the recipe lead to large fluctuations in energy and result in a sphere, not a faceted crystal, she explained. With the correct ratio, the energies fluctuate less and result in a crystal every time. \"Imagine having a million balls of two colors, some red, some blue, in a container, and you try shaking them until you get alternating red and blue balls,\" Mirkin explained. \"It will never happen. \"But if you attach DNA that is complementary to nanoparticles—the red has one kind of DNA, say, the blue its complement—and now you shake, or in our case, just stir in water, all the particles will find one another and link together,\" he said. \"They beautifully assemble into a three-dimensional crystal that we predicted computationally and realized experimentally.\" To achieve a self-assembling single crystal in the lab, the research team reports taking two sets of gold nanoparticles outfitted with complementary DNA linker strands. Working with approximately 1 million nanoparticles in water, they heated the solution to a temperature just above the DNA linkers' melting point and then slowly cooled the solution to room temperature, which took two or three days. The very slow cooling process encouraged the single-stranded DNA to find its complement, resulting in a high-quality single crystal approximately three microns wide. \"The process gives the system enough time and energy for all the particles to arrange themselves and find the spots they should be in,\" Mirkin said. The researchers determined that the length of DNA connected to each gold nanoparticle can't be much longer than the size of the nanoparticle. In the study, the gold nanoparticles varied from five to 20 nanometers in diameter; for each, the DNA length that led to crystal formation was about 18 base pairs and six single-base \"sticky ends.\" \"There's no reason we can't grow extraordinarily large single crystals in the future using modifications of our technique,\" said Mirkin, who also is a professor of medicine, chemical and biological engineering, biomedical engineering and materials science and engineering and director of Northwestern's International Institute for Nanotechnology. The title of the paper is \"DNA-mediated nanoparticle crystallization into Wulff polyhedra.\" In addition to Mirkin and Olvera de la Cruz, authors of the paper are Evelyn Auyeung (first author), Ting I. N. G. Li, Andrew J. Senesi, Abrin L. Schmucker and Bridget C. Pals, all from Northwestern. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Crystallization is a fundamental and ubiquitous process much studied over the centuries. But although the crystallization of atoms is fairly well understood 1 , 2 , it remains challenging to predict reliably the outcome of molecular crystallization processes that are complicated by various molecular interactions and solvent involvement. This difficulty also applies to nanoparticles: high-quality three-dimensional crystals 3 , 4 , 5 , 6 are mostly produced using drying and sedimentation techniques that are often impossible to rationalize and control to give a desired crystal symmetry, lattice spacing and habit (crystal shape). In principle, DNA-mediated assembly of nanoparticles offers an ideal opportunity for studying nanoparticle crystallization 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 : a well-defined set of rules have been developed to target desired lattice symmetries and lattice constants 8 , 9 , 18 , and the occurrence of features such as grain boundaries and twinning in DNA superlattices and traditional crystals comprised of molecular or atomic building blocks suggests that similar principles govern their crystallization. But the presence of charged biomolecules, interparticle spacings of tens of nanometres, and the realization so far of only polycrystalline DNA-interconnected nanoparticle superlattices, all suggest that DNA-guided crystallization may differ from traditional crystal growth. Here we show that very slow cooling, over several days, of solutions of complementary-DNA-modified nanoparticles through the melting temperature of the system gives the thermodynamic product with a specific and uniform crystal habit. We find that our nanoparticle assemblies have the Wulff equilibrium crystal structure that is predicted from theoretical considerations and molecular dynamics simulations, thus establishing that DNA hybridization can direct nanoparticle assembly along a pathway that mimics atomic crystallization. Main The crystallization of nanoparticles mediated by DNA typically involves initial assembly of a disordered aggregate, which upon thermal annealing slightly below its melting temperature transforms into an ordered superlattice ( Fig. 1a , blue arrows) 12 . Transmission electron microscopy (TEM) images and the presence of rings in the small-angle X-ray scattering (SAXS) data show that all superlattices formed using this approach thus far are polycrystalline, with ordered micrometre-sized domains randomly oriented with respect to one another 9 , 19 . Considering that traditional crystallization techniques for atoms and molecules typically rely on slow cooling through the melting temperature 20 , we hypothesized that such a slow cooling approach applied to DNA-based assembly strategies might yield faceted crystals. DNA-functionalized nanoparticle solutions were therefore heated to above the melting temperature of the DNA links designed to connect particles and then slowly cooled to room temperature ( Fig. 1a , red arrows), in a process which typically took two to three days to complete. A key parameter known to the researcher before doing the experiments is the aggregate melting temperature, which is well defined and directly correlated with the nucleic acid sequences used for assembly 12 . Figure 1: Superlattices formed by the slow-cooling method. a , Two approaches for DNA-mediated nanoparticle crystallization are designated by arrows on a thermal melting curve of a DNA-linked gold nanoparticle aggregate. The traditional method (blue arrow), in which the aggregate is annealed a few degrees below the melting temperature, produces polycrystalline superlattices with no defined shape. The slow-cooling method (red arrow), in which the aggregate is heated above its melting temperature and cooled at a rate of 0.01 °C min −1 , produced well-defined, faceted microcrystals in each of the dozens of experiments conducted using these conditions. Extinction wavelength measured from the ultraviolet–visible spectrum, 520 nm (a.u.). b , Representative one-dimensional (top) and two-dimensional (bottom) SAXS data for b.c.c. (i) and CsCl (ii) superlattices synthesized from the slow-cooling technique. In the one-dimensional data, the red trace is the experimentally obtained scattering pattern and the black trace is the predicted scattering pattern for a perfect lattice. SAXS data are shown as plots of superlattice structure factor ( S ( q ), in arbitrary units) versus scattering vector ( q , in units of Å −1 ). c , TEM images of shape-controlled b.c.c. (i)–(ii) and CsCl (iii)–(iv) microcrystals. Scale bars are 1.5 µm for (i), 1.0 µm for (ii), 0.5 µm for (iii) and 0.5 µm for (iv). d , SEM image of a representative b.c.c. microcrystal with visible faceting where constituent nanoparticles can readily be seen (20-nm gold nanoparticles shown; scale bar is 1 µm). The inset shows a high-magnification (×52,500) view of the crystal facet with labelled surface defects. PowerPoint slide Full size image The slow cooling of the combination of two sets of gold nanoparticles functionalized with complementary DNA linker strands 9 produces superlattices with the expected body-centred cubic (b.c.c.) packing when using 20-nm gold nanoparticles and CsCl packing when using 20-nm and 15-nm gold nanoparticles, as confirmed by the radially averaged one-dimensional SAXS data ( Fig. 1b , (i) and (ii)). To enable direct visualization, the superlattices were also stabilized by embedding in silica 19 . TEM images of these structures reveal uniform crystals with square- and hexagonal-shaped domains for both the b.c.c. ( Fig. 1c , (i) and (ii)) and the CsCl ( Fig. 1c , (iii) and (iv)) particle packing symmetries, whereas scanning electron microscopy (SEM) allows us to observe surface features and the overall crystal habit ( Fig. 1d ). Evidently, the slow-cooling process enables DNA-driven assembly and crystallization that favours faceted rhombic dodecahedron microcrystals over the polycrystalline assemblies obtained by annealing below the melting temperature. Although single-crystal formation by annealing below the melting temperature may in principle be possible, the kinetics of reorganization from an irregularly shaped crystal into a well-defined microcrystal are likely to be too slow to be observed experimentally. SEM images of the microcrystals in different orientations on the substrate are all consistent with rhombic dodecahedron formation ( Fig. 2a ). Closer inspection of one of the crystals ( Fig. 2a , bottom) reveals extraordinarily well ordered nanoparticles at the surface, as well as the presence of common surface defects including ‘particle adatoms’ (a surface defect in<|im_end|> <|im_start|>assistant Nature builds flawless diamonds, sapphires and other gems. Now a Northwestern University research team is the first to build near-perfect single crystals out of nanoparticles and DNA, using the same structure favored by nature. "Single crystals are the backbone of many things we rely on—diamonds for beauty as well as industrial applications, sapphires for lasers and silicon for electronics," said nanoscientist Chad A. Mirkin. "The precise placement of atoms within a well-defined lattice defines these high-quality crystals. "Now we can do the same with nanomaterials and DNA, the blueprint of life," Mirkin said. "Our method could lead to novel technologies and even enable new industries, much as the ability to grow silicon in perfect crystalline arrangements made possible the multibillion-dollar semiconductor industry." His research group developed the "recipe" for using nanomaterials as atoms, DNA as bonds and a little heat to form tiny crystals. This single-crystal recipe builds on superlattice techniques Mirkin's lab has been developing for nearly two decades. In this recent work, Mirkin, an experimentalist, teamed up with Monica Olvera de la Cruz, a theoretician, to evaluate the new technique and develop an understanding of it. Given a set of nanoparticles and a specific type of DNA, Olvera de la Cruz showed they can accurately predict the 3-D structure, or crystal shape, into which the disordered components will self-assemble. Mirkin is the George B. Rathmann Professor of Chemistry in the Weinberg College of Arts and Sciences. Olvera de la Cruz is a Lawyer Taylor Professor and professor of materials science and engineering in the McCormick School of Engineering and Applied Science. The two are senior co-authors of the study. The results will be published Nov. 27 in the journal Nature. The general set of instructions gives researchers unprecedented control over the type and shape of crystals they can build. The Northwestern team worked with gold nanoparticles, but the recipe can be applied to a variety of materials, with potential applications in the fields of materials science, photonics, electronics and catalysis. DNA is used as both the blueprint and the basic building block for the construction of well-defined crystals. Through the use of programmed DNA interactions, nanoparticles are assembled into ordered lattices which form the structural components that make up three-dimensional crystals with a well-defined shape. Credit: Evelyn Auyeung/Ting Li/Chad A. Mirkin/Monica Olvera de la Cruz A single crystal has order: its crystal lattice is continuous and unbroken throughout. The absence of defects in the material can give these crystals unique mechanical, optical and electrical properties, making them very desirable. In the Northwestern study, strands of complementary DNA act as bonds between disordered gold nanoparticles, transforming them into an orderly crystal. The researchers determined that the ratio of the DNA linker's length to the size of the nanoparticle is critical. "If you get the right ratio it makes a perfect crystal—isn't that fun?" said Olvera de la Cruz, who also is a professor of chemistry in the Weinberg College of Arts and Sciences. "That's the fascinating thing, that you have to have the right ratio. We are learning so many rules for calculating things that other people cannot compute in atoms, in atomic crystals." The ratio affects the energy of the faces of the crystals, which determines the final crystal shape. Ratios that don't follow the recipe lead to large fluctuations in energy and result in a sphere, not a faceted crystal, she explained. With the correct ratio, the energies fluctuate less and result in a crystal every time. "Imagine having a million balls of two colors, some red, some blue, in a container, and you try shaking them until you get alternating red and blue balls," Mirkin explained. "It will never happen. "But if you attach DNA that is complementary to nanoparticles—the red has one kind of DNA, say, the blue its complement—and now you shake, or in our case, just stir in water, all the particles will find one another and link together," he said. "They beautifully assemble into a three-dimensional crystal that we predicted computationally and realized experimentally." To achieve a self-assembling single crystal in the lab, the research team reports taking two sets of gold nanoparticles outfitted with complementary DNA linker strands. Working with approximately 1 million nanoparticles in water, they heated the solution to a temperature just above the DNA linkers' melting point and then slowly cooled the solution to room temperature, which took two or three days. The very slow cooling process encouraged the single-stranded DNA to find its complement, resulting in a high-quality single crystal approximately three microns wide. "The process gives the system enough time and energy for all the particles to arrange themselves and find the spots they should be in," Mirkin said. The researchers determined that the length of DNA connected to each gold nanoparticle can't be much longer than the size of the nanoparticle. In the study, the gold nanoparticles varied from five to 20 nanometers in diameter; for each, the DNA length that led to crystal formation was about 18 base pairs and six single-base "sticky ends." "There's no reason we can't grow extraordinarily large single crystals in the future using modifications of our technique," said Mirkin, who also is a professor of medicine, chemical and biological engineering, biomedical engineering and materials science and engineering and director of Northwestern's International Institute for Nanotechnology. The title of the paper is "DNA-mediated nanoparticle crystallization into Wulff polyhedra." In addition to Mirkin and Olvera de la Cruz, authors of the paper are Evelyn Auyeung (first author), Ting I. N. G. Li, Andrew J. Senesi, Abrin L. Schmucker and Bridget C. Pals, all from Northwestern. <|im_end|>

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2,650

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Performing large calculations with a quantum computer will likely require a fault-tolerant architecture based on quantum error-correcting codes. The challenge is to design practical quantum error-correcting codes that perform well against realistic noise using modest resources. Here we show that a variant of the surface code—the XZZX code—offers remarkable performance for fault-tolerant quantum computation. The error threshold of this code matches what can be achieved with random codes (hashing) for every single-qubit Pauli noise channel; it is the first explicit code shown to have this universal property. We present numerical evidence that the threshold even exceeds this hashing bound for an experimentally relevant range of noise parameters. Focusing on the common situation where qubit dephasing is the dominant noise, we show that this code has a practical, high-performance decoder and surpasses all previously known thresholds in the realistic setting where syndrome measurements are unreliable. We go on to demonstrate the favourable sub-threshold resource scaling that can be obtained by specialising a code to exploit structure in the noise. We show that it is possible to maintain all of these advantages when we perform fault-tolerant quantum computation. Introduction A large-scale quantum computer must be able to reliably process data encoded in a nearly noiseless quantum system. To build such a quantum computer using physical qubits that experience errors from noise and faulty control, we require an architecture that operates fault-tolerantly 1 , 2 , 3 , 4 , using quantum error correction to repair errors that occur throughout the computation. For a fault-tolerant architecture to be practical, it will need to correct for physically relevant errors with only a modest overhead. That is, quantum error correction can be used to create near-perfect logical qubits if the rate of relevant errors on the physical qubits is below some threshold, and a good architecture should have a sufficiently high threshold for this to be achievable in practice. These fault-tolerant designs should also be efficient, using a reasonable number of physical qubits to achieve the desired logical error rate. The most common architecture for fault-tolerant quantum computing is based on the surface code 5 . It offers thresholds against depolarising noise that are already high, and encouraging recent results have shown that its performance against more structured noise can be considerably improved by tailoring the code to the noise model 6 , 7 , 8 , 9 , 10 . While the surface code has already demonstrated promising thresholds, its overheads are daunting 5 , 11 . Practical fault-tolerant quantum computing will need architectures that provide high thresholds against relevant noise models while minimising overheads through efficiencies in physical qubits and logic gates. In this paper, we present a highly efficient fault-tolerant architecture design that exploits the common structures in the noise experienced by physical qubits. Our central tool is a variant of the surface code 12 , 13 , 14 where the stabilizer checks are given by the product XZZX of Pauli operators around each face on a square lattice 15 . This seemingly innocuous local change of basis offers a number of significant advantages over its more conventional counterpart for structured noise models that deviate from depolarising noise. We first consider preserving a logical qubit in a quantum memory using the XZZX code. While some two-dimensional codes have been shown to have high error thresholds for certain types of biased noise 7 , 16 , we find that the XZZX code gives exceptional thresholds for all single-qubit Pauli noise channels, matching what is known to be achievable with random coding according to the hashing bound 17 , 18 . It is particularly striking that the XZZX code can match the threshold performance of a random code, for any single-qubit Pauli error model, while retaining the practical benefits of local stabilizers and an efficient decoder. Intriguingly, for noise that is strongly biased towards X or Z, we have numerical evidence to suggest that the XZZX threshold exceeds this hashing bound, meaning this code could potentially provide a practical demonstration of the superadditivity of coherent information 19 , 20 , 21 , 22 , 23 . We show that these high thresholds persist with efficient, practical decoders by using a generalisation of a matching decoder in the regime where dephasing noise is dominant. In the fault-tolerant setting when stabilizer measurements are unreliable, we obtain thresholds in the biased-noise regime that surpass all previously known thresholds. With qubits and operations that perform below the threshold error rate, the practicality of scalable quantum computation is determined by the overhead, i.e. the number of physical qubits and gates we need to obtain a target logical failure rate. Along with offering high thresholds against structured noise, we show that architectures based on the XZZX code require very low overhead to achieve a given target logical failure rate. Generically, we expect the logical failure rate to decay like O ( p d /2 ) at low error rates p where \$d=O(\\sqrt{n})\$ is the distance of a surface code and n is the number of physical qubits used in the system. By considering a biased-noise model where dephasing errors occur a factor η more frequently than other types of errors we demonstrate an improved logical failure rate scaling like \$O({(p/\\sqrt{\\eta })}^{d/2})\$ . We can therefore achieve a target logical failure rate using considerably fewer qubits at large bias because its scaling is improved by a factor ~ η − d /4 . We also show that near-term devices, i.e. small-sized systems with error rates near to threshold, can have a logical failure rate with quadratically improved scaling as a function of distance; \$O({p}^{{d}^{2}/2})\$ . Thus, we should expect to achieve low logical failure rates using a modest number of physical qubits for experimentally plausible values of the noise bias, for example, 10 ≲ η ≲ 1000 24 , 25 . Finally, we consider fault-tolerant quantum computation with biased noise 26 , 27 , 28 , and we show that the advantages of the XZZX code persist in this context.", "role": "user" }, { "content": "A simple yet elegant change to code studied for more than 20 years could shorten timeline to achieve scalable quantum computation and has attracted the attention of quantum computing programs at Amazon Web Services and Yale University. What started out as a second-year physics project is making its way into Amazon Web Service's (AWS) quantum computing program. University of Sydney science undergraduate Pablo Bonilla Ataides has tweaked some computing code to effectively double its capacity to correct errors in the quantum machines being designed in the emerging technology sector. The simple but ingenious change to quantum error correcting code has grabbed the attention of quantum researchers at the AWS Center for Quantum Computing in Pasadena, California, and the quantum technology programs at Yale University and Duke University in the United States. \"Quantum technology is in its infancy, partly because we haven't been able to overcome the inherent instability in the machines that produce so many errors,\" 21-year-old Mr Bonilla said. \"In second-year physics I was asked to look at some commonly used error correcting code to see if we could improve it. By flipping half of the quantum switches, or qubits, in our design, we found we could effectively double our ability to suppress errors.\" The research is published today in Nature Communications. The results of the study, co-authored by Dr. Steve Flammia who has recently moved from the University of Sydney to AWS's quantum computing effort, are to feature in the tech company's arsenal of error correction techniques as it develops its quantum hardware. Dr. Earl Campbell is a senior quantum research scientist at AWS. He said: \"We have considerable work ahead of us as an industry before anyone sees real, practical benefits from quantum computers. \"This research surprised me. I was amazed that such a slight change to a quantum error correction code could lead to such a big impact in predicted performance. \"The AWS Center for Quantum Computing team looks forward to collaborating further as we explore other promising alternatives to bring new, more powerful computing technologies one step closer to reality.\" Quantum errors Errors are extremely rare in the digital transistors, or switches, that classical computers use to run our phones, laptops and even the fastest supercomputers. However, the 'switches' in quantum computers, known as qubits, are particularly sensitive to interference, or 'noise,\" from the external environment. In order to make quantum machines work, scientists need to produce a large number of high-quality qubits. This can be done by improving the machines so they are less noisy and by using some capacity of the machines to suppress qubit errors below a certain threshold in order for them to be useful. That is where quantum error correction comes in. Assistant Professor Shruti Puri from the quantum research program at Yale University said her team is interested in using the new code for its work. \"What amazes me about this new code is its sheer elegance. It's remarkable error-correcting properties are coming from a simple modification to a code that has been studied extensively for almost two decades,\" Assistant Professor Puri said. \"It is extremely relevant for a new generation of quantum technology being developed at Yale and elsewhere. With this new code, I believe, we have considerably shortened the timeline to achieve scalable quantum computation.\" Co-author Dr. David Tuckett from the School of Physics said: \"It's a bit like playing battleships with a quantum opponent. Theoretically, they could place their pieces anywhere on the board. But after playing millions of games, we know that certain moves are more likely.\" Retrofit for industry Co-author and Associate Dean (Research) in the Faculty of Science Professor Stephen Bartlett said: \"What's great about this design is that we can effectively retrofit it to the surface codes being developed across the industry. \"Having the code work on a two-dimensional surface is ideal for application in an industry that has historically produced 2D chip designs. We are optimistic that this work will help the industry build better experimental devices.\" Co-author Dr. Ben Brown from the University of Sydney Nano Institute and School of Physics worked closely with Mr Bonilla on the project. He said: \"Building a functional quantum computer is a bit like trying to build the Wright Brothers' plane, and we haven't even gotten off the ground yet. \"Experimentalists are producing the strong, light-weight materials to build the plane, and we've just come up with a more aerodynamic design for the wings that have more lift. We might have just come up with the design that will help large-scale quantum computing take off.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Performing large calculations with a quantum computer will likely require a fault-tolerant architecture based on quantum error-correcting codes. The challenge is to design practical quantum error-correcting codes that perform well against realistic noise using modest resources. Here we show that a variant of the surface code—the XZZX code—offers remarkable performance for fault-tolerant quantum computation. The error threshold of this code matches what can be achieved with random codes (hashing) for every single-qubit Pauli noise channel; it is the first explicit code shown to have this universal property. We present numerical evidence that the threshold even exceeds this hashing bound for an experimentally relevant range of noise parameters. Focusing on the common situation where qubit dephasing is the dominant noise, we show that this code has a practical, high-performance decoder and surpasses all previously known thresholds in the realistic setting where syndrome measurements are unreliable. We go on to demonstrate the favourable sub-threshold resource scaling that can be obtained by specialising a code to exploit structure in the noise. We show that it is possible to maintain all of these advantages when we perform fault-tolerant quantum computation. Introduction A large-scale quantum computer must be able to reliably process data encoded in a nearly noiseless quantum system. To build such a quantum computer using physical qubits that experience errors from noise and faulty control, we require an architecture that operates fault-tolerantly 1 , 2 , 3 , 4 , using quantum error correction to repair errors that occur throughout the computation. For a fault-tolerant architecture to be practical, it will need to correct for physically relevant errors with only a modest overhead. That is, quantum error correction can be used to create near-perfect logical qubits if the rate of relevant errors on the physical qubits is below some threshold, and a good architecture should have a sufficiently high threshold for this to be achievable in practice. These fault-tolerant designs should also be efficient, using a reasonable number of physical qubits to achieve the desired logical error rate. The most common architecture for fault-tolerant quantum computing is based on the surface code 5 . It offers thresholds against depolarising noise that are already high, and encouraging recent results have shown that its performance against more structured noise can be considerably improved by tailoring the code to the noise model 6 , 7 , 8 , 9 , 10 . While the surface code has already demonstrated promising thresholds, its overheads are daunting 5 , 11 . Practical fault-tolerant quantum computing will need architectures that provide high thresholds against relevant noise models while minimising overheads through efficiencies in physical qubits and logic gates. In this paper, we present a highly efficient fault-tolerant architecture design that exploits the common structures in the noise experienced by physical qubits. Our central tool is a variant of the surface code 12 , 13 , 14 where the stabilizer checks are given by the product XZZX of Pauli operators around each face on a square lattice 15 . This seemingly innocuous local change of basis offers a number of significant advantages over its more conventional counterpart for structured noise models that deviate from depolarising noise. We first consider preserving a logical qubit in a quantum memory using the XZZX code. While some two-dimensional codes have been shown to have high error thresholds for certain types of biased noise 7 , 16 , we find that the XZZX code gives exceptional thresholds for all single-qubit Pauli noise channels, matching what is known to be achievable with random coding according to the hashing bound 17 , 18 . It is particularly striking that the XZZX code can match the threshold performance of a random code, for any single-qubit Pauli error model, while retaining the practical benefits of local stabilizers and an efficient decoder. Intriguingly, for noise that is strongly biased towards X or Z, we have numerical evidence to suggest that the XZZX threshold exceeds this hashing bound, meaning this code could potentially provide a practical demonstration of the superadditivity of coherent information 19 , 20 , 21 , 22 , 23 . We show that these high thresholds persist with efficient, practical decoders by using a generalisation of a matching decoder in the regime where dephasing noise is dominant. In the fault-tolerant setting when stabilizer measurements are unreliable, we obtain thresholds in the biased-noise regime that surpass all previously known thresholds. With qubits and operations that perform below the threshold error rate, the practicality of scalable quantum computation is determined by the overhead, i.e. the number of physical qubits and gates we need to obtain a target logical failure rate. Along with offering high thresholds against structured noise, we show that architectures based on the XZZX code require very low overhead to achieve a given target logical failure rate. Generically, we expect the logical failure rate to decay like O ( p d /2 ) at low error rates p where $d=O(\sqrt{n})$ is the distance of a surface code and n is the number of physical qubits used in the system. By considering a biased-noise model where dephasing errors occur a factor η more frequently than other types of errors we demonstrate an improved logical failure rate scaling like $O({(p/\sqrt{\eta })}^{d/2})$ . We can therefore achieve a target logical failure rate using considerably fewer qubits at large bias because its scaling is improved by a factor ~ η − d /4 . We also show that near-term devices, i.e. small-sized systems with error rates near to threshold, can have a logical failure rate with quadratically improved scaling as a function of distance; $O({p}^{{d}^{2}/2})$ . Thus, we should expect to achieve low logical failure rates using a modest number of physical qubits for experimentally plausible values of the noise bias, for example, 10 ≲ η ≲ 1000 24 , 25 . Finally, we consider fault-tolerant quantum computation with biased noise 26 , 27 , 28 , and we show that the advantages of the XZZX code persist in this context.<|im_end|> <|im_start|>assistant A simple yet elegant change to code studied for more than 20 years could shorten timeline to achieve scalable quantum computation and has attracted the attention of quantum computing programs at Amazon Web Services and Yale University. What started out as a second-year physics project is making its way into Amazon Web Service's (AWS) quantum computing program. University of Sydney science undergraduate Pablo Bonilla Ataides has tweaked some computing code to effectively double its capacity to correct errors in the quantum machines being designed in the emerging technology sector. The simple but ingenious change to quantum error correcting code has grabbed the attention of quantum researchers at the AWS Center for Quantum Computing in Pasadena, California, and the quantum technology programs at Yale University and Duke University in the United States. "Quantum technology is in its infancy, partly because we haven't been able to overcome the inherent instability in the machines that produce so many errors," 21-year-old Mr Bonilla said. "In second-year physics I was asked to look at some commonly used error correcting code to see if we could improve it. By flipping half of the quantum switches, or qubits, in our design, we found we could effectively double our ability to suppress errors." The research is published today in Nature Communications. The results of the study, co-authored by Dr. Steve Flammia who has recently moved from the University of Sydney to AWS's quantum computing effort, are to feature in the tech company's arsenal of error correction techniques as it develops its quantum hardware. Dr. Earl Campbell is a senior quantum research scientist at AWS. He said: "We have considerable work ahead of us as an industry before anyone sees real, practical benefits from quantum computers. "This research surprised me. I was amazed that such a slight change to a quantum error correction code could lead to such a big impact in predicted performance. "The AWS Center for Quantum Computing team looks forward to collaborating further as we explore other promising alternatives to bring new, more powerful computing technologies one step closer to reality." Quantum errors Errors are extremely rare in the digital transistors, or switches, that classical computers use to run our phones, laptops and even the fastest supercomputers. However, the 'switches' in quantum computers, known as qubits, are particularly sensitive to interference, or 'noise," from the external environment. In order to make quantum machines work, scientists need to produce a large number of high-quality qubits. This can be done by improving the machines so they are less noisy and by using some capacity of the machines to suppress qubit errors below a certain threshold in order for them to be useful. That is where quantum error correction comes in. Assistant Professor Shruti Puri from the quantum research program at Yale University said her team is interested in using the new code for its work. "What amazes me about this new code is its sheer elegance. It's remarkable error-correcting properties are coming from a simple modification to a code that has been studied extensively for almost two decades," Assistant Professor Puri said. "It is extremely relevant for a new generation of quantum technology being developed at Yale and elsewhere. With this new code, I believe, we have considerably shortened the timeline to achieve scalable quantum computation." Co-author Dr. David Tuckett from the School of Physics said: "It's a bit like playing battleships with a quantum opponent. Theoretically, they could place their pieces anywhere on the board. But after playing millions of games, we know that certain moves are more likely." Retrofit for industry Co-author and Associate Dean (Research) in the Faculty of Science Professor Stephen Bartlett said: "What's great about this design is that we can effectively retrofit it to the surface codes being developed across the industry. "Having the code work on a two-dimensional surface is ideal for application in an industry that has historically produced 2D chip designs. We are optimistic that this work will help the industry build better experimental devices." Co-author Dr. Ben Brown from the University of Sydney Nano Institute and School of Physics worked closely with Mr Bonilla on the project. He said: "Building a functional quantum computer is a bit like trying to build the Wright Brothers' plane, and we haven't even gotten off the ground yet. "Experimentalists are producing the strong, light-weight materials to build the plane, and we've just come up with a more aerodynamic design for the wings that have more lift. We might have just come up with the design that will help large-scale quantum computing take off." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract In the 1950s, Pomeranchuk 1 predicted that, counterintuitively, liquid 3 He may solidify on heating. This effect arises owing to high excess nuclear spin entropy in the solid phase, where the atoms are spatially localized. Here we find that an analogous effect occurs in magic-angle twisted bilayer graphene 2 , 3 , 4 , 5 , 6 . Using both local and global electronic entropy measurements, we show that near a filling of one electron per moiré unit cell, there is a marked increase in the electronic entropy to about 1 k B per unit cell ( k B is the Boltzmann constant). This large excess entropy is quenched by an in-plane magnetic field, pointing to its magnetic origin. A sharp drop in the compressibility as a function of the electron density, associated with a reset of the Fermi level back to the vicinity of the Dirac point, marks a clear boundary between two phases. We map this jump as a function of electron density, temperature and magnetic field. This reveals a phase diagram that is consistent with a Pomeranchuk-like temperature- and field-driven transition from a low-entropy electronic liquid to a high-entropy correlated state with nearly free magnetic moments. The correlated state features an unusual combination of seemingly contradictory properties, some associated with itinerant electrons—such as the absence of a thermodynamic gap, metallicity and a Dirac-like compressibility—and others associated with localized moments, such as a large entropy and its disappearance under a magnetic field. Moreover, the energy scales characterizing these two sets of properties are very different: whereas the compressibility jump has an onset at a temperature of about 30 kelvin, the bandwidth of magnetic excitations is about 3 kelvin or smaller. The hybrid nature of the present correlated state and the large separation of energy scales have implications for the thermodynamic and transport properties of the correlated states in twisted bilayer graphene. Main Systems of strongly interacting fermions exhibit competition between localization, which minimizes the potential energy, and itineracy, which minimizes the kinetic energy. The advent of two-dimensional moiré systems, such as magic-angle twisted bilayer graphene 2 , 3 , 4 , 5 , 6 (MATBG), allows this physics to be studied by controlling the ratio between the electronic interactions and bandwidth in a highly tunable way. When this ratio is large, electrons tend to localize and form Mott insulators 7 , 8 . When the bandwidth dominates, a Fermi liquid state is formed in which electrons are itinerant. MATBG is at the boundary between these two extremes, showing a host of fascinating electronic phases, including correlated insulators 3 , 9 , 10 , Chern insulators 11 , 12 , 13 , superconductors 4 , 9 , 10 and ferromagnets 14 , 15 . Scanning tunnelling spectroscopy 16 , 17 , 18 , 19 and electronic compressibility measurements 20 , 21 indicate that in this system the strengths of the Coulomb interaction and the kinetic energy are indeed comparable. In this regime, there is an inherent tension between localized and itinerant descriptions of the physics. Moreover, the topological character 22 , 23 , 24 of the nearly-flat bands in MATBG implies that a simple ‘atomic’ description, in which electrons are localized to individual moiré lattice sites, may not be appropriate. Instead, a picture analogous to that of quantum Hall ferromagnetism has been proposed 25 , 26 , 27 . Understanding this interplay between itineracy and localization, and the new physics that emerges from it, remains a major challenge. In this work we find that, surprisingly, the correlated state in MATBG above a filling of one electron per moiré site has a hybrid nature, with some properties resembling those of an itinerant system, and others resembling those of localized electrons. At temperatures of a few kelvin we measure unusually large excess entropy, which is rapidly suppressed by a moderate in-plane magnetic field. This suggests that even at such low temperatures, there are strongly fluctuating magnetic moments in the system, a behaviour typically associated with local moments. On the other hand, our measurements find that this state is metallic and has no thermodynamic gap, naturally fitting an itinerant picture. The presence of fluctuating moments at temperatures much below the electronic bandwidth indicates the existence of a new, anomalously small energy scale associated with the bandwidth of magnetic excitations, which is an order of magnitude smaller than the scale where a jump appears in the compressibility 21 , 28 . This jump marks the boundary between the new state at filling factor ν > +1 and the state at lower densities. By tracking the dependence of this boundary on temperature and magnetic field, we find that it exhibits an electronic analogue 29 , 30 , 31 , 32 of the Pomeranchuk effect 1 in 3 He. In that system, a transition from a Fermi liquid to a solid occurs on increasing the temperature, driven by the high nuclear spin entropy of the atoms in the solid. Similarly, we find that the new state above ν = +1 is favoured relative to the metallic state at ν < +1 on raising the temperature, owing to the former’s high magnetic entropy. The transition near ν = +1 can also be driven by an in-plane magnetic field that polarizes the free moments. (A related effect near ν = −1 was proposed very recently, on the basis of transport measurements 33 .) The hybrid state observed here, with itinerant electrons coexisting with strongly fluctuating magnetic moments, calls for a new understanding of electron correlations in MATBG. Our data are measured using two independent techniques on two conceptually different devices. The bulk of the results are obtained from local measurements of the electronic entropy 34 , 35 and compressibility using a scanning nanotube single-electron transistor (SET) that probes a hexagonal boron nitride (hBN)-encapsulated MATBG device (device 1, Fig. 1a ). We focus on a large (5 μm × 4 μm) region with an extremely homogenous twist angle that is close to the theoretical magic angle θ", "role": "user" }, { "content": "Most materials go from being solids to liquids when they are heated. One rare counter-example is helium-3, which can solidify upon heating. This counterintuitive and exotic effect, known as the Pomeranchuk effect, may now have found its electronic analog in a material known as magic-angle graphene, says a team of researchers from the Weizmann Institute of Science led by Prof. Shahal Ilani, in collaboration with Prof. Pablo Jarillo-Herrero's group at the Massachusetts Institute of Technology (MIT). This result, published today in Nature, comes thanks to the first ever measurement of electronic entropy in an atomically-thin two dimensional material. \"Entropy describes the level of disorder in a material and determines which of its phases is stable at different temperatures,\" explains Ilani. \"Our team set up to measure the electronic entropy in magic angle graphene to resolve some of its outstanding mysteries, but discovered another surprise.\" Giant magnetic entropy Entropy is a basic physical quantities that is not easy to grasp or measure directly. At low temperatures, most of the degrees of freedom in a conducting material freeze out, and only the electrons contribute to the entropy. In bulk materials, there is an abundance of electrons, and thus it is possible to measure their heat capacity and from that deduce the entropy. In an atomically-thin two-dimensional material, due to the small number of electrons, such a measurement becomes extremely challenging. So far, no experiments succeeded in measuring the entropy in such systems. To measure the entropy, the Weizmann team used a unique scanning microscope comprising of a carbon nanotube single-electron transistor positioned at the edge of a scanning probe cantilever. This instrument can spatially image the electrostatic potential produced by electrons in a material, with an unprecedented sensitivity. Based on Maxwell's relations that connect the different thermodynamic properties of a material, one can use these electrostatic measurements to directly probe the entropy of the electrons. \"When we performed the measurements at high magnetic fields, the entropy looked absolutely normal, following the expected behavior of a conventional (Fermi) liquid of electrons, which is the most standard state in which electrons exist at low temperatures. Surprisingly, however, at zero magnetic field, the electrons exhibited giant excess entropy, whose presence was very mysterious.\" says Ilani. This giant entropy emerged when the number of electrons in the system was about one per each site of the artificial \"superlattice\" formed in magic angle graphene. Artificial \"superlattice\" in twisted layers of graphene Graphene is a one atom thick crystal of carbon atoms arranged in a hexagonal lattice. When two graphene sheets are placed on top of each other with a small and special, or \"magic,\" misalignment angle, a periodic moiré pattern appears that acts as an artificial \"superlattice\" for the electrons in the material. Moiré patterns are a popular effect in fabrics and emerge wherever one mesh overlays another at a slight angle. In magic angle graphene, the electrons come in four flavors: spin 'up' or spin 'down,\" and two 'valleys.\" Each moiré site can thus hold up to four electrons, one of each flavor. Researchers already knew that this system behaves as a simple insulator when all moiré sites are completely full (four electrons per site). In 2018, however, Prof. Jarillo-Herrero and colleagues discovered to their surprise that it can be insulating at other integer fillings (two or three electrons per moiré site), which could only be explained if a correlated state of electrons is formed. However, near a filling of one electron per moiré site, the vast majority of transport measurements indicated that the system is quite simple, behaving as an ordinary metal. This is exactly where the entropy measurements by the Weizmann-MIT team found the most surprising results. \"In contrast to the behavior seen in transport near a filling of one electron per moiré site, which is quite featureless, our measurements indicated that thermodynamically, the most dramatic phase transition occurs at this filling,\" says Dr. Asaf Rozen, a lead author in this work. \"We realized that near this filling, upon heating the material, a rather conventional Fermi liquid transforms into a correlated metal with a giant magnetic entropy. This giant entropy (of about 1 Boltzmann constant per lattice site) could only be explained if each moiré site has a degree of freedom that is completely free to fluctuate.\" An electronic analog of the Pomeranchuk effect \"This unusual excess entropy reminded us of an exotic effect that was discovered about 70 years ago in helium-3,\" says Weizmann theorist Prof. Erez Berg. \"Most materials, when heated up, transform from a solid to a liquid. This is because a liquid always has more entropy than the solid, as the atoms move more erratically in the liquid than in the solid.\" In helium-3, however, in a small part of the phase diagram, the material behaves completely oppositely, and the higher temperature phase is the solid. This behavior, predicted by Soviet theoretical physicist Isaak Pomeranchuk in the 1950s, can only be explained by the existence of another \"hidden\" source of entropy in the system. In the case of helium-3, this entropy comes from the freely rotating nuclear spins. \"Each atom has a spin in its nucleus (an 'arrow' that can point in any direction),\" explains Berg. \"In liquid helium-3, due to the Pauli exclusion principle, exactly half of the spins must point up and half must point down, so spins cannot freely rotate. In the solid phase, however, the atoms are localized and never come close to each other, so their nuclear spins can freely rotate.\" \"The giant excess entropy that we observed in the correlated state with one electron per moiré site is analogous to the entropy in solid helium-3, but instead of atoms and nuclear spins, in the case of magic angle graphene we have electrons and electronic spins (or valley magnetic moments),\" he says. The magnetic phase diagram To establish the relation with the Pomeranchuk effect further, the team performed detailed measurements of the phase diagram. This was done by measuring the \"compressibility\" of the electrons in the system- that is, how hard it is to squeeze additional electrons into a given lattice site (such a measurement was demonstrated in twisted bilayer graphene in the team's previous work). This measurement revealed two distinct phases separated by a sharp drop in the compressibility: a low-entropy, electronic liquid-like phase, and a high-entropy solid-like phase with free magnetic moments. By following the drop in the compressibility, the researchers mapped the boundary between the two phases as a function of temperature and magnetic field, demonstrating that the phase boundary behaves precisely as expected from the Pomerachuk effect. \"This new result challenges our understanding of magic angle graphene,\" says Berg. \"We imagined that the phases in this material were simple—either conducting or insulating, and expected that at such low temperatures, all the electronic fluctuations are frozen out. This turns out not to be the case, as the giant magnetic entropy shows.\" \"The new findings will provide fresh insights into the physics of strongly correlated electron systems and perhaps even help explain how such fluctuating spins affect superconductivity,\" he adds. The researchers acknowledge that they do not yet know how to explain the Pomeranchuk effect in magic angle graphene. Is it exactly as in helium-3 in that the electrons in the solid-like phase remain at a great distance from each other, allowing their magnetic moments to stay completely free? \"We are not sure,\" admits Ilani, \"since the phase we have observed has a 'spit personality' - some of its properties are associated with itinerant electrons while others can only be explained by thinking of the electrons as being localized on a lattice.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract In the 1950s, Pomeranchuk 1 predicted that, counterintuitively, liquid 3 He may solidify on heating. This effect arises owing to high excess nuclear spin entropy in the solid phase, where the atoms are spatially localized. Here we find that an analogous effect occurs in magic-angle twisted bilayer graphene 2 , 3 , 4 , 5 , 6 . Using both local and global electronic entropy measurements, we show that near a filling of one electron per moiré unit cell, there is a marked increase in the electronic entropy to about 1 k B per unit cell ( k B is the Boltzmann constant). This large excess entropy is quenched by an in-plane magnetic field, pointing to its magnetic origin. A sharp drop in the compressibility as a function of the electron density, associated with a reset of the Fermi level back to the vicinity of the Dirac point, marks a clear boundary between two phases. We map this jump as a function of electron density, temperature and magnetic field. This reveals a phase diagram that is consistent with a Pomeranchuk-like temperature- and field-driven transition from a low-entropy electronic liquid to a high-entropy correlated state with nearly free magnetic moments. The correlated state features an unusual combination of seemingly contradictory properties, some associated with itinerant electrons—such as the absence of a thermodynamic gap, metallicity and a Dirac-like compressibility—and others associated with localized moments, such as a large entropy and its disappearance under a magnetic field. Moreover, the energy scales characterizing these two sets of properties are very different: whereas the compressibility jump has an onset at a temperature of about 30 kelvin, the bandwidth of magnetic excitations is about 3 kelvin or smaller. The hybrid nature of the present correlated state and the large separation of energy scales have implications for the thermodynamic and transport properties of the correlated states in twisted bilayer graphene. Main Systems of strongly interacting fermions exhibit competition between localization, which minimizes the potential energy, and itineracy, which minimizes the kinetic energy. The advent of two-dimensional moiré systems, such as magic-angle twisted bilayer graphene 2 , 3 , 4 , 5 , 6 (MATBG), allows this physics to be studied by controlling the ratio between the electronic interactions and bandwidth in a highly tunable way. When this ratio is large, electrons tend to localize and form Mott insulators 7 , 8 . When the bandwidth dominates, a Fermi liquid state is formed in which electrons are itinerant. MATBG is at the boundary between these two extremes, showing a host of fascinating electronic phases, including correlated insulators 3 , 9 , 10 , Chern insulators 11 , 12 , 13 , superconductors 4 , 9 , 10 and ferromagnets 14 , 15 . Scanning tunnelling spectroscopy 16 , 17 , 18 , 19 and electronic compressibility measurements 20 , 21 indicate that in this system the strengths of the Coulomb interaction and the kinetic energy are indeed comparable. In this regime, there is an inherent tension between localized and itinerant descriptions of the physics. Moreover, the topological character 22 , 23 , 24 of the nearly-flat bands in MATBG implies that a simple ‘atomic’ description, in which electrons are localized to individual moiré lattice sites, may not be appropriate. Instead, a picture analogous to that of quantum Hall ferromagnetism has been proposed 25 , 26 , 27 . Understanding this interplay between itineracy and localization, and the new physics that emerges from it, remains a major challenge. In this work we find that, surprisingly, the correlated state in MATBG above a filling of one electron per moiré site has a hybrid nature, with some properties resembling those of an itinerant system, and others resembling those of localized electrons. At temperatures of a few kelvin we measure unusually large excess entropy, which is rapidly suppressed by a moderate in-plane magnetic field. This suggests that even at such low temperatures, there are strongly fluctuating magnetic moments in the system, a behaviour typically associated with local moments. On the other hand, our measurements find that this state is metallic and has no thermodynamic gap, naturally fitting an itinerant picture. The presence of fluctuating moments at temperatures much below the electronic bandwidth indicates the existence of a new, anomalously small energy scale associated with the bandwidth of magnetic excitations, which is an order of magnitude smaller than the scale where a jump appears in the compressibility 21 , 28 . This jump marks the boundary between the new state at filling factor ν > +1 and the state at lower densities. By tracking the dependence of this boundary on temperature and magnetic field, we find that it exhibits an electronic analogue 29 , 30 , 31 , 32 of the Pomeranchuk effect 1 in 3 He. In that system, a transition from a Fermi liquid to a solid occurs on increasing the temperature, driven by the high nuclear spin entropy of the atoms in the solid. Similarly, we find that the new state above ν = +1 is favoured relative to the metallic state at ν < +1 on raising the temperature, owing to the former’s high magnetic entropy. The transition near ν = +1 can also be driven by an in-plane magnetic field that polarizes the free moments. (A related effect near ν = −1 was proposed very recently, on the basis of transport measurements 33 .) The hybrid state observed here, with itinerant electrons coexisting with strongly fluctuating magnetic moments, calls for a new understanding of electron correlations in MATBG. Our data are measured using two independent techniques on two conceptually different devices. The bulk of the results are obtained from local measurements of the electronic entropy 34 , 35 and compressibility using a scanning nanotube single-electron transistor (SET) that probes a hexagonal boron nitride (hBN)-encapsulated MATBG device (device 1, Fig. 1a ). We focus on a large (5 μm × 4 μm) region with an extremely homogenous twist angle that is close to the theoretical magic angle θ<|im_end|> <|im_start|>assistant Most materials go from being solids to liquids when they are heated. One rare counter-example is helium-3, which can solidify upon heating. This counterintuitive and exotic effect, known as the Pomeranchuk effect, may now have found its electronic analog in a material known as magic-angle graphene, says a team of researchers from the Weizmann Institute of Science led by Prof. Shahal Ilani, in collaboration with Prof. Pablo Jarillo-Herrero's group at the Massachusetts Institute of Technology (MIT). This result, published today in Nature, comes thanks to the first ever measurement of electronic entropy in an atomically-thin two dimensional material. "Entropy describes the level of disorder in a material and determines which of its phases is stable at different temperatures," explains Ilani. "Our team set up to measure the electronic entropy in magic angle graphene to resolve some of its outstanding mysteries, but discovered another surprise." Giant magnetic entropy Entropy is a basic physical quantities that is not easy to grasp or measure directly. At low temperatures, most of the degrees of freedom in a conducting material freeze out, and only the electrons contribute to the entropy. In bulk materials, there is an abundance of electrons, and thus it is possible to measure their heat capacity and from that deduce the entropy. In an atomically-thin two-dimensional material, due to the small number of electrons, such a measurement becomes extremely challenging. So far, no experiments succeeded in measuring the entropy in such systems. To measure the entropy, the Weizmann team used a unique scanning microscope comprising of a carbon nanotube single-electron transistor positioned at the edge of a scanning probe cantilever. This instrument can spatially image the electrostatic potential produced by electrons in a material, with an unprecedented sensitivity. Based on Maxwell's relations that connect the different thermodynamic properties of a material, one can use these electrostatic measurements to directly probe the entropy of the electrons. "When we performed the measurements at high magnetic fields, the entropy looked absolutely normal, following the expected behavior of a conventional (Fermi) liquid of electrons, which is the most standard state in which electrons exist at low temperatures. Surprisingly, however, at zero magnetic field, the electrons exhibited giant excess entropy, whose presence was very mysterious." says Ilani. This giant entropy emerged when the number of electrons in the system was about one per each site of the artificial "superlattice" formed in magic angle graphene. Artificial "superlattice" in twisted layers of graphene Graphene is a one atom thick crystal of carbon atoms arranged in a hexagonal lattice. When two graphene sheets are placed on top of each other with a small and special, or "magic," misalignment angle, a periodic moiré pattern appears that acts as an artificial "superlattice" for the electrons in the material. Moiré patterns are a popular effect in fabrics and emerge wherever one mesh overlays another at a slight angle. In magic angle graphene, the electrons come in four flavors: spin 'up' or spin 'down," and two 'valleys." Each moiré site can thus hold up to four electrons, one of each flavor. Researchers already knew that this system behaves as a simple insulator when all moiré sites are completely full (four electrons per site). In 2018, however, Prof. Jarillo-Herrero and colleagues discovered to their surprise that it can be insulating at other integer fillings (two or three electrons per moiré site), which could only be explained if a correlated state of electrons is formed. However, near a filling of one electron per moiré site, the vast majority of transport measurements indicated that the system is quite simple, behaving as an ordinary metal. This is exactly where the entropy measurements by the Weizmann-MIT team found the most surprising results. "In contrast to the behavior seen in transport near a filling of one electron per moiré site, which is quite featureless, our measurements indicated that thermodynamically, the most dramatic phase transition occurs at this filling," says Dr. Asaf Rozen, a lead author in this work. "We realized that near this filling, upon heating the material, a rather conventional Fermi liquid transforms into a correlated metal with a giant magnetic entropy. This giant entropy (of about 1 Boltzmann constant per lattice site) could only be explained if each moiré site has a degree of freedom that is completely free to fluctuate." An electronic analog of the Pomeranchuk effect "This unusual excess entropy reminded us of an exotic effect that was discovered about 70 years ago in helium-3," says Weizmann theorist Prof. Erez Berg. "Most materials, when heated up, transform from a solid to a liquid. This is because a liquid always has more entropy than the solid, as the atoms move more erratically in the liquid than in the solid." In helium-3, however, in a small part of the phase diagram, the material behaves completely oppositely, and the higher temperature phase is the solid. This behavior, predicted by Soviet theoretical physicist Isaak Pomeranchuk in the 1950s, can only be explained by the existence of another "hidden" source of entropy in the system. In the case of helium-3, this entropy comes from the freely rotating nuclear spins. "Each atom has a spin in its nucleus (an 'arrow' that can point in any direction)," explains Berg. "In liquid helium-3, due to the Pauli exclusion principle, exactly half of the spins must point up and half must point down, so spins cannot freely rotate. In the solid phase, however, the atoms are localized and never come close to each other, so their nuclear spins can freely rotate." "The giant excess entropy that we observed in the correlated state with one electron per moiré site is analogous to the entropy in solid helium-3, but instead of atoms and nuclear spins, in the case of magic angle graphene we have electrons and electronic spins (or valley magnetic moments)," he says. The magnetic phase diagram To establish the relation with the Pomeranchuk effect further, the team performed detailed measurements of the phase diagram. This was done by measuring the "compressibility" of the electrons in the system- that is, how hard it is to squeeze additional electrons into a given lattice site (such a measurement was demonstrated in twisted bilayer graphene in the team's previous work). This measurement revealed two distinct phases separated by a sharp drop in the compressibility: a low-entropy, electronic liquid-like phase, and a high-entropy solid-like phase with free magnetic moments. By following the drop in the compressibility, the researchers mapped the boundary between the two phases as a function of temperature and magnetic field, demonstrating that the phase boundary behaves precisely as expected from the Pomerachuk effect. "This new result challenges our understanding of magic angle graphene," says Berg. "We imagined that the phases in this material were simple—either conducting or insulating, and expected that at such low temperatures, all the electronic fluctuations are frozen out. This turns out not to be the case, as the giant magnetic entropy shows." "The new findings will provide fresh insights into the physics of strongly correlated electron systems and perhaps even help explain how such fluctuating spins affect superconductivity," he adds. The researchers acknowledge that they do not yet know how to explain the Pomeranchuk effect in magic angle graphene. Is it exactly as in helium-3 in that the electrons in the solid-like phase remain at a great distance from each other, allowing their magnetic moments to stay completely free? "We are not sure," admits Ilani, "since the phase we have observed has a 'spit personality' - some of its properties are associated with itinerant electrons while others can only be explained by thinking of the electrons as being localized on a lattice." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Autism is a common and frequently disabling neurodevelopmental disorder with a strong genetic basis. Human genetic studies have discovered mutations disrupting exons of the NRXN2 gene, which encodes the synaptic adhesion protein α-neurexin II (Nrxn2α), in two unrelated individuals with autism, but a causal link between NRXN2 and the disorder remains unclear. To begin to test the hypothesis that Nrxn2α deficiency contributes to the symptoms of autism, we employed Nrxn2α knockout (KO) mice that genetically model Nrxn2α deficiency in vivo . We report that Nrxn2α KO mice displayed deficits in sociability and social memory when exposed to novel conspecifics. In tests of exploratory activity, Nrxn2α KO mice displayed an anxiety-like phenotype in comparison with wild-type littermates, with thigmotaxis in an open field, less time spent in the open arms of an elevated plus maze, more time spent in the enclosure of an emergence test and less time spent exploring novel objects. However, Nrxn2α KO mice did not exhibit any obvious changes in prepulse inhibition or in passive avoidance learning. Real-time PCR analysis of the frontal cortex and hippocampus revealed significant decreases in the mRNA levels of genes encoding proteins involved in both excitatory and inhibitory transmission. Quantification of protein expression revealed that Munc18-1, encoded by Stxbp1 , was significantly decreased in the hippocampus of Nrxn2α KO mice, which is suggestive of deficiencies in presynaptic vesicular release. Our findings demonstrate a causal role for the loss of Nrxn2α in the genesis of autism-related behaviors in mice. Introduction Autism is a widespread cognitive disorder characterized by impairments in social interactions, communication and language development, that can be accompanied by stereotyped patterns of behavior. Autism is a highly heritable disorder with concordance rates as high as 90% for monozygotic twins, 1 but the underlying molecular and neuropathophysiological basis is unknown in most cases. However, recent genetic and genomic studies have implicated a large number of genes in autism, 2 many of which encode synaptic proteins, 3 indicating that synaptic dysfunction may have a critical role in autism. The neurexins are a family of synaptic adhesion proteins encoded by paralogous genes ( NRXN1 - 3 ) that have a key role in synaptic function. Each gene is transcribed in neurons from two independent promoters to yield longer (α) proteins with six laminin/neurexin/sex hormone (LNS) binding domains, and shorter (β) proteins with one LNS binding domain. Intracellularly, α-neurexin binds to CASK, Mint, Munc18, syntenin and synaptotagmin, suggesting a role in vesicular release. 4 , 5 , 6 Postsynaptic binding with PSD-95 or gephyrin via neuroligins (also associated with autism 7 ), leucine-rich repeat transmembrane proteins (LRRTMs) or dystroglycan can directly influence NMDA, AMPA or GABAergic receptors at the synapse, thereby altering a cell’s excitatory or inhibitory tone. 8 , 9 , 10 The promoter for α-neurexin II (Nrxn2α) transcripts lies upstream of NRXN2 exon 1, whereas the promoter for β-neurexin II is located in the intron downstream of exon 17. 11 The first evidence for a potential role of NRXN2 in autism was provided by a report of a frameshift mutation within NRXN2 exon 12 in a boy with autism and his father with severe language delay. 12 This mutation results in a truncated Nrxn2α protein that lacks the binding sites for the established postsynaptic binding partners LRRTM2 and neuroligin-2, but does not affect β-neurexin II. 12 Subsequently, a 21-year-old man with a clinical phenotype including autistic traits, such as speech and language deficits and insistence on routine, was reported to have a 570-kb de novo deletion of 24 genes at chromosome 11q13.1, including NRXN2 . 13 However, a clear causal relationship between NRXN2 and autism has not been established. To begin to test the hypothesis that Nrxn2α deficiency contributes to the symptoms of autism, we employed mice with a targeted mutation ( Nrxn2 tm1Sud ; MGI:3042719) that deletes the first exon of Nrxn2 and abolishes expression of Nrxn2α, but does not affect β-neurexin II. 14 The 30-day survival rate and gross brain anatomy of Nrxn2α null mutants are unaltered compared with wild-type littermates. 14 , 15 In light of the putative link between Nrxn2α and autism—diagnosis of which is based purely on behavioral assessment—we predicted that Nrxn2α knockout (Nrxn2α KO) mice might exhibit autism-relevant behavioral abnormalities. Herein, we report that Nrxn2α KO mice displayed altered anxiety-like and social behaviors consistent with a causal role for the loss of Nrxn2α in the genesis of autism-related behaviors. Materials and methods All the procedures were approved by the University of Leeds Animal Ethical and Welfare Review Board and were performed under the UK Home Office Project and Personal Licences. Animals B6;129- Nrxn3 tm1Sud /Nrxn1 tm1Sud /Nrxn2 tm1Sud /J mice (JAX #006377) were purchased from the Jackson Laboratory (Bar Harbor, ME, USA) as heterozygous KO at Nrxn1 , homozygous KO at Nrxn2 and wild-type at Nrxn3 . We subsequently outbred to the C57BL/6NCrl strain (Charles River, Margate, UK) to obtain mice that were Nrxn2α KO heterozygotes, but wild-type at Nrxn1 and Nrxn3 . Nrxn2α KO heterozygotes were then intercrossed to obtain wild-type (WT) and KO littermates. DNA extracted from ear biopsies was used for PCR-based genotyping according to the Jackson Laboratory Nrxn1 v5, Nrxn2 v5 and Nrxn3 v1 protocols ( ). Briefly, the primers 5′-GAGATGGAGAGCCAGACACC-3′ (common forward), 5′-CAGTGCCATGGACTCAGTAGC-3′ (WT reverse) and 5′-GCATCGCATTGTCTGAGTAGG-3′ (KO reverse) were used with HotShot Diamond (Clent Life Science, Stourbridge, UK) using the thermocycling program of: 94 °C for 5 min, followed by 35 cycles of 94 °C for 30 s, 64 °C for 60 s and 72 °C for 60 s, followed by 72 °C for 120 s. PCR products were visualized using electrophoresis, with a 190-bp band indicating the WT allele, and a 310-bp band indicating the KO allele. Litters were separated by sex at postnatal day 21, when mice were housed with at least one other mouse of the same sex and age, with a maximum of five mice per cage. Food and water were provided ad libitum , except for the buried food experiment. Lighting was provided in a 12:12", "role": "user" }, { "content": "Researchers at the University of Leeds have shed light on a gene mutation linked to autistic traits. The team already knew that some people with autism were deficient in a gene called neurexin-II. To investigate whether the gene was associated with autism symptoms, the Leeds team studied mice with the same defect. They found behavioural features that were similar to autism symptoms, including a lack of sociability or interest in other mice. Dr Steven Clapcote, Lecturer in Pharmacology in the University's Faculty of Biological Sciences, who led the study published in the journal Translational Psychiatry today, said: \"In other respects, these mice were functioning normally. The gene deficiency mapped closely with certain autism symptoms.\" Dr Clapcote added: \"This is exciting because we now have an animal model to investigate new treatments for autism.\" The researchers also looked at how the absence of neurexin-II was affecting the brain. Co-author Dr James Dachtler, Wellcome Trust Junior Investigator Development Fellow in the Faculty of Biological Sciences at Leeds, said: \"We found that the affected mice had lower levels of a protein called Munc18-1 in the brain. Munc18-1 usually helps to release neurotransmitter chemicals across synaptic connections in the brain, so neurotransmitter release could be impaired in the affected mice and possibly in some cases of autism.\" Research by Professor Thomas Südhof, a Nobel prize-winning biochemist at Stanford University, previously established a link between autism symptoms and neuroligin-1, another gene associated with synapse signalling. The Leeds-led study is the first to find a connection with neurexin-II. Dr Clapcote said: \"Not all people with autism will have the neurexin-II defect, just as not all will have the neuroligin defect, but we are starting to build up a picture of the important role of genes involved in these synapse communications in better understanding autism.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Autism is a common and frequently disabling neurodevelopmental disorder with a strong genetic basis. Human genetic studies have discovered mutations disrupting exons of the NRXN2 gene, which encodes the synaptic adhesion protein α-neurexin II (Nrxn2α), in two unrelated individuals with autism, but a causal link between NRXN2 and the disorder remains unclear. To begin to test the hypothesis that Nrxn2α deficiency contributes to the symptoms of autism, we employed Nrxn2α knockout (KO) mice that genetically model Nrxn2α deficiency in vivo . We report that Nrxn2α KO mice displayed deficits in sociability and social memory when exposed to novel conspecifics. In tests of exploratory activity, Nrxn2α KO mice displayed an anxiety-like phenotype in comparison with wild-type littermates, with thigmotaxis in an open field, less time spent in the open arms of an elevated plus maze, more time spent in the enclosure of an emergence test and less time spent exploring novel objects. However, Nrxn2α KO mice did not exhibit any obvious changes in prepulse inhibition or in passive avoidance learning. Real-time PCR analysis of the frontal cortex and hippocampus revealed significant decreases in the mRNA levels of genes encoding proteins involved in both excitatory and inhibitory transmission. Quantification of protein expression revealed that Munc18-1, encoded by Stxbp1 , was significantly decreased in the hippocampus of Nrxn2α KO mice, which is suggestive of deficiencies in presynaptic vesicular release. Our findings demonstrate a causal role for the loss of Nrxn2α in the genesis of autism-related behaviors in mice. Introduction Autism is a widespread cognitive disorder characterized by impairments in social interactions, communication and language development, that can be accompanied by stereotyped patterns of behavior. Autism is a highly heritable disorder with concordance rates as high as 90% for monozygotic twins, 1 but the underlying molecular and neuropathophysiological basis is unknown in most cases. However, recent genetic and genomic studies have implicated a large number of genes in autism, 2 many of which encode synaptic proteins, 3 indicating that synaptic dysfunction may have a critical role in autism. The neurexins are a family of synaptic adhesion proteins encoded by paralogous genes ( NRXN1 - 3 ) that have a key role in synaptic function. Each gene is transcribed in neurons from two independent promoters to yield longer (α) proteins with six laminin/neurexin/sex hormone (LNS) binding domains, and shorter (β) proteins with one LNS binding domain. Intracellularly, α-neurexin binds to CASK, Mint, Munc18, syntenin and synaptotagmin, suggesting a role in vesicular release. 4 , 5 , 6 Postsynaptic binding with PSD-95 or gephyrin via neuroligins (also associated with autism 7 ), leucine-rich repeat transmembrane proteins (LRRTMs) or dystroglycan can directly influence NMDA, AMPA or GABAergic receptors at the synapse, thereby altering a cell’s excitatory or inhibitory tone. 8 , 9 , 10 The promoter for α-neurexin II (Nrxn2α) transcripts lies upstream of NRXN2 exon 1, whereas the promoter for β-neurexin II is located in the intron downstream of exon 17. 11 The first evidence for a potential role of NRXN2 in autism was provided by a report of a frameshift mutation within NRXN2 exon 12 in a boy with autism and his father with severe language delay. 12 This mutation results in a truncated Nrxn2α protein that lacks the binding sites for the established postsynaptic binding partners LRRTM2 and neuroligin-2, but does not affect β-neurexin II. 12 Subsequently, a 21-year-old man with a clinical phenotype including autistic traits, such as speech and language deficits and insistence on routine, was reported to have a 570-kb de novo deletion of 24 genes at chromosome 11q13.1, including NRXN2 . 13 However, a clear causal relationship between NRXN2 and autism has not been established. To begin to test the hypothesis that Nrxn2α deficiency contributes to the symptoms of autism, we employed mice with a targeted mutation ( Nrxn2 tm1Sud ; MGI:3042719) that deletes the first exon of Nrxn2 and abolishes expression of Nrxn2α, but does not affect β-neurexin II. 14 The 30-day survival rate and gross brain anatomy of Nrxn2α null mutants are unaltered compared with wild-type littermates. 14 , 15 In light of the putative link between Nrxn2α and autism—diagnosis of which is based purely on behavioral assessment—we predicted that Nrxn2α knockout (Nrxn2α KO) mice might exhibit autism-relevant behavioral abnormalities. Herein, we report that Nrxn2α KO mice displayed altered anxiety-like and social behaviors consistent with a causal role for the loss of Nrxn2α in the genesis of autism-related behaviors. Materials and methods All the procedures were approved by the University of Leeds Animal Ethical and Welfare Review Board and were performed under the UK Home Office Project and Personal Licences. Animals B6;129- Nrxn3 tm1Sud /Nrxn1 tm1Sud /Nrxn2 tm1Sud /J mice (JAX #006377) were purchased from the Jackson Laboratory (Bar Harbor, ME, USA) as heterozygous KO at Nrxn1 , homozygous KO at Nrxn2 and wild-type at Nrxn3 . We subsequently outbred to the C57BL/6NCrl strain (Charles River, Margate, UK) to obtain mice that were Nrxn2α KO heterozygotes, but wild-type at Nrxn1 and Nrxn3 . Nrxn2α KO heterozygotes were then intercrossed to obtain wild-type (WT) and KO littermates. DNA extracted from ear biopsies was used for PCR-based genotyping according to the Jackson Laboratory Nrxn1 v5, Nrxn2 v5 and Nrxn3 v1 protocols ( ). Briefly, the primers 5′-GAGATGGAGAGCCAGACACC-3′ (common forward), 5′-CAGTGCCATGGACTCAGTAGC-3′ (WT reverse) and 5′-GCATCGCATTGTCTGAGTAGG-3′ (KO reverse) were used with HotShot Diamond (Clent Life Science, Stourbridge, UK) using the thermocycling program of: 94 °C for 5 min, followed by 35 cycles of 94 °C for 30 s, 64 °C for 60 s and 72 °C for 60 s, followed by 72 °C for 120 s. PCR products were visualized using electrophoresis, with a 190-bp band indicating the WT allele, and a 310-bp band indicating the KO allele. Litters were separated by sex at postnatal day 21, when mice were housed with at least one other mouse of the same sex and age, with a maximum of five mice per cage. Food and water were provided ad libitum , except for the buried food experiment. Lighting was provided in a 12:12<|im_end|> <|im_start|>assistant Researchers at the University of Leeds have shed light on a gene mutation linked to autistic traits. The team already knew that some people with autism were deficient in a gene called neurexin-II. To investigate whether the gene was associated with autism symptoms, the Leeds team studied mice with the same defect. They found behavioural features that were similar to autism symptoms, including a lack of sociability or interest in other mice. Dr Steven Clapcote, Lecturer in Pharmacology in the University's Faculty of Biological Sciences, who led the study published in the journal Translational Psychiatry today, said: "In other respects, these mice were functioning normally. The gene deficiency mapped closely with certain autism symptoms." Dr Clapcote added: "This is exciting because we now have an animal model to investigate new treatments for autism." The researchers also looked at how the absence of neurexin-II was affecting the brain. Co-author Dr James Dachtler, Wellcome Trust Junior Investigator Development Fellow in the Faculty of Biological Sciences at Leeds, said: "We found that the affected mice had lower levels of a protein called Munc18-1 in the brain. Munc18-1 usually helps to release neurotransmitter chemicals across synaptic connections in the brain, so neurotransmitter release could be impaired in the affected mice and possibly in some cases of autism." Research by Professor Thomas Südhof, a Nobel prize-winning biochemist at Stanford University, previously established a link between autism symptoms and neuroligin-1, another gene associated with synapse signalling. The Leeds-led study is the first to find a connection with neurexin-II. Dr Clapcote said: "Not all people with autism will have the neurexin-II defect, just as not all will have the neuroligin defect, but we are starting to build up a picture of the important role of genes involved in these synapse communications in better understanding autism." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Although 22q11.2 deletion syndrome (22q11DS) is associated with early-life behavioral abnormalities, affected individuals are also at high risk for the development of schizophrenia symptoms, including psychosis, later in life. Auditory thalamocortical (TC) projections recently emerged as a neural circuit that is specifically disrupted in mouse models of 22q11DS (hereafter referred to as 22q11DS mice), in which haploinsufficiency of the microRNA (miRNA)-processing-factor-encoding gene Dgcr8 results in the elevation of the dopamine receptor Drd2 in the auditory thalamus, an abnormal sensitivity of thalamocortical projections to antipsychotics, and an abnormal acoustic-startle response. Here we show that these auditory TC phenotypes have a delayed onset in 22q11DS mice and are associated with an age-dependent reduction of miR-338-3p, a miRNA that targets Drd2 and is enriched in the thalamus of both humans and mice. Replenishing depleted miR-338-3p in mature 22q11DS mice rescued the TC abnormalities, and deletion of Mir338 (which encodes miR-338-3p) or reduction of miR-338-3p expression mimicked the TC and behavioral deficits and eliminated the age dependence of these deficits. Therefore, miR-338-3p depletion is necessary and sufficient to disrupt auditory TC signaling in 22q11DS mice, and it may mediate the pathogenic mechanism of 22q11DS-related psychosis and control its late onset. Main Thalamocortical projections to the auditory cortex (ACx), a brain region implicated in auditory hallucinations 1 , 2 , 3 , 4 , have emerged as a circuit that is specifically disrupted 5 in mouse models of 22q11DS 6 . This disorder, the most common microdeletion syndrome in humans 7 , 8 , is caused by a hemizygous microdeletion (1.5–3 Mb) on the long arm of chromosome 22 (ref. 9 ). 22q11DS is considered to be a leading genetic cause of schizophrenia 10 , 11 , 12 . Schizophrenia develops in 23–43% of individuals with 22q11DS 13 , 14 , 15 , 16 , 17 , 18 , most of whom experience psychosis 19 , 20 . Furthermore, 30–50% of individuals who do not have schizophrenia but have 22q11DS demonstrate subthreshold symptoms of psychosis 21 . Nonpsychotic behavioral abnormalities are present from early life in patients with 22q11DS 22 , 23 , but psychotic symptoms and schizophrenia are delayed; the median age of psychosis onset is 21 years 18 , 24 , 25 . In patients with schizophrenia, auditory hallucinations and other psychotic symptoms are similarly delayed until late adolescence or early adulthood 26 , 27 , present in 60–90% of cases 28 , and often alleviated by treatment with antipsychotics that inhibit D2 dopamine receptors (DRD2s) 29 , 30 . Given the germline occurrence of deleted genes in 22q11DS, it is unclear why the onset of positive symptoms is delayed. Recently, Dgcr8 emerged as a culprit gene responsible for several neuronal phenotypes in mouse models of 22q11DS 31 , 32 , including the disruption of synaptic transmission at TC projections to the ACx 5 . Dgcr8 is part of the microprocessor complex that mediates the biogenesis of miRNAs, small RNAs that negatively regulate the stability of target mRNAs, as well as protein translation 33 . Dgcr8 haploinsufficiency in individuals with 22q11DS leads to depletion of miRNAs and the resultant upregulation of respective targets, which in turn disrupts synaptic transmission, synaptic plasticity, and proper functioning of neural circuits 34 . In adult mouse models of 22q11DS, Dgcr8 haploinsufficiency is sufficient to upregulate Drd2 mRNA and Drd2 protein in the auditory thalamus, causing auditory abnormalities that include decreased glutamatergic synaptic transmission at TC projections to the ACx and deficient prepulse inhibition (PPI) of the acoustic-startle response 5 . Abnormally high levels of Drd2 in the thalamus of 22q11DS mice increase TC projection sensitivity to Drd2 antagonists, including antipsychotics. Consequently, auditory synaptic and behavioral abnormalities of 22q11DS mice are rescued by treatment with antipsychotics 5 . Here we tested whether TC disruption follows the same age-dependent trajectory as psychosis in patients with 22q11DS or schizophrenia and determined the molecular underpinnings of TC disruption in 22q11DS mice. Results Delayed disruption of TC synaptic transmission in mouse models of 22q11DS We compared basal synaptic transmission in young (2-month-old) and mature (4-month-old) Df(16)1 /+ mice, a murine model of 22q11DS 6 ( Fig. 1a ), and their wild-type (WT) littermates. Mice between the ages of 3 and 6 months correspond to mature human adults between the ages of 20 and 30 years 35 . Using whole-cell voltage-clamp recordings, we measured TC excitatory postsynaptic currents (EPSCs) from thalamorecipient ACx cortical layer (L) 3/4 pyramidal neurons 36 while stimulating TC projections in acute brain slices containing the auditory thalamus (i.e., the ventral part of the medial geniculate nucleus (MGv)) and the ACx ( Fig. 1b ). The input–output relationship between stimulation intensity and TC EPSC, a measure of basal synaptic transmission at TC projections, was deficient in older but not younger mutant mice as compared to that in WT controls ( Fig. 1c,d ). Consistent with the notion that the increased amount of Drd2 in thalamic relay neurons reduces glutamatergic synaptic transmission at auditory TC projections in Df(16)1 /+ mice 5 , the Drd2 mRNA level was elevated in the MGv of older but not younger Df(16)1 /+ mice ( Fig. 1e ). Figure 1: Adult onset of sensitivity to antipsychotics and of synaptic transmission disruption in auditory TC projections in mouse models of 22q11DS. ( a ) Map of mouse chromosome 16, showing 22q11DS-associated genes that are deleted in Df(16)1 /+ mice. ( b ) Illustration of voltage-clamp recordings of thalamorecipient L3/4 pyramidal neurons in TC slices. TC projections are shown in red. ACx, auditory cortex; TC, thalamocortical; MGv, ventral part of the medial geniculate nuclei. ( c , d ) Input–output relations between stimulation intensity and EPSCs at TC projections in the ACx of 2-month-old ( F (1,37) = 0.967; P = 0.338) ( c ) or 4-month-old ( F (1,46) = 11.56; P < 0.001) ( d ) WT (20 and 23 neurons, respectively) and Df(16)1 /+ mice (19 and 25 neurons, respectively). ( e ) Drd2 transcript levels in the MGv of 2-month-old ( n =", "role": "user" }, { "content": "St. Jude Children's Research Hospital scientists have identified a small RNA (microRNA) that may be essential to restoring normal function in a brain circuit associated with the \"voices\" and other hallucinations of schizophrenia. The microRNA provides a possible focus for antipsychotic drug development. The findings appear today in the journal Nature Medicine. The work was done in a mouse model of a human disorder that is one of the genetic causes of schizophrenia. Building on previous St. Jude research, the results offer important new details about the molecular mechanism that disrupts the flow of information along a neural circuit connecting two brain regions involved in processing auditory information. The findings also provide clues about why psychotic symptoms of schizophrenia are often delayed until late adolescence or early adulthood. \"In 2014, we identified the specific circuit in the brain that is targeted by antipsychotic drugs. However, the existing antipsychotics also cause devastating side effects,\" said corresponding author Stanislav Zakharenko, M.D., Ph.D., a member of the St. Jude Department of Developmental Neurobiology. \"In this study, we identified the microRNA that is a key player in disruption of that circuit and showed that depletion of the microRNA was necessary and sufficient to inhibit normal functioning of the circuit in the mouse models. \"We also found evidence suggesting that the microRNA, named miR-338-3p, could be targeted for development of a new class of antipsychotic drugs with fewer side effects.\" There are more than 2,000 microRNAs whose function is to silence expression of particular genes and regulate the supply of the corresponding proteins. Working in a mouse model of 22q11 deletion syndrome, researchers identified miR-338-3p as the microRNA that regulates production of the protein D2 dopamine receptor (Drd2), which is the prime target of antipsychotics. Individuals with the deletion syndrome are at risk for behavior problems as children. Between 23 and 43 percent develop schizophrenia, a severe chronic disorder that affects thinking, memory and behavior. Researchers at St. Jude are studying schizophrenia and other brain disorders to improve understanding of how normal brains develop, which provides insights into the origins of diseases like cancer. The scientists reported that Drd2 increased in the brain's auditory thalamus when levels of the microRNA declined. Previous research from Zakharenko's laboratory linked elevated levels of Drd2 in the auditory thalamus to brain-circuit disruptions in the mutant mice. Investigators also reported that the protein was elevated in the same brain region of individuals with schizophrenia, but not healthy adults. Individuals with the deletion syndrome are missing part of chromosome 22, which leaves them with one rather than the normal two copies of more than 25 genes. The missing genes included Dgcr8, which facilitates production of microRNAs. Working in mice, researchers have now linked the 22q11 deletion syndrome and deletion of a single Dgcr8 gene to age-related declines in miR-338-3p in the auditory thalamus. The decline was associated with an increase in Drd2 and reduced signaling in the circuit that links the thalamus and auditory cortex, a brain region implicated in auditory hallucination. Levels of miR-338-3p were lower in the thalamus of individuals with schizophrenia compared to individuals of the same age and sex without the diagnosis. The miR-338-3p depletion did not disrupt other brain circuits in the mutant mice, and the findings offer a possible explanation. Researchers found that miR-338-3p levels were higher in the thalamus than in other brain regions. In addition, miR-338-3p was one of the most abundant microRNAs present in the thalamus. Replenishing levels of the microRNA in the auditory thalamus of mutant mice reduced Drd2 protein and restored the circuit to normal functioning. That suggests that the microRNA could be the basis for a new class of antipsychotic drugs that act in a more targeted manner with fewer side effects. Antipsychotic drugs, which target Drd2, also restored circuit function. The findings provide insight into the age-related delay in the onset of schizophrenia symptoms. Researchers noted that microRNA levels declined with age in all mice, but that mutant mice began with lower levels of miR-338-3p. \"A minimum level of the microRNA may be necessary to prevent excessive production of the Drd2 that disrupts the circuit,\" Zakharenko said. \"While miR-338-3p levels decline as normal mice age, levels may remain above the threshold necessary to prevent overexpression of the protein. In contrast, the deletion syndrome may leave mice at risk for dropping below that threshold.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Although 22q11.2 deletion syndrome (22q11DS) is associated with early-life behavioral abnormalities, affected individuals are also at high risk for the development of schizophrenia symptoms, including psychosis, later in life. Auditory thalamocortical (TC) projections recently emerged as a neural circuit that is specifically disrupted in mouse models of 22q11DS (hereafter referred to as 22q11DS mice), in which haploinsufficiency of the microRNA (miRNA)-processing-factor-encoding gene Dgcr8 results in the elevation of the dopamine receptor Drd2 in the auditory thalamus, an abnormal sensitivity of thalamocortical projections to antipsychotics, and an abnormal acoustic-startle response. Here we show that these auditory TC phenotypes have a delayed onset in 22q11DS mice and are associated with an age-dependent reduction of miR-338-3p, a miRNA that targets Drd2 and is enriched in the thalamus of both humans and mice. Replenishing depleted miR-338-3p in mature 22q11DS mice rescued the TC abnormalities, and deletion of Mir338 (which encodes miR-338-3p) or reduction of miR-338-3p expression mimicked the TC and behavioral deficits and eliminated the age dependence of these deficits. Therefore, miR-338-3p depletion is necessary and sufficient to disrupt auditory TC signaling in 22q11DS mice, and it may mediate the pathogenic mechanism of 22q11DS-related psychosis and control its late onset. Main Thalamocortical projections to the auditory cortex (ACx), a brain region implicated in auditory hallucinations 1 , 2 , 3 , 4 , have emerged as a circuit that is specifically disrupted 5 in mouse models of 22q11DS 6 . This disorder, the most common microdeletion syndrome in humans 7 , 8 , is caused by a hemizygous microdeletion (1.5–3 Mb) on the long arm of chromosome 22 (ref. 9 ). 22q11DS is considered to be a leading genetic cause of schizophrenia 10 , 11 , 12 . Schizophrenia develops in 23–43% of individuals with 22q11DS 13 , 14 , 15 , 16 , 17 , 18 , most of whom experience psychosis 19 , 20 . Furthermore, 30–50% of individuals who do not have schizophrenia but have 22q11DS demonstrate subthreshold symptoms of psychosis 21 . Nonpsychotic behavioral abnormalities are present from early life in patients with 22q11DS 22 , 23 , but psychotic symptoms and schizophrenia are delayed; the median age of psychosis onset is 21 years 18 , 24 , 25 . In patients with schizophrenia, auditory hallucinations and other psychotic symptoms are similarly delayed until late adolescence or early adulthood 26 , 27 , present in 60–90% of cases 28 , and often alleviated by treatment with antipsychotics that inhibit D2 dopamine receptors (DRD2s) 29 , 30 . Given the germline occurrence of deleted genes in 22q11DS, it is unclear why the onset of positive symptoms is delayed. Recently, Dgcr8 emerged as a culprit gene responsible for several neuronal phenotypes in mouse models of 22q11DS 31 , 32 , including the disruption of synaptic transmission at TC projections to the ACx 5 . Dgcr8 is part of the microprocessor complex that mediates the biogenesis of miRNAs, small RNAs that negatively regulate the stability of target mRNAs, as well as protein translation 33 . Dgcr8 haploinsufficiency in individuals with 22q11DS leads to depletion of miRNAs and the resultant upregulation of respective targets, which in turn disrupts synaptic transmission, synaptic plasticity, and proper functioning of neural circuits 34 . In adult mouse models of 22q11DS, Dgcr8 haploinsufficiency is sufficient to upregulate Drd2 mRNA and Drd2 protein in the auditory thalamus, causing auditory abnormalities that include decreased glutamatergic synaptic transmission at TC projections to the ACx and deficient prepulse inhibition (PPI) of the acoustic-startle response 5 . Abnormally high levels of Drd2 in the thalamus of 22q11DS mice increase TC projection sensitivity to Drd2 antagonists, including antipsychotics. Consequently, auditory synaptic and behavioral abnormalities of 22q11DS mice are rescued by treatment with antipsychotics 5 . Here we tested whether TC disruption follows the same age-dependent trajectory as psychosis in patients with 22q11DS or schizophrenia and determined the molecular underpinnings of TC disruption in 22q11DS mice. Results Delayed disruption of TC synaptic transmission in mouse models of 22q11DS We compared basal synaptic transmission in young (2-month-old) and mature (4-month-old) Df(16)1 /+ mice, a murine model of 22q11DS 6 ( Fig. 1a ), and their wild-type (WT) littermates. Mice between the ages of 3 and 6 months correspond to mature human adults between the ages of 20 and 30 years 35 . Using whole-cell voltage-clamp recordings, we measured TC excitatory postsynaptic currents (EPSCs) from thalamorecipient ACx cortical layer (L) 3/4 pyramidal neurons 36 while stimulating TC projections in acute brain slices containing the auditory thalamus (i.e., the ventral part of the medial geniculate nucleus (MGv)) and the ACx ( Fig. 1b ). The input–output relationship between stimulation intensity and TC EPSC, a measure of basal synaptic transmission at TC projections, was deficient in older but not younger mutant mice as compared to that in WT controls ( Fig. 1c,d ). Consistent with the notion that the increased amount of Drd2 in thalamic relay neurons reduces glutamatergic synaptic transmission at auditory TC projections in Df(16)1 /+ mice 5 , the Drd2 mRNA level was elevated in the MGv of older but not younger Df(16)1 /+ mice ( Fig. 1e ). Figure 1: Adult onset of sensitivity to antipsychotics and of synaptic transmission disruption in auditory TC projections in mouse models of 22q11DS. ( a ) Map of mouse chromosome 16, showing 22q11DS-associated genes that are deleted in Df(16)1 /+ mice. ( b ) Illustration of voltage-clamp recordings of thalamorecipient L3/4 pyramidal neurons in TC slices. TC projections are shown in red. ACx, auditory cortex; TC, thalamocortical; MGv, ventral part of the medial geniculate nuclei. ( c , d ) Input–output relations between stimulation intensity and EPSCs at TC projections in the ACx of 2-month-old ( F (1,37) = 0.967; P = 0.338) ( c ) or 4-month-old ( F (1,46) = 11.56; P < 0.001) ( d ) WT (20 and 23 neurons, respectively) and Df(16)1 /+ mice (19 and 25 neurons, respectively). ( e ) Drd2 transcript levels in the MGv of 2-month-old ( n =<|im_end|> <|im_start|>assistant St. Jude Children's Research Hospital scientists have identified a small RNA (microRNA) that may be essential to restoring normal function in a brain circuit associated with the "voices" and other hallucinations of schizophrenia. The microRNA provides a possible focus for antipsychotic drug development. The findings appear today in the journal Nature Medicine. The work was done in a mouse model of a human disorder that is one of the genetic causes of schizophrenia. Building on previous St. Jude research, the results offer important new details about the molecular mechanism that disrupts the flow of information along a neural circuit connecting two brain regions involved in processing auditory information. The findings also provide clues about why psychotic symptoms of schizophrenia are often delayed until late adolescence or early adulthood. "In 2014, we identified the specific circuit in the brain that is targeted by antipsychotic drugs. However, the existing antipsychotics also cause devastating side effects," said corresponding author Stanislav Zakharenko, M.D., Ph.D., a member of the St. Jude Department of Developmental Neurobiology. "In this study, we identified the microRNA that is a key player in disruption of that circuit and showed that depletion of the microRNA was necessary and sufficient to inhibit normal functioning of the circuit in the mouse models. "We also found evidence suggesting that the microRNA, named miR-338-3p, could be targeted for development of a new class of antipsychotic drugs with fewer side effects." There are more than 2,000 microRNAs whose function is to silence expression of particular genes and regulate the supply of the corresponding proteins. Working in a mouse model of 22q11 deletion syndrome, researchers identified miR-338-3p as the microRNA that regulates production of the protein D2 dopamine receptor (Drd2), which is the prime target of antipsychotics. Individuals with the deletion syndrome are at risk for behavior problems as children. Between 23 and 43 percent develop schizophrenia, a severe chronic disorder that affects thinking, memory and behavior. Researchers at St. Jude are studying schizophrenia and other brain disorders to improve understanding of how normal brains develop, which provides insights into the origins of diseases like cancer. The scientists reported that Drd2 increased in the brain's auditory thalamus when levels of the microRNA declined. Previous research from Zakharenko's laboratory linked elevated levels of Drd2 in the auditory thalamus to brain-circuit disruptions in the mutant mice. Investigators also reported that the protein was elevated in the same brain region of individuals with schizophrenia, but not healthy adults. Individuals with the deletion syndrome are missing part of chromosome 22, which leaves them with one rather than the normal two copies of more than 25 genes. The missing genes included Dgcr8, which facilitates production of microRNAs. Working in mice, researchers have now linked the 22q11 deletion syndrome and deletion of a single Dgcr8 gene to age-related declines in miR-338-3p in the auditory thalamus. The decline was associated with an increase in Drd2 and reduced signaling in the circuit that links the thalamus and auditory cortex, a brain region implicated in auditory hallucination. Levels of miR-338-3p were lower in the thalamus of individuals with schizophrenia compared to individuals of the same age and sex without the diagnosis. The miR-338-3p depletion did not disrupt other brain circuits in the mutant mice, and the findings offer a possible explanation. Researchers found that miR-338-3p levels were higher in the thalamus than in other brain regions. In addition, miR-338-3p was one of the most abundant microRNAs present in the thalamus. Replenishing levels of the microRNA in the auditory thalamus of mutant mice reduced Drd2 protein and restored the circuit to normal functioning. That suggests that the microRNA could be the basis for a new class of antipsychotic drugs that act in a more targeted manner with fewer side effects. Antipsychotic drugs, which target Drd2, also restored circuit function. The findings provide insight into the age-related delay in the onset of schizophrenia symptoms. Researchers noted that microRNA levels declined with age in all mice, but that mutant mice began with lower levels of miR-338-3p. "A minimum level of the microRNA may be necessary to prevent excessive production of the Drd2 that disrupts the circuit," Zakharenko said. "While miR-338-3p levels decline as normal mice age, levels may remain above the threshold necessary to prevent overexpression of the protein. In contrast, the deletion syndrome may leave mice at risk for dropping below that threshold." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Epitaxy is a process by which a thin layer of one crystal is deposited in an ordered fashion onto a substrate crystal. The direct epitaxial growth of semiconductor heterostructures on top of crystalline superconductors has proved challenging. Here, however, we report the successful use of molecular beam epitaxy to grow and integrate niobium nitride (NbN)-based superconductors with the wide-bandgap family of semiconductors—silicon carbide, gallium nitride (GaN) and aluminium gallium nitride (AlGaN). We apply molecular beam epitaxy to grow an AlGaN/GaN quantum-well heterostructure directly on top of an ultrathin crystalline NbN superconductor. The resulting high-mobility, two-dimensional electron gas in the semiconductor exhibits quantum oscillations, and thus enables a semiconductor transistor—an electronic gain element—to be grown and fabricated directly on a crystalline superconductor. Using the epitaxial superconductor as the source load of the transistor, we observe in the transistor output characteristics a negative differential resistance—a feature often used in amplifiers and oscillators. Our demonstration of the direct epitaxial growth of high-quality semiconductor heterostructures and devices on crystalline nitride superconductors opens up the possibility of combining the macroscopic quantum effects of superconductors with the electronic, photonic and piezoelectric properties of the group III/nitride semiconductor family. Main The experimental discovery 1 of superconductivity in 1911 predated the controllable synthesis and understanding of semiconductors 2 by nearly three decades. However, in the time it took to uncover the correlated physics behind superconductivity, rapid advances in the band-theory of semiconductors, perfection in crystal growth, and discoveries such as donor- and acceptor-doping and quantum heterostructure 3 , 4 design had unleashed their technological potential, enabling electronic amplifiers and switches, as well as light-emitting diodes and diode lasers that operate at room temperature. These solid-state devices have replaced bulky and slow vacuum tubes and table-top lasers, and have shrunk information processing, storage, and communication systems onto a chip. Today, semiconductor transistors are reaching their fundamental Boltzmann limits in terms of switching energy and power consumption in the digital von-Neumann computational architecture 5 , and communication systems are approaching their Shannon limits in terms of bandwidth and security. Quantum technologies have been envisaged to offer exponentially faster computation and guaranteed secure communications 6 , and the leading materials for these emerging technologies make use of the macroscopic manifestation of quantum properties in superconductors. Devices such as Josephson junction flux qubits 7 , lossless microwave resonators 8 , AC Josephson junction lasers 9 and superconducting single-photon detectors 10 are the building blocks of these new quantum-information systems. Substantial advances in such systems would be expected if the power of semiconductors could be combined with that of superconductors on a single epitaxial platform 11 , 12 , 13 . The group III/nitride semiconductors GaN (with a bandgap, E g , of about 3.4 eV), indium nitride (InN; E g ≈ 0.6 eV) and AlN ( E g ≈ 6.2 eV) constitute the most revolutionary semiconductor family since silicon. That is because they offer, in a single heterostructure material family (see Fig. 1 ), the necessary ingredients for ultrafast microwave communications 14 , ultralow-power computation 15 , high-voltage switches 16 , infrared through visible to deep-ultraviolet photonic emitters and detectors 17 , 18 , and high-frequency circuit components such as surface acoustic wave and bulk acoustic wave filters 19 . On the other hand, one of the most technologically important superconductor families comprises the nitride compounds NbN x , which have been used for superconducting radio-frequency circuits 20 , squid magnetometers 21 , Josephson junctions 22 , single-photon detectors 10 for quantum communications and astronomy, and a host of other applications 23 . Here, we report the successful epitaxial integration of the semiconducting and superconducting nitride families as a crucial enabler for several applications. Figure 1: Bandgap, lattice constant, crystallinity and superconductivity in epitaxial NbN x on SiC. a , Bandgap versus lattice constant for select nitride semiconductors as well as for SiC. b , Cross-section HAADF-STEM images in black/white (left) and false-colour (right) of 5-nm NbN x grown on an SiC substrate with a AlN capping layer. c , Resistance versus temperature (normalized to the resistance at 16 K), showing the superconducting phase transition of 5-nm (red) and 35-nm (blue) epitaxial NbN x on SiC. Inset, resistance measured up to 300 K. d , The Meissner effect measured on the 5-nm and 35-nm samples, showing clear magnetic-flux expulsion accompanying the superconducting phase transition. These measurements are consistent with the T c obtained in panel c . ×10 and ×0.14 indicate multiplication of the data by 10 or 0.14, respectively, to allow data of different scales to be shown on the same plot. PowerPoint slide Full size image Figure 1a shows that the lattice constants of Nb-based nitride metals—such as hexagonal Nb 2 N and NbN, as well as cubic NbN rotated onto the (111) plane—are very close to the lattice constants of SiC, AlN and the GaN family. Wurtzite GaN and AlN can be grown on cubic (111) silicon, and hexagonal SiC serves as the substrate for the epitaxial growth of AlN- and GaN-based heterostructures for microwave transistors 24 and for quantum-well visible-light-emitting diodes 18 . Recently, we succeeded in growing crystalline epitaxial metal (epiMetal) niobium nitride layers by molecular beam epitaxy (MBE) on SiC, and further grew GaN and AlN layers on the epiMetal layers 25 , 26 . We found that the epiMetal layers retained high crystallinity and electronic conductivity down to thicknesses of a few nanometres 25 , 26 . The crystalline phases of the epilayers could be either hexagonal Nb 2 N or NbN, or cubic NbN. In this study, we have determined that our films are cubic NbN x , with x being around 0.75–0.88 as measured by secondary-ion mass spectrometry (SIMS). In what follows, we will simply refer to the phase and stoichiometry as NbN x . The use of NbN x enables an unprecedented level of epitaxial integration of buried metallic layers with wide-bandgap semiconductors and insulators. While investigating the low-temperature transport properties of the thin MBE-grown NbN x layers, we find a", "role": "user" }, { "content": "Silicon has been the semiconductor material of choice for electronics pretty much since the transistor effect was first observed and identified nearly 80 years ago. There's a valley in California named for it, after all. But a relatively new family of semiconductors – group III-nitrides, including gallium nitride (GaN), indium nitride and aluminum nitride – offers greater versatility than silicon with capabilities for ultrafast wireless communications, high-voltage switches and high intensity lighting and photonics. A team led by Debdeep Jena, professor of electrical and computer engineering (ECE), and David Meyer, head of the Wide Bandgap Materials and Devices section at the Naval Research Laboratory, has successfully devised a semiconductor-superconductor crystal structure featuring GaN grown directly onto a crystal of niobium nitride (NbN), a proven superconductor material used in quantum communications, astronomy and a host of other applications. The group's paper, \"GaN/NbN Epitaxial Semiconductor/Superconductor Heterostructures,\" is being published online March 8 in Nature. Former postdoctoral researcher Rusen Yan and current postdoc Guru Khalsa are co-lead authors. Other key contributors were Grace Xing, the Richard Lundquist Sesquicentennial Professor in ECE and MSE, and David Muller, the Samuel B. Eckert Professor of Engineering in the Department of Applied and Engineering Physics. The method for combining the two materials – molecular beam epitaxy (MBE), essentially spray painting of gallium and nitrogen atoms onto the NbN in a vacuum environment – creates an extremely clean interface and is key to the success of the novel structure. This advance, the group says, opens up a range of possibilities that can now combine the macroscopic quantum effects of superconductors with the rich electronic and photonic properties of group III-nitride semiconductors. \"People have tried it with other semiconductors, like silicon and gallium arsenide, but I don't think anything has been as successful as what we've managed to do with GaN,\" said Jena, who has a dual appointment with the Department of Materials Science and Engineering (MSE). Gallium nitride-based semiconductors have recently made major inroads in the areas of LED lighting, Blu-ray laser diodes, energy and communications. In fact, the 2014 Nobel Prize in physics was given to a trio of Japanese scientists for their invention of energy-efficient blue light-emitting diodes (LEDs) using GaN. Technological advances – particularly the type of MBE used in this work, which was developed at the Naval Research Laboratory – has made it possible for scientists to think about semiconductor-superconductor heterostructures such as the one Jena's group has developed. The specialized nitride MBE system includes an electron beam evaporator source, which \"melts\" the niobium – which has a melting point of around 4,500 degrees – but not the crucible it's in. Atoms of niobium are deposited onto a silicon carbide wafer, and the GaN semiconductor layers are then grown on top of that, also by MBE. \"This new source allowed us to overcome the temperature limitations of conventional sources, and bring high-melting-point, refractory transition metals like niobium and tantalum into the picture,\" Meyer said. The team demonstrated for the first time the growth and fabrication of a semiconductor transistor switch, the prototypical gain element in electronics, directly on top of a crystalline superconductor layer. This heterostructure is a kind of \"best of both worlds,\" Jena said, offering a method for devising quantum computation and highly secure communications systems. \"There are some things that we would love to do with quantum systems – quantum computation and cryptography, things that are not possible in classical systems,\" he said. \"On the other hand, there are things that classical systems are much better at than quantum systems. And there is this mesozone where you can do wonderful things by mixing and matching the two.\" \"We think this presents a wonderful opportunity for rapid technology development of next-generation communications and computation systems,\" Meyer said. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Epitaxy is a process by which a thin layer of one crystal is deposited in an ordered fashion onto a substrate crystal. The direct epitaxial growth of semiconductor heterostructures on top of crystalline superconductors has proved challenging. Here, however, we report the successful use of molecular beam epitaxy to grow and integrate niobium nitride (NbN)-based superconductors with the wide-bandgap family of semiconductors—silicon carbide, gallium nitride (GaN) and aluminium gallium nitride (AlGaN). We apply molecular beam epitaxy to grow an AlGaN/GaN quantum-well heterostructure directly on top of an ultrathin crystalline NbN superconductor. The resulting high-mobility, two-dimensional electron gas in the semiconductor exhibits quantum oscillations, and thus enables a semiconductor transistor—an electronic gain element—to be grown and fabricated directly on a crystalline superconductor. Using the epitaxial superconductor as the source load of the transistor, we observe in the transistor output characteristics a negative differential resistance—a feature often used in amplifiers and oscillators. Our demonstration of the direct epitaxial growth of high-quality semiconductor heterostructures and devices on crystalline nitride superconductors opens up the possibility of combining the macroscopic quantum effects of superconductors with the electronic, photonic and piezoelectric properties of the group III/nitride semiconductor family. Main The experimental discovery 1 of superconductivity in 1911 predated the controllable synthesis and understanding of semiconductors 2 by nearly three decades. However, in the time it took to uncover the correlated physics behind superconductivity, rapid advances in the band-theory of semiconductors, perfection in crystal growth, and discoveries such as donor- and acceptor-doping and quantum heterostructure 3 , 4 design had unleashed their technological potential, enabling electronic amplifiers and switches, as well as light-emitting diodes and diode lasers that operate at room temperature. These solid-state devices have replaced bulky and slow vacuum tubes and table-top lasers, and have shrunk information processing, storage, and communication systems onto a chip. Today, semiconductor transistors are reaching their fundamental Boltzmann limits in terms of switching energy and power consumption in the digital von-Neumann computational architecture 5 , and communication systems are approaching their Shannon limits in terms of bandwidth and security. Quantum technologies have been envisaged to offer exponentially faster computation and guaranteed secure communications 6 , and the leading materials for these emerging technologies make use of the macroscopic manifestation of quantum properties in superconductors. Devices such as Josephson junction flux qubits 7 , lossless microwave resonators 8 , AC Josephson junction lasers 9 and superconducting single-photon detectors 10 are the building blocks of these new quantum-information systems. Substantial advances in such systems would be expected if the power of semiconductors could be combined with that of superconductors on a single epitaxial platform 11 , 12 , 13 . The group III/nitride semiconductors GaN (with a bandgap, E g , of about 3.4 eV), indium nitride (InN; E g ≈ 0.6 eV) and AlN ( E g ≈ 6.2 eV) constitute the most revolutionary semiconductor family since silicon. That is because they offer, in a single heterostructure material family (see Fig. 1 ), the necessary ingredients for ultrafast microwave communications 14 , ultralow-power computation 15 , high-voltage switches 16 , infrared through visible to deep-ultraviolet photonic emitters and detectors 17 , 18 , and high-frequency circuit components such as surface acoustic wave and bulk acoustic wave filters 19 . On the other hand, one of the most technologically important superconductor families comprises the nitride compounds NbN x , which have been used for superconducting radio-frequency circuits 20 , squid magnetometers 21 , Josephson junctions 22 , single-photon detectors 10 for quantum communications and astronomy, and a host of other applications 23 . Here, we report the successful epitaxial integration of the semiconducting and superconducting nitride families as a crucial enabler for several applications. Figure 1: Bandgap, lattice constant, crystallinity and superconductivity in epitaxial NbN x on SiC. a , Bandgap versus lattice constant for select nitride semiconductors as well as for SiC. b , Cross-section HAADF-STEM images in black/white (left) and false-colour (right) of 5-nm NbN x grown on an SiC substrate with a AlN capping layer. c , Resistance versus temperature (normalized to the resistance at 16 K), showing the superconducting phase transition of 5-nm (red) and 35-nm (blue) epitaxial NbN x on SiC. Inset, resistance measured up to 300 K. d , The Meissner effect measured on the 5-nm and 35-nm samples, showing clear magnetic-flux expulsion accompanying the superconducting phase transition. These measurements are consistent with the T c obtained in panel c . ×10 and ×0.14 indicate multiplication of the data by 10 or 0.14, respectively, to allow data of different scales to be shown on the same plot. PowerPoint slide Full size image Figure 1a shows that the lattice constants of Nb-based nitride metals—such as hexagonal Nb 2 N and NbN, as well as cubic NbN rotated onto the (111) plane—are very close to the lattice constants of SiC, AlN and the GaN family. Wurtzite GaN and AlN can be grown on cubic (111) silicon, and hexagonal SiC serves as the substrate for the epitaxial growth of AlN- and GaN-based heterostructures for microwave transistors 24 and for quantum-well visible-light-emitting diodes 18 . Recently, we succeeded in growing crystalline epitaxial metal (epiMetal) niobium nitride layers by molecular beam epitaxy (MBE) on SiC, and further grew GaN and AlN layers on the epiMetal layers 25 , 26 . We found that the epiMetal layers retained high crystallinity and electronic conductivity down to thicknesses of a few nanometres 25 , 26 . The crystalline phases of the epilayers could be either hexagonal Nb 2 N or NbN, or cubic NbN. In this study, we have determined that our films are cubic NbN x , with x being around 0.75–0.88 as measured by secondary-ion mass spectrometry (SIMS). In what follows, we will simply refer to the phase and stoichiometry as NbN x . The use of NbN x enables an unprecedented level of epitaxial integration of buried metallic layers with wide-bandgap semiconductors and insulators. While investigating the low-temperature transport properties of the thin MBE-grown NbN x layers, we find a<|im_end|> <|im_start|>assistant Silicon has been the semiconductor material of choice for electronics pretty much since the transistor effect was first observed and identified nearly 80 years ago. There's a valley in California named for it, after all. But a relatively new family of semiconductors – group III-nitrides, including gallium nitride (GaN), indium nitride and aluminum nitride – offers greater versatility than silicon with capabilities for ultrafast wireless communications, high-voltage switches and high intensity lighting and photonics. A team led by Debdeep Jena, professor of electrical and computer engineering (ECE), and David Meyer, head of the Wide Bandgap Materials and Devices section at the Naval Research Laboratory, has successfully devised a semiconductor-superconductor crystal structure featuring GaN grown directly onto a crystal of niobium nitride (NbN), a proven superconductor material used in quantum communications, astronomy and a host of other applications. The group's paper, "GaN/NbN Epitaxial Semiconductor/Superconductor Heterostructures," is being published online March 8 in Nature. Former postdoctoral researcher Rusen Yan and current postdoc Guru Khalsa are co-lead authors. Other key contributors were Grace Xing, the Richard Lundquist Sesquicentennial Professor in ECE and MSE, and David Muller, the Samuel B. Eckert Professor of Engineering in the Department of Applied and Engineering Physics. The method for combining the two materials – molecular beam epitaxy (MBE), essentially spray painting of gallium and nitrogen atoms onto the NbN in a vacuum environment – creates an extremely clean interface and is key to the success of the novel structure. This advance, the group says, opens up a range of possibilities that can now combine the macroscopic quantum effects of superconductors with the rich electronic and photonic properties of group III-nitride semiconductors. "People have tried it with other semiconductors, like silicon and gallium arsenide, but I don't think anything has been as successful as what we've managed to do with GaN," said Jena, who has a dual appointment with the Department of Materials Science and Engineering (MSE). Gallium nitride-based semiconductors have recently made major inroads in the areas of LED lighting, Blu-ray laser diodes, energy and communications. In fact, the 2014 Nobel Prize in physics was given to a trio of Japanese scientists for their invention of energy-efficient blue light-emitting diodes (LEDs) using GaN. Technological advances – particularly the type of MBE used in this work, which was developed at the Naval Research Laboratory – has made it possible for scientists to think about semiconductor-superconductor heterostructures such as the one Jena's group has developed. The specialized nitride MBE system includes an electron beam evaporator source, which "melts" the niobium – which has a melting point of around 4,500 degrees – but not the crucible it's in. Atoms of niobium are deposited onto a silicon carbide wafer, and the GaN semiconductor layers are then grown on top of that, also by MBE. "This new source allowed us to overcome the temperature limitations of conventional sources, and bring high-melting-point, refractory transition metals like niobium and tantalum into the picture," Meyer said. The team demonstrated for the first time the growth and fabrication of a semiconductor transistor switch, the prototypical gain element in electronics, directly on top of a crystalline superconductor layer. This heterostructure is a kind of "best of both worlds," Jena said, offering a method for devising quantum computation and highly secure communications systems. "There are some things that we would love to do with quantum systems – quantum computation and cryptography, things that are not possible in classical systems," he said. "On the other hand, there are things that classical systems are much better at than quantum systems. And there is this mesozone where you can do wonderful things by mixing and matching the two." "We think this presents a wonderful opportunity for rapid technology development of next-generation communications and computation systems," Meyer said. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Currently, no oral medications are available for type 1 diabetes (T1D). While our recent randomized placebo-controlled T1D trial revealed that oral verapamil had short-term beneficial effects, their duration and underlying mechanisms remained elusive. Now, our global T1D serum proteomics analysis identified chromogranin A (CHGA), a T1D-autoantigen, as the top protein altered by verapamil and as a potential therapeutic marker and revealed that verapamil normalizes serum CHGA levels and reverses T1D-induced elevations in circulating proinflammatory T-follicular-helper cell markers. RNA-sequencing further confirmed that verapamil regulates the thioredoxin system and promotes an anti-oxidative, anti-apoptotic and immunomodulatory gene expression profile in human islets. Moreover, continuous use of oral verapamil delayed T1D progression, promoted endogenous beta-cell function and lowered insulin requirements and serum CHGA levels for at least 2 years and these benefits were lost upon discontinuation. Thus, the current studies provide crucial mechanistic and clinical insight into the beneficial effects of verapamil in T1D. Introduction Diabetes continues to grow as a chronic global health problem, affecting people of all ages. Since the discovery of insulin, a century ago, therapies have improved dramatically, but many critical needs and hurdles remain and prevent subjects with diabetes from living a truly normal life. In the case of type 1 diabetes (T1D), which involves autoimmune and inflammatory processes and destruction of insulin-producing pancreatic beta cells, exogenous insulin is still the only available therapy, and it is associated with the inherent risk of low blood glucose levels or hypoglycemic episodes that can be life-threatening. In addition, administration of insulin entails either continuous infusion via a pump or multiple daily injections and no oral medications are available. Recently, we reported the results of a small, phase 2, randomized placebo-controlled trial, using oral verapamil, an approved blood pressure medication, in new-onset T1D subjects 1 . Subjects receiving verapamil had improved endogenous beta cell function (as measured by a 2 h mixed-meal-stimulated C-peptide area under the curve (AUC)), lower insulin requirements, and fewer hypoglycemic events as compared to individuals getting placebo added to their standard insulin regimen 1 . Even though all subjects were normotensive, verapamil did not lead to any hypotension or any adverse events. While highly promising, these findings also raised a number of new mechanistic questions, including what exact biological changes verapamil elicits in humans with T1D, how long they may last, and how these changes and any potential associated therapeutic success could be monitored. The current studies were aimed at addressing these questions using proteomics, transcriptomics, and pathophysiological approaches. In this work, we now show that verapamil reverses T1D associated increases in serum CHGA levels, proinflammatory interleukin-21 (IL-21) levels, and T-follicular-helper (Tfh) cell markers and promotes an anti-oxidative, anti-apoptotic and immunomodulatory gene expression profile in human islets. In addition, our results suggest that continuous use of oral verapamil in subjects with T1D may delay loss of beta cell function and lower insulin requirements for at least 2 years post-diagnosis and that such therapeutic success or disease progression can be monitored by changes in serum CHGA. Results To assess potential systemic changes in response to verapamil treatment, we conducted a global proteomics analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS) of serum samples from subjects at baseline and after 1 year of receiving verapamil or placebo and determined the effect of treatment on changes over time. 10 subjects had sufficient usable serum for LC-MS/MS at both of these time points resulting in 20 samples used for proteomics analysis (Supplementary Fig. 1 ). The baseline subject characteristics of this subset and of the full set of study participants are shown in Supplementary Table 1 and they demonstrate that there were no significant differences between the treatment groups with respect to age, gender, race, BMI, or HbA1C. Also, analysis of serum from the same subject before and 1 year after treatment allowed each subject to provide its own baseline control and avoid confounding effects from inter-individual variability. Applying a global serum proteomics workflow (Supplementary Fig. 1 ) along with this tightly controlled design, we were able to quantify 31,457 unique peptides and 867 proteins (<1% false discovery rate, FDR) with TMT reporter ion intensity data across all channels without missing data in the 20 serum samples (Supplementary Fig. 2 ). The raw dataset from this study is available at ProteomeXchange (accession # PXD026601). Following statistical analysis on treatment effect using a linear regression model, 53 proteins were identified whose relative abundance over time was significantly altered ( P < 0.05) by verapamil treatment (Supplementary Table 2 ). Enrichr 2 analysis of these proteins revealed enrichment for gene ontology biological processes such as neutrophil-mediated immunity and regulation of acute inflammatory and humoral immune responses as well as regulation of cellular metabolic processes (Supplementary Table 3 ). In fact, we observed a downregulation of leukocyte immunoglobulin-like receptor subfamily A member 3 (LILRA3 aka CD85e) and of secreted and transmembrane protein 1 (SECTM1) in response to verapamil, both proteins known to be involved in immune modulation (Supplementary Table 2 ). The cluster of differentiation 81 (CD81), which associates with CD4 and CD8 on T cells and provides a costimulatory signal with CD3 was also downregulated by verapamil, as was osteoclast-associated immunoglobulin-like receptor (OSCAR), a member of the leukocyte receptor complex protein family that regulates innate and adaptive immune responses. Interestingly though, chromogranin A (CHGA) emerged as the top serum protein altered by verapamil treatment in subjects with T1D exhibiting the most significant change in relative abundance over time in response to treatment as assessed by linear regression (Supplementary Table 2 ). In addition, two-sided t-test and paired t-test demonstrated that CHGA (unlike most other proteins) was also significantly downregulated in the verapamil group at year 1 as compared to placebo ( P = 0.007) and as compared to baseline ( P = 0.004), respectively. CHGA is a secreted glycoprotein produced by neuroendocrine cells and as such, it has been well established as a marker of neuroendocrine tumors. Within the cells, CHGA is localized in secretory granules including those of pancreatic beta cells, raising the", "role": "user" }, { "content": "Use of the drug verapamil to treat Type 1 diabetes continues to show benefits lasting at least two years, researchers report in the journal Nature Communications. Patients taking the oral blood pressure medication not only required less daily insulin two years after first diagnosis of the disease, but also showed evidence of surprising immunomodulatory benefits. Continuing medication was necessary. In the two-year study, subjects who stopped daily doses of verapamil at one year saw their disease at two years worsen at rates similar to those of the control group of diabetes patients who did not use verapamil at all. Type 1 diabetes is an autoimmune disease that causes loss of pancreatic beta cells, which produce endogenous insulin. To replace that, patients must take exogenous insulin by shots or pump and are at risk of dangerous low blood sugar events. There is no current oral treatment for this disease. The suggestion that verapamil might serve as a potential Type 1 diabetes drug was the serendipitous discovery of study leader Anath Shalev, M.D., director of the Comprehensive Diabetes Center at the University of Alabama at Birmingham. This finding stemmed from more than two decades of her basic research into a gene in pancreatic islets called TXNIP. In 2014, Shalev's UAB research lab reported that verapamil completely reversed diabetes in animal models, and she announced plans to test the effects of the drug in a human clinical trial. The United States Food and Drug Administration approved verapamil for the treatment of high blood pressure in 1981. In 2018, Shalev and colleagues reported the benefits of verapamil in a one-year clinical study of Type 1 diabetes patients, finding that regular oral administration of verapamil enabled patients to produce higher levels of their own insulin, thus limiting their need for injected insulin to regulate blood sugar levels. The current study extends on that finding and provides crucial mechanistic and clinical insights into the beneficial effects of verapamil in Type 1 diabetes, using proteomics analysis and RNA sequencing. To examine changes in circulating proteins in response to verapamil treatment, the researchers used liquid chromatography-tandem mass spectrometry of blood serum samples from subjects diagnosed with Type 1 diabetes within three months of diagnosis and at one year of follow-up. Fifty-three proteins showed significantly altered relative abundance over time in response to verapamil. These included proteins known to be involved in immune modulation and autoimmunity of Type 1 diabetes. The top serum protein altered by verapamil treatment was chromogranin A, or CHGA, which was downregulated with treatment. CHGA is localized in secretory granules, including those of pancreatic beta cells, suggesting that changed CHGA levels might reflect alterations in beta cell integrity. In contrast, the elevated levels of CHGA at Type 1 diabetes onset did not change in control subjects who did not take verapamil. CHGA levels were also easily measured directly in serum using a simple ELISA assay after a blood draw, and lower levels in verapamil-treated subjects correlated with better endogenous insulin production as measured by mixed-meal-stimulated C-peptide, a standard test of Type 1 diabetes progression. Also, serum CHGA levels in healthy, non-diabetic volunteers were about twofold lower compared to subjects with Type 1 diabetes, and after one year of verapamil treatment, verapamil-treated Type 1 diabetes subjects had similar CHGA levels compared with healthy individuals. In the second year, CHGA levels continued to drop in verapamil-treated subjects, but they rose in Type 1 diabetes subjects who discontinued verapamil during year two. \"Thus, serum CHGA seems to reflect changes in beta cell function in response to verapamil treatment or Type 1 diabetes progression and therefore may provide a longitudinal marker of treatment success or disease worsening,\" Shalev said. \"This would address a critical need, as the lack of a simple longitudinal marker has been a major challenge in the Type 1 diabetes field.\" Other labs have identified CHGA as an autoantigen in Type 1 diabetes that provokes immune T cells involved in the autoimmune disease. Thus, Shalev and colleagues asked whether verapamil affected T cells. They found that several proinflammatory markers of T follicular helper cells, including CXCR5 and interleukin 21, were significantly elevated in monocytes from subjects with Type 1 diabetes, as compared to healthy controls, and they found that these changes were reversed by verapamil treatment. \"Now our results reveal for the first time that verapamil treatment may also affect the immune system and reverse these Type 1 diabetes-induced changes,\" Shalev said. \"This suggests that verapamil, and/or the Type 1 diabetes improvements achieved by it, can modulate some circulating proinflammatory cytokines and T helper cell subsets, which in turn may contribute to the overall beneficial effects observed clinically.\" To assess changes in gene expression, RNA sequencing of human pancreatic islet samples exposed to glucose, with or without verapamil was performed and revealed a large number of genes that were either upregulated or downregulated. Analysis of these genes showed that verapamil regulates the thioredoxin system, including TXNIP, and promotes an anti-oxidative, anti-apoptotic and immunomodulatory gene expression profile in human islets. Such protective changes in the pancreatic islets might further explain the sustained improvements in pancreatic beta cell function observed with continuous verapamil use. Shalev and colleagues caution that their study, with its small number of subjects, needs to be confirmed by larger clinical studies, such as a current verapamil-Type 1 diabetes study ongoing in Europe. But the preservation of some beta cell function is promising. \"In humans with Type 1 diabetes, even a small amount of preserved endogenous insulin production—as opposed to higher exogenous insulin requirements—has been shown to be associated with improved outcomes and could help improve quality of life and lower the high costs associated with insulin use,\" Shalev said. \"The fact that these beneficial verapamil effects seemed to persist for two years, whereas discontinuation of verapamil led to disease progression, provides some additional support for its potential usefulness for long-term treatment.\" At UAB, Shalev is a professor in the Department of Medicine Division of Endocrinology, Diabetes and Metabolism, and she holds the Nancy R. and Eugene C. Gwaltney Family Endowed Chair in Juvenile Diabetes Research. Co-authors with Shalev, in the Nature Communications report \"Exploratory study reveals far reaching systemic and cellular effects of verapamil treatment in subjects with type 1 diabetes,\" are Guanlan Xu, Tiffany D. Grimes, Truman B. Grayson, Junqin Chen, Lance A. Thielen and Fernando Ovalle, UAB Department of Medicine, Division of Endocrinology, Diabetes and Metabolism; Hubert M. Tse, UAB Department of Microbiology; Peng Li, UAB School of Nursing; Matt Kanke and Praveen Sethupathy, College of Veterinary Medicine, Cornell University, Ithaca, New York; and Tai-Tu Lin, Athena A. Schepmoes, Adam C. Swensen, Vladislav A. Petyuk and Wei-Jun Qian, Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Currently, no oral medications are available for type 1 diabetes (T1D). While our recent randomized placebo-controlled T1D trial revealed that oral verapamil had short-term beneficial effects, their duration and underlying mechanisms remained elusive. Now, our global T1D serum proteomics analysis identified chromogranin A (CHGA), a T1D-autoantigen, as the top protein altered by verapamil and as a potential therapeutic marker and revealed that verapamil normalizes serum CHGA levels and reverses T1D-induced elevations in circulating proinflammatory T-follicular-helper cell markers. RNA-sequencing further confirmed that verapamil regulates the thioredoxin system and promotes an anti-oxidative, anti-apoptotic and immunomodulatory gene expression profile in human islets. Moreover, continuous use of oral verapamil delayed T1D progression, promoted endogenous beta-cell function and lowered insulin requirements and serum CHGA levels for at least 2 years and these benefits were lost upon discontinuation. Thus, the current studies provide crucial mechanistic and clinical insight into the beneficial effects of verapamil in T1D. Introduction Diabetes continues to grow as a chronic global health problem, affecting people of all ages. Since the discovery of insulin, a century ago, therapies have improved dramatically, but many critical needs and hurdles remain and prevent subjects with diabetes from living a truly normal life. In the case of type 1 diabetes (T1D), which involves autoimmune and inflammatory processes and destruction of insulin-producing pancreatic beta cells, exogenous insulin is still the only available therapy, and it is associated with the inherent risk of low blood glucose levels or hypoglycemic episodes that can be life-threatening. In addition, administration of insulin entails either continuous infusion via a pump or multiple daily injections and no oral medications are available. Recently, we reported the results of a small, phase 2, randomized placebo-controlled trial, using oral verapamil, an approved blood pressure medication, in new-onset T1D subjects 1 . Subjects receiving verapamil had improved endogenous beta cell function (as measured by a 2 h mixed-meal-stimulated C-peptide area under the curve (AUC)), lower insulin requirements, and fewer hypoglycemic events as compared to individuals getting placebo added to their standard insulin regimen 1 . Even though all subjects were normotensive, verapamil did not lead to any hypotension or any adverse events. While highly promising, these findings also raised a number of new mechanistic questions, including what exact biological changes verapamil elicits in humans with T1D, how long they may last, and how these changes and any potential associated therapeutic success could be monitored. The current studies were aimed at addressing these questions using proteomics, transcriptomics, and pathophysiological approaches. In this work, we now show that verapamil reverses T1D associated increases in serum CHGA levels, proinflammatory interleukin-21 (IL-21) levels, and T-follicular-helper (Tfh) cell markers and promotes an anti-oxidative, anti-apoptotic and immunomodulatory gene expression profile in human islets. In addition, our results suggest that continuous use of oral verapamil in subjects with T1D may delay loss of beta cell function and lower insulin requirements for at least 2 years post-diagnosis and that such therapeutic success or disease progression can be monitored by changes in serum CHGA. Results To assess potential systemic changes in response to verapamil treatment, we conducted a global proteomics analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS) of serum samples from subjects at baseline and after 1 year of receiving verapamil or placebo and determined the effect of treatment on changes over time. 10 subjects had sufficient usable serum for LC-MS/MS at both of these time points resulting in 20 samples used for proteomics analysis (Supplementary Fig. 1 ). The baseline subject characteristics of this subset and of the full set of study participants are shown in Supplementary Table 1 and they demonstrate that there were no significant differences between the treatment groups with respect to age, gender, race, BMI, or HbA1C. Also, analysis of serum from the same subject before and 1 year after treatment allowed each subject to provide its own baseline control and avoid confounding effects from inter-individual variability. Applying a global serum proteomics workflow (Supplementary Fig. 1 ) along with this tightly controlled design, we were able to quantify 31,457 unique peptides and 867 proteins (<1% false discovery rate, FDR) with TMT reporter ion intensity data across all channels without missing data in the 20 serum samples (Supplementary Fig. 2 ). The raw dataset from this study is available at ProteomeXchange (accession # PXD026601). Following statistical analysis on treatment effect using a linear regression model, 53 proteins were identified whose relative abundance over time was significantly altered ( P < 0.05) by verapamil treatment (Supplementary Table 2 ). Enrichr 2 analysis of these proteins revealed enrichment for gene ontology biological processes such as neutrophil-mediated immunity and regulation of acute inflammatory and humoral immune responses as well as regulation of cellular metabolic processes (Supplementary Table 3 ). In fact, we observed a downregulation of leukocyte immunoglobulin-like receptor subfamily A member 3 (LILRA3 aka CD85e) and of secreted and transmembrane protein 1 (SECTM1) in response to verapamil, both proteins known to be involved in immune modulation (Supplementary Table 2 ). The cluster of differentiation 81 (CD81), which associates with CD4 and CD8 on T cells and provides a costimulatory signal with CD3 was also downregulated by verapamil, as was osteoclast-associated immunoglobulin-like receptor (OSCAR), a member of the leukocyte receptor complex protein family that regulates innate and adaptive immune responses. Interestingly though, chromogranin A (CHGA) emerged as the top serum protein altered by verapamil treatment in subjects with T1D exhibiting the most significant change in relative abundance over time in response to treatment as assessed by linear regression (Supplementary Table 2 ). In addition, two-sided t-test and paired t-test demonstrated that CHGA (unlike most other proteins) was also significantly downregulated in the verapamil group at year 1 as compared to placebo ( P = 0.007) and as compared to baseline ( P = 0.004), respectively. CHGA is a secreted glycoprotein produced by neuroendocrine cells and as such, it has been well established as a marker of neuroendocrine tumors. Within the cells, CHGA is localized in secretory granules including those of pancreatic beta cells, raising the<|im_end|> <|im_start|>assistant Use of the drug verapamil to treat Type 1 diabetes continues to show benefits lasting at least two years, researchers report in the journal Nature Communications. Patients taking the oral blood pressure medication not only required less daily insulin two years after first diagnosis of the disease, but also showed evidence of surprising immunomodulatory benefits. Continuing medication was necessary. In the two-year study, subjects who stopped daily doses of verapamil at one year saw their disease at two years worsen at rates similar to those of the control group of diabetes patients who did not use verapamil at all. Type 1 diabetes is an autoimmune disease that causes loss of pancreatic beta cells, which produce endogenous insulin. To replace that, patients must take exogenous insulin by shots or pump and are at risk of dangerous low blood sugar events. There is no current oral treatment for this disease. The suggestion that verapamil might serve as a potential Type 1 diabetes drug was the serendipitous discovery of study leader Anath Shalev, M.D., director of the Comprehensive Diabetes Center at the University of Alabama at Birmingham. This finding stemmed from more than two decades of her basic research into a gene in pancreatic islets called TXNIP. In 2014, Shalev's UAB research lab reported that verapamil completely reversed diabetes in animal models, and she announced plans to test the effects of the drug in a human clinical trial. The United States Food and Drug Administration approved verapamil for the treatment of high blood pressure in 1981. In 2018, Shalev and colleagues reported the benefits of verapamil in a one-year clinical study of Type 1 diabetes patients, finding that regular oral administration of verapamil enabled patients to produce higher levels of their own insulin, thus limiting their need for injected insulin to regulate blood sugar levels. The current study extends on that finding and provides crucial mechanistic and clinical insights into the beneficial effects of verapamil in Type 1 diabetes, using proteomics analysis and RNA sequencing. To examine changes in circulating proteins in response to verapamil treatment, the researchers used liquid chromatography-tandem mass spectrometry of blood serum samples from subjects diagnosed with Type 1 diabetes within three months of diagnosis and at one year of follow-up. Fifty-three proteins showed significantly altered relative abundance over time in response to verapamil. These included proteins known to be involved in immune modulation and autoimmunity of Type 1 diabetes. The top serum protein altered by verapamil treatment was chromogranin A, or CHGA, which was downregulated with treatment. CHGA is localized in secretory granules, including those of pancreatic beta cells, suggesting that changed CHGA levels might reflect alterations in beta cell integrity. In contrast, the elevated levels of CHGA at Type 1 diabetes onset did not change in control subjects who did not take verapamil. CHGA levels were also easily measured directly in serum using a simple ELISA assay after a blood draw, and lower levels in verapamil-treated subjects correlated with better endogenous insulin production as measured by mixed-meal-stimulated C-peptide, a standard test of Type 1 diabetes progression. Also, serum CHGA levels in healthy, non-diabetic volunteers were about twofold lower compared to subjects with Type 1 diabetes, and after one year of verapamil treatment, verapamil-treated Type 1 diabetes subjects had similar CHGA levels compared with healthy individuals. In the second year, CHGA levels continued to drop in verapamil-treated subjects, but they rose in Type 1 diabetes subjects who discontinued verapamil during year two. "Thus, serum CHGA seems to reflect changes in beta cell function in response to verapamil treatment or Type 1 diabetes progression and therefore may provide a longitudinal marker of treatment success or disease worsening," Shalev said. "This would address a critical need, as the lack of a simple longitudinal marker has been a major challenge in the Type 1 diabetes field." Other labs have identified CHGA as an autoantigen in Type 1 diabetes that provokes immune T cells involved in the autoimmune disease. Thus, Shalev and colleagues asked whether verapamil affected T cells. They found that several proinflammatory markers of T follicular helper cells, including CXCR5 and interleukin 21, were significantly elevated in monocytes from subjects with Type 1 diabetes, as compared to healthy controls, and they found that these changes were reversed by verapamil treatment. "Now our results reveal for the first time that verapamil treatment may also affect the immune system and reverse these Type 1 diabetes-induced changes," Shalev said. "This suggests that verapamil, and/or the Type 1 diabetes improvements achieved by it, can modulate some circulating proinflammatory cytokines and T helper cell subsets, which in turn may contribute to the overall beneficial effects observed clinically." To assess changes in gene expression, RNA sequencing of human pancreatic islet samples exposed to glucose, with or without verapamil was performed and revealed a large number of genes that were either upregulated or downregulated. Analysis of these genes showed that verapamil regulates the thioredoxin system, including TXNIP, and promotes an anti-oxidative, anti-apoptotic and immunomodulatory gene expression profile in human islets. Such protective changes in the pancreatic islets might further explain the sustained improvements in pancreatic beta cell function observed with continuous verapamil use. Shalev and colleagues caution that their study, with its small number of subjects, needs to be confirmed by larger clinical studies, such as a current verapamil-Type 1 diabetes study ongoing in Europe. But the preservation of some beta cell function is promising. "In humans with Type 1 diabetes, even a small amount of preserved endogenous insulin production—as opposed to higher exogenous insulin requirements—has been shown to be associated with improved outcomes and could help improve quality of life and lower the high costs associated with insulin use," Shalev said. "The fact that these beneficial verapamil effects seemed to persist for two years, whereas discontinuation of verapamil led to disease progression, provides some additional support for its potential usefulness for long-term treatment." At UAB, Shalev is a professor in the Department of Medicine Division of Endocrinology, Diabetes and Metabolism, and she holds the Nancy R. and Eugene C. Gwaltney Family Endowed Chair in Juvenile Diabetes Research. Co-authors with Shalev, in the Nature Communications report "Exploratory study reveals far reaching systemic and cellular effects of verapamil treatment in subjects with type 1 diabetes," are Guanlan Xu, Tiffany D. Grimes, Truman B. Grayson, Junqin Chen, Lance A. Thielen and Fernando Ovalle, UAB Department of Medicine, Division of Endocrinology, Diabetes and Metabolism; Hubert M. Tse, UAB Department of Microbiology; Peng Li, UAB School of Nursing; Matt Kanke and Praveen Sethupathy, College of Veterinary Medicine, Cornell University, Ithaca, New York; and Tai-Tu Lin, Athena A. Schepmoes, Adam C. Swensen, Vladislav A. Petyuk and Wei-Jun Qian, Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington. <|im_end|>

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16867, 40505, 5165, 32184, 11, 8269, 1974, 11, 6652, 13, 220, 128257, 198 ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Honeybee Apis mellifera swarms form large congested tree-hanging clusters made solely of bees attached to each other 1 . How these structures are maintained under the influence of dynamic mechanical forcing is unknown. To address this, we created pendant clusters and subject them to dynamic loads of varying orientation, amplitude, frequency and duration. We find that horizontally shaken clusters adapt by spreading out to form wider, flatter cones that recover their original shape when unloaded. Measuring the response of a cluster to an impulsive pendular excitation shows that flattened cones deform less and relax faster than the elongated ones (that is, they are more stable). Particle-based simulations of a passive assemblage suggest a behavioural hypothesis: individual bees respond to local variations in strain by moving up the strain gradient, which is qualitatively consistent with our observations of individual bee movement during dynamic loading. The simulations also suggest that vertical shaking will not lead to significant differential strains and thus no shape adaptation, which we confirmed experimentally. Together, our findings highlight how a super-organismal structure responds to dynamic loading by actively changing its morphology to improve the collective stability of the cluster at the expense of increasing the average mechanical burden of an individual. Main Collective dynamics allow super-organisms to function in ways that a single organism cannot, by virtue of their emergent size, shape, physiology and behaviour 2 . Classic examples include the physiological and behavioural strategies seen in social insects (for example, ants that link their bodies to form rafts to survive floods 3 , 4 , 5 , 6 , assemble pulling chains to move food items 7 , and form bivouacs 8 and towers 9 , as well as bridges and ladders to traverse rough terrain 10 ). Similarly, groups of `daddy longlegs’ (order Opiliones) huddle together and emperor penguins cluster together for thermoregulation purposes 11 . While much is known about the static forms that are seen in such situations, the stability of these forms to dynamic perturbation, and their global adaptation to environmental changes is much less understood. European honeybees, Apis mellifera L., show many of these collective behaviours during their life cycle 1 . For example, colonies reproduce through colony fission, a process in which a subset of the colony’s workers and a queen leave the hive, separate from the parent colony and form a cluster on a nearby tree branch 1 . In these swarm clusters (which we will refer to as clusters), the bees adhere to each other and form a large structure made of ~10,000 individuals and hundreds of times the size of a single organism (Fig. 1a ). Generally, this hanging mass of adhered bees takes on the shape of an inverted pendant cone; however, the resultant shape is also influenced by the surface to which the cluster is clinging to (see two different examples in Fig. 1a ). The cluster can stay in place for several days as scout bees search the surrounding area for suitable nest sites 1 . Fig. 1: A mechanically adaptive honeybee cluster. a , Bee clusters on a tree branch. b , The experimental set-up consists of a motor driving a wooden board, on which a cluster of bees grips a roughly circular contact area. The motor can produce periodic movement in the horizontal or vertical axis at different frequencies and amplitudes. See Supplementary Fig. 1 for the full set-up. c , The top panel shows the acceleration of the board versus time. The middle and bottom panels show how the bee cluster adapts its shape dynamically: elongated cluster at t = 0 (left column), spread-out cluster after horizontal shaking for 10 min and 30 min (middle columns), and elongated cluster after relaxation (right column); side and bottom views. The contact area before and after shaking is highlighted in blue and red, respectively. Full size image The colony is exposed to the environment during this stage and shows several behaviours to cope with the fluctuating thermal and mechanical environment. For instance, clusters tune their density and surface area to volume ratio to maintain a near constant core temperature despite large fluctuations in the ambient temperature 12 , 13 , 14 . Furthermore, at high temperatures, the swarm expands and forms channels that are presumed to aid in air circulation 12 . Moreover, in response to rain, bees at the surface arrange themselves to form `shingles’, shedding moisture efficiently from the surface of the cluster 15 . Similarly, the cluster is mechanically stable; while it sways from side to side in the wind (for example, see Supplementary Video 1 ), it could be catastrophic if the cluster breaks (when a critical load occurs) as the bees would lose the ability to minimize surface area to prevent hypothermia, while still being mechanically stable. However, the mechanism by which a multitude of bees work together to create and maintain a stable structure that handles both static gravity and dynamic shaking stimuli (for example, wind and predators) remains elusive. To understand this, we develop a laboratory experimental set-up, for ease of visualization and manipulation, to quantify the response of a honeybee cluster to mechanical shaking over short and long times. To prepare a cluster, we attach a caged queen (see Supplementary Section A ) to a board and allowed a cluster to form around her (Fig. 1b ). The bees at the base grip onto an area that is roughly circular. The board is controlled by a motor that can produce movement in the horizontal direction at different frequencies (0.5–5 Hz) and accelerations (ranged 0–0.1 g ). We apply both discontinuous shaking in which the acceleration is kept constant and the frequency is modified, and vice versa, continuous shaking in which the frequency is kept constant and the acceleration is modified (see Supplementary Fig. 2 ). For the case of horizontal shaking (for both discontinuous and continuous), the tall conical cluster swings to and fro in a pendular mode (one of the lowest energy modes of motion,", "role": "user" }, { "content": "If it's a bad idea to kick a hornet's nest, it's certainly a bad idea to shake a bee swarm. Unless, of course, it's for science. A team of Harvard University researchers spent months shaking and rattling swarms of thousands of honey bees to better understand how bees collectively collaborate to stabilize structures in the presence of external loads. The research is published in Nature Physics. \"Our study shows how living systems harness physics to solve complex problems on scales much larger than the individual,\" said L. Mahadevan, the Lola England de Valpine Professor of Applied Mathematics at the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS), Professor of Organismic and Evolutionary Biology (OEB), and Professor of Physics and senior author of the study. \"We demonstrated that bees can harness the physicality of the environment solve a global mechanical stability problem by using local sensing and action\" This research follows earlier work by the group that showed how bees can also collectively maintain the temperature of a cluster using local sensing and actuation to prevent overheating or overcooling. Bee swarms form when a queen bee strikes out with a large group of worker bees to form a new colony. While scouts look for a new nest location, the colony forms a living, breathing structure, made of their own bodies, on a nearby tree branch. These clusters maintain their structure and stability for days in the presence of wind, rain and other external loads. A team of Harvard University researchers spent months shaking and rattling swarms of thousands of honey bees to better understand how bees collectively collaborate to stabilize structures in the presence of external loads. Credit: Jacob Peters, Orit Peleg/Harvard University \"The primary question of our research was, given that individual bees can likely only sense their interactions with their neighbors, how do they make changes to maintain the overall structure of the cluster?\" said Orit Peleg, a former postdoctoral fellow at SEAS and co-first author of the paper. Peleg is now an Assistant Professor of Computer Science at the University of Colorado—Boulder. The researchers built a bee swarm by attaching a caged queen bee to a moveable board and waiting for worker bees to cluster around her. Once the cluster was formed, the researchers simulated wind by shaking the board horizontally and vertically. They observed that the swarm starts with a cone-like structure, with a certain height and base area. When shaken horizontally, the bees create a flatter cone by decreasing the height and increasing the base area. When the shaking stops, they go back to their original shape. The bees know which way to move because they respond to the local changes from their neighbors. \"Individual bees can tell the direction of the strain based on their connection to their neighbors,\" said Jacob Peters, who recently defended his Ph.D. in OEB, and co-first author of the paper. \"Because the strains on the swarm are highest at the top of the swarm, where its connected to the branch—or in this case, the board—they know to move up. All the bees move up together because they're influenced by this gradient, so it leads to a coordinated movement.\" The experimental setup consists of a motor driving a wooden board, on which a cluster of honey bees form around a caged queen bee. The board can be moved in the horizontal or vertical axis at different frequencies and amplitudes. Credit: Jacob Peters, Orit Peleg/Harvard University Imagine playing Ring-a-Round-the-Rosy blindfolded. You don't know which direction everyone in the circle is moving, but you do know the direction your neighbor is moving because you're holding their hand. You don't know when everyone falls down, but you know when to fall down because your neighbor falls down. Like bees in a swarm, you follow the cues associated with the local strain from your neighbor. When the cluster flattens during horizontal shaking, load sharing by individual bees increases but the colony overall is more stable—similar to crouching when the ground is shaking. The researchers were able to mimic this behavior in a computer simulation by imposing rules at the local level. The researchers also found that when the bees were shaken vertically, the cluster did not adapt its shape because the local variations in deformations were smaller. This research could have broader implications for how we think of control algorithms and collaborative machines. \"When we build machines or materials, we use simple control algorithms that are top down, where you have a centralized command that controls all of the moving parts in the machine,\" said Peters. \"But in this system, the bees are achieving this coordinated change in shape without a central controller. Instead, they are like a set of distributed agents with their own controllers and they have to find a way to coordinate without explicit long-range communication. By studying these types of systems, it could inspire new ways of thinking about distributed control of systems as opposed to traditional centralized control.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Honeybee Apis mellifera swarms form large congested tree-hanging clusters made solely of bees attached to each other 1 . How these structures are maintained under the influence of dynamic mechanical forcing is unknown. To address this, we created pendant clusters and subject them to dynamic loads of varying orientation, amplitude, frequency and duration. We find that horizontally shaken clusters adapt by spreading out to form wider, flatter cones that recover their original shape when unloaded. Measuring the response of a cluster to an impulsive pendular excitation shows that flattened cones deform less and relax faster than the elongated ones (that is, they are more stable). Particle-based simulations of a passive assemblage suggest a behavioural hypothesis: individual bees respond to local variations in strain by moving up the strain gradient, which is qualitatively consistent with our observations of individual bee movement during dynamic loading. The simulations also suggest that vertical shaking will not lead to significant differential strains and thus no shape adaptation, which we confirmed experimentally. Together, our findings highlight how a super-organismal structure responds to dynamic loading by actively changing its morphology to improve the collective stability of the cluster at the expense of increasing the average mechanical burden of an individual. Main Collective dynamics allow super-organisms to function in ways that a single organism cannot, by virtue of their emergent size, shape, physiology and behaviour 2 . Classic examples include the physiological and behavioural strategies seen in social insects (for example, ants that link their bodies to form rafts to survive floods 3 , 4 , 5 , 6 , assemble pulling chains to move food items 7 , and form bivouacs 8 and towers 9 , as well as bridges and ladders to traverse rough terrain 10 ). Similarly, groups of `daddy longlegs’ (order Opiliones) huddle together and emperor penguins cluster together for thermoregulation purposes 11 . While much is known about the static forms that are seen in such situations, the stability of these forms to dynamic perturbation, and their global adaptation to environmental changes is much less understood. European honeybees, Apis mellifera L., show many of these collective behaviours during their life cycle 1 . For example, colonies reproduce through colony fission, a process in which a subset of the colony’s workers and a queen leave the hive, separate from the parent colony and form a cluster on a nearby tree branch 1 . In these swarm clusters (which we will refer to as clusters), the bees adhere to each other and form a large structure made of ~10,000 individuals and hundreds of times the size of a single organism (Fig. 1a ). Generally, this hanging mass of adhered bees takes on the shape of an inverted pendant cone; however, the resultant shape is also influenced by the surface to which the cluster is clinging to (see two different examples in Fig. 1a ). The cluster can stay in place for several days as scout bees search the surrounding area for suitable nest sites 1 . Fig. 1: A mechanically adaptive honeybee cluster. a , Bee clusters on a tree branch. b , The experimental set-up consists of a motor driving a wooden board, on which a cluster of bees grips a roughly circular contact area. The motor can produce periodic movement in the horizontal or vertical axis at different frequencies and amplitudes. See Supplementary Fig. 1 for the full set-up. c , The top panel shows the acceleration of the board versus time. The middle and bottom panels show how the bee cluster adapts its shape dynamically: elongated cluster at t = 0 (left column), spread-out cluster after horizontal shaking for 10 min and 30 min (middle columns), and elongated cluster after relaxation (right column); side and bottom views. The contact area before and after shaking is highlighted in blue and red, respectively. Full size image The colony is exposed to the environment during this stage and shows several behaviours to cope with the fluctuating thermal and mechanical environment. For instance, clusters tune their density and surface area to volume ratio to maintain a near constant core temperature despite large fluctuations in the ambient temperature 12 , 13 , 14 . Furthermore, at high temperatures, the swarm expands and forms channels that are presumed to aid in air circulation 12 . Moreover, in response to rain, bees at the surface arrange themselves to form `shingles’, shedding moisture efficiently from the surface of the cluster 15 . Similarly, the cluster is mechanically stable; while it sways from side to side in the wind (for example, see Supplementary Video 1 ), it could be catastrophic if the cluster breaks (when a critical load occurs) as the bees would lose the ability to minimize surface area to prevent hypothermia, while still being mechanically stable. However, the mechanism by which a multitude of bees work together to create and maintain a stable structure that handles both static gravity and dynamic shaking stimuli (for example, wind and predators) remains elusive. To understand this, we develop a laboratory experimental set-up, for ease of visualization and manipulation, to quantify the response of a honeybee cluster to mechanical shaking over short and long times. To prepare a cluster, we attach a caged queen (see Supplementary Section A ) to a board and allowed a cluster to form around her (Fig. 1b ). The bees at the base grip onto an area that is roughly circular. The board is controlled by a motor that can produce movement in the horizontal direction at different frequencies (0.5–5 Hz) and accelerations (ranged 0–0.1 g ). We apply both discontinuous shaking in which the acceleration is kept constant and the frequency is modified, and vice versa, continuous shaking in which the frequency is kept constant and the acceleration is modified (see Supplementary Fig. 2 ). For the case of horizontal shaking (for both discontinuous and continuous), the tall conical cluster swings to and fro in a pendular mode (one of the lowest energy modes of motion,<|im_end|> <|im_start|>assistant If it's a bad idea to kick a hornet's nest, it's certainly a bad idea to shake a bee swarm. Unless, of course, it's for science. A team of Harvard University researchers spent months shaking and rattling swarms of thousands of honey bees to better understand how bees collectively collaborate to stabilize structures in the presence of external loads. The research is published in Nature Physics. "Our study shows how living systems harness physics to solve complex problems on scales much larger than the individual," said L. Mahadevan, the Lola England de Valpine Professor of Applied Mathematics at the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS), Professor of Organismic and Evolutionary Biology (OEB), and Professor of Physics and senior author of the study. "We demonstrated that bees can harness the physicality of the environment solve a global mechanical stability problem by using local sensing and action" This research follows earlier work by the group that showed how bees can also collectively maintain the temperature of a cluster using local sensing and actuation to prevent overheating or overcooling. Bee swarms form when a queen bee strikes out with a large group of worker bees to form a new colony. While scouts look for a new nest location, the colony forms a living, breathing structure, made of their own bodies, on a nearby tree branch. These clusters maintain their structure and stability for days in the presence of wind, rain and other external loads. A team of Harvard University researchers spent months shaking and rattling swarms of thousands of honey bees to better understand how bees collectively collaborate to stabilize structures in the presence of external loads. Credit: Jacob Peters, Orit Peleg/Harvard University "The primary question of our research was, given that individual bees can likely only sense their interactions with their neighbors, how do they make changes to maintain the overall structure of the cluster?" said Orit Peleg, a former postdoctoral fellow at SEAS and co-first author of the paper. Peleg is now an Assistant Professor of Computer Science at the University of Colorado—Boulder. The researchers built a bee swarm by attaching a caged queen bee to a moveable board and waiting for worker bees to cluster around her. Once the cluster was formed, the researchers simulated wind by shaking the board horizontally and vertically. They observed that the swarm starts with a cone-like structure, with a certain height and base area. When shaken horizontally, the bees create a flatter cone by decreasing the height and increasing the base area. When the shaking stops, they go back to their original shape. The bees know which way to move because they respond to the local changes from their neighbors. "Individual bees can tell the direction of the strain based on their connection to their neighbors," said Jacob Peters, who recently defended his Ph.D. in OEB, and co-first author of the paper. "Because the strains on the swarm are highest at the top of the swarm, where its connected to the branch—or in this case, the board—they know to move up. All the bees move up together because they're influenced by this gradient, so it leads to a coordinated movement." The experimental setup consists of a motor driving a wooden board, on which a cluster of honey bees form around a caged queen bee. The board can be moved in the horizontal or vertical axis at different frequencies and amplitudes. Credit: Jacob Peters, Orit Peleg/Harvard University Imagine playing Ring-a-Round-the-Rosy blindfolded. You don't know which direction everyone in the circle is moving, but you do know the direction your neighbor is moving because you're holding their hand. You don't know when everyone falls down, but you know when to fall down because your neighbor falls down. Like bees in a swarm, you follow the cues associated with the local strain from your neighbor. When the cluster flattens during horizontal shaking, load sharing by individual bees increases but the colony overall is more stable—similar to crouching when the ground is shaking. The researchers were able to mimic this behavior in a computer simulation by imposing rules at the local level. The researchers also found that when the bees were shaken vertically, the cluster did not adapt its shape because the local variations in deformations were smaller. This research could have broader implications for how we think of control algorithms and collaborative machines. "When we build machines or materials, we use simple control algorithms that are top down, where you have a centralized command that controls all of the moving parts in the machine," said Peters. "But in this system, the bees are achieving this coordinated change in shape without a central controller. Instead, they are like a set of distributed agents with their own controllers and they have to find a way to coordinate without explicit long-range communication. By studying these types of systems, it could inspire new ways of thinking about distributed control of systems as opposed to traditional centralized control." <|im_end|>

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2,258

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Streptomyces thermoautotrophicus UBT1 has been described as a moderately thermophilic chemolithoautotroph with a novel nitrogenase enzyme that is oxygen-insensitive. We have cultured the UBT1 strain and have isolated two new strains (H1 and P1-2) of very similar phenotypic and genetic characters. These strains show minimal growth on ammonium-free media and fail to incorporate isotopically labeled N 2 gas into biomass in multiple independent assays. The sdn genes previously published as the putative nitrogenase of S. thermoautotrophicus have little similarity to anything found in draft genome sequences, published here, for strains H1 and UBT1, but share >99% nucleotide identity with genes from Hydrogenibacillus schlegelii , a draft genome for which is also presented here. H. schlegelii similarly lacks nitrogenase genes and is a non-diazotroph. We propose reclassification of the species containing strains UBT1, H1 and P1-2 as a non-Streptomycete, non-diazotrophic, facultative chemolithoautotroph and conclude that the existence of the previously proposed oxygen-tolerant nitrogenase is extremely unlikely. Introduction Biological fixation of gaseous elemental nitrogen into ammonia is an important part of the global nitrogen cycle 1 . Several bacteria and archaea are known to carry out this process, either solely for their own biosynthetic needs 2 , or else as symbiotic partners with certain eukaryotes 3 . In many environments, bioavailable nitrogen is limiting for net primary productivity 4 and this relevance for agriculture and ecology has ensured that the biology of nitrogen fixation has been an active area of research since its discovery in the 19 th century. Bacteria synthesize ammonia from dinitrogen via a family of homologous nitrogenase enzymes, of which the molybdenum-iron (MoFe) nitrogenase is the most common 5 . The MoFe nitrogenase protein combines with the homodimeric nitrogenase reductase Fe-protein to form an (αβγ 2 ) 2 octameric enzyme complex 6 , encoded by the structural genes nifHDK . Each enzyme complex contains two iron-sulfur (4Fe:4S) clusters, two (8Fe:7S) P-clusters and two (7Fe:Mo:9S:C:homocitrate) FeMo cofactor active sites. Several accessory proteins are required for the synthesis and insertion of these complex cofactors and thus various subsets of some 16 different additional nif genes are present in diazotrophs 7 . A set of six nif genes, nifHDKENB , has been proposed as a diagnostic criterion for diazotrophy 8 . The MoFe nitrogenase has promiscuous activity and is able to reduce a number of substrates besides dinitrogen 9 . Of particular interest is its ability to convert acetylene into ethylene, which is often used as a proxy assay for nitrogenase activity. While the exact mechanism of nitrogenase function remains unknown 10 , the stoichiometry is thought to require at least 16 molecules of ATP, as well as six low-potential electrons from ferredoxin or flavodoxin, per molecule of dinitrogen reduced 11 , plus two more electrons to generate one molecule of hydrogen, an obligatory side product of nitrogenase function. In addition to this high energetic cost, nitrogenase activity is reversibly inhibited by hydrogen (H 2 ) and carbon monoxide (CO) 12 ; the former of which is generated by nitrogenase itself and the latter generated by heme oxygenase in root nodules 13 , as well as being present in significant concentrations near sites of geothermal activity or combustion. More importantly, nitrogenase is rapidly and irreversibly damaged upon exposure to oxygen 14 , due to the effect of oxygen on the enzyme’s metal cofactors 15 , perhaps exposed to the solvent upon the cyclic dissociation of the nitrogenase and the nitrogenase reductase 16 . This sensitivity has led to a proliferation of evolutionary strategies to reduce oxygen tension near active nitrogenases 17 . In addition to the MoFe nitrogenase, some bacteria possess alternative nitrogenases that substitute iron or vanadium for molybdenum in the active site 18 , presumably for use when Mo is scarce. These alternative nitrogenases introduce a δ subunit encoded by vnfG or anfG , altering the stoichiometry of the nitrogenase complex, but the structural vnfHDK and anfHDK genes are homologous to their nif counterparts and the corresponding enzymes have even greater sensitivity to O 2 , as well as lower nitrogenase activity and greater relative hydrogen production, than the MoFe enzyme. A fourth, unrelated class of nitrogenase has been reported in the thermophilic carboxydotroph Streptomyces thermoautotrophicus UBT1 19 . This strain was isolated from the soil overlying burning charcoal piles and was studied by members of the laboratory of Ortwin Meyer, at the Universität Bayreuth, Bayreuth, Germany. UBT1 was described as an obligate chemolithoautotroph, capable of growth on CO or CO 2 and H 2 , but not on complex carbon sources 20 . Nitrogen fixation in this strain was found to be significantly different from that of other diazotrophs: it was not inhibited by H 2 , CO, or O 2 . Further, nif genes were not detected by Southern blot and the strain was not found to reduce acetylene to ethylene, suggesting that this was the first natural diazotroph to lack a nitrogenase homologous to MoFe. Fractionation of protein lysate was used to identify structural components of the nitrogenase and the N-termini of the proteins isolated showed no homology to known nitrogenase subunits 21 . The specific activities reported for this enzyme were unusually low in comparison to traditional nitrogenases. Most interesting of all, the enzyme was found to be insensitive to oxygen in cell lysates and actually depended upon its presence for the generation of the superoxide anion (O 2 − ), which was proposed to be used as an electron donor for the reduction of dinitrogen. A catalytic mechanism was proposed whereby CODH (enzyme St3) transfers electrons from water to oxygen via the oxidation of CO, a manganese superoxide dismutase (Mn-SOD; enzyme St2) transfers electrons from the resulting superoxide anion to a molybdenum hydroxylase, likely another CODH homolog (St1), which in turn uses them to reduce dinitrogen. The CODH that generates superoxide was found to have no nitrogenase activity 21 . Degenerate oligonucleotides designed against the N-termini of the purified proteins have been used to identify the candidate nitrogenase genes and they were found to", "role": "user" }, { "content": "Scientists chase unicorns because if they could prove the existence of the magical beasts, the world would be a better place. Take Maren Friesen, Michigan State University plant biologist, for example. Her quest was to find near-mythical bacteria that could fix their own nitrogen. Her search for such magical beasties was based on results from Germany published in the 1990s that seemed to confirm their existence. The end result, published in the current issue of Nature's Scientific Reports, proved that the elusive bacteria, Streptomyces thermoautotrophicus, did in fact exist but didn't have any mythical qualities. Most nitrogen-fixing bacteria use an enzyme that does not work when oxygen is present. The heat and toxic gas-loving strain that Friesen studied appeared to have exceptional properties, including harboring a special enzyme that was insensitive to oxygen. So why go on such a quest? \"If they actually existed, it would mean we could have plants that could fix their own nitrogen, a compound used in critical biological functions, with no need for nitrogen fertilizers,\" said Friesen. \"In this dream world, there would be less pollution, less nitrogen runoff into rivers and streams, less greenhouse gas emissions, less fuel being used to transport and apply fertilizer.\" That is a unicorn worth chasing, she added. So why is it worth proving that it's a myth, that it doesn't exist? While Friesen and an international team of scientists remained highly skeptical of the bacteria's existence, the positive result in the literature had long tantalized researchers. However, there were no other papers from independent labs to confirm the original findings. \"This outlying result was always there, always lingering in published papers,\" Friesen said. \"Now we've been able to bury this once and for all.\" The myth began in Germany, where the bacteria were discovered, and their mythical properties were suggested. They thrived in the hot, toxic fumes over traditional charcoal fires where large quantities of wood were buried and burnt down. Friesen's collaborators traveled to Germany and gathered samples while she went to Centralia, Pa., where underground coal fires have been burning for decades. She was somewhat surprised that she was able to find the bacteria, lending a bit of credence to the myth. The tale grew even more when they produced a positive result in the laboratory, demonstrating that the bacteria did indeed fix their own nitrogen. This, however, turned out to be a tainted result. \"We learned that the gas that everyone had been using for the experiments was contaminated,\" Friesen said. \"For the next experiments, we had to introduce a number of new controls, which included washing or purifying the gas we used.\" Dispelling the myth turned out to be a roller coaster of results and reactions - from actually finding the missing bacteria to a positive result that bolstered the tall tale, and from conducting many, many more experiments to finally killing the bacterial unicorn. While one mythical notion died, the concept of international collaboration and open data grew. Scientists from Harvard University, Imperial College (London), Aachen University (Germany) and Universidad Nacional de Rosario, Zavalla (Argentina) contributed to key aspects of the research. Rather than focus on one experiment, the team conducted many experiments around the world. \"By sharing data, you can have a lot of influence,\" Friesen said. \"The most-influential datasets are the ones that everyone is using. And as this research demonstrated, it's better to compare your results to other researcher's data than believe a singular result. Reproducibility is really key to good science.\" Even if it means a few unicorns must die. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Streptomyces thermoautotrophicus UBT1 has been described as a moderately thermophilic chemolithoautotroph with a novel nitrogenase enzyme that is oxygen-insensitive. We have cultured the UBT1 strain and have isolated two new strains (H1 and P1-2) of very similar phenotypic and genetic characters. These strains show minimal growth on ammonium-free media and fail to incorporate isotopically labeled N 2 gas into biomass in multiple independent assays. The sdn genes previously published as the putative nitrogenase of S. thermoautotrophicus have little similarity to anything found in draft genome sequences, published here, for strains H1 and UBT1, but share >99% nucleotide identity with genes from Hydrogenibacillus schlegelii , a draft genome for which is also presented here. H. schlegelii similarly lacks nitrogenase genes and is a non-diazotroph. We propose reclassification of the species containing strains UBT1, H1 and P1-2 as a non-Streptomycete, non-diazotrophic, facultative chemolithoautotroph and conclude that the existence of the previously proposed oxygen-tolerant nitrogenase is extremely unlikely. Introduction Biological fixation of gaseous elemental nitrogen into ammonia is an important part of the global nitrogen cycle 1 . Several bacteria and archaea are known to carry out this process, either solely for their own biosynthetic needs 2 , or else as symbiotic partners with certain eukaryotes 3 . In many environments, bioavailable nitrogen is limiting for net primary productivity 4 and this relevance for agriculture and ecology has ensured that the biology of nitrogen fixation has been an active area of research since its discovery in the 19 th century. Bacteria synthesize ammonia from dinitrogen via a family of homologous nitrogenase enzymes, of which the molybdenum-iron (MoFe) nitrogenase is the most common 5 . The MoFe nitrogenase protein combines with the homodimeric nitrogenase reductase Fe-protein to form an (αβγ 2 ) 2 octameric enzyme complex 6 , encoded by the structural genes nifHDK . Each enzyme complex contains two iron-sulfur (4Fe:4S) clusters, two (8Fe:7S) P-clusters and two (7Fe:Mo:9S:C:homocitrate) FeMo cofactor active sites. Several accessory proteins are required for the synthesis and insertion of these complex cofactors and thus various subsets of some 16 different additional nif genes are present in diazotrophs 7 . A set of six nif genes, nifHDKENB , has been proposed as a diagnostic criterion for diazotrophy 8 . The MoFe nitrogenase has promiscuous activity and is able to reduce a number of substrates besides dinitrogen 9 . Of particular interest is its ability to convert acetylene into ethylene, which is often used as a proxy assay for nitrogenase activity. While the exact mechanism of nitrogenase function remains unknown 10 , the stoichiometry is thought to require at least 16 molecules of ATP, as well as six low-potential electrons from ferredoxin or flavodoxin, per molecule of dinitrogen reduced 11 , plus two more electrons to generate one molecule of hydrogen, an obligatory side product of nitrogenase function. In addition to this high energetic cost, nitrogenase activity is reversibly inhibited by hydrogen (H 2 ) and carbon monoxide (CO) 12 ; the former of which is generated by nitrogenase itself and the latter generated by heme oxygenase in root nodules 13 , as well as being present in significant concentrations near sites of geothermal activity or combustion. More importantly, nitrogenase is rapidly and irreversibly damaged upon exposure to oxygen 14 , due to the effect of oxygen on the enzyme’s metal cofactors 15 , perhaps exposed to the solvent upon the cyclic dissociation of the nitrogenase and the nitrogenase reductase 16 . This sensitivity has led to a proliferation of evolutionary strategies to reduce oxygen tension near active nitrogenases 17 . In addition to the MoFe nitrogenase, some bacteria possess alternative nitrogenases that substitute iron or vanadium for molybdenum in the active site 18 , presumably for use when Mo is scarce. These alternative nitrogenases introduce a δ subunit encoded by vnfG or anfG , altering the stoichiometry of the nitrogenase complex, but the structural vnfHDK and anfHDK genes are homologous to their nif counterparts and the corresponding enzymes have even greater sensitivity to O 2 , as well as lower nitrogenase activity and greater relative hydrogen production, than the MoFe enzyme. A fourth, unrelated class of nitrogenase has been reported in the thermophilic carboxydotroph Streptomyces thermoautotrophicus UBT1 19 . This strain was isolated from the soil overlying burning charcoal piles and was studied by members of the laboratory of Ortwin Meyer, at the Universität Bayreuth, Bayreuth, Germany. UBT1 was described as an obligate chemolithoautotroph, capable of growth on CO or CO 2 and H 2 , but not on complex carbon sources 20 . Nitrogen fixation in this strain was found to be significantly different from that of other diazotrophs: it was not inhibited by H 2 , CO, or O 2 . Further, nif genes were not detected by Southern blot and the strain was not found to reduce acetylene to ethylene, suggesting that this was the first natural diazotroph to lack a nitrogenase homologous to MoFe. Fractionation of protein lysate was used to identify structural components of the nitrogenase and the N-termini of the proteins isolated showed no homology to known nitrogenase subunits 21 . The specific activities reported for this enzyme were unusually low in comparison to traditional nitrogenases. Most interesting of all, the enzyme was found to be insensitive to oxygen in cell lysates and actually depended upon its presence for the generation of the superoxide anion (O 2 − ), which was proposed to be used as an electron donor for the reduction of dinitrogen. A catalytic mechanism was proposed whereby CODH (enzyme St3) transfers electrons from water to oxygen via the oxidation of CO, a manganese superoxide dismutase (Mn-SOD; enzyme St2) transfers electrons from the resulting superoxide anion to a molybdenum hydroxylase, likely another CODH homolog (St1), which in turn uses them to reduce dinitrogen. The CODH that generates superoxide was found to have no nitrogenase activity 21 . Degenerate oligonucleotides designed against the N-termini of the purified proteins have been used to identify the candidate nitrogenase genes and they were found to<|im_end|> <|im_start|>assistant Scientists chase unicorns because if they could prove the existence of the magical beasts, the world would be a better place. Take Maren Friesen, Michigan State University plant biologist, for example. Her quest was to find near-mythical bacteria that could fix their own nitrogen. Her search for such magical beasties was based on results from Germany published in the 1990s that seemed to confirm their existence. The end result, published in the current issue of Nature's Scientific Reports, proved that the elusive bacteria, Streptomyces thermoautotrophicus, did in fact exist but didn't have any mythical qualities. Most nitrogen-fixing bacteria use an enzyme that does not work when oxygen is present. The heat and toxic gas-loving strain that Friesen studied appeared to have exceptional properties, including harboring a special enzyme that was insensitive to oxygen. So why go on such a quest? "If they actually existed, it would mean we could have plants that could fix their own nitrogen, a compound used in critical biological functions, with no need for nitrogen fertilizers," said Friesen. "In this dream world, there would be less pollution, less nitrogen runoff into rivers and streams, less greenhouse gas emissions, less fuel being used to transport and apply fertilizer." That is a unicorn worth chasing, she added. So why is it worth proving that it's a myth, that it doesn't exist? While Friesen and an international team of scientists remained highly skeptical of the bacteria's existence, the positive result in the literature had long tantalized researchers. However, there were no other papers from independent labs to confirm the original findings. "This outlying result was always there, always lingering in published papers," Friesen said. "Now we've been able to bury this once and for all." The myth began in Germany, where the bacteria were discovered, and their mythical properties were suggested. They thrived in the hot, toxic fumes over traditional charcoal fires where large quantities of wood were buried and burnt down. Friesen's collaborators traveled to Germany and gathered samples while she went to Centralia, Pa., where underground coal fires have been burning for decades. She was somewhat surprised that she was able to find the bacteria, lending a bit of credence to the myth. The tale grew even more when they produced a positive result in the laboratory, demonstrating that the bacteria did indeed fix their own nitrogen. This, however, turned out to be a tainted result. "We learned that the gas that everyone had been using for the experiments was contaminated," Friesen said. "For the next experiments, we had to introduce a number of new controls, which included washing or purifying the gas we used." Dispelling the myth turned out to be a roller coaster of results and reactions - from actually finding the missing bacteria to a positive result that bolstered the tall tale, and from conducting many, many more experiments to finally killing the bacterial unicorn. While one mythical notion died, the concept of international collaboration and open data grew. Scientists from Harvard University, Imperial College (London), Aachen University (Germany) and Universidad Nacional de Rosario, Zavalla (Argentina) contributed to key aspects of the research. Rather than focus on one experiment, the team conducted many experiments around the world. "By sharing data, you can have a lot of influence," Friesen said. "The most-influential datasets are the ones that everyone is using. And as this research demonstrated, it's better to compare your results to other researcher's data than believe a singular result. Reproducibility is really key to good science." Even if it means a few unicorns must die. <|im_end|>

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84495, 349, 574, 1511, 311, 10765, 24693, 6956, 315, 279, 47503, 521, 323, 279, 452, 12, 23827, 72, 315, 279, 28896, 25181, 8710, 912, 5105, 2508, 311, 3967, 47503, 521, 1207, 26726, 220, 1691, 662, 578, 3230, 7640, 5068, 369, 420, 49242, 1051, 57899, 3428, 304, 12593, 311, 8776, 47503, 2315, 13, 7648, 7185, 315, 682, 11, 279, 49242, 574, 1766, 311, 387, 71580, 311, 24463, 304, 2849, 84495, 988, 323, 3604, 79101, 5304, 1202, 9546, 369, 279, 9659, 315, 279, 2307, 55189, 459, 290, 320, 46, 220, 17, 25173, 7026, 902, 574, 11223, 311, 387, 1511, 439, 459, 17130, 35558, 369, 279, 14278, 315, 294, 2381, 26252, 13, 362, 34454, 70504, 17383, 574, 11223, 49001, 68501, 39, 320, 65728, 800, 18, 8, 31711, 57678, 505, 3090, 311, 24463, 4669, 279, 71162, 315, 7432, 11, 264, 87934, 2307, 55189, 834, 7129, 521, 320, 44, 77, 6354, 2114, 26, 49242, 800, 17, 8, 31711, 57678, 505, 279, 13239, 2307, 55189, 459, 290, 311, 264, 296, 5849, 65, 5294, 372, 17055, 87, 4010, 521, 11, 4461, 2500, 68501, 39, 5105, 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11, 40651, 264, 2766, 315, 4281, 768, 311, 279, 21849, 13, 578, 24162, 14264, 1524, 810, 994, 814, 9124, 264, 6928, 1121, 304, 279, 27692, 11, 45296, 430, 279, 24032, 1550, 13118, 5155, 872, 1866, 47503, 13, 1115, 11, 4869, 11, 6656, 704, 311, 387, 264, 85073, 1121, 13, 330, 1687, 9687, 430, 279, 6962, 430, 5127, 1047, 1027, 1701, 369, 279, 21896, 574, 52673, 1359, 435, 4108, 268, 1071, 13, 330, 2520, 279, 1828, 21896, 11, 584, 1047, 311, 19678, 264, 1396, 315, 502, 11835, 11, 902, 5343, 28786, 477, 4087, 7922, 279, 6962, 584, 1511, 1210, 70830, 6427, 279, 21849, 6656, 704, 311, 387, 264, 29551, 82168, 315, 3135, 323, 25481, 482, 505, 3604, 9455, 279, 7554, 24032, 311, 264, 6928, 1121, 430, 48227, 291, 279, 16615, 24162, 11, 323, 505, 31474, 1690, 11, 1690, 810, 21896, 311, 5616, 13419, 279, 45964, 82930, 13, 6104, 832, 84219, 23035, 8636, 11, 279, 7434, 315, 6625, 20632, 323, 1825, 828, 14264, 13, 57116, 505, 25996, 3907, 11, 31013, 9304, 320, 40672, 705, 362, 46799, 3907, 320, 51270, 8, 323, 67613, 45689, 409, 16870, 3370, 11, 1901, 402, 21575, 320, 96517, 8, 20162, 311, 1401, 13878, 315, 279, 3495, 13, 26848, 1109, 5357, 389, 832, 9526, 11, 279, 2128, 13375, 1690, 21896, 2212, 279, 1917, 13, 330, 1383, 11821, 828, 11, 499, 649, 617, 264, 2763, 315, 10383, 1359, 435, 4108, 268, 1071, 13, 330, 791, 1455, 3502, 27256, 2335, 30525, 527, 279, 6305, 430, 5127, 374, 1701, 13, 1628, 439, 420, 3495, 21091, 11, 433, 596, 2731, 311, 9616, 701, 3135, 311, 1023, 32185, 596, 828, 1109, 4510, 264, 35044, 1121, 13, 3402, 4653, 66, 3225, 374, 2216, 1401, 311, 1695, 8198, 1210, 7570, 422, 433, 3445, 264, 2478, 88649, 44129, 2011, 2815, 13, 220, 128257, 198 ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Clinical laboratory tests play a pivotal role in medical decision making, but little is known about their genetic variability between populations. We report a genome-wide association study with 45 clinically relevant traits from the population of Qatar using a whole genome sequencing approach in a discovery set of 6218 individuals and replication in 7768 subjects. Trait heritability is more similar between Qatari and European populations ( r = 0.81) than with Africans ( r = 0.44). We identify 281 distinct variant-trait-associations at genome wide significance that replicate known associations. Allele frequencies for replicated loci show higher correlations with European ( r = 0.94) than with African ( r = 0.85) or Japanese ( r = 0.80) populations. We find differences in linkage disequilibrium patterns and in effect sizes of the replicated loci compared to previous reports. We also report 17 novel and Qatari-predominate signals providing insights into the biological pathways regulating these traits. We observe that European-derived polygenic scores (PGS) have reduced predictive performance in the Qatari population which could have implications for the translation of PGS between populations and their future application in precision medicine. Introduction Genome-wide association studies (GWAS) have provided new insights into the genetic determinants of many clinically relevant traits and identified thousands of disease- or trait-associated genetic variants 1 , 2 . However, most of the published GWAS studies performed to-date are from European, or East Asian populations 3 , 4 . Middle Eastern populations are under-represented. Also, all GWAS conducted so far used genotyping arrays imputed on genome sequencing data from studies in which only few, if any, Middle Eastern genomes were present and therefore miss all population-specific signals. Large-scale GWAS of many traits and complex diseases in Africans and Asians indicated differences in the genetic architecture between populations, but included few, if any, study participants from Arab ethnicities. In addition, many trait-associated variants show differences in allele frequencies and effect sizes across populations 5 , 6 , 7 which may complicate the derivation of polygenic scores. Recent studies have shown that polygenic risk scores derived from studies in European populations have lower predictive performance when applied to non-European populations 8 , providing strong argument for conducting GWAS in non-European populations that are less represented in previously published studies. Here, we report the first comprehensive GWAS of 45 clinically relevant traits in a Middle Eastern population using a whole genome sequencing approach. We unveil differences in heritability of certain life-style related traits between populations, investigate differences in the genetic architecture of replicating loci, assess the performance of European-derived polygenic scores in Qatari population, and report novel trait associations that are predominant to the Middle Eastern population of Qatar. Results The qatar genome program (QGP) The QGP is a population-based study designed to perform whole genome sequencing of the Qatar Biobank (QBB) participants 9 with the aim to gain insights into the population structure and the genetic architecture of clinically relevant phenotypes in the Middle Eastern Qatari population. The present study is based on whole genome sequence data from 6218 participants of QBB and further replication in 7768 subjects from the second batch of QBB data. We performed a comprehensive heritability and genome-wide association study for 45 clinically relevant traits in the Middle Eastern population of Qatar. The investigated traits cover the following categories (Table 1 ): anthropometry ( N = 3), electrolytes ( N = 7), measures of enzyme activity or abundance ( N = 5), blood coagulation-related traits ( N = 4), blood cell composition ( N = 9), lipid traits ( N = 4), and other clinically-relevant biochemistry measurements ( N = 13). A detailed description of the study population and phenotype assessment is provided in the methods section, Supplementary Data 1 and Supplementary Table 1 . A pairwise correlation analysis of the analyzed traits (Supplementary Fig. 1 ) revealed correlations between related traits, such as the liver-derived enzymes ALT, AST, ALP, and GGT (abbreviations are given in Table 1 ), traits related to hemoglobin and red blood cells (Hb, Ht, MCV, MCH, MCHC, and Frtn), and traits related to iron metabolism, such as Fe, TIBC, Hb, and Ht. Table 1 Summary of clinically-relevant quantitative traits investigated in this study. Full size table Heritability of clinically relevant traits in the Qatari population The proportion of variation that can be attributed to genetic factors (heritability) has been investigated for many clinically-relevant traits, but mainly in populations of European descent 10 , 11 . A recent study in the Ugandan population of Africa showed marked differences in heritability estimates for many complex traits compared to European populations 6 . For example, estimates of heritability for body height in Ugandan populations was significantly lower (49%) than those from European populations (77%) suggesting differences in genetic loci and/or proportion of environmental contribution. The heritability of most traits in Middle Eastern populations remains undetermined. We therefore performed a comprehensive assessment of the heritability ( h 2 ) of the 45 traits in the QGP data. We found that h 2 estimates ranged from 13% for serum iron levels (Fe) to 59% for body height (Table 1 ). We compared our findings with heritability estimates from European 10 , 11 and African populations 6 . Overall, the correlation of h 2 between European and Middle Eastern populations was higher ( r = 0.81) compared to the correlation between African and Middle Eastern populations ( r = 0.44; Supplementary Fig. 2 ). For several traits, h 2 estimates in the Middle Eastern population were significantly different from European and African populations (Fig. 1 , Supplementary Tables 2 and 3 ). For example, estimates of h 2 for height in QGP (59%) was lower than in European (77%; P = 6.0 × 10 −7 ) but not significantly different from African populations (49%, P = 0.09). Similarly, heritability for BMI in QGP (31%) was lower than in Europeans; namely Sardinia (43%; P = 8.8 × 10 −4 ) and Iceland (42%; P = 2.3 × 10 −3 ). Interestingly,", "role": "user" }, { "content": "A group of researchers at Qatar Foundation have reported the first and largest genetic association study in the Middle East, that has been published online in Nature Communications—a leading a peer-reviewed, open access, scientific journal published by Nature Research. The study titled \"Whole genome sequencing in the Middle Eastern Qatari population identifies genetic associations with 45 clinically relevant traits\" highlights a vital piece of information wherein now there is a better understanding of the genetic risk factors that are specific to the Arab population, including those that are shared with other ethnicities. Qatar was among the first countries to launch its own large-scale, national genome project. Qatar Genome combines whole genome sequencing data with comprehensive phenotypic resource collected at Qatar Biobank, and is considered the first, largest and most ambitious population-based projects of its kind in the Middle East. This kind of studies can be considered as experiments conducted by nature, where the natural variation found in the genomes of thousands of Qataris is linked to variations in their respective blood tests. The results from this project are shared publicly, ensuring that the specificities of the Arab genomes will be taken into consideration in future research on new treatments and therapies. The study—led by researchers at Qatar Foundation's (QF's) Hamad Bin Khalifa University (HBKU) and QF's partner university Weill Cornell Medicine—Qatar (WCM-Q), along with other scientists from the Qatar Genome Research Consortium—includes over 6,000 Qatari individuals with whole genome sequence data. By performing detailed assessments of genetic variants across the whole genome in 6,218 individuals, comprising data from 45 clinically relevant traits, this study identified about 300 independent genetic signals. Some of these signals were predominantly found in the Qatari population. This observation was then confirmed in a further 7,768 subjects from QF's Qatar Biobank. Omar Albagha, Principal Investigator from HBKU's College of Health and Life Sciences, says: \"The study provides new insights into the genetic architecture of clinical laboratory tests and identifies for the first time genetic variations that are specific to the population of Qatar. The study also shows that findings from genetic studies in European populations don't translate well when applied to our population in the Middle East. This argues for further studies to define the genetic architecture of diseases in our region. We are excited because the study represents a foundation for the implementation of precision medicine in the Middle East.\" Karsten Suhre, Director of Bioinformatics Core at Weill Cornell Medicine—Qatar and joint senior author on the paper, says: \"It has been a long but successful journey from the first patient recruitments to Qatar Biobank to analyzing the resulting enormous genetic data set for associations with clinically relevant traits, and we as a consortium are proud to contribute with this paper to the international effort of obtaining an even better understanding of our human genome.\" \"Qatar Genome Research Consortium gave research groups the platform to study whole genome sequencing and other omics data to empower the genetic discoveries in this part of the world, which otherwise would be under-represented,\" said Professor Said Ismail, Director of QF's Qatar Genome, part of QF Research, Development, and Innovation. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Clinical laboratory tests play a pivotal role in medical decision making, but little is known about their genetic variability between populations. We report a genome-wide association study with 45 clinically relevant traits from the population of Qatar using a whole genome sequencing approach in a discovery set of 6218 individuals and replication in 7768 subjects. Trait heritability is more similar between Qatari and European populations ( r = 0.81) than with Africans ( r = 0.44). We identify 281 distinct variant-trait-associations at genome wide significance that replicate known associations. Allele frequencies for replicated loci show higher correlations with European ( r = 0.94) than with African ( r = 0.85) or Japanese ( r = 0.80) populations. We find differences in linkage disequilibrium patterns and in effect sizes of the replicated loci compared to previous reports. We also report 17 novel and Qatari-predominate signals providing insights into the biological pathways regulating these traits. We observe that European-derived polygenic scores (PGS) have reduced predictive performance in the Qatari population which could have implications for the translation of PGS between populations and their future application in precision medicine. Introduction Genome-wide association studies (GWAS) have provided new insights into the genetic determinants of many clinically relevant traits and identified thousands of disease- or trait-associated genetic variants 1 , 2 . However, most of the published GWAS studies performed to-date are from European, or East Asian populations 3 , 4 . Middle Eastern populations are under-represented. Also, all GWAS conducted so far used genotyping arrays imputed on genome sequencing data from studies in which only few, if any, Middle Eastern genomes were present and therefore miss all population-specific signals. Large-scale GWAS of many traits and complex diseases in Africans and Asians indicated differences in the genetic architecture between populations, but included few, if any, study participants from Arab ethnicities. In addition, many trait-associated variants show differences in allele frequencies and effect sizes across populations 5 , 6 , 7 which may complicate the derivation of polygenic scores. Recent studies have shown that polygenic risk scores derived from studies in European populations have lower predictive performance when applied to non-European populations 8 , providing strong argument for conducting GWAS in non-European populations that are less represented in previously published studies. Here, we report the first comprehensive GWAS of 45 clinically relevant traits in a Middle Eastern population using a whole genome sequencing approach. We unveil differences in heritability of certain life-style related traits between populations, investigate differences in the genetic architecture of replicating loci, assess the performance of European-derived polygenic scores in Qatari population, and report novel trait associations that are predominant to the Middle Eastern population of Qatar. Results The qatar genome program (QGP) The QGP is a population-based study designed to perform whole genome sequencing of the Qatar Biobank (QBB) participants 9 with the aim to gain insights into the population structure and the genetic architecture of clinically relevant phenotypes in the Middle Eastern Qatari population. The present study is based on whole genome sequence data from 6218 participants of QBB and further replication in 7768 subjects from the second batch of QBB data. We performed a comprehensive heritability and genome-wide association study for 45 clinically relevant traits in the Middle Eastern population of Qatar. The investigated traits cover the following categories (Table 1 ): anthropometry ( N = 3), electrolytes ( N = 7), measures of enzyme activity or abundance ( N = 5), blood coagulation-related traits ( N = 4), blood cell composition ( N = 9), lipid traits ( N = 4), and other clinically-relevant biochemistry measurements ( N = 13). A detailed description of the study population and phenotype assessment is provided in the methods section, Supplementary Data 1 and Supplementary Table 1 . A pairwise correlation analysis of the analyzed traits (Supplementary Fig. 1 ) revealed correlations between related traits, such as the liver-derived enzymes ALT, AST, ALP, and GGT (abbreviations are given in Table 1 ), traits related to hemoglobin and red blood cells (Hb, Ht, MCV, MCH, MCHC, and Frtn), and traits related to iron metabolism, such as Fe, TIBC, Hb, and Ht. Table 1 Summary of clinically-relevant quantitative traits investigated in this study. Full size table Heritability of clinically relevant traits in the Qatari population The proportion of variation that can be attributed to genetic factors (heritability) has been investigated for many clinically-relevant traits, but mainly in populations of European descent 10 , 11 . A recent study in the Ugandan population of Africa showed marked differences in heritability estimates for many complex traits compared to European populations 6 . For example, estimates of heritability for body height in Ugandan populations was significantly lower (49%) than those from European populations (77%) suggesting differences in genetic loci and/or proportion of environmental contribution. The heritability of most traits in Middle Eastern populations remains undetermined. We therefore performed a comprehensive assessment of the heritability ( h 2 ) of the 45 traits in the QGP data. We found that h 2 estimates ranged from 13% for serum iron levels (Fe) to 59% for body height (Table 1 ). We compared our findings with heritability estimates from European 10 , 11 and African populations 6 . Overall, the correlation of h 2 between European and Middle Eastern populations was higher ( r = 0.81) compared to the correlation between African and Middle Eastern populations ( r = 0.44; Supplementary Fig. 2 ). For several traits, h 2 estimates in the Middle Eastern population were significantly different from European and African populations (Fig. 1 , Supplementary Tables 2 and 3 ). For example, estimates of h 2 for height in QGP (59%) was lower than in European (77%; P = 6.0 × 10 −7 ) but not significantly different from African populations (49%, P = 0.09). Similarly, heritability for BMI in QGP (31%) was lower than in Europeans; namely Sardinia (43%; P = 8.8 × 10 −4 ) and Iceland (42%; P = 2.3 × 10 −3 ). Interestingly,<|im_end|> <|im_start|>assistant A group of researchers at Qatar Foundation have reported the first and largest genetic association study in the Middle East, that has been published online in Nature Communications—a leading a peer-reviewed, open access, scientific journal published by Nature Research. The study titled "Whole genome sequencing in the Middle Eastern Qatari population identifies genetic associations with 45 clinically relevant traits" highlights a vital piece of information wherein now there is a better understanding of the genetic risk factors that are specific to the Arab population, including those that are shared with other ethnicities. Qatar was among the first countries to launch its own large-scale, national genome project. Qatar Genome combines whole genome sequencing data with comprehensive phenotypic resource collected at Qatar Biobank, and is considered the first, largest and most ambitious population-based projects of its kind in the Middle East. This kind of studies can be considered as experiments conducted by nature, where the natural variation found in the genomes of thousands of Qataris is linked to variations in their respective blood tests. The results from this project are shared publicly, ensuring that the specificities of the Arab genomes will be taken into consideration in future research on new treatments and therapies. The study—led by researchers at Qatar Foundation's (QF's) Hamad Bin Khalifa University (HBKU) and QF's partner university Weill Cornell Medicine—Qatar (WCM-Q), along with other scientists from the Qatar Genome Research Consortium—includes over 6,000 Qatari individuals with whole genome sequence data. By performing detailed assessments of genetic variants across the whole genome in 6,218 individuals, comprising data from 45 clinically relevant traits, this study identified about 300 independent genetic signals. Some of these signals were predominantly found in the Qatari population. This observation was then confirmed in a further 7,768 subjects from QF's Qatar Biobank. Omar Albagha, Principal Investigator from HBKU's College of Health and Life Sciences, says: "The study provides new insights into the genetic architecture of clinical laboratory tests and identifies for the first time genetic variations that are specific to the population of Qatar. The study also shows that findings from genetic studies in European populations don't translate well when applied to our population in the Middle East. This argues for further studies to define the genetic architecture of diseases in our region. We are excited because the study represents a foundation for the implementation of precision medicine in the Middle East." Karsten Suhre, Director of Bioinformatics Core at Weill Cornell Medicine—Qatar and joint senior author on the paper, says: "It has been a long but successful journey from the first patient recruitments to Qatar Biobank to analyzing the resulting enormous genetic data set for associations with clinically relevant traits, and we as a consortium are proud to contribute with this paper to the international effort of obtaining an even better understanding of our human genome." "Qatar Genome Research Consortium gave research groups the platform to study whole genome sequencing and other omics data to empower the genetic discoveries in this part of the world, which otherwise would be under-represented," said Professor Said Ismail, Director of QF's Qatar Genome, part of QF Research, Development, and Innovation. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Magnesium is a lightweight structural metal but it exhibits low ductility—connected with unusual, mechanistically unexplained, dislocation and plasticity phenomena—which makes it difficult to form and use in energy-saving lightweight structures. We employ long-time molecular dynamics simulations utilizing a density-functional-theory-validated interatomic potential, and reveal the fundamental origins of the previously unexplained phenomena. Here we show that the key 〈 c + a 〉 dislocation (where 〈 c + a 〉 indicates the magnitude and direction of slip) is metastable on easy-glide pyramidal II planes; we find that it undergoes a thermally activated, stress-dependent transition to one of three lower-energy, basal-dissociated immobile dislocation structures, which cannot contribute to plastic straining and that serve as strong obstacles to the motion of all other dislocations. This transition is intrinsic to magnesium, driven by reduction in dislocation energy and predicted to occur at very high frequency at room temperature, thus eliminating all major dislocation slip systems able to contribute to c -axis strain and leading to the high hardening and low ductility of magnesium. Enhanced ductility can thus be achieved by increasing the time and temperature at which the transition from the easy-glide metastable dislocation to the immobile basal-dissociated structures occurs. Our results provide the underlying insights needed to guide the design of ductile magnesium alloys. Main Developing lightweight structural metal is a crucial step on the path towards reduced energy consumption in many industries, especially automotive 1 , 2 and aerospace 3 . Magnesium (Mg) is a lightweight metal, with a density that is 23% that of steel and 66% that of aluminium, and so has tremendous potential to achieve energy efficiency 4 . In spite of this tantalizing property, Mg generally exhibits low ductility, insufficient for the forming and performance of structural components. The low ductility is associated with the inability of hexagonal-close-packed (hcp) Mg to deform plastically in the crystallographic 〈 c 〉 direction, which is accomplished primarily by dislocation glide on the pyramidal II plane with the 〈 c + a 〉 Burgers vector 5 (see Fig. 1 ). Experiments reveal a range of unusual, confounding, conflicting, and mechanistically unexplained phenomena connected to 〈 c + a 〉 dislocations that coincide with the inability of Mg to achieve high plastic strains 6 . Uncovering and controlling the fundamental behaviour of 〈 c + a 〉 dislocations is thus the key issue in using Mg, and any solution would catapult Mg science, technology, and applications forward. Success would enable, for instance, lightweight automobiles that would consume less energy, independent of the energy source, and thus act as a multiplier for many other energy-reduction strategies. Figure 1: Transitions of the easy-glide pyramidal II edge 〈 c + a 〉 dislocation. The 〈 c + a 〉 dislocation transforms into basal-dissociated products, as observed during long-time MD simulations, for a , zero, b , moderate, and c , high compressive stresses (indicated by the purple arrows) normal to the pyramidal II plane (green plane in rightmost images). The first four columns show MD simulations at the indicated times; the rightmost column shows the transition of dislocation Burgers vectors in the hcp unit cell. All cases start from the same dislocation (leftmost image) and show a distinct thermally activated intermediate state (second image) before undergoing a rapid intrinsic ‘climb-like’ dissociation onto the basal plane (third and fourth images). The final core structure (fourth image) depends on the applied load, with increasing applied load able to drive an 〈 a 〉 or a partial 〈 a 〉 dislocation away from the 〈 c + a 〉 core. is the mean transition time to reach the intermediate state shown. Dislocation cores are indicated by the symbol ‘ ⊥ ’. Atoms in the atomistic images in this figure (first four columns) and subsequent ones are coloured on the basis of common neighbour analysis 37 : blue, hcp; green, face-centred cubic (fcc); purple, body-centred cubic (bcc); yellow, all others. Dislocation core atoms thus appear predominantly as yellow. In a – c , the rightmost column shows the composition of the 〈 c + a 〉 Burgers vector before (solid purple arrow) and after (dashed blue arrows) the transition; the green and orange circles depict the two alternating layers of atoms in basal planes. In the rightmost column in b , d is the midpoint between A and B, and α is the vertical projection of A 0 onto the basal plane. PowerPoint slide Full size image Because of its critical importance and promise, 〈 c + a 〉 slip has been extensively studied over five decades 7 , 8 , 9 , 10 , and reports on this system are being published at an increasing rate 11 , 12 , 13 , 14 . In Mg single crystals, 〈 c + a 〉 slip occurs predominantly on the pyramidal II system, and measurements show that pyramidal II 〈 c + a 〉 dislocations can glide at low stresses of ∼ 20 MPa at low temperatures 15 (77–133 K). However, transmission electron microscopy (TEM) studies frequently find 〈 c + a 〉 dislocations lying, mysteriously, along basal planes and coexisting with 〈 c 〉 and 〈 a 〉 dislocations 9 , 16 , 17 , 18 , 19 . Under c -axis compression, single crystal Mg also exhibits a rapid increase in stress with increasing strain, that is, high work hardening 9 , 15 , 18 , 19 , and fractures at low strains at temperatures up to 500 K (refs 9 , 15 , 19 ). New work shows the formation of a very high density of 〈 c + a 〉 dislocation loops also dissociated on, and lying on, the basal planes 14 , with similar observations dating back fifty years 7 , 8 , 20 . Many mechanisms have been proposed, all of which invoke extrinsic effects such as ‘heating’ by the electron beam 8 , vacancy and self-interstitial precipitation 21 , and dislocation obstacles of ‘unknown’ nature 7 . Also surprisingly, when loaded at slow", "role": "user" }, { "content": "Zhaoxuan Wu and William Curtin of the Laboratory for Multiscale Mechanics Modeling (LAMMM) have solved the 40-year-old scientific riddle of the low ductility magnesium. Magnesium is the lightest metal found on earth; it is four times lighter than steel and a third lighter than aluminum. It is also abundantly available, being the eight most common element in the earth's crust. These features should make it the ideal material for all kinds of uses, particularly in the automotive industry where fuel efficiency is greatly improved by reduced vehicle weight. However, the use of this metal remains marginal. \"Magnesium has low ductility, that is, it cannot be stretched very much before it breaks. It also shows unusual behavior, such as a regime of increasing strength with increasing temperature, which is the opposite of most metals\", said Prof. Curtin. The Director of the Institute of Mechanical Engineering and his collaborator Zhaoxuan Wu, a long-term visitor in LAMMM from the Institute for High Performance Computing in Singapore, were able to identify the atomistic origins of Magnesium's low ductility and unusual behavior. This breakthrough, published in the journal Nature, could open the way to many applications of this lightweight metal. Simulations to explain 40 years of experiments Solving this mystery had an interesting history: long struggles, tangential advances, a new collaboration, and a \"Eureka\" moment. \"I worked for 7 years on magnesium\", says Curtin. \"We had some accomplishments, but not on the most crucial issues, and I was about to give up, having exhausted what I thought we could do. But then Wu came from Singapore and brought renewed energy, an array of necessary technical skills, and exceptional motivation\". Fast forward two years and the mystery is solved: they managed to establish a picture that unified decades of experimentation. The real progress started with the development of a new description of the atomic interactions in magnesium, a feature essential if atomistic models are to reveal any true material behavior. \"We came across a rarely-used description of magnesium, and were able to tweak it and arrive at a new interatomic potential that predicted many well-established properties of magnesium with high accuracy.\" Most importantly, this new potential accurately predicted the structure of an important dislocation, the \"c a\" dislocation, which is essential for magnesium to flow easily. This dislocation, observed experimentally, could not previously be predicted. Then came the \"Eureka\" moment. \"We were performing atomic simulations of the normal \"c a\" dislocation to better understand its behavior, and suddenly it changed\". The atomic structure of the \"c a\" dislocation became entirely different, morphing into several possible geometries that locked it in place so that it could not move. Without \"c a\" motion, magnesium cannot flow plastically and so has low ductility. The new \"c a\" structures had been observed experimentally but how they occurred, whether they were real or experimental anomalies, and why there were several different structures, were all mysteries in the community. The work of Wu and Curtin showed that these new structures were intrinsic to magnesium, and they described why the different structures arise in different situations, and showed that all of these structures are more stable than the desirable \"c a\" structure. Thus, they found that it was inevitable that the new \"c a\" structures would form and kill the ductility of magnesium. A path to creating ductile magnesium \"To make magnesium malleable, we must fight against the forces of nature,\" said Wu. If science does not yet have a miracle solution to prevent the phenomenon, he notes that it is still possible to slow the morphing process of the \"c a\" dislocations. \"At room temperature, the morphing occurs almost instantly but when immersed in liquid nitrogen (temperature -195.79 ° C), it could take several months or one year.\" If the process could be delayed for a few seconds at normal temperatures, this could be enough to allow an industrial use. Several recent experimental studies in Germany have shown that it is possible to increase the ductility of magnesium by creating alloys with rare elements, such as yttrium, erbium, or holonium. Curtin believes these alloying elements bind to the normal \"c a\" and stabilize it somewhat, relative to the immovable \"c a\" dislocations. So, this is very promising, but these rare materials are very expensive and therefore unlikely to be used extensively by the automotive industry. Curtin and Wu are starting new research on how the expensive alloys, and other cheaper alloys, might stabilize the normal \"c a\" . \"We must find a compromise between the cost of the alloy and the material performance\" says Prof. Curtin. While he cannot predict when magnesium will be used heavily, he believes that the insights revealed by this new work will generate new ideas and approaches because the underlying origin of the poor behavior of magnesium is now more clearly understood. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Magnesium is a lightweight structural metal but it exhibits low ductility—connected with unusual, mechanistically unexplained, dislocation and plasticity phenomena—which makes it difficult to form and use in energy-saving lightweight structures. We employ long-time molecular dynamics simulations utilizing a density-functional-theory-validated interatomic potential, and reveal the fundamental origins of the previously unexplained phenomena. Here we show that the key 〈 c + a 〉 dislocation (where 〈 c + a 〉 indicates the magnitude and direction of slip) is metastable on easy-glide pyramidal II planes; we find that it undergoes a thermally activated, stress-dependent transition to one of three lower-energy, basal-dissociated immobile dislocation structures, which cannot contribute to plastic straining and that serve as strong obstacles to the motion of all other dislocations. This transition is intrinsic to magnesium, driven by reduction in dislocation energy and predicted to occur at very high frequency at room temperature, thus eliminating all major dislocation slip systems able to contribute to c -axis strain and leading to the high hardening and low ductility of magnesium. Enhanced ductility can thus be achieved by increasing the time and temperature at which the transition from the easy-glide metastable dislocation to the immobile basal-dissociated structures occurs. Our results provide the underlying insights needed to guide the design of ductile magnesium alloys. Main Developing lightweight structural metal is a crucial step on the path towards reduced energy consumption in many industries, especially automotive 1 , 2 and aerospace 3 . Magnesium (Mg) is a lightweight metal, with a density that is 23% that of steel and 66% that of aluminium, and so has tremendous potential to achieve energy efficiency 4 . In spite of this tantalizing property, Mg generally exhibits low ductility, insufficient for the forming and performance of structural components. The low ductility is associated with the inability of hexagonal-close-packed (hcp) Mg to deform plastically in the crystallographic 〈 c 〉 direction, which is accomplished primarily by dislocation glide on the pyramidal II plane with the 〈 c + a 〉 Burgers vector 5 (see Fig. 1 ). Experiments reveal a range of unusual, confounding, conflicting, and mechanistically unexplained phenomena connected to 〈 c + a 〉 dislocations that coincide with the inability of Mg to achieve high plastic strains 6 . Uncovering and controlling the fundamental behaviour of 〈 c + a 〉 dislocations is thus the key issue in using Mg, and any solution would catapult Mg science, technology, and applications forward. Success would enable, for instance, lightweight automobiles that would consume less energy, independent of the energy source, and thus act as a multiplier for many other energy-reduction strategies. Figure 1: Transitions of the easy-glide pyramidal II edge 〈 c + a 〉 dislocation. The 〈 c + a 〉 dislocation transforms into basal-dissociated products, as observed during long-time MD simulations, for a , zero, b , moderate, and c , high compressive stresses (indicated by the purple arrows) normal to the pyramidal II plane (green plane in rightmost images). The first four columns show MD simulations at the indicated times; the rightmost column shows the transition of dislocation Burgers vectors in the hcp unit cell. All cases start from the same dislocation (leftmost image) and show a distinct thermally activated intermediate state (second image) before undergoing a rapid intrinsic ‘climb-like’ dissociation onto the basal plane (third and fourth images). The final core structure (fourth image) depends on the applied load, with increasing applied load able to drive an 〈 a 〉 or a partial 〈 a 〉 dislocation away from the 〈 c + a 〉 core. is the mean transition time to reach the intermediate state shown. Dislocation cores are indicated by the symbol ‘ ⊥ ’. Atoms in the atomistic images in this figure (first four columns) and subsequent ones are coloured on the basis of common neighbour analysis 37 : blue, hcp; green, face-centred cubic (fcc); purple, body-centred cubic (bcc); yellow, all others. Dislocation core atoms thus appear predominantly as yellow. In a – c , the rightmost column shows the composition of the 〈 c + a 〉 Burgers vector before (solid purple arrow) and after (dashed blue arrows) the transition; the green and orange circles depict the two alternating layers of atoms in basal planes. In the rightmost column in b , d is the midpoint between A and B, and α is the vertical projection of A 0 onto the basal plane. PowerPoint slide Full size image Because of its critical importance and promise, 〈 c + a 〉 slip has been extensively studied over five decades 7 , 8 , 9 , 10 , and reports on this system are being published at an increasing rate 11 , 12 , 13 , 14 . In Mg single crystals, 〈 c + a 〉 slip occurs predominantly on the pyramidal II system, and measurements show that pyramidal II 〈 c + a 〉 dislocations can glide at low stresses of ∼ 20 MPa at low temperatures 15 (77–133 K). However, transmission electron microscopy (TEM) studies frequently find 〈 c + a 〉 dislocations lying, mysteriously, along basal planes and coexisting with 〈 c 〉 and 〈 a 〉 dislocations 9 , 16 , 17 , 18 , 19 . Under c -axis compression, single crystal Mg also exhibits a rapid increase in stress with increasing strain, that is, high work hardening 9 , 15 , 18 , 19 , and fractures at low strains at temperatures up to 500 K (refs 9 , 15 , 19 ). New work shows the formation of a very high density of 〈 c + a 〉 dislocation loops also dissociated on, and lying on, the basal planes 14 , with similar observations dating back fifty years 7 , 8 , 20 . Many mechanisms have been proposed, all of which invoke extrinsic effects such as ‘heating’ by the electron beam 8 , vacancy and self-interstitial precipitation 21 , and dislocation obstacles of ‘unknown’ nature 7 . Also surprisingly, when loaded at slow<|im_end|> <|im_start|>assistant Zhaoxuan Wu and William Curtin of the Laboratory for Multiscale Mechanics Modeling (LAMMM) have solved the 40-year-old scientific riddle of the low ductility magnesium. Magnesium is the lightest metal found on earth; it is four times lighter than steel and a third lighter than aluminum. It is also abundantly available, being the eight most common element in the earth's crust. These features should make it the ideal material for all kinds of uses, particularly in the automotive industry where fuel efficiency is greatly improved by reduced vehicle weight. However, the use of this metal remains marginal. "Magnesium has low ductility, that is, it cannot be stretched very much before it breaks. It also shows unusual behavior, such as a regime of increasing strength with increasing temperature, which is the opposite of most metals", said Prof. Curtin. The Director of the Institute of Mechanical Engineering and his collaborator Zhaoxuan Wu, a long-term visitor in LAMMM from the Institute for High Performance Computing in Singapore, were able to identify the atomistic origins of Magnesium's low ductility and unusual behavior. This breakthrough, published in the journal Nature, could open the way to many applications of this lightweight metal. Simulations to explain 40 years of experiments Solving this mystery had an interesting history: long struggles, tangential advances, a new collaboration, and a "Eureka" moment. "I worked for 7 years on magnesium", says Curtin. "We had some accomplishments, but not on the most crucial issues, and I was about to give up, having exhausted what I thought we could do. But then Wu came from Singapore and brought renewed energy, an array of necessary technical skills, and exceptional motivation". Fast forward two years and the mystery is solved: they managed to establish a picture that unified decades of experimentation. The real progress started with the development of a new description of the atomic interactions in magnesium, a feature essential if atomistic models are to reveal any true material behavior. "We came across a rarely-used description of magnesium, and were able to tweak it and arrive at a new interatomic potential that predicted many well-established properties of magnesium with high accuracy." Most importantly, this new potential accurately predicted the structure of an important dislocation, the "c a" dislocation, which is essential for magnesium to flow easily. This dislocation, observed experimentally, could not previously be predicted. Then came the "Eureka" moment. "We were performing atomic simulations of the normal "c a" dislocation to better understand its behavior, and suddenly it changed". The atomic structure of the "c a" dislocation became entirely different, morphing into several possible geometries that locked it in place so that it could not move. Without "c a" motion, magnesium cannot flow plastically and so has low ductility. The new "c a" structures had been observed experimentally but how they occurred, whether they were real or experimental anomalies, and why there were several different structures, were all mysteries in the community. The work of Wu and Curtin showed that these new structures were intrinsic to magnesium, and they described why the different structures arise in different situations, and showed that all of these structures are more stable than the desirable "c a" structure. Thus, they found that it was inevitable that the new "c a" structures would form and kill the ductility of magnesium. A path to creating ductile magnesium "To make magnesium malleable, we must fight against the forces of nature," said Wu. If science does not yet have a miracle solution to prevent the phenomenon, he notes that it is still possible to slow the morphing process of the "c a" dislocations. "At room temperature, the morphing occurs almost instantly but when immersed in liquid nitrogen (temperature -195.79 ° C), it could take several months or one year." If the process could be delayed for a few seconds at normal temperatures, this could be enough to allow an industrial use. Several recent experimental studies in Germany have shown that it is possible to increase the ductility of magnesium by creating alloys with rare elements, such as yttrium, erbium, or holonium. Curtin believes these alloying elements bind to the normal "c a" and stabilize it somewhat, relative to the immovable "c a" dislocations. So, this is very promising, but these rare materials are very expensive and therefore unlikely to be used extensively by the automotive industry. Curtin and Wu are starting new research on how the expensive alloys, and other cheaper alloys, might stabilize the normal "c a" . "We must find a compromise between the cost of the alloy and the material performance" says Prof. Curtin. While he cannot predict when magnesium will be used heavily, he believes that the insights revealed by this new work will generate new ideas and approaches because the underlying origin of the poor behavior of magnesium is now more clearly understood. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Visual speech recognition (VSR) aims to recognize the content of speech based on lip movements, without relying on the audio stream. Advances in deep learning and the availability of large audio-visual datasets have led to the development of much more accurate and robust VSR models than ever before. However, these advances are usually due to the larger training sets rather than the model design. Here we demonstrate that designing better models is equally as important as using larger training sets. We propose the addition of prediction-based auxiliary tasks to a VSR model, and highlight the importance of hyperparameter optimization and appropriate data augmentations. We show that such a model works for different languages and outperforms all previous methods trained on publicly available datasets by a large margin. It even outperforms models that were trained on non-publicly available datasets containing up to to 21 times more data. We show, furthermore, that using additional training data, even in other languages or with automatically generated transcriptions, results in further improvement. Main Visual speech recognition (VSR), also known as lipreading, is the task of automatically recognizing speech from video based only on lip movements. In the past, this field has attracted a lot of research attention within the speech recognition community 1 , 2 , but it has failed to meet the initial high expectations. There are two main reasons why the first generation of VSR models fell short: (1) the lack of large transcribed audio-visual datasets resulted in models that could only recognize a limited vocabulary and work only in a laboratory environment and (2) the use of handcrafted visual features, which might not have been optimal for VSR applications, prevented the development of high-accuracy models. Recently, large audio-visual transcribed datasets, like LRS2 3 and LRS3 4 , have become available, and these have allowed the development of a large vocabulary and robust models. In addition, advances in deep learning have made possible the use of end-to-end models, which learn to extract VSR-related features directly from raw images. These developments have led to a new generation of deep-learning-based VSR models that achieve much higher accuracy than older models and also work in unseen real-life situations. The recent advances in VSR models are mainly fuelled by using increasingly larger transcribed datasets and the development of models that work well when trained with huge amounts of data. Some recent works 5 , 6 use tens of thousands of hours of non-publicly available training data to achieve state-of-the-art performance on standard benchmarks. In contrast to this recent trend, we demonstrate that carefully designing a model is equally as important as using larger training sets. Our approach revolves around (1) addition of prediction-based auxiliary tasks to a VSR model, (2) appropriate data augmentations and (3) hyperparameter optimization of an existing architecture. This leads to a great reduction in word error rate (WER) and results in state-of-the-art performance on almost all benchmarks. This is achieved by using only publicly available datasets, which are two orders of magnitude smaller than those used in previous works. We also show that combining multiple datasets further improves the performance (which is in line with the results reported in the literature). Hence, we argue that further progress in the field can be achieved not only by increasing the size of the training data but also by careful model design and optimization. The vast majority of existing works focus on improving the performance of English-only VSR models. There are also a few works that design models tailored to a specific language, like Mandarin 7 , 8 , 9 . In contrast to previous works, our approach is evaluated not only on English but also on Mandarin and Spanish (the two other widely spoken languages), Italian, French and Portuguese. State-of-the-art performance is achieved in all languages. Specifically, in this Article, we make the following contributions: We propose a novel method for VSR that outperforms state-of-the-art methods trained on publicly available data by a large margin. We do so with a VSR model with auxiliary tasks that jointly performs VSR and prediction of audio and visual representations. We demonstrate that the proposed VSR model performs well, not only in English, but also in other languages, such as Spanish, Mandarin, Italian, French and Portuguese. We show that enlarging the training sets, even by including unlabelled data with automatically generated transcriptions or videos in other languages, results in improved performance. This provides further evidence for the hypothesis that the recent improvements presented in the literature are probably the result of larger training sets and not necessarily of better models. We discuss challenges for VSR systems that need to be solved and ethical considerations that must be taken into account before this technology can be widely applied. Baseline VSR model The baseline VSR model that we extend in this work is based on ref. 10 . The model consists of a three-dimensional (3D) convolutional layer with a receptive field of five frames, followed by a 2D ResNet-18 (Fig. 1e ), a 12-layer Conformer model 11 and a transformer decoder as shown in Fig. 1b . The model is trained end to end using a combination of the connectionist temporal classification (CTC) loss with an attention mechanism. Data augmentation is also used during training in the form of random cropping and image flipping (applied to all frames in the same sequence). This model achieves state-of-the-art VSR performance on the LRS2 and LRS3 datasets, when only publicly available data are used for training. Fig. 1: Model architecture overview. a – c , Baseline ASR model ( a ), baseline VSR model ( b ) and proposed model ( c ) with prediction-based auxiliary tasks. The frame rate of the extracted visual features and audio features is 25. d , The architecture of the ASR encoder from a . e , The architecture of the VSR encoder from b . Full size image Baseline ASR model The baseline Automatic Speech Recognition (ASR) model that we use is based on ref. 10", "role": "user" }, { "content": "In recent years, deep learning techniques have achieved remarkable results in numerous language and image-processing tasks. This includes visual speech recognition (VSR), which entails identifying the content of speech solely by analyzing a speaker's lip movements. While some deep learning algorithms have achieved highly promising results on VSR tasks, they were primarily trained to detect speech in English, as most existing training datasets only include English speech. This limits their potential user base to people who live or work in English-speaking contexts. Researchers at Imperial College London have recently developed a new model that can tackle VSR tasks in multiple languages. This model, introduced in a paper published in Nature Machine Intelligence, was found to outperform some previously proposed models trained on far larger datasets. \"Visual speech recognition (VSR) was one of the main topics of my Ph.D. thesis,\" Pingchuan Ma, a Ph.D. graduate from Imperial College who carried out the study, told TechXplore. \"During my studies, I worked on several topics, for instance exploring how to combine visual information with audio for audio-visual speech recognition and how to recognize visual speech independently of the head pose of participants. I realized that the vast majority of existing literature only dealt with English speech.\" The key objective of the recent study by Ma and his colleagues was to train a deep learning model to recognize speech in languages other than English from the lip movements of speakers and then compare its performance to that of other models trained to recognize English speech. The model created by the researchers is similar to those introduced by other teams in the past, but but some of its hyper-parameters were optimized, the dataset was augmented (i.e., increased in size by adding synthetic, slightly modified versions of data) and additional loss functions were used. \"We showed that we can use the same models to train VSR models in other languages,\" Ma explained. \"Our model takes raw images as input, without extracting any features, and then automatically learns what useful features to extract from these images to complete VSR tasks. The main novelty of this work is that we train a model to perform VSR and also add some additional data augmentation methods and loss functions.\" In initial evaluations, the model created by Ma and his colleagues performed remarkably well, outperforming other VSR models trained on much larger datasets, even if it required less original training data. As expected, however, it did not perform as well as English-speech recognition models, mainly due to smaller datasets available for training. \"We achieved state-of-the-art results in multiple languages by carefully designing the model, rather than by simply using larger datasets or larger models, which is the current trend in the literature,\" Ma said. \"In other words, we showed that how a model is designed is equally important to its performance than increasing its size or using more training data. This can potentially lead to a shift in the way researchers try to improve VSR models.\" Ma and his colleagues showed that one can achieve state-of-the-art performances in VSR tasks by carefully designing deep learning models, instead of using larger versions of the same model or collecting additional training data, which is both expensive and time consuming. In the future, their work could inspire other research teams to develop alternative VSR models that can effectively recognize speech from lip movements in languages other than English. \"One of the main research areas I'm interested in is how we can combine VSR models with existing (audio-only) speech recognition,\" Ma added. \"I'm particularly interested in how these models can be dynamically weighted, i.e., how the model can learn which model should rely on depending on the noise. In other words, in a noisy environment an audio-visual model should rely more on the visual stream, but when the mouth region is occluded it should rely more on the audio stream. Existing models are essentially frozen once trained and they cannot adapt to changes in the environment.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Visual speech recognition (VSR) aims to recognize the content of speech based on lip movements, without relying on the audio stream. Advances in deep learning and the availability of large audio-visual datasets have led to the development of much more accurate and robust VSR models than ever before. However, these advances are usually due to the larger training sets rather than the model design. Here we demonstrate that designing better models is equally as important as using larger training sets. We propose the addition of prediction-based auxiliary tasks to a VSR model, and highlight the importance of hyperparameter optimization and appropriate data augmentations. We show that such a model works for different languages and outperforms all previous methods trained on publicly available datasets by a large margin. It even outperforms models that were trained on non-publicly available datasets containing up to to 21 times more data. We show, furthermore, that using additional training data, even in other languages or with automatically generated transcriptions, results in further improvement. Main Visual speech recognition (VSR), also known as lipreading, is the task of automatically recognizing speech from video based only on lip movements. In the past, this field has attracted a lot of research attention within the speech recognition community 1 , 2 , but it has failed to meet the initial high expectations. There are two main reasons why the first generation of VSR models fell short: (1) the lack of large transcribed audio-visual datasets resulted in models that could only recognize a limited vocabulary and work only in a laboratory environment and (2) the use of handcrafted visual features, which might not have been optimal for VSR applications, prevented the development of high-accuracy models. Recently, large audio-visual transcribed datasets, like LRS2 3 and LRS3 4 , have become available, and these have allowed the development of a large vocabulary and robust models. In addition, advances in deep learning have made possible the use of end-to-end models, which learn to extract VSR-related features directly from raw images. These developments have led to a new generation of deep-learning-based VSR models that achieve much higher accuracy than older models and also work in unseen real-life situations. The recent advances in VSR models are mainly fuelled by using increasingly larger transcribed datasets and the development of models that work well when trained with huge amounts of data. Some recent works 5 , 6 use tens of thousands of hours of non-publicly available training data to achieve state-of-the-art performance on standard benchmarks. In contrast to this recent trend, we demonstrate that carefully designing a model is equally as important as using larger training sets. Our approach revolves around (1) addition of prediction-based auxiliary tasks to a VSR model, (2) appropriate data augmentations and (3) hyperparameter optimization of an existing architecture. This leads to a great reduction in word error rate (WER) and results in state-of-the-art performance on almost all benchmarks. This is achieved by using only publicly available datasets, which are two orders of magnitude smaller than those used in previous works. We also show that combining multiple datasets further improves the performance (which is in line with the results reported in the literature). Hence, we argue that further progress in the field can be achieved not only by increasing the size of the training data but also by careful model design and optimization. The vast majority of existing works focus on improving the performance of English-only VSR models. There are also a few works that design models tailored to a specific language, like Mandarin 7 , 8 , 9 . In contrast to previous works, our approach is evaluated not only on English but also on Mandarin and Spanish (the two other widely spoken languages), Italian, French and Portuguese. State-of-the-art performance is achieved in all languages. Specifically, in this Article, we make the following contributions: We propose a novel method for VSR that outperforms state-of-the-art methods trained on publicly available data by a large margin. We do so with a VSR model with auxiliary tasks that jointly performs VSR and prediction of audio and visual representations. We demonstrate that the proposed VSR model performs well, not only in English, but also in other languages, such as Spanish, Mandarin, Italian, French and Portuguese. We show that enlarging the training sets, even by including unlabelled data with automatically generated transcriptions or videos in other languages, results in improved performance. This provides further evidence for the hypothesis that the recent improvements presented in the literature are probably the result of larger training sets and not necessarily of better models. We discuss challenges for VSR systems that need to be solved and ethical considerations that must be taken into account before this technology can be widely applied. Baseline VSR model The baseline VSR model that we extend in this work is based on ref. 10 . The model consists of a three-dimensional (3D) convolutional layer with a receptive field of five frames, followed by a 2D ResNet-18 (Fig. 1e ), a 12-layer Conformer model 11 and a transformer decoder as shown in Fig. 1b . The model is trained end to end using a combination of the connectionist temporal classification (CTC) loss with an attention mechanism. Data augmentation is also used during training in the form of random cropping and image flipping (applied to all frames in the same sequence). This model achieves state-of-the-art VSR performance on the LRS2 and LRS3 datasets, when only publicly available data are used for training. Fig. 1: Model architecture overview. a – c , Baseline ASR model ( a ), baseline VSR model ( b ) and proposed model ( c ) with prediction-based auxiliary tasks. The frame rate of the extracted visual features and audio features is 25. d , The architecture of the ASR encoder from a . e , The architecture of the VSR encoder from b . Full size image Baseline ASR model The baseline Automatic Speech Recognition (ASR) model that we use is based on ref. 10<|im_end|> <|im_start|>assistant In recent years, deep learning techniques have achieved remarkable results in numerous language and image-processing tasks. This includes visual speech recognition (VSR), which entails identifying the content of speech solely by analyzing a speaker's lip movements. While some deep learning algorithms have achieved highly promising results on VSR tasks, they were primarily trained to detect speech in English, as most existing training datasets only include English speech. This limits their potential user base to people who live or work in English-speaking contexts. Researchers at Imperial College London have recently developed a new model that can tackle VSR tasks in multiple languages. This model, introduced in a paper published in Nature Machine Intelligence, was found to outperform some previously proposed models trained on far larger datasets. "Visual speech recognition (VSR) was one of the main topics of my Ph.D. thesis," Pingchuan Ma, a Ph.D. graduate from Imperial College who carried out the study, told TechXplore. "During my studies, I worked on several topics, for instance exploring how to combine visual information with audio for audio-visual speech recognition and how to recognize visual speech independently of the head pose of participants. I realized that the vast majority of existing literature only dealt with English speech." The key objective of the recent study by Ma and his colleagues was to train a deep learning model to recognize speech in languages other than English from the lip movements of speakers and then compare its performance to that of other models trained to recognize English speech. The model created by the researchers is similar to those introduced by other teams in the past, but but some of its hyper-parameters were optimized, the dataset was augmented (i.e., increased in size by adding synthetic, slightly modified versions of data) and additional loss functions were used. "We showed that we can use the same models to train VSR models in other languages," Ma explained. "Our model takes raw images as input, without extracting any features, and then automatically learns what useful features to extract from these images to complete VSR tasks. The main novelty of this work is that we train a model to perform VSR and also add some additional data augmentation methods and loss functions." In initial evaluations, the model created by Ma and his colleagues performed remarkably well, outperforming other VSR models trained on much larger datasets, even if it required less original training data. As expected, however, it did not perform as well as English-speech recognition models, mainly due to smaller datasets available for training. "We achieved state-of-the-art results in multiple languages by carefully designing the model, rather than by simply using larger datasets or larger models, which is the current trend in the literature," Ma said. "In other words, we showed that how a model is designed is equally important to its performance than increasing its size or using more training data. This can potentially lead to a shift in the way researchers try to improve VSR models." Ma and his colleagues showed that one can achieve state-of-the-art performances in VSR tasks by carefully designing deep learning models, instead of using larger versions of the same model or collecting additional training data, which is both expensive and time consuming. In the future, their work could inspire other research teams to develop alternative VSR models that can effectively recognize speech from lip movements in languages other than English. "One of the main research areas I'm interested in is how we can combine VSR models with existing (audio-only) speech recognition," Ma added. "I'm particularly interested in how these models can be dynamically weighted, i.e., how the model can learn which model should rely on depending on the noise. In other words, in a noisy environment an audio-visual model should rely more on the visual stream, but when the mouth region is occluded it should rely more on the audio stream. Existing models are essentially frozen once trained and they cannot adapt to changes in the environment." <|im_end|>

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2,059

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Long-duration observations of Neptune’s brightness at two visible wavelengths provide a disk-averaged estimate of its atmospheric aerosol. Brightness variations were previously associated with the 11-year solar cycle, through solar-modulated mechanisms linked with either ultraviolet or galactic cosmic ray (GCR) effects on atmospheric particles. Here, we use a recently extended brightness data set (1972–2014), with physically realistic modelling to show, rather than alternatives, ultraviolet and GCR are likely to be modulating Neptune’s atmosphere in combination. The importance of GCR is further supported by the response of Neptune’s atmosphere to an intermittent 1.5- to 1.9-year periodicity, which occurred preferentially in GCR (not ultraviolet) during the mid-1980s. This periodicity was detected both at Earth, and in GCR measured by Voyager 2, then near Neptune. A similar coincident variability in Neptune’s brightness suggests nucleation onto GCR ions. Both GCR and ultraviolet mechanisms may occur more rapidly than the subsequent atmospheric particle transport. Introduction Long-term observations of Neptune from a ground-based telescope show variations in the planet’s disk-averaged brightness, which are associated with changes in the reflectivity (albedo) of the planet from its atmospheric aerosol and clouds. Although seasonal variations dominate the time series, Lockwood and Thompson 1 showed, using data from 1972 to 1996, that small fluctuations in Neptune’s brightness at two visible wavelengths followed the 11-year solar cycle. They examined two quantities known to vary closely with solar activity. The first, solar ultraviolet radiation, is linked to photochemical variations in Neptune’s atmospheric aerosol particles, and the second, galactic cosmic rays (GCR), may create some of Neptune’s aerosol through ion-induced nucleation. It was not possible to discriminate between the ultraviolet and GCR effects, although the relationship with ultraviolet was slightly more statistically robust 1 . The Neptune magnitude-solar activity relationship broke down after 1996 (refs 1 , 2 ), but recent extension of the data 3 encourages its re-examination. Supporting evidence for a solar cycle in infrared observations from 1975 to 2007 (ref. 4 ) further motivates a fresh consideration of the origin of the short-term variability in Neptune’s albedo. Both the ultraviolet and GCR mechanisms can, in principle, account for the changes observed in the photometric observations, which originate in Neptune’s stratosphere and troposphere 1 , 5 . The ultraviolet mechanism was originally proposed 6 to explain the solar cycle signal when it was first reported in Neptune’s albedo 7 . It was suggested that ultraviolet-triggered surface chemistry on pre-existing aerosol particles varied the optical properties of Neptune’s stratospheric aerosol through a darkening in colour (‘tanning’), detectable in the photometric measurements. The GCR-driven mechanism was proposed for Neptune 8 , 9 , through direct (‘Wilson’) condensation of supersaturated gas onto atmospheric ions 10 , causing particle growth ultimately detectable at optical wavelengths. The possibility that charge-related effects could modulate the atmospheres of the outer planets, where variations in solar irradiance are proportionately less important 11 , contrasts with the small likely role of energetic particles in Earth’s atmosphere 12 and provides a further motivation for this study. The two proposed mechanisms for external solar forcing of Neptune are essentially heliospheric (through GCR) or photospheric (through solar ultraviolet) in origin. The analysis to investigate them here uses two approaches. First, the relationships between Neptune’s magnitude, solar ultraviolet radiation and GCRs are studied with multiple regression, allowing both the proposed mechanisms to act together. We find that, when the extra degrees of freedom are accounted for, including both ultraviolet and GCR improves prediction of the magnitude fluctuations. Second, we examine the relatively rapid fluctuations apparent during the mid-1980s in the Neptune astronomical data. This enhanced variability coincided with a known episode of quasi-periodic fluctuations present in GCR 13 , centred around 1.68 years. Investigating Neptune’s atmospheric variability in the 1.5 to 2 year range therefore presents a method by which to separate the two different suggested solar-modulated influences, an approach previously used to separate coincident terrestrial atmospheric responses 14 . Results The extended Neptune photometric data set 1972–2014 Regular photometric observations of the magnitude (brightness) of Neptune have been made since 1972, through well-characterised visible bandpass filters of width ∼ 20 nm centred at 472 nm (‘b’, blue) and 551 nm (‘y’, green) using a 21-in telescope at Lowell Observatory, Arizona 2 , Fig. 1a . Each magnitude value is typically determined from between 4 and 39 nights of data (median 9 nights), taken around the time the planet is brightest in the sky (opposition) 3 . Standard errors in the magnitude measurements, determined from the standard deviations and number of nights of observation were typically ±0.001 (ref. 3 ). Sampling intervals varied between 0.7 and 1.2 years, with median interval of 1.04 years. Figure 1 summarizes the data, with Fig. 1a showing the measured magnitudes, Fig 1b showing the magnitude fluctuations, Fig. 1c showing the ultraviolet data and Fig. 1d showing GCR measured both at Earth and in space. More information on the data is given in the ‘Methods’ section. Figure 1: Time series of Neptune’s brightness and solar modulated parameters. ( a ) Neptune brightness (astronomical magnitude, where smaller values represent a greater signal) time series at 472 nm (blue squares) and 551 nm (green circles), from ref. 3 , each smoothed with a lowess fit (blue dashed line or green solid line). ( b ) Magnitude fluctuations after detrending ( a ) with a lowess fit. The maximum s.e.m. in each data set is shown as a single error bar on the far left. ( c ) Lyman-alpha (ultraviolet) radiation at 121.5 nm. ( d ) Cosmic ray count rate at Earth’s surface and in the heliosphere, showing terrestrial neutron monitor data from Oulu, Finland, (black) and Voyager 2 LECP instrument daily mean flux of cosmic ray protons >70 MeV (grey). Data are described in full in the ‘Methods’ section. Full size image The correlation between the 29 data points and 30-day running means of ultraviolet, sunspots and GCR with a range of lags was calculated previously 1 . The correlation between Neptune’s magnitude fluctuations and ultraviolet was statistically significant, whereas", "role": "user" }, { "content": "Autonomous robots capable of walking, swimming and climbing, will replicate insects, birds, animals and even humans on future missions of space exploration within decades, according to a new UK-RAS Network white paper led by Professor Yang Gao, Head of STAR Lab at the University of Surrey. Space Robotics and Autonomous Systems: Widening the horizon of space exploration also reveals that the rapid evolution of technologies powering space RAS will have beneficial applications in sectors such as healthcare, mining and agriculture. Lead author Professor Yang Gao, Head of STAR Lab at the University of Surrey's Space Centre explained, \"Since the 1990s, a new generation of planetary exploration has travelled further into the solar system and is required to become increasingly more convincing as a human proxy in space. This will lead to the development of robotic explorers and assistants that can carry out such complex tasks that they could tangibly replace humans in space or assist astronauts on a mission.\" Such skills include the ability for space robotics to be equipped with new sensing techniques in order to acquire 3D perception, and to have the ability to climb, swim, dig, fly, sail, navigate and dock spacecraft without humans, as well as to interact with humans. European Space Agency (ESA) Astronaut Roberto Vittori who launched the white paper, said: \"Space robotics is central to the future of space exploration. The importance of this area of science cannot be understated, something I can personally attest to having been responsible for the space shuttle's robotic arm in the instillation of a six-tonne cosmic ray detector to the International Space Station. This Space Robotics white paper will be instrumental in providing a clear vision as we continue to push new boundaries in both man and unmanned spaceflight.\" The University of Surrey is at the forefront of research in this area. Part of Surrey Space Centre (SSC), the Surrey Technology for Autonomous Systems and Robotics (STAR) Lab specialises in developing contemporary robotics solutions and autonomous systems that monitor and service spacecraft, remove space debris and explore new space frontiers and extra-terrestrial surfaces. Examples include robotic arms capable of grabbing space debris and consigning it to a recycling bin, and ideas to 'modularise' spacecraft so that individual subsystem modules can be replaced if they fail. These are all tasks which would be extremely dangerous and hugely expensive if performed by human astronauts without using robots. Bringing benefits back down to earth While space robotics and autonomous systems (RAS) are broadening what is possible in space, they are also bringing benefits closer to home. Professor Gao explained, \"Increasingly we are seeing non-space industries interested in applying our expertise to their own areas, such as the nuclear sector which also has to deal with a high radiation, hazardous environment. \"We're now developing robotic vision-based software for Sellafield which can help sort and segregate nuclear waste autonomously. Also, for the agricultural sector we've been asked to develop a small autonomous vehicle that can identify diseased crops, take high resolution images and deploy a robotic arm to take samples if required.\" Other industries that will benefit as a direct result from the technical advancements in space robotics include: The healthcare industry through advancements in robotic surgery, diagnostics, independent living, nursing systems, prosthetic analysis and therapy opportunitiesThe emergency services through improved responsiveness, reduced risk to life and more efficient deploymentThe deep mining industry through enhanced exploration, excavation, refinement and health condition monitoring The water industry through more efficient asset inspection, maintenance and health condition monitoring The white paper report highlights technological needs, challenges and solutions that space robotics are likely to overcome over the coming decades. At an estimated $10,000 per kilogram to launch a satellite merely into low Earth orbit, cost saving solutions such as the ability to repair spacecraft in orbit using space RAS is becoming very attractive to the rapidly expanding space industry. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Long-duration observations of Neptune’s brightness at two visible wavelengths provide a disk-averaged estimate of its atmospheric aerosol. Brightness variations were previously associated with the 11-year solar cycle, through solar-modulated mechanisms linked with either ultraviolet or galactic cosmic ray (GCR) effects on atmospheric particles. Here, we use a recently extended brightness data set (1972–2014), with physically realistic modelling to show, rather than alternatives, ultraviolet and GCR are likely to be modulating Neptune’s atmosphere in combination. The importance of GCR is further supported by the response of Neptune’s atmosphere to an intermittent 1.5- to 1.9-year periodicity, which occurred preferentially in GCR (not ultraviolet) during the mid-1980s. This periodicity was detected both at Earth, and in GCR measured by Voyager 2, then near Neptune. A similar coincident variability in Neptune’s brightness suggests nucleation onto GCR ions. Both GCR and ultraviolet mechanisms may occur more rapidly than the subsequent atmospheric particle transport. Introduction Long-term observations of Neptune from a ground-based telescope show variations in the planet’s disk-averaged brightness, which are associated with changes in the reflectivity (albedo) of the planet from its atmospheric aerosol and clouds. Although seasonal variations dominate the time series, Lockwood and Thompson 1 showed, using data from 1972 to 1996, that small fluctuations in Neptune’s brightness at two visible wavelengths followed the 11-year solar cycle. They examined two quantities known to vary closely with solar activity. The first, solar ultraviolet radiation, is linked to photochemical variations in Neptune’s atmospheric aerosol particles, and the second, galactic cosmic rays (GCR), may create some of Neptune’s aerosol through ion-induced nucleation. It was not possible to discriminate between the ultraviolet and GCR effects, although the relationship with ultraviolet was slightly more statistically robust 1 . The Neptune magnitude-solar activity relationship broke down after 1996 (refs 1 , 2 ), but recent extension of the data 3 encourages its re-examination. Supporting evidence for a solar cycle in infrared observations from 1975 to 2007 (ref. 4 ) further motivates a fresh consideration of the origin of the short-term variability in Neptune’s albedo. Both the ultraviolet and GCR mechanisms can, in principle, account for the changes observed in the photometric observations, which originate in Neptune’s stratosphere and troposphere 1 , 5 . The ultraviolet mechanism was originally proposed 6 to explain the solar cycle signal when it was first reported in Neptune’s albedo 7 . It was suggested that ultraviolet-triggered surface chemistry on pre-existing aerosol particles varied the optical properties of Neptune’s stratospheric aerosol through a darkening in colour (‘tanning’), detectable in the photometric measurements. The GCR-driven mechanism was proposed for Neptune 8 , 9 , through direct (‘Wilson’) condensation of supersaturated gas onto atmospheric ions 10 , causing particle growth ultimately detectable at optical wavelengths. The possibility that charge-related effects could modulate the atmospheres of the outer planets, where variations in solar irradiance are proportionately less important 11 , contrasts with the small likely role of energetic particles in Earth’s atmosphere 12 and provides a further motivation for this study. The two proposed mechanisms for external solar forcing of Neptune are essentially heliospheric (through GCR) or photospheric (through solar ultraviolet) in origin. The analysis to investigate them here uses two approaches. First, the relationships between Neptune’s magnitude, solar ultraviolet radiation and GCRs are studied with multiple regression, allowing both the proposed mechanisms to act together. We find that, when the extra degrees of freedom are accounted for, including both ultraviolet and GCR improves prediction of the magnitude fluctuations. Second, we examine the relatively rapid fluctuations apparent during the mid-1980s in the Neptune astronomical data. This enhanced variability coincided with a known episode of quasi-periodic fluctuations present in GCR 13 , centred around 1.68 years. Investigating Neptune’s atmospheric variability in the 1.5 to 2 year range therefore presents a method by which to separate the two different suggested solar-modulated influences, an approach previously used to separate coincident terrestrial atmospheric responses 14 . Results The extended Neptune photometric data set 1972–2014 Regular photometric observations of the magnitude (brightness) of Neptune have been made since 1972, through well-characterised visible bandpass filters of width ∼ 20 nm centred at 472 nm (‘b’, blue) and 551 nm (‘y’, green) using a 21-in telescope at Lowell Observatory, Arizona 2 , Fig. 1a . Each magnitude value is typically determined from between 4 and 39 nights of data (median 9 nights), taken around the time the planet is brightest in the sky (opposition) 3 . Standard errors in the magnitude measurements, determined from the standard deviations and number of nights of observation were typically ±0.001 (ref. 3 ). Sampling intervals varied between 0.7 and 1.2 years, with median interval of 1.04 years. Figure 1 summarizes the data, with Fig. 1a showing the measured magnitudes, Fig 1b showing the magnitude fluctuations, Fig. 1c showing the ultraviolet data and Fig. 1d showing GCR measured both at Earth and in space. More information on the data is given in the ‘Methods’ section. Figure 1: Time series of Neptune’s brightness and solar modulated parameters. ( a ) Neptune brightness (astronomical magnitude, where smaller values represent a greater signal) time series at 472 nm (blue squares) and 551 nm (green circles), from ref. 3 , each smoothed with a lowess fit (blue dashed line or green solid line). ( b ) Magnitude fluctuations after detrending ( a ) with a lowess fit. The maximum s.e.m. in each data set is shown as a single error bar on the far left. ( c ) Lyman-alpha (ultraviolet) radiation at 121.5 nm. ( d ) Cosmic ray count rate at Earth’s surface and in the heliosphere, showing terrestrial neutron monitor data from Oulu, Finland, (black) and Voyager 2 LECP instrument daily mean flux of cosmic ray protons >70 MeV (grey). Data are described in full in the ‘Methods’ section. Full size image The correlation between the 29 data points and 30-day running means of ultraviolet, sunspots and GCR with a range of lags was calculated previously 1 . The correlation between Neptune’s magnitude fluctuations and ultraviolet was statistically significant, whereas<|im_end|> <|im_start|>assistant Autonomous robots capable of walking, swimming and climbing, will replicate insects, birds, animals and even humans on future missions of space exploration within decades, according to a new UK-RAS Network white paper led by Professor Yang Gao, Head of STAR Lab at the University of Surrey. Space Robotics and Autonomous Systems: Widening the horizon of space exploration also reveals that the rapid evolution of technologies powering space RAS will have beneficial applications in sectors such as healthcare, mining and agriculture. Lead author Professor Yang Gao, Head of STAR Lab at the University of Surrey's Space Centre explained, "Since the 1990s, a new generation of planetary exploration has travelled further into the solar system and is required to become increasingly more convincing as a human proxy in space. This will lead to the development of robotic explorers and assistants that can carry out such complex tasks that they could tangibly replace humans in space or assist astronauts on a mission." Such skills include the ability for space robotics to be equipped with new sensing techniques in order to acquire 3D perception, and to have the ability to climb, swim, dig, fly, sail, navigate and dock spacecraft without humans, as well as to interact with humans. European Space Agency (ESA) Astronaut Roberto Vittori who launched the white paper, said: "Space robotics is central to the future of space exploration. The importance of this area of science cannot be understated, something I can personally attest to having been responsible for the space shuttle's robotic arm in the instillation of a six-tonne cosmic ray detector to the International Space Station. This Space Robotics white paper will be instrumental in providing a clear vision as we continue to push new boundaries in both man and unmanned spaceflight." The University of Surrey is at the forefront of research in this area. Part of Surrey Space Centre (SSC), the Surrey Technology for Autonomous Systems and Robotics (STAR) Lab specialises in developing contemporary robotics solutions and autonomous systems that monitor and service spacecraft, remove space debris and explore new space frontiers and extra-terrestrial surfaces. Examples include robotic arms capable of grabbing space debris and consigning it to a recycling bin, and ideas to 'modularise' spacecraft so that individual subsystem modules can be replaced if they fail. These are all tasks which would be extremely dangerous and hugely expensive if performed by human astronauts without using robots. Bringing benefits back down to earth While space robotics and autonomous systems (RAS) are broadening what is possible in space, they are also bringing benefits closer to home. Professor Gao explained, "Increasingly we are seeing non-space industries interested in applying our expertise to their own areas, such as the nuclear sector which also has to deal with a high radiation, hazardous environment. "We're now developing robotic vision-based software for Sellafield which can help sort and segregate nuclear waste autonomously. Also, for the agricultural sector we've been asked to develop a small autonomous vehicle that can identify diseased crops, take high resolution images and deploy a robotic arm to take samples if required." Other industries that will benefit as a direct result from the technical advancements in space robotics include: The healthcare industry through advancements in robotic surgery, diagnostics, independent living, nursing systems, prosthetic analysis and therapy opportunitiesThe emergency services through improved responsiveness, reduced risk to life and more efficient deploymentThe deep mining industry through enhanced exploration, excavation, refinement and health condition monitoring The water industry through more efficient asset inspection, maintenance and health condition monitoring The white paper report highlights technological needs, challenges and solutions that space robotics are likely to overcome over the coming decades. At an estimated $10,000 per kilogram to launch a satellite merely into low Earth orbit, cost saving solutions such as the ability to repair spacecraft in orbit using space RAS is becoming very attractive to the rapidly expanding space industry. <|im_end|>

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2,215

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Background Increasing use of silver nanoparticles (Ag-NPs) in various products is resulting in a greater likelihood of human exposure to these materials. Nevertheless, little is still known about the influence of carbohydrates on the toxicity and cellular uptake of nanoparticles. Methods Ag-NPs functionalized with three different monosaccharides and ethylene glycol were synthesized and characterised. Oxidative stress and toxicity was evaluated by protein carbonylation and MTT assay, respectively. Cellular uptake was evaluated by confocal microscopy and ICP-MS. Results Ag-NPs coated with galactose and mannose were considerably less toxic to neuronal-like cells and hepatocytes compared to particles functionalized by glucose, ethylene glycol or citrate. Toxicity correlated to oxidative stress but not to cellular uptake. Conclusions Carbohydrate coating on silver nanoparticles modulates both oxidative stress and cellular uptake, but mainly the first has an impact on toxicity. These findings provide new perspectives on modulating the bioactivity of Ag-NPs by using carbohydrates. Introduction Nanoparticles are playing an increasing role in the development of novel diagnosis methods and in the advanced design of drug delivery systems [ 1 ],[ 2 ]. Silver nanoparticles (Ag-NPs) in particular, show excellent anti-microbial properties and therefore are rapidly being incorporated into a wide array of consumer products such as textiles, cosmetics or packaging materials, increasing the likelihood of human and environmental exposure [ 3 ],[ 4 ]. Moreover, due to their optical properties Ag-NPs are attracting more attention in the fields of biological and chemical sensors [ 5 ]. However, Ag-NPs exist in variety of different sizes and shapes but also, very important, with different coatings. Recently, among surface coatings there is an increasing interest in using carbohydrates as biomimetic functional molecules on the surface of nanoparticles [ 2 ],[ 6 ]-[ 8 ] for the diagnosis and treatment, for instance, of brain diseases like glioma and stroke [ 9 ],[ 10 ]. Glycan functionalised NPs offer several advantages: (i) their synthesis can be performed under biomimetic conditions resulting later on in nanoparticles without traces of chemicals responsible for adverse cellular responses. (ii) the carbohydrates on the surface can serve as targeting molecules and trigger cellular uptake via specific receptors or mediate specific cellular responses [ 10 ]. Concurrently, the importance of carbohydrates in cellular signalling and in the regulation of cellular processes continues to emerge [ 11 ]. The inherently weak interactions between carbohydrates and proteins or other biomolecules makes these interactions difficult to study. However, because these interactions tend to be multivalent in nature, the use of nanoparticles to mimic the multivalent presentation of carbohydrates found on biomolecular surfaces make carbohydrate-functionalized nanoparticles important systems to study [ 12 ]. Several factors like surface charge and particle size can contribute to the selective binding and uptake of nanomaterials [ 13 ],[ 14 ]. In addition to labelling with a targeting molecule, nanoparticles can induce multivalent effects by clustering antigens on the surface of the particle. Thereby, the binding of relatively weak targeting agents can be enhanced. Nevertheless, despite the importance of carbohydrates in biology and the vast array of literature on functionalized nanomaterials, little is known about the effects of carbohydrates on the uptake and toxicity of nanoparticles by different type of cells. Although it has been reported that polysaccharides can reduce the toxicity of silver nanoparticles [ 15 ] less is known about the influence of monosaccaharides [ 16 ] thus, the different results are difficult to rationalise. Moreover, as pointed out by Johnston et al. [ 17 ], the increasing importance of Ag-NPs in the development of novel consumer materials intended for human exposure requires more in depth studies on toxicity mechanisms, as well as, on how silver particles interact with biological molecules and how different surface modifications can be used to reduce or eliminate possible toxic effects. Here, we discuss the toxicity and the cellular uptake of different silver nanoparticles functionalized with citrate, three different monosaccharides as well as ethylene glycol on two different cell lines. It was found that toxicity correlates with oxidative stress rather than with cellular uptake. Experimental Materials Silver nitrate, sodium citrate, D-glucose, D-mannose, D-galactose and ethylenglycol with MW = 200 (EG-3) with purity >99% were purchased from Sigma-Aldrich. Synthesis of silver nanoparticles Citrate-capped silver nanoparticles were synthesized using a standard method [ 18 ]: A solution of AgNO 3 (10 −3 M) in deionized water was heated until boiling point. Then, sodium citrate solution in water was added dropwise. The color of the solution slowly turned into gray-yellow after few minutes, indicating the formation of nanoparticles. Heating was continued for an additional 10 min. The solution was then cooled to room temperature and stored in dark before functionalization. Synthesis of carbohydrate ligands Thiol-functionalized carbohydrates were synthesized using the following process: glucose, galactose and mannose were each reacted with thiopropionic acid to form the corresponding glycoside in approximately 50% yield. The products were isolated as DMAP-H+ salts. Solutions of these thiolate salts were then directly added to solutions of silver nanoparticles to prepare the carbohydrate functionalized particles. Functionalization of nanoparticles To a glass vial charged with a stir bar was added 1 mL of citrate capper silver nanoparticles (1 nM) and 60 μL of a 2 mM stock solution of the corresponding ligand. The solutions were stirred for 3 h at which time each solution was transferred to a 1.5 mL Eppendorf tube and centrifuged for 10 min at 8000 rpm. The supernatant was discarded and the pellet was resuspended in 1 mL of H 2 O. These nanoparticle solutions were then used for subsequent reactions and analyses. Scheme of synthesized nanoparticles is shown in Figure 1 . Figure 1 Prepared nanoparticles. (A) Different biomolecules on the surface of prepared silver nanoparticles (linker not shown); (B) in cell culture media the nanoparticle-water interface is composed of ligands and ions but also of proteins, the so-called protein corona. Full size image Nanoparticles characterization Dynamic light scattering (DLS) Most of DLS measurements were carried out at 37°C (to simulate physiological temperature) by use of a Malvern Zeta Nanosizer in water and in", "role": "user" }, { "content": "The use of colloidal silver to treat illnesses has become more popular in recent years, but its ingestion, prohibited in countries like the US, can be harmful to health. Scientists from the Max Planck Institute in Germany have now confirmed that silver nanoparticles are significantly toxic when they penetrate cells, although the number of toxic radicals they generate can vary by coating them with carbohydrates. Silver salts have been used externally for centuries for their antiseptic properties in the treatment of pains and as a surface disinfectant for materials. There are currently people who use silver nanoparticles to make homemade potions to combat infections and illnesses such as cancer and AIDS, although in some cases the only thing they achieve is argyria or blue-tinged skin. Health authorities warn that there is no scientific evidence that supports the therapeutic efficiency of colloidal silver and in fact, in some countries like the US, its ingestion is prohibited. On the contrary, there are numerous studies which demonstrate the toxicity of silver nanoparticles on cells. One of these studies has just been published in the Journal of Nanobiotechnology by an international team of researchers coordinated from the Max Planck Institute of Colloids and Interfaces (Germany). \"We have observed that it is only when silver nanoparticles enter inside the cells that they produce serious harm, and that their toxicity is basically due to the oxidative stress they create,\" explains the Spanish chemist Guillermo Orts-Gil, project co-ordinator, to SINC. To carry out the study, the team has analysed how different carbohydrates act on the surface of silver nanoparticles (Ag-NP) of around 50 nanometres, which have been introduced into cultures of liver cells and tumour cells from the nervous system of mice. The results reveal that, for example, the toxic effects of the Ag-NP are much greater if they are covered with glucose instead of galactose or mannose. 'Trojan horse' mechanism Although not all the details on the complex toxicological mechanisms are known, it is known that the nanoparticles use a 'Trojan horse' mechanism to trick the membrane's defences and get inside the cell. \"The new data shows how the different carbohydrate coatings regulate the way in which they do this, and this is hugely interesting for controlling their toxicity and designing future trials,\" points out Orts-Gil. The researcher highlights that there is a \"clear correlation between the coating of the nanoparticles, the oxidative stress and toxicity, and thus, these results open up new perspectives on regulating the bioactivity of the Ag-NP through the use of carbohydrates\". Silver nanoparticles are not only used to make homemade remedies; they are also increasingly used in drugs such as vaccines, as well as products such as clothes and cleaning cloths. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Background Increasing use of silver nanoparticles (Ag-NPs) in various products is resulting in a greater likelihood of human exposure to these materials. Nevertheless, little is still known about the influence of carbohydrates on the toxicity and cellular uptake of nanoparticles. Methods Ag-NPs functionalized with three different monosaccharides and ethylene glycol were synthesized and characterised. Oxidative stress and toxicity was evaluated by protein carbonylation and MTT assay, respectively. Cellular uptake was evaluated by confocal microscopy and ICP-MS. Results Ag-NPs coated with galactose and mannose were considerably less toxic to neuronal-like cells and hepatocytes compared to particles functionalized by glucose, ethylene glycol or citrate. Toxicity correlated to oxidative stress but not to cellular uptake. Conclusions Carbohydrate coating on silver nanoparticles modulates both oxidative stress and cellular uptake, but mainly the first has an impact on toxicity. These findings provide new perspectives on modulating the bioactivity of Ag-NPs by using carbohydrates. Introduction Nanoparticles are playing an increasing role in the development of novel diagnosis methods and in the advanced design of drug delivery systems [ 1 ],[ 2 ]. Silver nanoparticles (Ag-NPs) in particular, show excellent anti-microbial properties and therefore are rapidly being incorporated into a wide array of consumer products such as textiles, cosmetics or packaging materials, increasing the likelihood of human and environmental exposure [ 3 ],[ 4 ]. Moreover, due to their optical properties Ag-NPs are attracting more attention in the fields of biological and chemical sensors [ 5 ]. However, Ag-NPs exist in variety of different sizes and shapes but also, very important, with different coatings. Recently, among surface coatings there is an increasing interest in using carbohydrates as biomimetic functional molecules on the surface of nanoparticles [ 2 ],[ 6 ]-[ 8 ] for the diagnosis and treatment, for instance, of brain diseases like glioma and stroke [ 9 ],[ 10 ]. Glycan functionalised NPs offer several advantages: (i) their synthesis can be performed under biomimetic conditions resulting later on in nanoparticles without traces of chemicals responsible for adverse cellular responses. (ii) the carbohydrates on the surface can serve as targeting molecules and trigger cellular uptake via specific receptors or mediate specific cellular responses [ 10 ]. Concurrently, the importance of carbohydrates in cellular signalling and in the regulation of cellular processes continues to emerge [ 11 ]. The inherently weak interactions between carbohydrates and proteins or other biomolecules makes these interactions difficult to study. However, because these interactions tend to be multivalent in nature, the use of nanoparticles to mimic the multivalent presentation of carbohydrates found on biomolecular surfaces make carbohydrate-functionalized nanoparticles important systems to study [ 12 ]. Several factors like surface charge and particle size can contribute to the selective binding and uptake of nanomaterials [ 13 ],[ 14 ]. In addition to labelling with a targeting molecule, nanoparticles can induce multivalent effects by clustering antigens on the surface of the particle. Thereby, the binding of relatively weak targeting agents can be enhanced. Nevertheless, despite the importance of carbohydrates in biology and the vast array of literature on functionalized nanomaterials, little is known about the effects of carbohydrates on the uptake and toxicity of nanoparticles by different type of cells. Although it has been reported that polysaccharides can reduce the toxicity of silver nanoparticles [ 15 ] less is known about the influence of monosaccaharides [ 16 ] thus, the different results are difficult to rationalise. Moreover, as pointed out by Johnston et al. [ 17 ], the increasing importance of Ag-NPs in the development of novel consumer materials intended for human exposure requires more in depth studies on toxicity mechanisms, as well as, on how silver particles interact with biological molecules and how different surface modifications can be used to reduce or eliminate possible toxic effects. Here, we discuss the toxicity and the cellular uptake of different silver nanoparticles functionalized with citrate, three different monosaccharides as well as ethylene glycol on two different cell lines. It was found that toxicity correlates with oxidative stress rather than with cellular uptake. Experimental Materials Silver nitrate, sodium citrate, D-glucose, D-mannose, D-galactose and ethylenglycol with MW = 200 (EG-3) with purity >99% were purchased from Sigma-Aldrich. Synthesis of silver nanoparticles Citrate-capped silver nanoparticles were synthesized using a standard method [ 18 ]: A solution of AgNO 3 (10 −3 M) in deionized water was heated until boiling point. Then, sodium citrate solution in water was added dropwise. The color of the solution slowly turned into gray-yellow after few minutes, indicating the formation of nanoparticles. Heating was continued for an additional 10 min. The solution was then cooled to room temperature and stored in dark before functionalization. Synthesis of carbohydrate ligands Thiol-functionalized carbohydrates were synthesized using the following process: glucose, galactose and mannose were each reacted with thiopropionic acid to form the corresponding glycoside in approximately 50% yield. The products were isolated as DMAP-H+ salts. Solutions of these thiolate salts were then directly added to solutions of silver nanoparticles to prepare the carbohydrate functionalized particles. Functionalization of nanoparticles To a glass vial charged with a stir bar was added 1 mL of citrate capper silver nanoparticles (1 nM) and 60 μL of a 2 mM stock solution of the corresponding ligand. The solutions were stirred for 3 h at which time each solution was transferred to a 1.5 mL Eppendorf tube and centrifuged for 10 min at 8000 rpm. The supernatant was discarded and the pellet was resuspended in 1 mL of H 2 O. These nanoparticle solutions were then used for subsequent reactions and analyses. Scheme of synthesized nanoparticles is shown in Figure 1 . Figure 1 Prepared nanoparticles. (A) Different biomolecules on the surface of prepared silver nanoparticles (linker not shown); (B) in cell culture media the nanoparticle-water interface is composed of ligands and ions but also of proteins, the so-called protein corona. Full size image Nanoparticles characterization Dynamic light scattering (DLS) Most of DLS measurements were carried out at 37°C (to simulate physiological temperature) by use of a Malvern Zeta Nanosizer in water and in<|im_end|> <|im_start|>assistant The use of colloidal silver to treat illnesses has become more popular in recent years, but its ingestion, prohibited in countries like the US, can be harmful to health. Scientists from the Max Planck Institute in Germany have now confirmed that silver nanoparticles are significantly toxic when they penetrate cells, although the number of toxic radicals they generate can vary by coating them with carbohydrates. Silver salts have been used externally for centuries for their antiseptic properties in the treatment of pains and as a surface disinfectant for materials. There are currently people who use silver nanoparticles to make homemade potions to combat infections and illnesses such as cancer and AIDS, although in some cases the only thing they achieve is argyria or blue-tinged skin. Health authorities warn that there is no scientific evidence that supports the therapeutic efficiency of colloidal silver and in fact, in some countries like the US, its ingestion is prohibited. On the contrary, there are numerous studies which demonstrate the toxicity of silver nanoparticles on cells. One of these studies has just been published in the Journal of Nanobiotechnology by an international team of researchers coordinated from the Max Planck Institute of Colloids and Interfaces (Germany). "We have observed that it is only when silver nanoparticles enter inside the cells that they produce serious harm, and that their toxicity is basically due to the oxidative stress they create," explains the Spanish chemist Guillermo Orts-Gil, project co-ordinator, to SINC. To carry out the study, the team has analysed how different carbohydrates act on the surface of silver nanoparticles (Ag-NP) of around 50 nanometres, which have been introduced into cultures of liver cells and tumour cells from the nervous system of mice. The results reveal that, for example, the toxic effects of the Ag-NP are much greater if they are covered with glucose instead of galactose or mannose. 'Trojan horse' mechanism Although not all the details on the complex toxicological mechanisms are known, it is known that the nanoparticles use a 'Trojan horse' mechanism to trick the membrane's defences and get inside the cell. "The new data shows how the different carbohydrate coatings regulate the way in which they do this, and this is hugely interesting for controlling their toxicity and designing future trials," points out Orts-Gil. The researcher highlights that there is a "clear correlation between the coating of the nanoparticles, the oxidative stress and toxicity, and thus, these results open up new perspectives on regulating the bioactivity of the Ag-NP through the use of carbohydrates". Silver nanoparticles are not only used to make homemade remedies; they are also increasingly used in drugs such as vaccines, as well as products such as clothes and cleaning cloths. <|im_end|>

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1,911

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Global maps of plant functional traits are essential for studying the dynamics of the terrestrial biosphere, yet the spatial distribution of trait measurements remains sparse. With the increasing popularity of species identification apps, citizen scientists contribute to growing vegetation data collections. The question emerges whether such opportunistic citizen science data can help map plant functional traits globally. Here we show that we can map global trait patterns by complementing vascular plant observations from the global citizen science project iNaturalist with measurements from the plant trait database TRY. We evaluate these maps using sPlotOpen, a global collection of vegetation plot data. Our results show high correlations between the iNaturalist- and sPlotOpen-based maps of up to 0.69 ( r ) and higher correlations than to previously published trait maps. As citizen science data collections continue to grow, we can expect them to play a significant role in further improving maps of plant functional traits. Main Global maps of plant functional traits provide an indispensable foundation for understanding interactions of the environment and the terrestrial biosphere. Information on plant traits, such as tissue properties or morphological characteristics, is urgently needed as input for dynamic global vegetation models 1 , 2 or to understand geographic patterns of plant community structure and functional diversity 3 , 4 . Yet, the spatial distribution of plant trait observations remains sparse 5 , 6 . Measuring traits directly often involves destructive sampling and expensive laboratory protocols 7 . Plant trait databases, such as the TRY plant trait database 8 , 9 , curate these single measurements from numerous independent studies and projects. Although TRY provides an impressive collection of trait measurements, its cover cannot display global trait patterns 9 , 10 . Alternative approaches have upscaled trait expressions from trait databases for a few traits 5 , 11 , 12 , 13 , 14 . However, the resulting maps still feature huge uncertainties as they extrapolate into unknown areas 12 , 15 —uncertainties reflected in often-large discrepancies among the different trait maps 16 . The potential of satellite remote sensing to generate large-scale maps of trait distributions has also been explored 6 , 17 . Yet, remote sensing retrieves only a few traits 18 , 19 , 20 and primarily informs on upper canopies, while lower layers may not be well represented 21 . One potential source to complement existing trait data could be crowd-sourced observations classified via automated species classification 22 , which is increasingly accessible to a wide audience via smartphone apps (for a recent comparison of apps see Jones 23 ). Such technology now enables collecting plant observations in very large sample sizes 24 , 25 , 26 , 27 . Recent evaluations of crowd-sourced data demonstrate the potential of using crowd-sourced plant occurrence data to study species distribution and macroecological floristic gradients 28 , 29 . iNaturalist, one of the largest and increasingly popular citizen science projects, has motivated users to collect and verify a total of over 14 million vascular plant ‘research-grade’ observations 30 (Extended Data Fig. 1 ). Considering the growth rate and the fact that iNaturalist is only one among many citizen science projects that add to the global boost in vegetation data availability, we can expect that such data will play a crucial role in our understanding of global plant functions in ecosystems 31 . Yet, the actual value of using citizen science plant occurrence data for mapping global trait patterns remains largely unknown. Many citizen science projects, including iNaturalist, have no sampling design, so the resulting datasets cannot be considered to be representative of space, time, vegetation types or taxa. Biases may depend on site popularity or accessibility, cell phone reception, users’ interest in specific plants (for example, noticeable flowers) or temporal patterns in user activity, such as during vacations, weekends or linked to plant phenology 28 , 32 , 33 , 34 , 35 . However, if we were able—despite all the potential biases—to make use of the functional information encoded in these data and extract reliable trait information from the iNaturalist citizen science observations, we would have a quickly growing data source for biodiversity monitoring and long-term observation at our disposal. Here, we explore whether opportunistic iNaturalist research-grade occurrence data of vascular plants 36 could help map trait patterns on a global scale; we assess whether these data reflect global functional community composition when complemented with trait information from the global plant trait database TRY 9 and aggregated spatially into global trait grids. As a reference for evaluating the iNaturalist observations, we use trait community-weighted mean (cwm) from the database sPlotOpen 37 , 38 . Database sPlotOpen is curated from globally distributed plots with vegetation abundance measurements, balanced over global climate and soil conditions. It provides a cwm for each vegetation plot for 18 traits. These cwm are also derived from TRY measurements. We thus compare the functional trait information derived from spatially and taxonomically biased occurrence samples provided by iNaturalist citizen scientists to professionally sampled environmentally balanced plot-based abundance weighted data. Results iNaturalist and sPlotOpen observation density and cover We matched the iNaturalist species observations of vascular plants ( n = 14,019,405) with trait measurements from TRY, using the species name as the link. We were able to match 85% of the iNaturalist vascular plant observations and 32% of the species. A total of 55% of the species listed in the TRY database for the traits of interest were matched. This provided us with nearly 12 million observations ( n = 11,895,453) of 28,500 vascular plant species, for which we have information on at least one trait (see Table 1 for sample sizes of each trait). Table 1 Plant traits Full size table The density and distribution of iNaturalist observations after linking to TRY in comparison to the sPlotOpen plot data ( n = 95,104) show an almost global coverage (Fig. 1 ); for density before linking to TRY see Extended Data Fig. 2 . There is a strong imbalance in the density of observations,", "role": "user" }, { "content": "Nature and climate are mutually dependent. Plant growth is absolutely dependent on climate, but this is, in turn, strongly influenced by plants, such as in a forest, which evaporates a lot of water. In order to be able to make accurate predictions about how the living world may develop, extensive knowledge of the characteristics of the vegetation at the different locations is necessary, for example, leaf surface size, tissue properties and plant height. However, such data usually have to be recorded manually by professional scientists in a painstaking, time-consuming process. Consequently, the available worldwide plant trait data are very sparse and cover only certain regions. The TRY database, managed by iDiv and the Max Planck Institute for Biogeochemistry in Jena, currently provides such data on plant traits for almost 280,000 plant species. This makes it one of the most comprehensive databases for plant characteristics mapping in the world. Up to now, global maps of plant traits have been created using extrapolations (estimation beyond the original observation range) from this geographically limited database. However, the resulting maps are not particularly reliable. In order to fill large data gaps, the Leipzig researchers have now taken a different approach. Instead of extrapolating existing trait data geographically from the TRY database, they have linked it to the vast dataset from the citizen science project iNaturalist. With iNaturalist, users of the associated smartphone app share their observations of nature, providing species names, photos and geolocation. In this way, more than 19 million data points have been recorded, worldwide, for terrestrial plants alone. The data also feeds the world's largest biodiversity database, the Global Biodiversity Information Facility (GBIF). This is accessible to the public and also serves as an important database for biodiversity research. In order to test the accuracy of the maps based on the combination of iNaturalist observations and TRY plant traits, they were compared to the plant trait evaluations based on sPlotOpen; the iDiv sPlot platform is the world's largest archive of plant community data. It contains nearly 2 million datasets with complete lists of plant species which occur in the locations (plots) studied by professional researchers. The database is also enhanced with plant trait data from the TRY database. The conclusion: The new iNaturalist-based map corresponded to the sPlot data map significantly more closely than previous map products based on extrapolation. \"That the new maps, based on the citizen science data, seem to be even more precise than the extrapolations was both surprising and impressive,\" says first author Sophie Wolf, a doctoral researcher at Leipzig University. \"Particularly because iNaturalist and our reference sPlotOpen are very different in structure.\" \"Our study convincingly demonstrates the potential for research into voluntary data,\" says last author, Dr. Teja Kattenborn from Leipzig University and iDiv. \"It is encouraging to make increasing use of the synergies between the combined data from thousands of citizens and professional scientists.\" \"This work is the result of an initiative of the National Research Data Infrastructure for Biodiversity Research (NFDI4Biodiversity), with which we are pushing for a change in culture towards the open provision of data,\" says co-author Prof Miguel Mahecha, head of the working group Modeling Approaches in Remote Sensing at Leipzig University and iDiv. \"The free availability of data is an absolute prerequisite for a better understanding of our planet.\" The research was published in Nature Ecology & Evolution. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Global maps of plant functional traits are essential for studying the dynamics of the terrestrial biosphere, yet the spatial distribution of trait measurements remains sparse. With the increasing popularity of species identification apps, citizen scientists contribute to growing vegetation data collections. The question emerges whether such opportunistic citizen science data can help map plant functional traits globally. Here we show that we can map global trait patterns by complementing vascular plant observations from the global citizen science project iNaturalist with measurements from the plant trait database TRY. We evaluate these maps using sPlotOpen, a global collection of vegetation plot data. Our results show high correlations between the iNaturalist- and sPlotOpen-based maps of up to 0.69 ( r ) and higher correlations than to previously published trait maps. As citizen science data collections continue to grow, we can expect them to play a significant role in further improving maps of plant functional traits. Main Global maps of plant functional traits provide an indispensable foundation for understanding interactions of the environment and the terrestrial biosphere. Information on plant traits, such as tissue properties or morphological characteristics, is urgently needed as input for dynamic global vegetation models 1 , 2 or to understand geographic patterns of plant community structure and functional diversity 3 , 4 . Yet, the spatial distribution of plant trait observations remains sparse 5 , 6 . Measuring traits directly often involves destructive sampling and expensive laboratory protocols 7 . Plant trait databases, such as the TRY plant trait database 8 , 9 , curate these single measurements from numerous independent studies and projects. Although TRY provides an impressive collection of trait measurements, its cover cannot display global trait patterns 9 , 10 . Alternative approaches have upscaled trait expressions from trait databases for a few traits 5 , 11 , 12 , 13 , 14 . However, the resulting maps still feature huge uncertainties as they extrapolate into unknown areas 12 , 15 —uncertainties reflected in often-large discrepancies among the different trait maps 16 . The potential of satellite remote sensing to generate large-scale maps of trait distributions has also been explored 6 , 17 . Yet, remote sensing retrieves only a few traits 18 , 19 , 20 and primarily informs on upper canopies, while lower layers may not be well represented 21 . One potential source to complement existing trait data could be crowd-sourced observations classified via automated species classification 22 , which is increasingly accessible to a wide audience via smartphone apps (for a recent comparison of apps see Jones 23 ). Such technology now enables collecting plant observations in very large sample sizes 24 , 25 , 26 , 27 . Recent evaluations of crowd-sourced data demonstrate the potential of using crowd-sourced plant occurrence data to study species distribution and macroecological floristic gradients 28 , 29 . iNaturalist, one of the largest and increasingly popular citizen science projects, has motivated users to collect and verify a total of over 14 million vascular plant ‘research-grade’ observations 30 (Extended Data Fig. 1 ). Considering the growth rate and the fact that iNaturalist is only one among many citizen science projects that add to the global boost in vegetation data availability, we can expect that such data will play a crucial role in our understanding of global plant functions in ecosystems 31 . Yet, the actual value of using citizen science plant occurrence data for mapping global trait patterns remains largely unknown. Many citizen science projects, including iNaturalist, have no sampling design, so the resulting datasets cannot be considered to be representative of space, time, vegetation types or taxa. Biases may depend on site popularity or accessibility, cell phone reception, users’ interest in specific plants (for example, noticeable flowers) or temporal patterns in user activity, such as during vacations, weekends or linked to plant phenology 28 , 32 , 33 , 34 , 35 . However, if we were able—despite all the potential biases—to make use of the functional information encoded in these data and extract reliable trait information from the iNaturalist citizen science observations, we would have a quickly growing data source for biodiversity monitoring and long-term observation at our disposal. Here, we explore whether opportunistic iNaturalist research-grade occurrence data of vascular plants 36 could help map trait patterns on a global scale; we assess whether these data reflect global functional community composition when complemented with trait information from the global plant trait database TRY 9 and aggregated spatially into global trait grids. As a reference for evaluating the iNaturalist observations, we use trait community-weighted mean (cwm) from the database sPlotOpen 37 , 38 . Database sPlotOpen is curated from globally distributed plots with vegetation abundance measurements, balanced over global climate and soil conditions. It provides a cwm for each vegetation plot for 18 traits. These cwm are also derived from TRY measurements. We thus compare the functional trait information derived from spatially and taxonomically biased occurrence samples provided by iNaturalist citizen scientists to professionally sampled environmentally balanced plot-based abundance weighted data. Results iNaturalist and sPlotOpen observation density and cover We matched the iNaturalist species observations of vascular plants ( n = 14,019,405) with trait measurements from TRY, using the species name as the link. We were able to match 85% of the iNaturalist vascular plant observations and 32% of the species. A total of 55% of the species listed in the TRY database for the traits of interest were matched. This provided us with nearly 12 million observations ( n = 11,895,453) of 28,500 vascular plant species, for which we have information on at least one trait (see Table 1 for sample sizes of each trait). Table 1 Plant traits Full size table The density and distribution of iNaturalist observations after linking to TRY in comparison to the sPlotOpen plot data ( n = 95,104) show an almost global coverage (Fig. 1 ); for density before linking to TRY see Extended Data Fig. 2 . There is a strong imbalance in the density of observations,<|im_end|> <|im_start|>assistant Nature and climate are mutually dependent. Plant growth is absolutely dependent on climate, but this is, in turn, strongly influenced by plants, such as in a forest, which evaporates a lot of water. In order to be able to make accurate predictions about how the living world may develop, extensive knowledge of the characteristics of the vegetation at the different locations is necessary, for example, leaf surface size, tissue properties and plant height. However, such data usually have to be recorded manually by professional scientists in a painstaking, time-consuming process. Consequently, the available worldwide plant trait data are very sparse and cover only certain regions. The TRY database, managed by iDiv and the Max Planck Institute for Biogeochemistry in Jena, currently provides such data on plant traits for almost 280,000 plant species. This makes it one of the most comprehensive databases for plant characteristics mapping in the world. Up to now, global maps of plant traits have been created using extrapolations (estimation beyond the original observation range) from this geographically limited database. However, the resulting maps are not particularly reliable. In order to fill large data gaps, the Leipzig researchers have now taken a different approach. Instead of extrapolating existing trait data geographically from the TRY database, they have linked it to the vast dataset from the citizen science project iNaturalist. With iNaturalist, users of the associated smartphone app share their observations of nature, providing species names, photos and geolocation. In this way, more than 19 million data points have been recorded, worldwide, for terrestrial plants alone. The data also feeds the world's largest biodiversity database, the Global Biodiversity Information Facility (GBIF). This is accessible to the public and also serves as an important database for biodiversity research. In order to test the accuracy of the maps based on the combination of iNaturalist observations and TRY plant traits, they were compared to the plant trait evaluations based on sPlotOpen; the iDiv sPlot platform is the world's largest archive of plant community data. It contains nearly 2 million datasets with complete lists of plant species which occur in the locations (plots) studied by professional researchers. The database is also enhanced with plant trait data from the TRY database. The conclusion: The new iNaturalist-based map corresponded to the sPlot data map significantly more closely than previous map products based on extrapolation. "That the new maps, based on the citizen science data, seem to be even more precise than the extrapolations was both surprising and impressive," says first author Sophie Wolf, a doctoral researcher at Leipzig University. "Particularly because iNaturalist and our reference sPlotOpen are very different in structure." "Our study convincingly demonstrates the potential for research into voluntary data," says last author, Dr. Teja Kattenborn from Leipzig University and iDiv. "It is encouraging to make increasing use of the synergies between the combined data from thousands of citizens and professional scientists." "This work is the result of an initiative of the National Research Data Infrastructure for Biodiversity Research (NFDI4Biodiversity), with which we are pushing for a change in culture towards the open provision of data," says co-author Prof Miguel Mahecha, head of the working group Modeling Approaches in Remote Sensing at Leipzig University and iDiv. "The free availability of data is an absolute prerequisite for a better understanding of our planet." The research was published in Nature Ecology & Evolution. <|im_end|>

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1,976

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Chaotic dynamics are thought to be rare in natural populations but this may be due to methodological and data limitations, rather than the inherent stability of ecosystems. Following extensive simulation testing, we applied multiple chaos detection methods to a global database of 172 population time series and found evidence for chaos in >30%. In contrast, fitting traditional one-dimensional models identified <10% as chaotic. Chaos was most prevalent among plankton and insects and least among birds and mammals. Lyapunov exponents declined with generation time and scaled as the −1/6 power of body mass among chaotic populations. These results demonstrate that chaos is not rare in natural populations, indicating that there may be intrinsic limits to ecological forecasting and cautioning against the use of steady-state approaches to conservation and management. Main Chaos was introduced to ecology nearly 50 years ago 1 , 2 to provide an explanation for widespread fluctuations in abundance of natural populations. The defining characteristics of chaos are bounded, deterministic, aperiodic dynamics that depend sensitively on initial conditions. If common, chaos would offer the promise of short-term predictability while setting hard limits on long-term forecasting 3 . It would also mean that the ‘stable ecosystem’ paradigm—the theoretical justification for linear statistical models of ecological dynamics 4 and steady-state management policies 5 —would need rethinking. Chaos has been observed in many ecological models 6 , 7 , 8 , 9 , demonstrated in laboratory experiments (for example, insects 10 , microbes 11 and plankton 12 ) and detected in a handful of well-studied field systems 13 , 14 , 15 , 16 . However, most meta-analyses assessing the prevalence of chaos in natural field populations have found chaos to be absent or rare 17 , 18 , 19 , 20 , 21 . The most recent global meta-analysis concluded that only 1 out of 634 ecological time series was chaotic 18 . The apparent rarity of chaos in free-living natural populations is a mystery for several reasons. Ecosystems involve tens to thousands of species and large complex systems are prone to chaos 9 , 22 , 23 . Nonlinear dynamics, a necessary condition for chaos, are also common in ecological time series 24 and many abiotic drivers of population dynamics are themselves chaotic 25 . In light of this, we hypothesize that the dearth of evidence for ecological chaos reflects methodological and data limitations, rather than genuine rarity. Importantly, many meta-analyses in ecology have tested for chaos by fitting one-dimensional, parametric population models to time series 17 , 18 , 19 , 20 —models in which the current state depends only on the last state and this dependency is constrained to a particular functional form. We know from theory and focused empirical studies that overcompensation is not the only mechanism that can generate chaos and that chaos often arises through ecological interactions 16 , 26 . Although seminal models of ecological chaos were one-dimensional 1 , using one-dimensional models to classify natural populations treats ecological complexity (for example, species interactions) as noise, thereby hindering chaos detection 27 , 28 . Non-parametric, multidimensional methods for chaos detection that make minimal assumptions about the dynamics 27 , 29 , 30 are more mathematically robust and potentially more accurate, particularly in cases where the underlying dynamics are complex and not well understood. In contrast to the one-dimensional parametric studies, the last global meta-analysis to use flexible, higher-dimensional methods, published in 1995, found evidence for chaos in 11% of 27 field time series (excluding four series on measles cases), noting that this was probably an underestimate 30 . The question of chaos prevalence using comparable methods has not been revisited and, in the interim, many more time series of sufficient length have become available—a critical factor for detecting chaos 31 . In addition, new chaos detection tools are also now available 32 , 33 , 34 , 35 but how these methods, developed outside ecology, will perform on ecological time series is unknown. Here, we revisit whether chaos is, in fact, rare in ecological systems using a suite of flexible, higher-dimensional approaches. The definitive and most widely used index of chaos is the Lyapunov exponent (LE), which measures the average rate of divergence between nearby points in phase space 36 (Supplementary Note 2 ). Positive LE values are indicative of chaotic dynamics. We selected two methods of estimating LEs (direct 37 and Jacobian 31 ) and four additional chaos detection algorithms (recurrence quantification analysis 32 , permutation entropy 33 , horizontal visibility graphs 34 and the chaos decision tree 35 ). We tested the six methods on data simulated with a variety of chaotic, periodic and stochastic models to benchmark misclassification rates under ecologically relevant time series lengths and levels of noise ( Supplementary Notes 2 – 4 ). We tested the generality of this classification accuracy using two additional suites of simulation models. Three methods had error rates >0.5 and so were not pursued further (Table 1 and Extended Data Fig. 1 ). This included the direct LE method, which was unable to differentiate divergence due to chaos from divergence due to noise 38 . We applied the remaining three methods (Jacobian, recurrence quantification and permutation entropy) to time series from the Global Population Dynamics Database (GPDD) 39 . The GPDD aggregates 4,471 time series from 1,891 taxa. Previous analyses of the GPDD have concluded that many of these time series are too noisy to permit accurate modelling 40 , 41 . Therefore, we restricted our attention to the subset of the GPDD where chaos could be detected if present; that is, relatively long time series of good data quality without any major gaps ( Methods ). Applying these criteria produced a dataset of 172 time series representing 138 different taxa from 57 distinct locations with between 30 and 197 observations. To confirm the prevalence of chaos among plankton in the GPDD, which were sampled largely from one location, we also analysed an independent dataset of 34 zooplankton time series from three", "role": "user" }, { "content": "Chaos in natural populations appears to be much more common than previously recognized, according to a new analysis by scientists at UC Santa Cruz and NOAA Fisheries. Populations of organisms in natural ecosystems fluctuate a lot, and a key question for ecologists is whether those fluctuations are regular (varying around some theoretically \"stable\" equilibrium), random (completely unpredictable), or chaotic. Chaotic systems, like the weather, can be predictable in the short term but not in the long term, and they are highly sensitive to small differences in the initial conditions. \"Knowing whether these fluctuations are regular, chaotic, or random has major implications for how well, and how far into the future, we can predict population sizes and how they will respond to management interventions,\" said Tanya Rogers, a NOAA Fisheries ecologist and research fellow at UCSC's Institute of Marine Sciences. Rogers is first author of the new study, published June 27 in Nature Ecology & Evolution. Her coauthors are Bethany Johnson, a UCSC graduate student in applied mathematics, and Stephan Munch, a NOAA Fisheries ecologist and adjunct professor at UCSC in the Departments of Applied Mathematics and Ecology and Evolutionary Biology. The researchers found evidence of chaotic dynamics in over 30 percent of the populations they analyzed in an ecological database. Previous meta-analyses assessing the prevalence of chaos in natural field populations had found chaos to be absent or rare. But that may have been due to limited amounts of data and the use of inadequate methods, rather than the inherent stability of ecosystems, the authors said. \"There's a lot more data now, and how long a time series you have makes a big difference for detecting chaotic dynamics,\" Munch said. \"We also showed that methodological assumptions made in prior meta-analyses were biased against detecting chaos.\" For the new study, the researchers used new and updated chaos detection algorithms and put them through rigorous testing on simulated data sets. Then they applied the three best methods to a dataset of 172 population time series from the Global Population Dynamics Database. Their analysis revealed interesting associations between chaotic dynamics, lifespan, and body size. Chaos was most prevalent among plankton and insects, least prevalent among birds and mammals, and intermediate among fishes. \"A lot of short-lived species tend to have chaotic population dynamics, and these are also species that tend to have boom-and-bust dynamics,\" Rogers said. The results suggest there may be intrinsic limits to ecological forecasting and caution against the use of equilibrium-based approaches to conservation and management, particularly for short-lived species. \"From the fisheries management perspective, we want to predict fish populations so we can set limits for fishery harvests,\" Rogers explained. \"If we don't recognize the existence of chaos, we could be losing out on short-term forecasting possibilities using methods appropriate for chaotic systems, while being overconfident about our ability to make long-term predictions.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Chaotic dynamics are thought to be rare in natural populations but this may be due to methodological and data limitations, rather than the inherent stability of ecosystems. Following extensive simulation testing, we applied multiple chaos detection methods to a global database of 172 population time series and found evidence for chaos in >30%. In contrast, fitting traditional one-dimensional models identified <10% as chaotic. Chaos was most prevalent among plankton and insects and least among birds and mammals. Lyapunov exponents declined with generation time and scaled as the −1/6 power of body mass among chaotic populations. These results demonstrate that chaos is not rare in natural populations, indicating that there may be intrinsic limits to ecological forecasting and cautioning against the use of steady-state approaches to conservation and management. Main Chaos was introduced to ecology nearly 50 years ago 1 , 2 to provide an explanation for widespread fluctuations in abundance of natural populations. The defining characteristics of chaos are bounded, deterministic, aperiodic dynamics that depend sensitively on initial conditions. If common, chaos would offer the promise of short-term predictability while setting hard limits on long-term forecasting 3 . It would also mean that the ‘stable ecosystem’ paradigm—the theoretical justification for linear statistical models of ecological dynamics 4 and steady-state management policies 5 —would need rethinking. Chaos has been observed in many ecological models 6 , 7 , 8 , 9 , demonstrated in laboratory experiments (for example, insects 10 , microbes 11 and plankton 12 ) and detected in a handful of well-studied field systems 13 , 14 , 15 , 16 . However, most meta-analyses assessing the prevalence of chaos in natural field populations have found chaos to be absent or rare 17 , 18 , 19 , 20 , 21 . The most recent global meta-analysis concluded that only 1 out of 634 ecological time series was chaotic 18 . The apparent rarity of chaos in free-living natural populations is a mystery for several reasons. Ecosystems involve tens to thousands of species and large complex systems are prone to chaos 9 , 22 , 23 . Nonlinear dynamics, a necessary condition for chaos, are also common in ecological time series 24 and many abiotic drivers of population dynamics are themselves chaotic 25 . In light of this, we hypothesize that the dearth of evidence for ecological chaos reflects methodological and data limitations, rather than genuine rarity. Importantly, many meta-analyses in ecology have tested for chaos by fitting one-dimensional, parametric population models to time series 17 , 18 , 19 , 20 —models in which the current state depends only on the last state and this dependency is constrained to a particular functional form. We know from theory and focused empirical studies that overcompensation is not the only mechanism that can generate chaos and that chaos often arises through ecological interactions 16 , 26 . Although seminal models of ecological chaos were one-dimensional 1 , using one-dimensional models to classify natural populations treats ecological complexity (for example, species interactions) as noise, thereby hindering chaos detection 27 , 28 . Non-parametric, multidimensional methods for chaos detection that make minimal assumptions about the dynamics 27 , 29 , 30 are more mathematically robust and potentially more accurate, particularly in cases where the underlying dynamics are complex and not well understood. In contrast to the one-dimensional parametric studies, the last global meta-analysis to use flexible, higher-dimensional methods, published in 1995, found evidence for chaos in 11% of 27 field time series (excluding four series on measles cases), noting that this was probably an underestimate 30 . The question of chaos prevalence using comparable methods has not been revisited and, in the interim, many more time series of sufficient length have become available—a critical factor for detecting chaos 31 . In addition, new chaos detection tools are also now available 32 , 33 , 34 , 35 but how these methods, developed outside ecology, will perform on ecological time series is unknown. Here, we revisit whether chaos is, in fact, rare in ecological systems using a suite of flexible, higher-dimensional approaches. The definitive and most widely used index of chaos is the Lyapunov exponent (LE), which measures the average rate of divergence between nearby points in phase space 36 (Supplementary Note 2 ). Positive LE values are indicative of chaotic dynamics. We selected two methods of estimating LEs (direct 37 and Jacobian 31 ) and four additional chaos detection algorithms (recurrence quantification analysis 32 , permutation entropy 33 , horizontal visibility graphs 34 and the chaos decision tree 35 ). We tested the six methods on data simulated with a variety of chaotic, periodic and stochastic models to benchmark misclassification rates under ecologically relevant time series lengths and levels of noise ( Supplementary Notes 2 – 4 ). We tested the generality of this classification accuracy using two additional suites of simulation models. Three methods had error rates >0.5 and so were not pursued further (Table 1 and Extended Data Fig. 1 ). This included the direct LE method, which was unable to differentiate divergence due to chaos from divergence due to noise 38 . We applied the remaining three methods (Jacobian, recurrence quantification and permutation entropy) to time series from the Global Population Dynamics Database (GPDD) 39 . The GPDD aggregates 4,471 time series from 1,891 taxa. Previous analyses of the GPDD have concluded that many of these time series are too noisy to permit accurate modelling 40 , 41 . Therefore, we restricted our attention to the subset of the GPDD where chaos could be detected if present; that is, relatively long time series of good data quality without any major gaps ( Methods ). Applying these criteria produced a dataset of 172 time series representing 138 different taxa from 57 distinct locations with between 30 and 197 observations. To confirm the prevalence of chaos among plankton in the GPDD, which were sampled largely from one location, we also analysed an independent dataset of 34 zooplankton time series from three<|im_end|> <|im_start|>assistant Chaos in natural populations appears to be much more common than previously recognized, according to a new analysis by scientists at UC Santa Cruz and NOAA Fisheries. Populations of organisms in natural ecosystems fluctuate a lot, and a key question for ecologists is whether those fluctuations are regular (varying around some theoretically "stable" equilibrium), random (completely unpredictable), or chaotic. Chaotic systems, like the weather, can be predictable in the short term but not in the long term, and they are highly sensitive to small differences in the initial conditions. "Knowing whether these fluctuations are regular, chaotic, or random has major implications for how well, and how far into the future, we can predict population sizes and how they will respond to management interventions," said Tanya Rogers, a NOAA Fisheries ecologist and research fellow at UCSC's Institute of Marine Sciences. Rogers is first author of the new study, published June 27 in Nature Ecology & Evolution. Her coauthors are Bethany Johnson, a UCSC graduate student in applied mathematics, and Stephan Munch, a NOAA Fisheries ecologist and adjunct professor at UCSC in the Departments of Applied Mathematics and Ecology and Evolutionary Biology. The researchers found evidence of chaotic dynamics in over 30 percent of the populations they analyzed in an ecological database. Previous meta-analyses assessing the prevalence of chaos in natural field populations had found chaos to be absent or rare. But that may have been due to limited amounts of data and the use of inadequate methods, rather than the inherent stability of ecosystems, the authors said. "There's a lot more data now, and how long a time series you have makes a big difference for detecting chaotic dynamics," Munch said. "We also showed that methodological assumptions made in prior meta-analyses were biased against detecting chaos." For the new study, the researchers used new and updated chaos detection algorithms and put them through rigorous testing on simulated data sets. Then they applied the three best methods to a dataset of 172 population time series from the Global Population Dynamics Database. Their analysis revealed interesting associations between chaotic dynamics, lifespan, and body size. Chaos was most prevalent among plankton and insects, least prevalent among birds and mammals, and intermediate among fishes. "A lot of short-lived species tend to have chaotic population dynamics, and these are also species that tend to have boom-and-bust dynamics," Rogers said. The results suggest there may be intrinsic limits to ecological forecasting and caution against the use of equilibrium-based approaches to conservation and management, particularly for short-lived species. "From the fisheries management perspective, we want to predict fish populations so we can set limits for fishery harvests," Rogers explained. "If we don't recognize the existence of chaos, we could be losing out on short-term forecasting possibilities using methods appropriate for chaotic systems, while being overconfident about our ability to make long-term predictions." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract In recent years, statisticians and psychologists have provided the critique that p -values do not capture the evidence afforded by data and are, consequently, ill suited for analysis in scientific endeavors. The issue is particular salient in the assessment of the recent evidence provided for ESP by Bem ( 2011 ) in the mainstream Journal of Personality and Social Psychology . Wagenmakers, Wetzels, Borsboom, and van der Maas ( Journal of Personality and Social Psychology, 100 , 426–432, 2011 ) have provided an alternative Bayes factor assessment of Bem’s data, but their assessment was limited to examining each experiment in isolation. We show here that the variant of the Bayes factor employed by Wagenmakers et al. is inappropriate for making assessments across multiple experiments, and cannot be used to gain an accurate assessment of the total evidence in Bem’s data. We develop a meta-analytic Bayes factor that describes how researchers should update their prior beliefs about the odds of hypotheses in light of data across several experiments. We find that the evidence that people can feel the future with neutral and erotic stimuli to be slight, with Bayes factors of 3.23 and 1.57, respectively. There is some evidence, however, for the hypothesis that people can feel the future with emotionally valenced nonerotic stimuli, with a Bayes factor of about 40. Although this value is certainly noteworthy, we believe it is orders of magnitude lower than what is required to overcome appropriate skepticism of ESP. Working on a manuscript? Avoid the common mistakes Bem ( 2011 ) has claimed that people can feel or sense salient events in the future that could not otherwise be anticipated. For example, in his Experiment 2, Bem presented participants with two rather ordinary pictures and asked them to indicate which one would be chosen subsequently by a random number generator. If a participant correctly anticipated the random choice, he or she was rewarded with a brief display of a positively valenced picture. Conversely, if a participant incorrectly anticipated the random choice, he or she was punished with a negatively valenced picture. Bem claimed that people could indeed feel these future reward and punishment events and, consequently, were able to anticipate the random choice at a rate deemed statistically above chance. Bem presented a sequence of similar experiments and results and, on this basis, concluded that people can feel the future. This phenomenon and others like it in which people can show seemingly impossible awareness of events are termed psi phenomena , or, more colloquially, extrasensory perception (ESP). If ESP is substantiated, it would be among the most important findings in the history of psychology. The existence of ESP would force us to revise not only our theories of psychology, but also those of biology and physics. In our view, when seemingly implausible claims are made with conventional methods, it provides an ideal moment to reexamine these methods. The conventional approach used by Bem ( 2011 ) has two properties. First, as is typical in many empirical investigations, Bem presented a sequence of experiments, each targeting the same basic phenomena from a slightly different angle. Second, Bem employed null-hypothesis significance testing in which p -values are reported as evidence and evaluated against a fixed criterion to reach judgments. In previous work, we joined a growing consensus that conventional inference by significance testing overstates the evidence for an effect (see Berger & Sellke, 1987 ; Edwards, Lindman, & Savage, 1963 ; Wagenmakers, 2007 , among several others), and proposed a Bayes factor replacement for the t -test (Rouder, Speckman, Sun, Morey & Iverson, 2009 ).This Bayes factor quantifies the evidence in data for competing hypotheses from a single experiment or, more precisely, for a single comparison. Unfortunately, while this Bayes factor is appropriate for assessing evidence for a single contrast, it is ill suited for meta-analytically combining evidence across several experiments. Herein, we develop a meta-analytic version of the Bayes factor t -test and use it to assess the evidence across Bem’s experiments. We find some support for ESP; the probability of the combined data are 40 times more likely under an ESP alternative than under a no-ESP null. This evaluation differs from that of Bem, who, in our opinion, overstated the evidence. It also differs from that of Wagenmakers, Wetzels, Borsboom and van der Maas ( 2011 ), who found no support for ESP. Our interpretation of this Bayes factor is that while it is noteworthy, it is insufficient in magnitude to sway the beliefs of an appropriately skeptical reader. The evidence from p -values and Bayes factor There is a well-known asymmetry in significance testing: Researchers can reject the null hypothesis but can never accept it. This asymmetry works against the goals of scientific inquiry, because null hypotheses often correspond to theoretically useful statements of invariance and constraint (Gallistel, 2009 ; Kass, 1992 ; Rouder et al., 2009 ). For Bem’s ( 2011 ) case, the null hypothesis is the theoretically attractive, reasonable, and highly interpretable constraint that ESP does not exist. In order to fairly assess the evidence for ESP, it is necessary to be able to state the evidence for or against the null provided by the data. Yet, with significance testing, we may only accept ESP and never reject it. The above point about asymmetry is easy to grasp. Its implications, however, are subtle and consequential, because they extend beyond not being able to state evidence for the null hypothesis; they extend to assessing evidence in the data for the alternative as well. A good starting point is consideration of the distribution of p -values under two competing hypotheses (examples are shown in Fig. 1A ). If the null hypothesis is false, p -values tend to be small, and they decrease as sample size is increased. The dashed green line shows the distribution of p -values when the underlying effect size is .2 and the sample size is 50; the dashed-dotted red line shows the same when the sample size is", "role": "user" }, { "content": "Can people truly feel the future? Researchers remain skeptical, according to a new study by Jeffrey Rouder and Richard Morey from the University of Missouri in the US, and the University of Groningen in the Netherlands, respectively. Their work appears online in the Psychonomic Bulletin & Review, published by Springer. Although extra-sensory perception (ESP) seems impossible given our current scientific knowledge, and certainly runs counter to our everyday experience, a leading psychologist, Daryl Bem of Cornell University, is claiming evidence for ESP. Rouder and Morey look at the strength of the evidence in Dr. Bem's experiments. Their application of a relatively new statistical method that quantifies how beliefs should change in light of data, suggests that there is only modest evidence behind Dr. Bem's findings (that people can feel, or sense, salient events in the future that could not otherwise be anticipated, and cannot be explained by chance alone), certainly not enough to sway the beliefs of a skeptic. They highlight the limitations of conventional statistical significance testing (p values), and apply a new technique (meta-analytical Bayes factor) to Dr. Bem's data, which overcomes some of these limitations. According to Rouder and Morey, in order to accurately assess the total evidence in Bem's data, it is necessary to combine the evidence across several of his experiments, not look at each one in isolation, which is what researchers have done up till now. They find there is some evidence for ESP – people should update their beliefs by a factor of 40. In other words, beliefs are odds. For example, a skeptic might hold odds that ESP is a long shot at a million-to-one, while a believer might believe it is as possible as not (one-to-one odds). Whatever one's beliefs, Rouder and Morey show that Bem's experiments indicate they should change by a factor of 40 in favor of ESP. The believer should now be 40-to-1 sure of ESP, while the skeptic should be 25000-to-1 sure against it. Rouder and Morey conclude that the skeptics odds are appropriate: \"We remain unconvinced of the viability of ESP. There is no plausible mechanism for it, and it seems contradicted by well-substantiated theories in both physics and biology. Against this background, a change in odds of 40 is negligible.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract In recent years, statisticians and psychologists have provided the critique that p -values do not capture the evidence afforded by data and are, consequently, ill suited for analysis in scientific endeavors. The issue is particular salient in the assessment of the recent evidence provided for ESP by Bem ( 2011 ) in the mainstream Journal of Personality and Social Psychology . Wagenmakers, Wetzels, Borsboom, and van der Maas ( Journal of Personality and Social Psychology, 100 , 426–432, 2011 ) have provided an alternative Bayes factor assessment of Bem’s data, but their assessment was limited to examining each experiment in isolation. We show here that the variant of the Bayes factor employed by Wagenmakers et al. is inappropriate for making assessments across multiple experiments, and cannot be used to gain an accurate assessment of the total evidence in Bem’s data. We develop a meta-analytic Bayes factor that describes how researchers should update their prior beliefs about the odds of hypotheses in light of data across several experiments. We find that the evidence that people can feel the future with neutral and erotic stimuli to be slight, with Bayes factors of 3.23 and 1.57, respectively. There is some evidence, however, for the hypothesis that people can feel the future with emotionally valenced nonerotic stimuli, with a Bayes factor of about 40. Although this value is certainly noteworthy, we believe it is orders of magnitude lower than what is required to overcome appropriate skepticism of ESP. Working on a manuscript? Avoid the common mistakes Bem ( 2011 ) has claimed that people can feel or sense salient events in the future that could not otherwise be anticipated. For example, in his Experiment 2, Bem presented participants with two rather ordinary pictures and asked them to indicate which one would be chosen subsequently by a random number generator. If a participant correctly anticipated the random choice, he or she was rewarded with a brief display of a positively valenced picture. Conversely, if a participant incorrectly anticipated the random choice, he or she was punished with a negatively valenced picture. Bem claimed that people could indeed feel these future reward and punishment events and, consequently, were able to anticipate the random choice at a rate deemed statistically above chance. Bem presented a sequence of similar experiments and results and, on this basis, concluded that people can feel the future. This phenomenon and others like it in which people can show seemingly impossible awareness of events are termed psi phenomena , or, more colloquially, extrasensory perception (ESP). If ESP is substantiated, it would be among the most important findings in the history of psychology. The existence of ESP would force us to revise not only our theories of psychology, but also those of biology and physics. In our view, when seemingly implausible claims are made with conventional methods, it provides an ideal moment to reexamine these methods. The conventional approach used by Bem ( 2011 ) has two properties. First, as is typical in many empirical investigations, Bem presented a sequence of experiments, each targeting the same basic phenomena from a slightly different angle. Second, Bem employed null-hypothesis significance testing in which p -values are reported as evidence and evaluated against a fixed criterion to reach judgments. In previous work, we joined a growing consensus that conventional inference by significance testing overstates the evidence for an effect (see Berger & Sellke, 1987 ; Edwards, Lindman, & Savage, 1963 ; Wagenmakers, 2007 , among several others), and proposed a Bayes factor replacement for the t -test (Rouder, Speckman, Sun, Morey & Iverson, 2009 ).This Bayes factor quantifies the evidence in data for competing hypotheses from a single experiment or, more precisely, for a single comparison. Unfortunately, while this Bayes factor is appropriate for assessing evidence for a single contrast, it is ill suited for meta-analytically combining evidence across several experiments. Herein, we develop a meta-analytic version of the Bayes factor t -test and use it to assess the evidence across Bem’s experiments. We find some support for ESP; the probability of the combined data are 40 times more likely under an ESP alternative than under a no-ESP null. This evaluation differs from that of Bem, who, in our opinion, overstated the evidence. It also differs from that of Wagenmakers, Wetzels, Borsboom and van der Maas ( 2011 ), who found no support for ESP. Our interpretation of this Bayes factor is that while it is noteworthy, it is insufficient in magnitude to sway the beliefs of an appropriately skeptical reader. The evidence from p -values and Bayes factor There is a well-known asymmetry in significance testing: Researchers can reject the null hypothesis but can never accept it. This asymmetry works against the goals of scientific inquiry, because null hypotheses often correspond to theoretically useful statements of invariance and constraint (Gallistel, 2009 ; Kass, 1992 ; Rouder et al., 2009 ). For Bem’s ( 2011 ) case, the null hypothesis is the theoretically attractive, reasonable, and highly interpretable constraint that ESP does not exist. In order to fairly assess the evidence for ESP, it is necessary to be able to state the evidence for or against the null provided by the data. Yet, with significance testing, we may only accept ESP and never reject it. The above point about asymmetry is easy to grasp. Its implications, however, are subtle and consequential, because they extend beyond not being able to state evidence for the null hypothesis; they extend to assessing evidence in the data for the alternative as well. A good starting point is consideration of the distribution of p -values under two competing hypotheses (examples are shown in Fig. 1A ). If the null hypothesis is false, p -values tend to be small, and they decrease as sample size is increased. The dashed green line shows the distribution of p -values when the underlying effect size is .2 and the sample size is 50; the dashed-dotted red line shows the same when the sample size is<|im_end|> <|im_start|>assistant Can people truly feel the future? Researchers remain skeptical, according to a new study by Jeffrey Rouder and Richard Morey from the University of Missouri in the US, and the University of Groningen in the Netherlands, respectively. Their work appears online in the Psychonomic Bulletin & Review, published by Springer. Although extra-sensory perception (ESP) seems impossible given our current scientific knowledge, and certainly runs counter to our everyday experience, a leading psychologist, Daryl Bem of Cornell University, is claiming evidence for ESP. Rouder and Morey look at the strength of the evidence in Dr. Bem's experiments. Their application of a relatively new statistical method that quantifies how beliefs should change in light of data, suggests that there is only modest evidence behind Dr. Bem's findings (that people can feel, or sense, salient events in the future that could not otherwise be anticipated, and cannot be explained by chance alone), certainly not enough to sway the beliefs of a skeptic. They highlight the limitations of conventional statistical significance testing (p values), and apply a new technique (meta-analytical Bayes factor) to Dr. Bem's data, which overcomes some of these limitations. According to Rouder and Morey, in order to accurately assess the total evidence in Bem's data, it is necessary to combine the evidence across several of his experiments, not look at each one in isolation, which is what researchers have done up till now. They find there is some evidence for ESP – people should update their beliefs by a factor of 40. In other words, beliefs are odds. For example, a skeptic might hold odds that ESP is a long shot at a million-to-one, while a believer might believe it is as possible as not (one-to-one odds). Whatever one's beliefs, Rouder and Morey show that Bem's experiments indicate they should change by a factor of 40 in favor of ESP. The believer should now be 40-to-1 sure of ESP, while the skeptic should be 25000-to-1 sure against it. Rouder and Morey conclude that the skeptics odds are appropriate: "We remain unconvinced of the viability of ESP. There is no plausible mechanism for it, and it seems contradicted by well-substantiated theories in both physics and biology. Against this background, a change in odds of 40 is negligible." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Vascular contributions to dementia and Alzheimer’s disease are increasingly recognized 1 , 2 , 3 , 4 , 5 , 6 . Recent studies have suggested that breakdown of the blood–brain barrier (BBB) is an early biomarker of human cognitive dysfunction 7 , including the early clinical stages of Alzheimer’s disease 5 , 8 , 9 , 10 . The E4 variant of apolipoprotein E ( APOE4 ), the main susceptibility gene for Alzheimer’s disease 11 , 12 , 13 , 14 , leads to accelerated breakdown of the BBB and degeneration of brain capillary pericytes 15 , 16 , 17 , 18 , 19 , which maintain BBB integrity 20 , 21 , 22 . It is unclear, however, whether the cerebrovascular effects of APOE4 contribute to cognitive impairment. Here we show that individuals bearing APOE4 (with the ε3/ε4 or ε4/ε4 alleles) are distinguished from those without APOE4 (ε3/ε3) by breakdown of the BBB in the hippocampus and medial temporal lobe. This finding is apparent in cognitively unimpaired APOE4 carriers and more severe in those with cognitive impairment, but is not related to amyloid-β or tau pathology measured in cerebrospinal fluid or by positron emission tomography 23 . High baseline levels of the BBB pericyte injury biomarker soluble PDGFRβ 7 , 8 in the cerebrospinal fluid predicted future cognitive decline in APOE4 carriers but not in non-carriers, even after controlling for amyloid-β and tau status, and were correlated with increased activity of the BBB-degrading cyclophilin A-matrix metalloproteinase-9 pathway 19 in cerebrospinal fluid. Our findings suggest that breakdown of the BBB contributes to APOE4 -associated cognitive decline independently of Alzheimer’s disease pathology, and might be a therapeutic target in APOE4 carriers. Main Analysis of BBB permeability by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) 7 , 8 (Fig. 1a ; see Methods ) in 245 participants (Extended Data Table 1 ) indicated that there was increased BBB breakdown in the hippocampus (HC) and parahippocampal gyrus (PHG) in cognitively normal APOE4 (ε3/ε4 and ε4/ε4) carriers, compared to cognitively normal APOE3 homozygotes (ε3/ε3), both with clinical dementia rating (CDR) scores of 0. The BBB breakdown in the HC and PHG in APOE4 carriers increased further with cognitive impairment at a CDR score of 0.5 (Fig. 1b–d ). This increase was independent of differences in amyloid-β (Aβ) and phosphorylated tau (pTau) in the cerebrospinal fluid (CSF) (Fig. 1e–h ); that is, whether individuals were Aβ+ or Aβ− and pTau+ or pTau− using the accepted cut-off values 7 , 24 , 25 (see Methods ), where Aβ+ and pTau+ status indicates classical Alzheimer’s disease (AD)-associated pathways 23 . By contrast, APOE3 carriers with cognitive impairment developed less pronounced BBB changes in the HC and PHG (Fig. 1b–d ). We found no significant BBB differences in other grey or white matter brain regions between APOE4 carriers and APOE3 homozygotes, except for increased BBB permeability in the caudate nucleus and minor leaks in the frontal cortex and corpus callosum in cognitively normal APOE4 carriers (Extended Data Fig. 1 ). These findings held when cognitive dysfunction was evaluated by neuropsychological performance (see Methods ) (Extended Data Figs. 2 , 3 ). Fig. 1: BBB breakdown in the HC and PHG in APOE4 carriers increases with cognitive impairment, independently of CSF Aβ and tau status. a , b , Maps of BBB permeability transfer constant ( K trans ) generated by DCE-MRI ( a ) in the HC of APOE3 homozygotes ( APOE3 ) and APOE4 carriers ( APOE4 ) with CDR scores of 0 or 0.5 ( b ). FA, flip angle; T1w, T1 weighted. c , d , BBB K trans in the HC ( c ) and PHG ( d ) in individuals with CDR 0 bearing APOE3 (black, n = 128) or APOE4 (red, n = 68) and with CDR 0.5 bearing APOE3 (black, n = 14) or APOE4 (red, n = 25). e , f , K trans in the HC ( e ) and PHG ( f ) in APOE4 carriers with CDR 0 who were Aβ 1–42 negative (Aβ−; n = 37) or positive (Aβ+; n = 16), or with CDR 0.5 who were Aβ− ( n = 7) or Aβ+ ( n = 10). g , h , K trans in the HC ( g ) and PHG ( h ) in APOE4 carriers with CDR 0 who were pTau− ( n = 42) or pTau+ ( n = 10), and with CDR 0.5 who were pTau− ( n = 13) or pTau+ ( n = 5). i , HC (blue) and PHG (orange) overlaid on a 3D template. j , k , Volumes of the HC ( j ) and PHG ( k ) in individuals with CDR 0 bearing APOE3 ( n = 124) or APOE4 ( n = 75) and with CDR 0.5 bearing APOE3 ( n = 13) or APOE4 ( n = 20). l , m , K trans (estimated marginal means ± s.e.m. from ANCOVA models corrected for age, sex, education, CSF Aβ 1–42 and pTau status, and HC and PHG volumes) in the HC ( l ) and PHG ( m ) in individuals with CDR 0 bearing APOE3 (black, HC n = 125; PHG n = 128) or APOE4 (red, HC and PHG n = 68) and with CDR 0.5 bearing APOE3 (black, HC n = 12; PHG n = 14) or APOE4 (red, HC n = 20; PHG n = 25). c – h , j , k , Continuous line, median; dotted line, interquartile range (IQR). Significance by ANCOVA for main effects and post hoc comparisons controlling for age, sex, and education. All ANCOVA omnibus tests remained significant at false discovery rate (FDR) threshold of 0.05. Source Data Full size image The volumes of the HC and PHG decreased with cognitive impairment in APOE4 but not APOE3 carriers (Fig. 1i–k ). The breakdown of the BBB in the HC and PHG in APOE4 carriers, but not APOE3 homozygotes, remained a", "role": "user" }, { "content": "New USC research reveals how APOE4, a genetic culprit for Alzheimer's disease, triggers leaks in the brain's plumbing system, allowing toxic substances to seep into the brain areas responsible for memory encoding and other cognitive functions. The damage is linked to future problems in learning and memory, even when the disease's signature sticky plaques have not appeared. The findings suggest that the smallest blood vessels in the brain, which form the blood-brain barrier, might be a potential target for early treatment. The study appears today in Nature. \"This study sheds light on a new way of looking at this disease and possibly treatment in people with the APOE4 gene, looking at blood vessels and improving their function to potentially slow down or arrest cognitive decline,\" said senior author Berislav Zlokovic, director of the Zilkha Neurogenetic Institute at the Keck School of Medicine of USC. \"Severe damage to vascular cells called pericytes was linked to more severe cognitive problems in APOE4 carriers. APOE4 seems to speed up breakdown of the blood-brain barrier by activating an inflammatory pathway in blood vessels, which is associated with pericyte injury.\" Scientists have long known that the APOE4 gene—which occurs in up to 14 percent of the population—increases the probability of developing Alzheimer's disease. Until now, it's been unclear how different pathologies determine the course of the disease in its early stages, or what underlying mechanisms lead to cognitive decline in APOE4 carriers. Zlokovic's previous research shows that people who develop early memory problems also experience the most leakage in their brain's blood vessels—independent of amyloid plaque or tau, two common contributors to Alzheimer's. The leakage starts when cells called pericytes, which line the walls of blood vessels in the brain and maintain blood-brain barrier integrity, are damaged. These injured pericytes can be detected with a unique biomarker, developed by Zlokovic's lab in 2015, which shows up in cerebrospinal fluid. For this study, scientists used standard memory tests to check the participants' cognitive abilities and their neuropsychological performance. They also used advanced neuroimaging and employed the biomarker that indicates damage to the brain's blood vessels. In participants who had the APOE4 gene, researchers found damaged capillaries in the brain's memory center, the hippocampus and medial temporal lobe. The damage correlated with increased levels of a protein that causes inflammation, cyclophilin A—an early sign of the disease in people already at higher risk of developing Alzheimer's. Zlokovic, who became director of the Zilkha Neurogenetic Institute in 2012, pioneered the concept that a breakdown in the blood-brain barrier contributes to cognitive impairment and dementia. The Zilkha Neurogenetic Institute opened at Keck School of Medicine in 2003 with a $20 million donation from Los Angeles businessman Selim Zilkha, who later contributed $10 million more to the effort. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Vascular contributions to dementia and Alzheimer’s disease are increasingly recognized 1 , 2 , 3 , 4 , 5 , 6 . Recent studies have suggested that breakdown of the blood–brain barrier (BBB) is an early biomarker of human cognitive dysfunction 7 , including the early clinical stages of Alzheimer’s disease 5 , 8 , 9 , 10 . The E4 variant of apolipoprotein E ( APOE4 ), the main susceptibility gene for Alzheimer’s disease 11 , 12 , 13 , 14 , leads to accelerated breakdown of the BBB and degeneration of brain capillary pericytes 15 , 16 , 17 , 18 , 19 , which maintain BBB integrity 20 , 21 , 22 . It is unclear, however, whether the cerebrovascular effects of APOE4 contribute to cognitive impairment. Here we show that individuals bearing APOE4 (with the ε3/ε4 or ε4/ε4 alleles) are distinguished from those without APOE4 (ε3/ε3) by breakdown of the BBB in the hippocampus and medial temporal lobe. This finding is apparent in cognitively unimpaired APOE4 carriers and more severe in those with cognitive impairment, but is not related to amyloid-β or tau pathology measured in cerebrospinal fluid or by positron emission tomography 23 . High baseline levels of the BBB pericyte injury biomarker soluble PDGFRβ 7 , 8 in the cerebrospinal fluid predicted future cognitive decline in APOE4 carriers but not in non-carriers, even after controlling for amyloid-β and tau status, and were correlated with increased activity of the BBB-degrading cyclophilin A-matrix metalloproteinase-9 pathway 19 in cerebrospinal fluid. Our findings suggest that breakdown of the BBB contributes to APOE4 -associated cognitive decline independently of Alzheimer’s disease pathology, and might be a therapeutic target in APOE4 carriers. Main Analysis of BBB permeability by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) 7 , 8 (Fig. 1a ; see Methods ) in 245 participants (Extended Data Table 1 ) indicated that there was increased BBB breakdown in the hippocampus (HC) and parahippocampal gyrus (PHG) in cognitively normal APOE4 (ε3/ε4 and ε4/ε4) carriers, compared to cognitively normal APOE3 homozygotes (ε3/ε3), both with clinical dementia rating (CDR) scores of 0. The BBB breakdown in the HC and PHG in APOE4 carriers increased further with cognitive impairment at a CDR score of 0.5 (Fig. 1b–d ). This increase was independent of differences in amyloid-β (Aβ) and phosphorylated tau (pTau) in the cerebrospinal fluid (CSF) (Fig. 1e–h ); that is, whether individuals were Aβ+ or Aβ− and pTau+ or pTau− using the accepted cut-off values 7 , 24 , 25 (see Methods ), where Aβ+ and pTau+ status indicates classical Alzheimer’s disease (AD)-associated pathways 23 . By contrast, APOE3 carriers with cognitive impairment developed less pronounced BBB changes in the HC and PHG (Fig. 1b–d ). We found no significant BBB differences in other grey or white matter brain regions between APOE4 carriers and APOE3 homozygotes, except for increased BBB permeability in the caudate nucleus and minor leaks in the frontal cortex and corpus callosum in cognitively normal APOE4 carriers (Extended Data Fig. 1 ). These findings held when cognitive dysfunction was evaluated by neuropsychological performance (see Methods ) (Extended Data Figs. 2 , 3 ). Fig. 1: BBB breakdown in the HC and PHG in APOE4 carriers increases with cognitive impairment, independently of CSF Aβ and tau status. a , b , Maps of BBB permeability transfer constant ( K trans ) generated by DCE-MRI ( a ) in the HC of APOE3 homozygotes ( APOE3 ) and APOE4 carriers ( APOE4 ) with CDR scores of 0 or 0.5 ( b ). FA, flip angle; T1w, T1 weighted. c , d , BBB K trans in the HC ( c ) and PHG ( d ) in individuals with CDR 0 bearing APOE3 (black, n = 128) or APOE4 (red, n = 68) and with CDR 0.5 bearing APOE3 (black, n = 14) or APOE4 (red, n = 25). e , f , K trans in the HC ( e ) and PHG ( f ) in APOE4 carriers with CDR 0 who were Aβ 1–42 negative (Aβ−; n = 37) or positive (Aβ+; n = 16), or with CDR 0.5 who were Aβ− ( n = 7) or Aβ+ ( n = 10). g , h , K trans in the HC ( g ) and PHG ( h ) in APOE4 carriers with CDR 0 who were pTau− ( n = 42) or pTau+ ( n = 10), and with CDR 0.5 who were pTau− ( n = 13) or pTau+ ( n = 5). i , HC (blue) and PHG (orange) overlaid on a 3D template. j , k , Volumes of the HC ( j ) and PHG ( k ) in individuals with CDR 0 bearing APOE3 ( n = 124) or APOE4 ( n = 75) and with CDR 0.5 bearing APOE3 ( n = 13) or APOE4 ( n = 20). l , m , K trans (estimated marginal means ± s.e.m. from ANCOVA models corrected for age, sex, education, CSF Aβ 1–42 and pTau status, and HC and PHG volumes) in the HC ( l ) and PHG ( m ) in individuals with CDR 0 bearing APOE3 (black, HC n = 125; PHG n = 128) or APOE4 (red, HC and PHG n = 68) and with CDR 0.5 bearing APOE3 (black, HC n = 12; PHG n = 14) or APOE4 (red, HC n = 20; PHG n = 25). c – h , j , k , Continuous line, median; dotted line, interquartile range (IQR). Significance by ANCOVA for main effects and post hoc comparisons controlling for age, sex, and education. All ANCOVA omnibus tests remained significant at false discovery rate (FDR) threshold of 0.05. Source Data Full size image The volumes of the HC and PHG decreased with cognitive impairment in APOE4 but not APOE3 carriers (Fig. 1i–k ). The breakdown of the BBB in the HC and PHG in APOE4 carriers, but not APOE3 homozygotes, remained a<|im_end|> <|im_start|>assistant New USC research reveals how APOE4, a genetic culprit for Alzheimer's disease, triggers leaks in the brain's plumbing system, allowing toxic substances to seep into the brain areas responsible for memory encoding and other cognitive functions. The damage is linked to future problems in learning and memory, even when the disease's signature sticky plaques have not appeared. The findings suggest that the smallest blood vessels in the brain, which form the blood-brain barrier, might be a potential target for early treatment. The study appears today in Nature. "This study sheds light on a new way of looking at this disease and possibly treatment in people with the APOE4 gene, looking at blood vessels and improving their function to potentially slow down or arrest cognitive decline," said senior author Berislav Zlokovic, director of the Zilkha Neurogenetic Institute at the Keck School of Medicine of USC. "Severe damage to vascular cells called pericytes was linked to more severe cognitive problems in APOE4 carriers. APOE4 seems to speed up breakdown of the blood-brain barrier by activating an inflammatory pathway in blood vessels, which is associated with pericyte injury." Scientists have long known that the APOE4 gene—which occurs in up to 14 percent of the population—increases the probability of developing Alzheimer's disease. Until now, it's been unclear how different pathologies determine the course of the disease in its early stages, or what underlying mechanisms lead to cognitive decline in APOE4 carriers. Zlokovic's previous research shows that people who develop early memory problems also experience the most leakage in their brain's blood vessels—independent of amyloid plaque or tau, two common contributors to Alzheimer's. The leakage starts when cells called pericytes, which line the walls of blood vessels in the brain and maintain blood-brain barrier integrity, are damaged. These injured pericytes can be detected with a unique biomarker, developed by Zlokovic's lab in 2015, which shows up in cerebrospinal fluid. For this study, scientists used standard memory tests to check the participants' cognitive abilities and their neuropsychological performance. They also used advanced neuroimaging and employed the biomarker that indicates damage to the brain's blood vessels. In participants who had the APOE4 gene, researchers found damaged capillaries in the brain's memory center, the hippocampus and medial temporal lobe. The damage correlated with increased levels of a protein that causes inflammation, cyclophilin A—an early sign of the disease in people already at higher risk of developing Alzheimer's. Zlokovic, who became director of the Zilkha Neurogenetic Institute in 2012, pioneered the concept that a breakdown in the blood-brain barrier contributes to cognitive impairment and dementia. The Zilkha Neurogenetic Institute opened at Keck School of Medicine in 2003 with a $20 million donation from Los Angeles businessman Selim Zilkha, who later contributed $10 million more to the effort. <|im_end|>

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2,250

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract There have been significant advancements in radical reactions using organocatalysts in modern organic synthesis. Recently, NHC-catalyzed radical reactions initiated by single electron transfer processes have been actively studied. However, the reported examples have been limited to catalysis mediated by alkyl radicals. In this article, the NHC organocatalysis mediated by aryl radicals has been achieved. The enolate form of the Breslow intermediate derived from an aldehyde and thiazolium-type NHC in the presence of a base undergoes single electron transfer to an aryl iodide, providing an aryl radical. The catalytically generated aryl radical could be exploited as an arylating reagent for radical relay-type arylacylation of styrenes and as a hydrogen atom abstraction reagent for α-amino C(sp 3 )–H acylation of secondary amides. Introduction Aryl halides (Ar–X) have been broadly utilized as versatile reagents for chemical reactions due to their availability and bench stability. Specifically, oxidative addition of the C(sp 2 )–X bond in an aryl halide to a transition-metal complex enables the generation of an arylmetal species that induces various transformations (Fig. 1a ) 1 , 2 . The generation of an aryl radical 3 , 4 through single electron reduction of an aryl halide followed by mesolytic cleavage of the C(sp 2 )–X bond has emerged as an alternative approach for the utilization of aryl halides as chemical reagents (Fig. 1b ). Due to the high reduction potential of aryl halides, metal sources such as samarium salts 5 , transition-metal complexes 6 and metal-based visible light photoredox catalysts 7 have been mainly utilized as single electron donors. Recently, organic electron donors 8 , 9 , 10 , 11 including visible light organic photoredox catalysts 12 , 13 , 14 have taken the place of metals to provide simple and rapid access to aryl radicals via single electron transfer (SET). These approaches enable the generation of aryl radicals without using metal sources, but still require either a stoichiometric amount of the organic electron donor or light irradiation. Fig. 1: Activation of aryl halides and aryl radical-mediated NHC catalysis. a Oxidative addition of aryl halide to transition metal. TM, transition metal. b Organic electron donor induced aryl radical generation (recent advance). SET, single electron transfer. OED, organic electron donor. c Generation of aryl radical through NHC catalysis (working hypothesis). d Arylacylation of alkene and C(sp 3 )–H acylation through NHC catalysis (this work). 1,5-HAT, 1,5-hydrogen atom transfer. Full size image There has been significant advancement in the use of radical reactions catalyzed by N-heterocyclic carbenes (NHC) with SET from a Breslow intermediate, based on enzymatic pyruvate transformations 15 , 16 , 17 , 18 . Recently, we developed NHC-catalyzed decarboxylative radical cross-coupling between aldehydes and aliphatic carboxylic acid derived-redox active esters 19 , 20 . The reaction involves SET from the enolate form of the Breslow intermediate derived from an aldehyde and NHC in the presence of a base to the redox active ester, followed by radical–radical coupling between the resultant Breslow intermediate-derived radical and alkyl radical. Thus, the enolate form of the Breslow intermediate can serve as a single electron donor and an acyl radical equivalent. Since this report, a series of NHC-catalyzed radical cross-coupling reactions have been developed by us and other groups 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 . However, these reported examples have been limited to catalysis mediated by C(sp 3 )-centered radicals. To expand the scope of radical NHC catalysis, we questioned whether an aryl radical could be generated and utilized (Fig. 1c ). Considering the gap in redox potential between the enolate form of the Breslow intermediate ( E ox = −0.97 V vs. SCE) 34 and iodobenzene ( E red = −2.24 V vs. SCE) 35 , the corresponding electron transfer seems to be thermodynamically unfavored. However, two kinetic features, (1) a small reorganization energy of the enolate form of the Breslow intermediate 34 and (2) a fast mesolytic cleavage of the radical anion derived from aryl iodide 35 , encouraged us to pursue this research program. Here, we report an aryl radical-mediated NHC organocatalysis method. The aryl radical that is generated catalytically through thermodynamically unfavored SET from the enolate form of the Breslow intermediate to an aryl iodide could be exploited as an arylating reagent for radical relay-type arylacylation of styrenes (Fig. 1d , top) and as a hydrogen atom abstraction reagent for α-amino C(sp 3 )–H acylation of secondary amides (Fig. 1d , bottom). It should be noted that this protocol eliminates the requirement for metals, oxidants/reductants and light. Results and discussion Development of the reaction and screening of conditions To test the generation of an aryl radical by the radical NHC catalysis, we designed intramolecular arylacylation reactions with benzaldehyde ( 1a ) and aryl electrophiles 2a – d bearing a cinnamyl tether group that can trap the aryl radical immediately (Table 1 ) 36 . Based on our previous studies on the NHC-catalyzed decarboxylative radical cross-coupling between aldehydes and redox-active esters 19 , we used a thiazolium salt ( N1 ) 37 possessing a N-2,6-diisopropylphenyl substituent and a seven-membered backbone structure as the NHC precursor and Cs 2 CO 3 as the base. The reaction with aryl iodide 2a as a substrate proceeded to afford 3aa in 39% isolated yield with recovery of 2a (entry 1). The reactions with other azolium salts resulted in no product formation (data not shown). Neither bromide nor chloride leaving groups resulted in product formation (entries 2 and 3). The reaction using the corresponding aryldiazonium tetrafluoroborate 2d did not afford the desired coupling product 3aa (entry 4). This might be due to the low reduction potential of the aryldiazonium salt ( E red = −0.2 V vs. SCE), which would cause a second electron transfer from the Breslow-derived radical intermediate 38 . Table 1 Screening of reaction conditions. Full size table Radical relay-type arylacylation of styrenes The successful example of an NHC-catalyzed reaction involving the generation of an", "role": "user" }, { "content": "Aryl halides with a benzene ring directly bonded to a halogen atom are readily available and chemically stable, so they are used as a source of benzene rings in organic synthesis. For example, a chemical reaction that generates a highly reactive aryl radical from an aryl halide using a toxic tin compound has long been known as a method for supplying a benzene ring. In recent years, chemical reactions have been developed in which an aryl halide is reduced using a metal catalyst or a photocatalyst followed by cleavage of the bond between the benzene ring and the halogen atom to generate an aryl radical. However, since the methods previously reported require metal salts and/or excess amounts of an oxidizing agent or a reducing agent, chemical reactions with less environmental impact are desirable. The research group of Kanazawa University led by Prof. Ohmiya has been developing novel chemical reactions using newly developed metal-free organic catalysts to produce various useful chemicals in a much easier manner than with conventional methods. In the present study, the group succeeded in generating aryl radicals from aryl iodides, a type of aryl halide, under mild conditions without the need for light or metal salts, using an N-heterocyclic carbene catalyst and the aryl radicals thus formed were used for organic syntheses. A single electron transfer from an enolate intermediate consisting of a thiazolium-type N-heterocyclic carbene catalyst and an aldehyde to an aryl iodide and the subsequent cleavage of the bond between the benzene ring and the iodine atom generate an aryl radical in a catalytic manner. Considering the oxidation potential of the enolate intermediate (Eox = -0.97 V) and the reduction potential of the aryl iodide (Ered = -2.24 V), single electron transfer from the enolate intermediate to the aryl iodide, i.e. single electron reduction, is thermodynamically unfavorable. However, it is considered that the reaction took place due to kinetic factors because the two reaction steps, i.e. 1) single electron transfer from the enolate intermediate to the aryl iodide and 2) cleavage of the bond between the benzene ring and the iodine atom, proceed rapidly. The aryl radical generated acts as a source of the benzene ring, the difunctionalization of the alkene proceeds, and a benzene-ring substituted ketone is obtained. In addition, by using the aryl radical generated for the intramolecular hydrogen abstraction reaction, the dehydrogenative acylation of the amide proceeds, and an α-aminoketone compound can be obtained. Substrates with various functional groups can be used in these molecular conversion reactions. Derivatives of pharmaceuticals can also be synthesized by the dehydrogenative acylation of amides. The results of this study are the development of a chemical reaction that cleaves the bond between the benzene ring of an aryl halide and the halogen atom by using an organic catalyst that has a low impact on the environment, leading to generation of an aryl radical. Since aryl radicals can be easily generated from aryl halides that are widely used in organic synthesis, this is expected to be a powerful technology for precisely synthesizing medical and agricultural drugs as well as chemical materials. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract There have been significant advancements in radical reactions using organocatalysts in modern organic synthesis. Recently, NHC-catalyzed radical reactions initiated by single electron transfer processes have been actively studied. However, the reported examples have been limited to catalysis mediated by alkyl radicals. In this article, the NHC organocatalysis mediated by aryl radicals has been achieved. The enolate form of the Breslow intermediate derived from an aldehyde and thiazolium-type NHC in the presence of a base undergoes single electron transfer to an aryl iodide, providing an aryl radical. The catalytically generated aryl radical could be exploited as an arylating reagent for radical relay-type arylacylation of styrenes and as a hydrogen atom abstraction reagent for α-amino C(sp 3 )–H acylation of secondary amides. Introduction Aryl halides (Ar–X) have been broadly utilized as versatile reagents for chemical reactions due to their availability and bench stability. Specifically, oxidative addition of the C(sp 2 )–X bond in an aryl halide to a transition-metal complex enables the generation of an arylmetal species that induces various transformations (Fig. 1a ) 1 , 2 . The generation of an aryl radical 3 , 4 through single electron reduction of an aryl halide followed by mesolytic cleavage of the C(sp 2 )–X bond has emerged as an alternative approach for the utilization of aryl halides as chemical reagents (Fig. 1b ). Due to the high reduction potential of aryl halides, metal sources such as samarium salts 5 , transition-metal complexes 6 and metal-based visible light photoredox catalysts 7 have been mainly utilized as single electron donors. Recently, organic electron donors 8 , 9 , 10 , 11 including visible light organic photoredox catalysts 12 , 13 , 14 have taken the place of metals to provide simple and rapid access to aryl radicals via single electron transfer (SET). These approaches enable the generation of aryl radicals without using metal sources, but still require either a stoichiometric amount of the organic electron donor or light irradiation. Fig. 1: Activation of aryl halides and aryl radical-mediated NHC catalysis. a Oxidative addition of aryl halide to transition metal. TM, transition metal. b Organic electron donor induced aryl radical generation (recent advance). SET, single electron transfer. OED, organic electron donor. c Generation of aryl radical through NHC catalysis (working hypothesis). d Arylacylation of alkene and C(sp 3 )–H acylation through NHC catalysis (this work). 1,5-HAT, 1,5-hydrogen atom transfer. Full size image There has been significant advancement in the use of radical reactions catalyzed by N-heterocyclic carbenes (NHC) with SET from a Breslow intermediate, based on enzymatic pyruvate transformations 15 , 16 , 17 , 18 . Recently, we developed NHC-catalyzed decarboxylative radical cross-coupling between aldehydes and aliphatic carboxylic acid derived-redox active esters 19 , 20 . The reaction involves SET from the enolate form of the Breslow intermediate derived from an aldehyde and NHC in the presence of a base to the redox active ester, followed by radical–radical coupling between the resultant Breslow intermediate-derived radical and alkyl radical. Thus, the enolate form of the Breslow intermediate can serve as a single electron donor and an acyl radical equivalent. Since this report, a series of NHC-catalyzed radical cross-coupling reactions have been developed by us and other groups 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 . However, these reported examples have been limited to catalysis mediated by C(sp 3 )-centered radicals. To expand the scope of radical NHC catalysis, we questioned whether an aryl radical could be generated and utilized (Fig. 1c ). Considering the gap in redox potential between the enolate form of the Breslow intermediate ( E ox = −0.97 V vs. SCE) 34 and iodobenzene ( E red = −2.24 V vs. SCE) 35 , the corresponding electron transfer seems to be thermodynamically unfavored. However, two kinetic features, (1) a small reorganization energy of the enolate form of the Breslow intermediate 34 and (2) a fast mesolytic cleavage of the radical anion derived from aryl iodide 35 , encouraged us to pursue this research program. Here, we report an aryl radical-mediated NHC organocatalysis method. The aryl radical that is generated catalytically through thermodynamically unfavored SET from the enolate form of the Breslow intermediate to an aryl iodide could be exploited as an arylating reagent for radical relay-type arylacylation of styrenes (Fig. 1d , top) and as a hydrogen atom abstraction reagent for α-amino C(sp 3 )–H acylation of secondary amides (Fig. 1d , bottom). It should be noted that this protocol eliminates the requirement for metals, oxidants/reductants and light. Results and discussion Development of the reaction and screening of conditions To test the generation of an aryl radical by the radical NHC catalysis, we designed intramolecular arylacylation reactions with benzaldehyde ( 1a ) and aryl electrophiles 2a – d bearing a cinnamyl tether group that can trap the aryl radical immediately (Table 1 ) 36 . Based on our previous studies on the NHC-catalyzed decarboxylative radical cross-coupling between aldehydes and redox-active esters 19 , we used a thiazolium salt ( N1 ) 37 possessing a N-2,6-diisopropylphenyl substituent and a seven-membered backbone structure as the NHC precursor and Cs 2 CO 3 as the base. The reaction with aryl iodide 2a as a substrate proceeded to afford 3aa in 39% isolated yield with recovery of 2a (entry 1). The reactions with other azolium salts resulted in no product formation (data not shown). Neither bromide nor chloride leaving groups resulted in product formation (entries 2 and 3). The reaction using the corresponding aryldiazonium tetrafluoroborate 2d did not afford the desired coupling product 3aa (entry 4). This might be due to the low reduction potential of the aryldiazonium salt ( E red = −0.2 V vs. SCE), which would cause a second electron transfer from the Breslow-derived radical intermediate 38 . Table 1 Screening of reaction conditions. Full size table Radical relay-type arylacylation of styrenes The successful example of an NHC-catalyzed reaction involving the generation of an<|im_end|> <|im_start|>assistant Aryl halides with a benzene ring directly bonded to a halogen atom are readily available and chemically stable, so they are used as a source of benzene rings in organic synthesis. For example, a chemical reaction that generates a highly reactive aryl radical from an aryl halide using a toxic tin compound has long been known as a method for supplying a benzene ring. In recent years, chemical reactions have been developed in which an aryl halide is reduced using a metal catalyst or a photocatalyst followed by cleavage of the bond between the benzene ring and the halogen atom to generate an aryl radical. However, since the methods previously reported require metal salts and/or excess amounts of an oxidizing agent or a reducing agent, chemical reactions with less environmental impact are desirable. The research group of Kanazawa University led by Prof. Ohmiya has been developing novel chemical reactions using newly developed metal-free organic catalysts to produce various useful chemicals in a much easier manner than with conventional methods. In the present study, the group succeeded in generating aryl radicals from aryl iodides, a type of aryl halide, under mild conditions without the need for light or metal salts, using an N-heterocyclic carbene catalyst and the aryl radicals thus formed were used for organic syntheses. A single electron transfer from an enolate intermediate consisting of a thiazolium-type N-heterocyclic carbene catalyst and an aldehyde to an aryl iodide and the subsequent cleavage of the bond between the benzene ring and the iodine atom generate an aryl radical in a catalytic manner. Considering the oxidation potential of the enolate intermediate (Eox = -0.97 V) and the reduction potential of the aryl iodide (Ered = -2.24 V), single electron transfer from the enolate intermediate to the aryl iodide, i.e. single electron reduction, is thermodynamically unfavorable. However, it is considered that the reaction took place due to kinetic factors because the two reaction steps, i.e. 1) single electron transfer from the enolate intermediate to the aryl iodide and 2) cleavage of the bond between the benzene ring and the iodine atom, proceed rapidly. The aryl radical generated acts as a source of the benzene ring, the difunctionalization of the alkene proceeds, and a benzene-ring substituted ketone is obtained. In addition, by using the aryl radical generated for the intramolecular hydrogen abstraction reaction, the dehydrogenative acylation of the amide proceeds, and an α-aminoketone compound can be obtained. Substrates with various functional groups can be used in these molecular conversion reactions. Derivatives of pharmaceuticals can also be synthesized by the dehydrogenative acylation of amides. The results of this study are the development of a chemical reaction that cleaves the bond between the benzene ring of an aryl halide and the halogen atom by using an organic catalyst that has a low impact on the environment, leading to generation of an aryl radical. Since aryl radicals can be easily generated from aryl halides that are widely used in organic synthesis, this is expected to be a powerful technology for precisely synthesizing medical and agricultural drugs as well as chemical materials. <|im_end|>

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312, 55975, 320, 30035, 13, 220, 16, 65, 7609, 24586, 311, 279, 1579, 14278, 4754, 315, 802, 4010, 15104, 3422, 11, 9501, 8336, 1778, 439, 10167, 34765, 78235, 220, 20, 1174, 9320, 89932, 69125, 220, 21, 323, 9501, 6108, 9621, 3177, 4604, 461, 3055, 87, 51483, 82, 220, 22, 617, 1027, 14918, 34716, 439, 3254, 17130, 33149, 13, 42096, 11, 17808, 17130, 33149, 220, 23, 1174, 220, 24, 1174, 220, 605, 1174, 220, 806, 2737, 9621, 3177, 17808, 4604, 461, 3055, 87, 51483, 82, 220, 717, 1174, 220, 1032, 1174, 220, 975, 617, 4529, 279, 2035, 315, 37182, 311, 3493, 4382, 323, 11295, 2680, 311, 802, 4010, 74356, 4669, 3254, 17130, 8481, 320, 6008, 570, 4314, 20414, 7431, 279, 9659, 315, 802, 4010, 74356, 2085, 1701, 9501, 8336, 11, 719, 2103, 1397, 3060, 264, 43132, 41652, 24264, 3392, 315, 279, 17808, 17130, 35558, 477, 3177, 76327, 367, 13, 23966, 13, 220, 16, 25, 50747, 315, 802, 4010, 15104, 3422, 323, 802, 4010, 18336, 82076, 452, 23263, 34454, 4548, 13, 264, 51715, 307, 1413, 5369, 315, 802, 4010, 15104, 579, 311, 9320, 9501, 13, 24929, 11, 9320, 9501, 13, 293, 44037, 17130, 35558, 36572, 802, 4010, 18336, 9659, 320, 47743, 12178, 570, 9196, 11, 3254, 17130, 8481, 13, 507, 1507, 11, 17808, 17130, 35558, 13, 272, 24367, 315, 802, 4010, 18336, 1555, 452, 23263, 34454, 4548, 320, 21837, 31178, 570, 294, 87410, 75, 2826, 2354, 315, 58998, 1994, 323, 356, 23398, 220, 18, 883, 4235, 39, 1645, 79933, 1555, 452, 23263, 34454, 4548, 320, 576, 990, 570, 220, 16, 11, 20, 11529, 835, 11, 220, 16, 11, 20, 2902, 68107, 4469, 19670, 8481, 13, 8797, 1404, 2217, 2684, 706, 1027, 5199, 50925, 304, 279, 1005, 315, 18336, 25481, 34454, 88, 16284, 555, 452, 2902, 1430, 511, 66404, 1841, 8123, 288, 320, 45, 23263, 8, 449, 9196, 505, 264, 426, 417, 10516, 29539, 11, 3196, 389, 32011, 780, 4611, 2739, 85, 349, 54070, 220, 868, 1174, 220, 845, 1174, 220, 1114, 1174, 220, 972, 662, 42096, 11, 584, 8040, 452, 23263, 1824, 4306, 88, 16284, 1654, 277, 2054, 4010, 1413, 18336, 5425, 1824, 283, 12127, 1990, 453, 80660, 5919, 323, 453, 15619, 780, 1841, 2054, 88, 416, 13935, 14592, 32698, 5241, 4642, 1826, 388, 220, 777, 1174, 220, 508, 662, 578, 13010, 18065, 9196, 505, 279, 665, 34166, 1376, 315, 279, 426, 417, 10516, 29539, 14592, 505, 459, 453, 86836, 323, 452, 23263, 304, 279, 9546, 315, 264, 2385, 311, 279, 2579, 5241, 4642, 1826, 261, 11, 8272, 555, 18336, 4235, 13584, 950, 59086, 1990, 279, 84913, 426, 417, 10516, 29539, 72286, 18336, 323, 58998, 4010, 18336, 13, 14636, 11, 279, 665, 34166, 1376, 315, 279, 426, 417, 10516, 29539, 649, 8854, 439, 264, 3254, 17130, 35558, 323, 459, 1645, 4010, 18336, 13890, 13, 8876, 420, 1934, 11, 264, 4101, 315, 452, 23263, 1824, 4306, 88, 16284, 18336, 5425, 1824, 283, 12127, 25481, 617, 1027, 8040, 555, 603, 323, 1023, 5315, 220, 1691, 1174, 220, 1313, 1174, 220, 1419, 1174, 220, 1187, 1174, 220, 914, 1174, 220, 1627, 1174, 220, 1544, 1174, 220, 1591, 1174, 220, 1682, 1174, 220, 966, 1174, 220, 2148, 1174, 220, 843, 1174, 220, 1644, 662, 4452, 11, 1521, 5068, 10507, 617, 1027, 7347, 311, 34454, 4548, 78926, 555, 356, 23398, 220, 18, 883, 12, 3133, 291, 74356, 13, 2057, 9407, 279, 7036, 315, 18336, 452, 23263, 34454, 4548, 11, 584, 29440, 3508, 459, 802, 4010, 18336, 1436, 387, 8066, 323, 34716, 320, 30035, 13, 220, 16, 66, 7609, 56877, 279, 13225, 304, 2579, 5241, 4754, 1990, 279, 665, 34166, 1376, 315, 279, 426, 417, 10516, 29539, 320, 469, 19488, 284, 25173, 15, 13, 3534, 650, 6296, 13, 94181, 8, 220, 1958, 323, 80087, 677, 17007, 1994, 320, 469, 2579, 284, 25173, 17, 13, 1187, 650, 6296, 13, 94181, 8, 220, 1758, 1174, 279, 12435, 17130, 8481, 5084, 311, 387, 30945, 72931, 2740, 9662, 76486, 13, 4452, 11, 1403, 71423, 4519, 11, 320, 16, 8, 264, 2678, 312, 24844, 4907, 315, 279, 665, 34166, 1376, 315, 279, 426, 417, 10516, 29539, 220, 1958, 323, 320, 17, 8, 264, 5043, 11083, 5849, 29150, 11551, 68256, 315, 279, 18336, 459, 290, 14592, 505, 802, 4010, 80087, 579, 220, 1758, 1174, 21190, 603, 311, 23564, 420, 3495, 2068, 13, 5810, 11, 584, 1934, 459, 802, 4010, 18336, 82076, 452, 23263, 2942, 511, 4306, 4548, 1749, 13, 578, 802, 4010, 18336, 430, 374, 8066, 34454, 16820, 2740, 1555, 30945, 72931, 2740, 9662, 76486, 9196, 505, 279, 665, 34166, 1376, 315, 279, 426, 417, 10516, 29539, 311, 459, 802, 4010, 80087, 579, 1436, 387, 51763, 439, 459, 802, 4010, 1113, 312, 8252, 369, 18336, 32951, 10827, 802, 4010, 2826, 2354, 315, 18078, 1466, 288, 320, 30035, 13, 220, 16, 67, 1174, 1948, 8, 323, 439, 264, 35784, 19670, 59851, 312, 8252, 369, 19581, 33317, 3394, 356, 23398, 220, 18, 883, 4235, 39, 1645, 79933, 315, 14580, 1097, 3422, 320, 30035, 13, 220, 16, 67, 1174, 5740, 570, 1102, 1288, 387, 10555, 430, 420, 11766, 60944, 279, 16686, 369, 37182, 11, 36172, 1821, 10991, 1076, 1821, 323, 3177, 13, 18591, 323, 10430, 11050, 315, 279, 13010, 323, 23061, 315, 4787, 2057, 1296, 279, 9659, 315, 459, 802, 4010, 18336, 555, 279, 18336, 452, 23263, 34454, 4548, 11, 584, 6319, 10805, 309, 43943, 802, 4010, 2826, 2354, 25481, 449, 72046, 278, 86836, 320, 220, 16, 64, 883, 323, 802, 4010, 4135, 22761, 3742, 220, 17, 64, 1389, 294, 18534, 264, 272, 6258, 309, 4010, 80665, 1912, 430, 649, 23709, 279, 802, 4010, 18336, 7214, 320, 2620, 220, 16, 883, 220, 1927, 662, 20817, 389, 1057, 3766, 7978, 389, 279, 452, 23263, 1824, 4306, 88, 16284, 1654, 277, 2054, 4010, 1413, 18336, 5425, 1824, 283, 12127, 1990, 453, 80660, 5919, 323, 2579, 5241, 32344, 1826, 388, 220, 777, 1174, 584, 1511, 264, 270, 28073, 337, 2411, 12290, 320, 452, 16, 883, 220, 1806, 60662, 264, 452, 12, 17, 11, 21, 51389, 285, 454, 897, 4010, 15112, 4010, 32434, 11942, 323, 264, 8254, 44650, 291, 56527, 6070, 439, 279, 452, 23263, 71261, 323, 68432, 220, 17, 7432, 220, 18, 439, 279, 2385, 13, 578, 13010, 449, 802, 4010, 80087, 579, 220, 17, 64, 439, 264, 54057, 45374, 311, 10150, 220, 18, 5418, 304, 220, 2137, 4, 25181, 7692, 449, 13654, 315, 220, 17, 64, 320, 4177, 220, 16, 570, 578, 25481, 449, 1023, 12657, 337, 2411, 78235, 19543, 304, 912, 2027, 18488, 320, 695, 539, 6982, 570, 25215, 94571, 579, 6463, 82882, 9564, 5315, 19543, 304, 2027, 18488, 320, 13237, 220, 17, 323, 220, 18, 570, 578, 13010, 1701, 279, 12435, 74021, 509, 28073, 90344, 28953, 969, 27256, 269, 677, 38995, 220, 17, 67, 1550, 539, 10150, 279, 12974, 59086, 2027, 220, 18, 5418, 320, 4177, 220, 19, 570, 1115, 2643, 387, 4245, 311, 279, 3428, 14278, 4754, 315, 279, 74021, 509, 28073, 90344, 12290, 320, 469, 2579, 284, 25173, 15, 13, 17, 650, 6296, 13, 94181, 705, 902, 1053, 5353, 264, 2132, 17130, 8481, 505, 279, 426, 417, 10516, 72286, 18336, 29539, 220, 1987, 662, 6771, 220, 16, 70189, 315, 13010, 4787, 13, 8797, 1404, 2007, 88981, 32951, 10827, 802, 4010, 2826, 2354, 315, 18078, 1466, 288, 578, 6992, 3187, 315, 459, 452, 23263, 1824, 4306, 88, 16284, 13010, 16239, 279, 9659, 315, 459, 128257, 198, 128256, 78191, 198, 32, 894, 75, 15104, 3422, 449, 264, 72046, 1994, 10264, 6089, 70241, 311, 264, 15104, 11968, 19670, 527, 31368, 2561, 323, 8590, 2740, 15528, 11, 779, 814, 527, 1511, 439, 264, 2592, 315, 72046, 1994, 25562, 304, 17808, 39975, 13, 1789, 3187, 11, 264, 11742, 13010, 430, 27983, 264, 7701, 56563, 802, 4010, 18336, 505, 459, 802, 4010, 15104, 579, 1701, 264, 21503, 25826, 24549, 706, 1317, 1027, 3967, 439, 264, 1749, 369, 44413, 264, 72046, 1994, 10264, 13, 763, 3293, 1667, 11, 11742, 25481, 617, 1027, 8040, 304, 902, 459, 802, 4010, 15104, 579, 374, 11293, 1701, 264, 9501, 51483, 477, 264, 99336, 4306, 599, 8272, 555, 11551, 68256, 315, 279, 11049, 1990, 279, 72046, 1994, 10264, 323, 279, 15104, 11968, 19670, 311, 7068, 459, 802, 4010, 18336, 13, 4452, 11, 2533, 279, 5528, 8767, 5068, 1397, 9501, 78235, 323, 5255, 13937, 15055, 315, 459, 36172, 4954, 8479, 477, 264, 18189, 8479, 11, 11742, 25481, 449, 2753, 12434, 5536, 527, 35946, 13, 578, 3495, 1912, 315, 31663, 1394, 14406, 3907, 6197, 555, 8626, 13, 8840, 8318, 7911, 706, 1027, 11469, 11775, 11742, 25481, 1701, 13945, 8040, 9501, 12862, 17808, 51483, 82, 311, 8356, 5370, 5505, 26333, 304, 264, 1790, 8831, 11827, 1109, 449, 21349, 5528, 13, 763, 279, 3118, 4007, 11, 279, 1912, 26399, 304, 24038, 802, 4010, 74356, 505, 802, 4010, 80087, 3422, 11, 264, 955, 315, 802, 4010, 15104, 579, 11, 1234, 23900, 4787, 2085, 279, 1205, 369, 3177, 477, 9501, 78235, 11, 1701, 459, 452, 2902, 1430, 511, 66404, 35872, 1994, 51483, 323, 279, 802, 4010, 74356, 8617, 14454, 1051, 1511, 369, 17808, 6925, 39422, 13, 362, 3254, 17130, 8481, 505, 459, 665, 34166, 29539, 31706, 315, 264, 270, 28073, 337, 2411, 10827, 452, 2902, 1430, 511, 66404, 35872, 1994, 51483, 323, 459, 453, 86836, 311, 459, 802, 4010, 80087, 579, 323, 279, 17876, 11551, 68256, 315, 279, 11049, 1990, 279, 72046, 1994, 10264, 323, 279, 80087, 483, 19670, 7068, 459, 802, 4010, 18336, 304, 264, 34454, 70504, 11827, 13, 56877, 279, 71162, 4754, 315, 279, 665, 34166, 29539, 320, 36, 5241, 284, 482, 15, 13, 3534, 650, 8, 323, 279, 14278, 4754, 315, 279, 802, 4010, 80087, 579, 320, 36, 1171, 284, 482, 17, 13, 1187, 650, 705, 3254, 17130, 8481, 505, 279, 665, 34166, 29539, 311, 279, 802, 4010, 80087, 579, 11, 602, 1770, 13, 3254, 17130, 14278, 11, 374, 30945, 72931, 2740, 93071, 13, 4452, 11, 433, 374, 6646, 430, 279, 13010, 3952, 2035, 4245, 311, 71423, 9547, 1606, 279, 1403, 13010, 7504, 11, 602, 1770, 13, 220, 16, 8, 3254, 17130, 8481, 505, 279, 665, 34166, 29539, 311, 279, 802, 4010, 80087, 579, 323, 220, 17, 8, 11551, 68256, 315, 279, 11049, 1990, 279, 72046, 1994, 10264, 323, 279, 80087, 483, 19670, 11, 10570, 19019, 13, 578, 802, 4010, 18336, 8066, 14385, 439, 264, 2592, 315, 279, 72046, 1994, 10264, 11, 279, 1422, 600, 278, 2065, 315, 279, 58998, 1994, 34555, 11, 323, 264, 72046, 1994, 77029, 63196, 32381, 606, 374, 12457, 13, 763, 5369, 11, 555, 1701, 279, 802, 4010, 18336, 8066, 369, 279, 10805, 309, 43943, 35784, 59851, 13010, 11, 279, 409, 67229, 4469, 1413, 1645, 79933, 315, 279, 1097, 579, 34555, 11, 323, 459, 19581, 12, 8778, 564, 295, 606, 24549, 649, 387, 12457, 13, 3804, 496, 988, 449, 5370, 16003, 5315, 649, 387, 1511, 304, 1521, 31206, 14747, 25481, 13, 13031, 344, 5983, 315, 35410, 82, 649, 1101, 387, 92106, 555, 279, 409, 67229, 4469, 1413, 1645, 79933, 315, 1097, 3422, 13, 578, 3135, 315, 420, 4007, 527, 279, 4500, 315, 264, 11742, 13010, 430, 11551, 4798, 279, 11049, 1990, 279, 72046, 1994, 10264, 315, 459, 802, 4010, 15104, 579, 323, 279, 15104, 11968, 19670, 555, 1701, 459, 17808, 51483, 430, 706, 264, 3428, 5536, 389, 279, 4676, 11, 6522, 311, 9659, 315, 459, 802, 4010, 18336, 13, 8876, 802, 4010, 74356, 649, 387, 6847, 8066, 505, 802, 4010, 15104, 3422, 430, 527, 13882, 1511, 304, 17808, 39975, 11, 420, 374, 3685, 311, 387, 264, 8147, 5557, 369, 24559, 52389, 4954, 6593, 323, 29149, 11217, 439, 1664, 439, 11742, 7384, 13, 220, 128257, 198 ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The Non-Proliferation Treaty and other non-proliferation agreements are in place worldwide to ensure that nuclear material and facilities are used only for peaceful purposes. Antineutrino detectors, sensitive to reactor power and fuel changes, can complement the tools already at the disposal of international agencies to safeguard nuclear facilities and to verify the States’ compliance with the agreements. Recent advancement in these detectors has made it possible to leverage them to reduce the likelihood of an undetected diversion of irradiated nuclear material. Here we show the sensitivity of antineutrino monitors to fuel divergence from two reactor types: a traditional light-water reactor and an advanced sodium-cooled reactor design, a likely candidate for future deployment. The analysis demonstrates that a variety of potential diversion scenarios can be detected by such a system. We outline recent developments in monitoring capabilities and discuss their potential security implications to the international community. Introduction Nuclear energy is touted as a key tool for providing high-volume, low-carbon energy 1 , 2 , with about 450 nuclear power plants currently producing around 11% of world’s energy and 61 additional plants under construction 3 . As the number of nuclear energy-producing nations grows and the nuclear fuel cycle becomes ever more complex and internationalized, stresses on the existing safeguards infrastructure will only increase. With new, unconventional types of reactors introduced to the market, standard approaches to nuclear proliferation safeguards also become less reliable. A strongly advocated means of containing proliferation is to establish a provider-user fuel cycle, in which front-end and back-end processes are made available by states with such infrastructure already in place. These capabilities, specifically fuel enrichment and reprocessing, provide a direct path for a state to develop a nuclear weapon. A provider-user approach removes the incentive for user states to develop these proliferation-sensitive technologies. Existing agreements (for example, between the U.S. and the United Arab Emirates) 4 accomplish this by legally binding nations not to pursue enrichment or reprocessing technology. More novel approaches rely on a hub-spoke model 5 , 6 : advanced reactors of battery-type, which rely a single but long (10–30 years) fuel loading and usually have relatively low power, are leased to the user state and returned to the provider state at the end of their lifetime for disposal or recycling of spent fuel. While these proposals reduce proliferation risks associated with reactor fuel cycle, they do not eliminate it. Plutonium produced as a by-product of normal operation in any reactor could still be diverted for use in weapons 7 . Traditional safeguards and inspections have worked well, deterring material diversion from current reactors for many decades. The International Atomic Energy Agency (IAEA) relies on inspector presence during reactor refueling intervals, as well as seals on fuel assemblies to keep track of weapon-usable material. However, these checks are not infallible, since inspectors are not always present on a site and can be refused entry. Future reactor developments on the horizon are likely to strain the nonproliferation regime further. The shift in the industry towards more distributed generation using Small Modular Reactors (SMR) will stretch out monitoring resources. Advanced so-called “Generation IV” reactor designs often do not require any refueling or, conversely, continuously refuel their cores, complicating inspections efforts and requiring continuous monitoring of the fuel state. The development of long-life reactors also raises additional questions about safeguards, notably regarding when and how inspections should be conducted. Inspectors cannot rely on refueling cycles to monitor these reactors as they typically do for Pressurized Water Reactors (PWR), which operate on an 18–24-month cycle. The issue of inspections is exacerbated by the weapon-grade quality of plutonium in such cores (<7% 240 Pu) resulting from the fast neutron spectrum that is necessary to breed fissile material in the core and subsequently burn it in situ without loss of reactor criticality. Future safeguarding technologies deployed to combat these challenges will ideally possess always-on, real-time monitoring attributes and ensure the integrity of the collected data against attempts to falsify it. One potential route to meeting such continuous safeguarding requirements can be provided by antineutrino particles, a by-product of the nuclear fission process. Indeed, advances in antineutrino detector capabilities can yield a continuous, unobtrusive, and unfalsifiable way of obtaining information on a nuclear core. In this paper, such a system is termed Reactor Evaluation Through Inspection of Near-field Antineutrinos, or RETINA (see Fig. 1 ). Fig. 1 Principle of reactor operation verification with antineutrino monitors. The process for verifying reactor inventory integrity with antineutrinos bears similarities to biometric scans such as retinal identity verification. In retinal scans, an infrared beam traverses a person’s retina ( a ) and the blood vessels, distinguishable by their higher light absorption ( b ) relative to other tissue, are mapped. The mapping is extracted and compared to a copy stored in a database ( c ), and if the two match, the person’s identity is verified. Similarly, a nuclear reactor ( g ) continuously emits antineutrinos which vary in flux and spectrum with the particular fuel isotopes undergoing fission ( d ). Some interact in a nearby detector ( h ) via inverse beta decay ( e ). The measured signal is compared to a reference copy stored in a database for the relevant reactor, initial fuel, and burnup ( f ); a sufficiently matching signal indicates that the core inventory has not been covertly altered. If the antineutrino flux of a perturbed reactor is sufficiently different from expected, a diversion can be concluded to have taken place ( i ) Full size image At a 2008 workshop by the IAEA’s Division of Technical Support, experts evaluated how antineutrino detectors can improve the monitoring capabilities of the organization and complement the role of inspectors 8 . The report concluded that RETINA systems could complement safeguard capabilities by providing an independent, real-time measure of the reactor power and of its fissile inventory. Many antineutrino systems have been built and operated in the past to demonstrate some of these safeguarding capabilities, notably at SONGS 9 ,", "role": "user" }, { "content": "Technology to measure the flow of subatomic particles known as antineutrinos from nuclear reactors could allow continuous remote monitoring designed to detect fueling changes that might indicate the diversion of nuclear materials. The monitoring could be done from outside the reactor vessel, and the technology may be sensitive enough to detect substitution of a single fuel assembly. The technique, which could be used with existing pressurized water reactors as well as future designs expected to require less frequent refueling, could supplement other monitoring techniques, including the presence of human inspectors. The potential utility of the above-ground antineutrino monitoring technique for current and future reactors was confirmed through extensive simulations done by researchers at the Georgia Institute of Technology. \"Antineutrino detectors offer a solution for continuous, real-time verification of what is going on within a nuclear reactor without actually having to be in the reactor core,\" said Anna Erickson, associate professor in Georgia Tech's George W. Woodruff School of Mechanical Engineering. \"You cannot shield antineutrinos, so if the state running a reactor decides to use it for nefarious purposes, they can't prevent us from seeing that there was a change in reactor operations.\" The research, to be reported August 6 in the journal Nature Communications, was partially supported by a grant from the Nuclear Regulatory Commission (NRC). The research evaluated two types of reactors, and antineutrino detection technology based on a PROSPECT detector currently deployed at Oak Ridge National Laboratory's High Flux Isotope Reactor (HFIR). Antineutrinos are elementary subatomic particles with an infinitesimally small mass and no electrical charge. They are capable of passing through shielding around a nuclear reactor core, where they are produced as part of the nuclear fission process. The flux of antineutrinos produced in a nuclear reactor depends on the type of fission materials and the power level at which the reactor is operated. \"Traditional nuclear reactors slowly build up plutonium 239 in their cores as a consequence of uranium 238 absorption of neutrons, shifting the fission reaction from uranium 235 to plutonium 239 during the fuel cycle. We can see that in the signature of antineutrino emission changes over time,\" Erickson said. \"If the fuel is changed by a rogue nation attempting to divert plutonium for weapons by replacing fuel assemblies, we should be able to see that with a detector capable of measuring even small changes in the signatures.\" The antineutrino signature of the fuel can be as unique as a retinal scan, and how the signature changes over time can be predicted using simulations, she said. \"We could then verify that what we see with the antineutrino detector matches what we would expect to see.\" In the research, Erickson and recent Ph.D. graduates Christopher Stewart and Abdalla Abou-Jaoude used high-fidelity computer simulations to assess the capabilities of near-field antineutrino detectors that would be located near—but not inside—reactor containment vessels. Among the challenges is distinguishing between particles generated by fission and those from natural background. \"We would measure the energy, position and timing to determine whether a detection was an antineutrino from the reactor or something else,\" she said. \"Antineutrinos are difficult to detect and we cannot do that directly. These particles have a very small chance of interacting with a hydrogen nucleus, so we rely on those protons to convert the antineutrinos into positrons and neutrons.\" These images compare the evolution of antineutrino spectrum and antineutrino detector response as a function of reactor operational time in a pressurized water reactor and an ultra-long cycle fast reactor. Credit: Georgia Tech Nuclear reactors now used for power generation must be refueled on a regular basis, and that operation provides an opportunity for human inspection, but future generations of nuclear reactors may operate for as long as 30 years without refueling. The simulation showed that sodium-cooled reactors could also be monitored using antineutrino detectors, though their signatures will be different from those of the current generation of pressurized water reactors. Among the challenges ahead is reducing the size of the antineutrino detectors to make them portable enough to fit into a vehicle that could be driven past a nuclear reactor. Researchers also want to improve the directionality of the detectors to keep them focused on emissions from the reactor core to boost their ability to detect even small changes. The detection principle is similar in concept to that of retinal scans used for identity verification. In retinal scans, an infrared beam traverses a person's retina and the blood vessels, which are distinguishable by their higher light absorption relative to other tissue. This mapping information is then extracted and compared to a retinal scan taken earlier and stored in a database. If the two match, the person's identity can be verified. Similarly, a nuclear reactor continuously emits antineutrinos that vary in flux and spectrum with the particular fuel isotopes undergoing fission. Some antineutrinos interact in a nearby detector via inverse beta decay. The signal measured by that detector is compared to a reference copy stored in a database for the relevant reactor, initial fuel and burnup; a signal that sufficiently matches the reference copy would indicate that the core inventory has not been covertly altered. However, if the antineutrino flux of a perturbed reactor is sufficiently different from what would be expected, that could indicate that a diversion has taken place. The emission rates of antineutrino particles at different energies vary with operating lifetime as reactors shift from burning uranium to plutonium. The signal from a pressurized water reactor consists of a repeated 18-month operating cycle with a three-month refueling interval, while signal from an ultra-long cycle fast reactor (UCFR) would represent continuous operation, excluding maintenance interruptions. Preventing the proliferation of special nuclear materials suitable for weapons is a long-term concern of researchers from many different agencies and organizations, Erickson said. \"It goes all the way from mining of nuclear material to disposition of nuclear material, and at every step of that process, we have to be concerned about who's handling it and whether it might get into the wrong hands,\" she explained. \"The picture is more complicated because we don't want to prevent the use of nuclear materials for power generation because nuclear is a big contributor to non-carbon energy.\" The paper shows the feasibility of the technique and should encourage the continued development of detector technologies, Erickson said. \"One of the highlights of the research is a detailed analysis of assembly-level diversion that is critical to our understanding of the limitations on antineutrino detectors and the potential implications for policy that could be implemented,\" she said. \"I think the paper will encourage people to look into future systems in more detail.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The Non-Proliferation Treaty and other non-proliferation agreements are in place worldwide to ensure that nuclear material and facilities are used only for peaceful purposes. Antineutrino detectors, sensitive to reactor power and fuel changes, can complement the tools already at the disposal of international agencies to safeguard nuclear facilities and to verify the States’ compliance with the agreements. Recent advancement in these detectors has made it possible to leverage them to reduce the likelihood of an undetected diversion of irradiated nuclear material. Here we show the sensitivity of antineutrino monitors to fuel divergence from two reactor types: a traditional light-water reactor and an advanced sodium-cooled reactor design, a likely candidate for future deployment. The analysis demonstrates that a variety of potential diversion scenarios can be detected by such a system. We outline recent developments in monitoring capabilities and discuss their potential security implications to the international community. Introduction Nuclear energy is touted as a key tool for providing high-volume, low-carbon energy 1 , 2 , with about 450 nuclear power plants currently producing around 11% of world’s energy and 61 additional plants under construction 3 . As the number of nuclear energy-producing nations grows and the nuclear fuel cycle becomes ever more complex and internationalized, stresses on the existing safeguards infrastructure will only increase. With new, unconventional types of reactors introduced to the market, standard approaches to nuclear proliferation safeguards also become less reliable. A strongly advocated means of containing proliferation is to establish a provider-user fuel cycle, in which front-end and back-end processes are made available by states with such infrastructure already in place. These capabilities, specifically fuel enrichment and reprocessing, provide a direct path for a state to develop a nuclear weapon. A provider-user approach removes the incentive for user states to develop these proliferation-sensitive technologies. Existing agreements (for example, between the U.S. and the United Arab Emirates) 4 accomplish this by legally binding nations not to pursue enrichment or reprocessing technology. More novel approaches rely on a hub-spoke model 5 , 6 : advanced reactors of battery-type, which rely a single but long (10–30 years) fuel loading and usually have relatively low power, are leased to the user state and returned to the provider state at the end of their lifetime for disposal or recycling of spent fuel. While these proposals reduce proliferation risks associated with reactor fuel cycle, they do not eliminate it. Plutonium produced as a by-product of normal operation in any reactor could still be diverted for use in weapons 7 . Traditional safeguards and inspections have worked well, deterring material diversion from current reactors for many decades. The International Atomic Energy Agency (IAEA) relies on inspector presence during reactor refueling intervals, as well as seals on fuel assemblies to keep track of weapon-usable material. However, these checks are not infallible, since inspectors are not always present on a site and can be refused entry. Future reactor developments on the horizon are likely to strain the nonproliferation regime further. The shift in the industry towards more distributed generation using Small Modular Reactors (SMR) will stretch out monitoring resources. Advanced so-called “Generation IV” reactor designs often do not require any refueling or, conversely, continuously refuel their cores, complicating inspections efforts and requiring continuous monitoring of the fuel state. The development of long-life reactors also raises additional questions about safeguards, notably regarding when and how inspections should be conducted. Inspectors cannot rely on refueling cycles to monitor these reactors as they typically do for Pressurized Water Reactors (PWR), which operate on an 18–24-month cycle. The issue of inspections is exacerbated by the weapon-grade quality of plutonium in such cores (<7% 240 Pu) resulting from the fast neutron spectrum that is necessary to breed fissile material in the core and subsequently burn it in situ without loss of reactor criticality. Future safeguarding technologies deployed to combat these challenges will ideally possess always-on, real-time monitoring attributes and ensure the integrity of the collected data against attempts to falsify it. One potential route to meeting such continuous safeguarding requirements can be provided by antineutrino particles, a by-product of the nuclear fission process. Indeed, advances in antineutrino detector capabilities can yield a continuous, unobtrusive, and unfalsifiable way of obtaining information on a nuclear core. In this paper, such a system is termed Reactor Evaluation Through Inspection of Near-field Antineutrinos, or RETINA (see Fig. 1 ). Fig. 1 Principle of reactor operation verification with antineutrino monitors. The process for verifying reactor inventory integrity with antineutrinos bears similarities to biometric scans such as retinal identity verification. In retinal scans, an infrared beam traverses a person’s retina ( a ) and the blood vessels, distinguishable by their higher light absorption ( b ) relative to other tissue, are mapped. The mapping is extracted and compared to a copy stored in a database ( c ), and if the two match, the person’s identity is verified. Similarly, a nuclear reactor ( g ) continuously emits antineutrinos which vary in flux and spectrum with the particular fuel isotopes undergoing fission ( d ). Some interact in a nearby detector ( h ) via inverse beta decay ( e ). The measured signal is compared to a reference copy stored in a database for the relevant reactor, initial fuel, and burnup ( f ); a sufficiently matching signal indicates that the core inventory has not been covertly altered. If the antineutrino flux of a perturbed reactor is sufficiently different from expected, a diversion can be concluded to have taken place ( i ) Full size image At a 2008 workshop by the IAEA’s Division of Technical Support, experts evaluated how antineutrino detectors can improve the monitoring capabilities of the organization and complement the role of inspectors 8 . The report concluded that RETINA systems could complement safeguard capabilities by providing an independent, real-time measure of the reactor power and of its fissile inventory. Many antineutrino systems have been built and operated in the past to demonstrate some of these safeguarding capabilities, notably at SONGS 9 ,<|im_end|> <|im_start|>assistant Technology to measure the flow of subatomic particles known as antineutrinos from nuclear reactors could allow continuous remote monitoring designed to detect fueling changes that might indicate the diversion of nuclear materials. The monitoring could be done from outside the reactor vessel, and the technology may be sensitive enough to detect substitution of a single fuel assembly. The technique, which could be used with existing pressurized water reactors as well as future designs expected to require less frequent refueling, could supplement other monitoring techniques, including the presence of human inspectors. The potential utility of the above-ground antineutrino monitoring technique for current and future reactors was confirmed through extensive simulations done by researchers at the Georgia Institute of Technology. "Antineutrino detectors offer a solution for continuous, real-time verification of what is going on within a nuclear reactor without actually having to be in the reactor core," said Anna Erickson, associate professor in Georgia Tech's George W. Woodruff School of Mechanical Engineering. "You cannot shield antineutrinos, so if the state running a reactor decides to use it for nefarious purposes, they can't prevent us from seeing that there was a change in reactor operations." The research, to be reported August 6 in the journal Nature Communications, was partially supported by a grant from the Nuclear Regulatory Commission (NRC). The research evaluated two types of reactors, and antineutrino detection technology based on a PROSPECT detector currently deployed at Oak Ridge National Laboratory's High Flux Isotope Reactor (HFIR). Antineutrinos are elementary subatomic particles with an infinitesimally small mass and no electrical charge. They are capable of passing through shielding around a nuclear reactor core, where they are produced as part of the nuclear fission process. The flux of antineutrinos produced in a nuclear reactor depends on the type of fission materials and the power level at which the reactor is operated. "Traditional nuclear reactors slowly build up plutonium 239 in their cores as a consequence of uranium 238 absorption of neutrons, shifting the fission reaction from uranium 235 to plutonium 239 during the fuel cycle. We can see that in the signature of antineutrino emission changes over time," Erickson said. "If the fuel is changed by a rogue nation attempting to divert plutonium for weapons by replacing fuel assemblies, we should be able to see that with a detector capable of measuring even small changes in the signatures." The antineutrino signature of the fuel can be as unique as a retinal scan, and how the signature changes over time can be predicted using simulations, she said. "We could then verify that what we see with the antineutrino detector matches what we would expect to see." In the research, Erickson and recent Ph.D. graduates Christopher Stewart and Abdalla Abou-Jaoude used high-fidelity computer simulations to assess the capabilities of near-field antineutrino detectors that would be located near—but not inside—reactor containment vessels. Among the challenges is distinguishing between particles generated by fission and those from natural background. "We would measure the energy, position and timing to determine whether a detection was an antineutrino from the reactor or something else," she said. "Antineutrinos are difficult to detect and we cannot do that directly. These particles have a very small chance of interacting with a hydrogen nucleus, so we rely on those protons to convert the antineutrinos into positrons and neutrons." These images compare the evolution of antineutrino spectrum and antineutrino detector response as a function of reactor operational time in a pressurized water reactor and an ultra-long cycle fast reactor. Credit: Georgia Tech Nuclear reactors now used for power generation must be refueled on a regular basis, and that operation provides an opportunity for human inspection, but future generations of nuclear reactors may operate for as long as 30 years without refueling. The simulation showed that sodium-cooled reactors could also be monitored using antineutrino detectors, though their signatures will be different from those of the current generation of pressurized water reactors. Among the challenges ahead is reducing the size of the antineutrino detectors to make them portable enough to fit into a vehicle that could be driven past a nuclear reactor. Researchers also want to improve the directionality of the detectors to keep them focused on emissions from the reactor core to boost their ability to detect even small changes. The detection principle is similar in concept to that of retinal scans used for identity verification. In retinal scans, an infrared beam traverses a person's retina and the blood vessels, which are distinguishable by their higher light absorption relative to other tissue. This mapping information is then extracted and compared to a retinal scan taken earlier and stored in a database. If the two match, the person's identity can be verified. Similarly, a nuclear reactor continuously emits antineutrinos that vary in flux and spectrum with the particular fuel isotopes undergoing fission. Some antineutrinos interact in a nearby detector via inverse beta decay. The signal measured by that detector is compared to a reference copy stored in a database for the relevant reactor, initial fuel and burnup; a signal that sufficiently matches the reference copy would indicate that the core inventory has not been covertly altered. However, if the antineutrino flux of a perturbed reactor is sufficiently different from what would be expected, that could indicate that a diversion has taken place. The emission rates of antineutrino particles at different energies vary with operating lifetime as reactors shift from burning uranium to plutonium. The signal from a pressurized water reactor consists of a repeated 18-month operating cycle with a three-month refueling interval, while signal from an ultra-long cycle fast reactor (UCFR) would represent continuous operation, excluding maintenance interruptions. Preventing the proliferation of special nuclear materials suitable for weapons is a long-term concern of researchers from many different agencies and organizations, Erickson said. "It goes all the way from mining of nuclear material to disposition of nuclear material, and at every step of that process, we have to be concerned about who's handling it and whether it might get into the wrong hands," she explained. "The picture is more complicated because we don't want to prevent the use of nuclear materials for power generation because nuclear is a big contributor to non-carbon energy." The paper shows the feasibility of the technique and should encourage the continued development of detector technologies, Erickson said. "One of the highlights of the research is a detailed analysis of assembly-level diversion that is critical to our understanding of the limitations on antineutrino detectors and the potential implications for policy that could be implemented," she said. "I think the paper will encourage people to look into future systems in more detail." <|im_end|>

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2,664

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Various cancer cells have been demonstrated to have the capacity to form plasmonic gold nanoparticles when chloroauric acid is introduced to their cellular microenvironment. But their biomedical applications are limited, particularly considering the millimolar concentrations and longer incubation period of ionic gold. Here, we describe a simplistic method of intracellular biomineralization to produce plasmonic gold nanoparticles at micromolar concentrations within 30 min of application utilizing polyethylene glycol as delivery vector for ionic gold. We have characterized this process for intracellular gold nanoparticle formation, which progressively accumulates proteins as the ionic gold clusters migrate to the nucleus. This nano-vectorized application of ionic gold emphasizes its potential biomedical opportunities while reducing the quantity of ionic gold and required incubation time. To demonstrate its biomedical potential, we further induce in-situ biosynthesis of gold nanoparticles within MCF7 tumor mouse xenografts which is followed by its photothermal remediation. Introduction Gold nanoparticles have been extensively utilized for biological applications due to their simplistic and tunable chemistry which provides the ability to control and modify size, morphology, and surface functionality; combined with their morphology-dependent 1 , 2 , 3 , 4 . Typically, generating gold nanoparticles require, at the minimum, chloroauric acid as a precursor material and a reducing agent for catalyzing the reductive nucleation. Variations in the reducing agent molecule as well as reaction conditions (e.g. pH, temperature, incubation time) will result in different morphologies, sizes, and functionalities of the resulting nanoparticles 5 , 6 , 7 , 8 . For biomedical applications, these variations in morphology, size, and functionality are directly correlated to their cellular internalization 9 , 10 , 11 , biodistribution, biological half-life 11 , 12 , 13 , renal secretion 11 , 12 , 13 , 14 , 15 , and plasmon optical properties 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 . Because of their plasmon-optical properties, gold nanoparticles are inherently theranostic, providing imaging contrast through near infrared (NIR) 16 , 17 , 15 , 16 , fluorescence 18 , 19 , X-Ray 20 , 21 , photoacoustic 22 , 23 , 24 , and Raman enhancement 25 , 26 . This plasmonic optical property therefore allows gold nanoparticles to act as a vehicle to enhance ablative therapies both for photothermal 27 , 28 , and X-ray radiation 29 , 30 , 31 . On the other hand, the bio-inertness of gold nanoparticles combined with the diverse range of applicable reductant molecules has allowed researchers to develop biomimetic gold nanoparticles using biomolecules as scaffolds for its reduction 32 , 33 , 34 , 35 . Therefore, this approach requires no additional steps for bioconjugation since the reducing biomolecules remain attached as capping agents to the formed nanoparticles. Further to this, if cellular machinery are used to generate gold nanoparticles, the resulting plasmon-optical properties could act as a reporter of the affecting cell phenotype. This capability to generate gold nanoparticles via cellular biomolecules has already been demonstrated previously in mammalian cells 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 . The precise mechanism for this cellular bioreduction of gold nanoparticles is not fully understood, however, these treatments have been known to negatively impact cell health through cellular responses via shock and stress-related proteins 42 , decrease in viability 43 , 44 , and even cell fixation 44 . These previous works, wherein ionic gold was applied diffusely to generate gold nanoparticles via cellular mechanisms, could not be directly applied for cellular diagnostics or therapeutics, as the process is so deleterious to cell health and not cell-specific. However, this process of cellular bioreduction forming gold nanoparticles has been marketed as a means for generating biomimetic and biofunctional gold nanoparticles, which could potentially be applied to different physiological systems. One such recent work by A.V. Singh et al. demonstrated the photothermal effects from intracellular gold, reduced in vitro through the addition of prefabricated gold nanoparticle seeds 36 . This work demonstrated that the process of biomineralization could easily be modified through suitable tuning in the recipe of precursor materials. In this work, we hypothesize that if ionic gold are deployed to cells in discrete nanoscaled packets, this can largely reduce the concentration of gold necessary for the reduction, as well as decrease the time frame and overall impact on cell health, thereby broadening its use for diagnostic and therapeutic purposes. Accordingly, a simplistic delivery vehicle has been demonstrated herein for deploying ionic gold, which indicate intracellular nanoparticle formation within a time span of ~30 min, much less than the previous literature reports, with concentrations lower than previous applications, in complete cell media. Additionally, we have identified proteins and their respective subcellular locations involved in the cellular bioreduction of gold nanoparticles providing larger insight into this potential reduction pathway. The process of sequential and progressive reduction of gold nanoparticle has been shown to occur initially via secreted proteins in the extracellular space and finally within the nucleus for terminal reduction. Because this approach has minimal impact on protein expression/integrity and some of the bound proteins are nucleotide binding, there is a strong potential of the developed gold nanoparticles to be used for theranostic application to provide photothermal ablation directly to the nucleotides. Thus, we demonstrate a theranostic application through a MCF-7 cancer xenograft model, wherein fluorescent and photothermally active gold nanoparticles are formed intracellularly to remediate cancer xenografts. Results Vehicle design and characterization for ionic gold delivery For intracellular gold nanoparticle formation, all of the constituents (sans chloroauric acid) are innately present in cellular systems. This intracellular gold nanoparticle formation has been demonstrated previously in mammalian cells, however, only through bulk diffusive treatments, lasting more than 24 h, and typically those are in solutions which contain no cell nutrients (such as DPBS) 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 . These treatment scenarios are", "role": "user" }, { "content": "Dipanjan Pan, professor of chemical, biochemical, and environmental engineering at UMBC, and collaborators published a seminal study in Nature Communications that demonstrates for the first time a method of biosynthesizing plasmonic gold nanoparticles within cancer cells, without the need for conventional bench-top lab methods. It has the potential to notably expand biomedical applications. Conventional laboratory-based synthesis of gold nanoparticles require ionic precursors and reducing agents subjected to varying reaction conditions such as temperature, pH, and time. This leads to variation in nanoparticle size, morphology and functionalities that are directly correlated to their internalization in cells, their residence time in vivo, and clearance. In order to avoid these uncertainties, this work demonstrates that biosynthesis of gold nanoparticles can be achieved efficiently directly in human cells without requiring conventional laboratory methods. The researchers examined how various cancer cells responded to the introduction of chloroauric acid to their cellular microenvironment by forming gold nanoparticles. These nanoparticles generated within the cell can potentially be used for various biomedical applications, including in X-ray imaging and in therapy by destroying abnormal tissue or cells. In the paper, Pan and his team describe their new method of producing these plasmonic gold nanoparticles within cells in minutes, within a cell's nucleus, using polyethylene glycol as a delivery vector for ionic gold. \"We have developed a unique system where gold nanoparticles are reduced by cellular biomolecules and those are able to retain their functionality, including the capacity to guide the remaining cluster to the nucleus,\" says Pan. They also worked to further demonstrate the biomedical potential of this approach by inducing in-situ biosynthesis of gold nanoparticles within a mouse tumor, followed by photothermal remediation of the tumor. Pan explains that the mouse study exemplified how \"the intracellular formation and nuclear migration of these gold nanoparticles presents a highly promising approach for drug delivery application.\" \"Gold is the quintessential noble element that has been used in biomedical applications since its first colloidal synthesis more than three centuries ago,\" Pan notes. \"To appreciate its potential for clinical application, however, the most challenging research ahead of us will be to find new methods of producing these particles with uncompromised reproducibility with functionalities that can promote efficient cellular binding, clearance, and biocompatibility and to assess their long-term term effects on human health. This new study is a small but important step toward that overarching goal.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Various cancer cells have been demonstrated to have the capacity to form plasmonic gold nanoparticles when chloroauric acid is introduced to their cellular microenvironment. But their biomedical applications are limited, particularly considering the millimolar concentrations and longer incubation period of ionic gold. Here, we describe a simplistic method of intracellular biomineralization to produce plasmonic gold nanoparticles at micromolar concentrations within 30 min of application utilizing polyethylene glycol as delivery vector for ionic gold. We have characterized this process for intracellular gold nanoparticle formation, which progressively accumulates proteins as the ionic gold clusters migrate to the nucleus. This nano-vectorized application of ionic gold emphasizes its potential biomedical opportunities while reducing the quantity of ionic gold and required incubation time. To demonstrate its biomedical potential, we further induce in-situ biosynthesis of gold nanoparticles within MCF7 tumor mouse xenografts which is followed by its photothermal remediation. Introduction Gold nanoparticles have been extensively utilized for biological applications due to their simplistic and tunable chemistry which provides the ability to control and modify size, morphology, and surface functionality; combined with their morphology-dependent 1 , 2 , 3 , 4 . Typically, generating gold nanoparticles require, at the minimum, chloroauric acid as a precursor material and a reducing agent for catalyzing the reductive nucleation. Variations in the reducing agent molecule as well as reaction conditions (e.g. pH, temperature, incubation time) will result in different morphologies, sizes, and functionalities of the resulting nanoparticles 5 , 6 , 7 , 8 . For biomedical applications, these variations in morphology, size, and functionality are directly correlated to their cellular internalization 9 , 10 , 11 , biodistribution, biological half-life 11 , 12 , 13 , renal secretion 11 , 12 , 13 , 14 , 15 , and plasmon optical properties 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 . Because of their plasmon-optical properties, gold nanoparticles are inherently theranostic, providing imaging contrast through near infrared (NIR) 16 , 17 , 15 , 16 , fluorescence 18 , 19 , X-Ray 20 , 21 , photoacoustic 22 , 23 , 24 , and Raman enhancement 25 , 26 . This plasmonic optical property therefore allows gold nanoparticles to act as a vehicle to enhance ablative therapies both for photothermal 27 , 28 , and X-ray radiation 29 , 30 , 31 . On the other hand, the bio-inertness of gold nanoparticles combined with the diverse range of applicable reductant molecules has allowed researchers to develop biomimetic gold nanoparticles using biomolecules as scaffolds for its reduction 32 , 33 , 34 , 35 . Therefore, this approach requires no additional steps for bioconjugation since the reducing biomolecules remain attached as capping agents to the formed nanoparticles. Further to this, if cellular machinery are used to generate gold nanoparticles, the resulting plasmon-optical properties could act as a reporter of the affecting cell phenotype. This capability to generate gold nanoparticles via cellular biomolecules has already been demonstrated previously in mammalian cells 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 . The precise mechanism for this cellular bioreduction of gold nanoparticles is not fully understood, however, these treatments have been known to negatively impact cell health through cellular responses via shock and stress-related proteins 42 , decrease in viability 43 , 44 , and even cell fixation 44 . These previous works, wherein ionic gold was applied diffusely to generate gold nanoparticles via cellular mechanisms, could not be directly applied for cellular diagnostics or therapeutics, as the process is so deleterious to cell health and not cell-specific. However, this process of cellular bioreduction forming gold nanoparticles has been marketed as a means for generating biomimetic and biofunctional gold nanoparticles, which could potentially be applied to different physiological systems. One such recent work by A.V. Singh et al. demonstrated the photothermal effects from intracellular gold, reduced in vitro through the addition of prefabricated gold nanoparticle seeds 36 . This work demonstrated that the process of biomineralization could easily be modified through suitable tuning in the recipe of precursor materials. In this work, we hypothesize that if ionic gold are deployed to cells in discrete nanoscaled packets, this can largely reduce the concentration of gold necessary for the reduction, as well as decrease the time frame and overall impact on cell health, thereby broadening its use for diagnostic and therapeutic purposes. Accordingly, a simplistic delivery vehicle has been demonstrated herein for deploying ionic gold, which indicate intracellular nanoparticle formation within a time span of ~30 min, much less than the previous literature reports, with concentrations lower than previous applications, in complete cell media. Additionally, we have identified proteins and their respective subcellular locations involved in the cellular bioreduction of gold nanoparticles providing larger insight into this potential reduction pathway. The process of sequential and progressive reduction of gold nanoparticle has been shown to occur initially via secreted proteins in the extracellular space and finally within the nucleus for terminal reduction. Because this approach has minimal impact on protein expression/integrity and some of the bound proteins are nucleotide binding, there is a strong potential of the developed gold nanoparticles to be used for theranostic application to provide photothermal ablation directly to the nucleotides. Thus, we demonstrate a theranostic application through a MCF-7 cancer xenograft model, wherein fluorescent and photothermally active gold nanoparticles are formed intracellularly to remediate cancer xenografts. Results Vehicle design and characterization for ionic gold delivery For intracellular gold nanoparticle formation, all of the constituents (sans chloroauric acid) are innately present in cellular systems. This intracellular gold nanoparticle formation has been demonstrated previously in mammalian cells, however, only through bulk diffusive treatments, lasting more than 24 h, and typically those are in solutions which contain no cell nutrients (such as DPBS) 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 . These treatment scenarios are<|im_end|> <|im_start|>assistant Dipanjan Pan, professor of chemical, biochemical, and environmental engineering at UMBC, and collaborators published a seminal study in Nature Communications that demonstrates for the first time a method of biosynthesizing plasmonic gold nanoparticles within cancer cells, without the need for conventional bench-top lab methods. It has the potential to notably expand biomedical applications. Conventional laboratory-based synthesis of gold nanoparticles require ionic precursors and reducing agents subjected to varying reaction conditions such as temperature, pH, and time. This leads to variation in nanoparticle size, morphology and functionalities that are directly correlated to their internalization in cells, their residence time in vivo, and clearance. In order to avoid these uncertainties, this work demonstrates that biosynthesis of gold nanoparticles can be achieved efficiently directly in human cells without requiring conventional laboratory methods. The researchers examined how various cancer cells responded to the introduction of chloroauric acid to their cellular microenvironment by forming gold nanoparticles. These nanoparticles generated within the cell can potentially be used for various biomedical applications, including in X-ray imaging and in therapy by destroying abnormal tissue or cells. In the paper, Pan and his team describe their new method of producing these plasmonic gold nanoparticles within cells in minutes, within a cell's nucleus, using polyethylene glycol as a delivery vector for ionic gold. "We have developed a unique system where gold nanoparticles are reduced by cellular biomolecules and those are able to retain their functionality, including the capacity to guide the remaining cluster to the nucleus," says Pan. They also worked to further demonstrate the biomedical potential of this approach by inducing in-situ biosynthesis of gold nanoparticles within a mouse tumor, followed by photothermal remediation of the tumor. Pan explains that the mouse study exemplified how "the intracellular formation and nuclear migration of these gold nanoparticles presents a highly promising approach for drug delivery application." "Gold is the quintessential noble element that has been used in biomedical applications since its first colloidal synthesis more than three centuries ago," Pan notes. "To appreciate its potential for clinical application, however, the most challenging research ahead of us will be to find new methods of producing these particles with uncompromised reproducibility with functionalities that can promote efficient cellular binding, clearance, and biocompatibility and to assess their long-term term effects on human health. This new study is a small but important step toward that overarching goal." <|im_end|>

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439, 264, 3445, 369, 24038, 39538, 318, 5411, 323, 17332, 50328, 6761, 94753, 11, 902, 1436, 13893, 387, 9435, 311, 2204, 53194, 6067, 13, 3861, 1778, 3293, 990, 555, 362, 5168, 13, 27992, 1880, 453, 13, 21091, 279, 4604, 91096, 6372, 505, 10805, 65441, 6761, 11, 11293, 304, 55004, 1555, 279, 5369, 315, 19257, 29997, 660, 6761, 76307, 7203, 19595, 220, 1927, 662, 1115, 990, 21091, 430, 279, 1920, 315, 6160, 8129, 3333, 2065, 1436, 6847, 387, 11041, 1555, 14791, 42438, 304, 279, 11363, 315, 71261, 7384, 13, 763, 420, 990, 11, 584, 22601, 27985, 430, 422, 220, 21427, 6761, 527, 27167, 311, 7917, 304, 44279, 20622, 437, 26294, 28133, 11, 420, 649, 14090, 8108, 279, 20545, 315, 6761, 5995, 369, 279, 14278, 11, 439, 1664, 439, 18979, 279, 892, 4124, 323, 8244, 5536, 389, 2849, 2890, 11, 28592, 7353, 6147, 1202, 1005, 369, 15439, 323, 37471, 10096, 13, 63909, 11, 264, 78630, 9889, 7458, 706, 1027, 21091, 36881, 369, 61417, 220, 21427, 6761, 11, 902, 13519, 10805, 65441, 76307, 7203, 18488, 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1,854

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Background Traditionally, studies investigating diet and health associations have focused on single nutrients. However, key nutrients co-exist in many common foods, and studies focusing solely on individual nutrients may obscure their combined effects on cardiovascular disease (CVD) and all-cause mortality. We aimed to identify food-based dietary patterns which operate through excess energy intake and explain high variability in energy density, free sugars, saturated fat, and fiber intakes and to investigate their association with total and fatal CVD and all-cause mortality. Methods Detailed dietary data was collected using a 24-h online dietary assessment on two or more occasions ( n = 116,806). We used reduced rank regression to derive dietary patterns explaining the maximum variance. Multivariable Cox-proportional hazards models were used to investigate prospective associations with all-cause mortality and fatal and non-fatal CVD. Results Over an average of 4.9 years of follow-up, 4245 cases of total CVD, 838 cases of fatal CVD, and 3629 cases of all-cause mortality occurred. Two dietary patterns were retained that jointly explained 63% of variation in energy density, free sugars, saturated fat, and fiber intakes in total. The main dietary pattern was characterized by high intakes of chocolate and confectionery, butter and low-fiber bread, and low intakes of fresh fruit and vegetables. There was a positive linear association between the dietary pattern and total CVD [hazard ratio (HR) per z- score 1.07, 95% confidence interval (CI) 1.04–1.09; HR total CVD 1.40, 95% CI 1.31–1.50, and HR all-cause mortality 1.37, 95% CI 1.27–1.47 in highest quintile]. A second dietary pattern was characterized by a higher intakes of sugar-sweetened beverages, fruit juice, and table sugar/preserves. There was a non-linear association with total CVD risk and all-cause mortality, with increased risk in the highest quintile [HR total CVD 1.14, 95% CI 1.07–1.22; HR all-cause mortality 1.11, 95% CI 1.03–1.19]. Conclusions We identified dietary patterns which are associated with increased risk of CVD and all-cause mortality. These results help identify specific foods and beverages which are major contributors to unhealthy dietary patterns and provide evidence to underpin food-based dietary advice to reduce health risks. Peer Review reports Background Reducing the burden of cardiovascular disease (CVD) is a top public health priority in the UK and worldwide [ 1 ]. A poor diet is a major contributor to morbidity and premature mortality, especially CVD [ 2 , 3 ], in part by promoting excess weight, but also by raising total cholesterol and low-density lipoproteins concentrations (LDL) and increasing the risk of diabetes and hypertension [ 3 ]. Traditionally, the vast majority of epidemiological studies investigating diet and health associations have usually focused on single nutrients and this evidence is reflected in current dietary recommendations [ 4 , 5 , 6 ]. These emphasize the importance of achieving and maintaining a healthy weight, reductions in saturated fatty acids (SFAs) and free sugars [ 7 , 8 ], and increases in dietary fiber [ 5 ]. High dietary energy density and free sugars are associated with increased risk of weight gain [ 8 ] which can further increase CVD and mortality risk [ 8 , 9 ], while SFAs increase total blood cholesterol and LDL [ 10 , 11 ]. However, other recent meta-analyses and observational studies have not found evidence for a beneficial effect of reducing SFA intake on CVD and total mortality [ 12 , 13 ], or found protective effects against stroke [ 14 ]. Dietary fiber may lower the risk of CVD, through improved glucose control and lower serum cholesterol concentration [ 15 ]. However, despite years of public health efforts, population dietary change has been slow [ 1 , 16 ]. This may reflect in part the difficulties of translating present dietary recommendations into food-based public health advice [ 17 ], and some existing recommendations are not universally echoed across countries [ 18 ]. The public have frequently been confused by apparently conflicting messages, for example about the importance of reducing saturated fat or free sugars [ 12 ], without recognizing that these nutrients frequently co-exist in foods and that the consequence may be a diet that is high in both saturated fats and free sugars and they may have synergistic effects on health. Dietary guidelines which focus on foods rather than individual nutrient recommendations could help avoid confusion and avoid inadvertent increases in one nutrient of concern at the expense of another. Despite the inclusion of some food-based recommendations in recent dietary guidelines (especially regarding fruits, vegetables, dairy), nutrient-based advice still remains the most common, often co-existing with food-based guidance, as seen in the latest release of the Dietary Guidelines for Americans 2020–2025 [ 6 ]. Increasingly, researchers have sought to characterize complex dietary patterns using either a priori (based on adherence to a specific patterns, e.g., Mediterranean diet, or a score which reflects overall dietary quality) [ 19 ] or a posteriori (based on the observed dietary intake using empirical methods such as factor analysis or principal component analysis (PCA)) [ 20 , 21 ]. Reduced rank regression (RRR) is a data-dimension reduction technique that aims to identify the combination of food groups that explain the maximum amount of variation in a set of response variables (e.g., nutrients) hypothesized to be on the causal pathway between diet and health outcomes. This approach can test a priori hypotheses of the pathophysiology of disease [ 22 ]. To our knowledge, only six longitudinal cohort studies have examined overall CVD risk and/or all-cause mortality using RRR, but all included smaller populations and none was focused in the UK (Additional file 1 : Table S1). This population-specificity is important given that dietary patterns can vary substantially even when nutrient intakes are broadly similar, owing to cultural differences in food preference. Using data from the UK Biobank study, we aimed to identify food-based dietary patterns explaining the variability in known dietary risk factors which operate through excess energy intake, such as energy density, free sugars, saturated fat, and low fiber intakes, and to investigate their association with total and fatal", "role": "user" }, { "content": "Two common dietary patterns identified in British adults, which include high intakes of chocolate and confectionary, may be associated with an increased risk of cardiovascular disease and death in middle-age, according to a study published in the open access journal BMC Medicine. Carmen Piernas, the corresponding author said: \"Cardiovascular disease is one of the main causes of death and disability in the UK and poor diet is a major contributor to this. The most common dietary guidelines are based on the nutrients found in foods rather than foods themselves and this can be confusing for the public. Our findings help identify specific foods and beverages that are commonly eaten in Britain and that may increase the risk of cardiovascular disease and mortality.\" Researchers from the University of Oxford, UK identified two diets that were associated with an increased risk of cardiovascular disease and death in middle-age in Britain. The first was high in chocolate, confectionary, butter and white bread and low in fresh fruit and vegetables. The second was high in sugar-sweetened beverages, fruit juice, chocolate, confectionary, table sugar and preserves and low in butter and higher-fat cheese. The researchers found that those whose diet included higher amounts of chocolate, confectionary, butter and white bread, were more likely to be male, younger, experiencing economic deprivation, current smokers, less physically active, living with obesity or have hypertension compared to those whose diet did not include high amounts of these foods. In this group, individuals who were younger than 60 years old or living with overweight or obesity had a higher risk of cardiovascular disease than individuals who were older than 60 years or not living with overweight or obesity. Those whose diet was high in sugar-sweetened beverages, fruit juice and preserves were found to have an increased risk for cardiovascular disease and mortality, even though they also tended to be physically active and less likely to be current smokers or living with obesity, hypertension, diabetes or high cholesterol, than those who did not eat this diet. Women, individuals who were younger than 60 years old or who lived with obesity in particular had a higher risk of cardiovascular disease, if they consumed a diet high in these foods. To examine the effects of diet on the risk of cardiovascular disease and mortality, the authors analysed data collected from 116,806 adults from England, Scotland and Wales who were recruited to the UK Biobank between 2006 and 2010. Participants were aged between 37 and 73 years old, with an average age of 56 years old. Participants reported the food they ate during the previous 24 hours on between two and five occasions. The researchers then identified the nutrients and food groups eaten by participants. The incidence of cardiovascular disease and mortality was calculated using hospital admission and death registry records until 2017 and 2020, respectively. The authors caution that the observational nature of the study does not allow for conclusions about a causal relationship between diet, cardiovascular disease and mortality. Additionally, as dietary data was taken from individual 24 hour assessments rather than a continuous period of time, it may not be representative of participants' lifetime diets. Future research could investigate the potential reasons for the associations between the two diets investigated in this study and cardiovascular disease and mortality. Carmen Piernas said: \"Our research suggests that eating less chocolate, confectionery, butter, low-fibre bread, sugar-sweetened beverages, fruit juice, table sugar and preserves could be associated with a lower risk of cardiovascular disease or death during middle-age. This is consistent with previous research which has suggested that eating foods that contain less sugar and fewer calories may be associated with a lower risk of cardiovascular disease. The findings of this study could be used to create food-based dietary advice that could help people eat more healthily and reduce their risk of cardiovascular disease.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Background Traditionally, studies investigating diet and health associations have focused on single nutrients. However, key nutrients co-exist in many common foods, and studies focusing solely on individual nutrients may obscure their combined effects on cardiovascular disease (CVD) and all-cause mortality. We aimed to identify food-based dietary patterns which operate through excess energy intake and explain high variability in energy density, free sugars, saturated fat, and fiber intakes and to investigate their association with total and fatal CVD and all-cause mortality. Methods Detailed dietary data was collected using a 24-h online dietary assessment on two or more occasions ( n = 116,806). We used reduced rank regression to derive dietary patterns explaining the maximum variance. Multivariable Cox-proportional hazards models were used to investigate prospective associations with all-cause mortality and fatal and non-fatal CVD. Results Over an average of 4.9 years of follow-up, 4245 cases of total CVD, 838 cases of fatal CVD, and 3629 cases of all-cause mortality occurred. Two dietary patterns were retained that jointly explained 63% of variation in energy density, free sugars, saturated fat, and fiber intakes in total. The main dietary pattern was characterized by high intakes of chocolate and confectionery, butter and low-fiber bread, and low intakes of fresh fruit and vegetables. There was a positive linear association between the dietary pattern and total CVD [hazard ratio (HR) per z- score 1.07, 95% confidence interval (CI) 1.04–1.09; HR total CVD 1.40, 95% CI 1.31–1.50, and HR all-cause mortality 1.37, 95% CI 1.27–1.47 in highest quintile]. A second dietary pattern was characterized by a higher intakes of sugar-sweetened beverages, fruit juice, and table sugar/preserves. There was a non-linear association with total CVD risk and all-cause mortality, with increased risk in the highest quintile [HR total CVD 1.14, 95% CI 1.07–1.22; HR all-cause mortality 1.11, 95% CI 1.03–1.19]. Conclusions We identified dietary patterns which are associated with increased risk of CVD and all-cause mortality. These results help identify specific foods and beverages which are major contributors to unhealthy dietary patterns and provide evidence to underpin food-based dietary advice to reduce health risks. Peer Review reports Background Reducing the burden of cardiovascular disease (CVD) is a top public health priority in the UK and worldwide [ 1 ]. A poor diet is a major contributor to morbidity and premature mortality, especially CVD [ 2 , 3 ], in part by promoting excess weight, but also by raising total cholesterol and low-density lipoproteins concentrations (LDL) and increasing the risk of diabetes and hypertension [ 3 ]. Traditionally, the vast majority of epidemiological studies investigating diet and health associations have usually focused on single nutrients and this evidence is reflected in current dietary recommendations [ 4 , 5 , 6 ]. These emphasize the importance of achieving and maintaining a healthy weight, reductions in saturated fatty acids (SFAs) and free sugars [ 7 , 8 ], and increases in dietary fiber [ 5 ]. High dietary energy density and free sugars are associated with increased risk of weight gain [ 8 ] which can further increase CVD and mortality risk [ 8 , 9 ], while SFAs increase total blood cholesterol and LDL [ 10 , 11 ]. However, other recent meta-analyses and observational studies have not found evidence for a beneficial effect of reducing SFA intake on CVD and total mortality [ 12 , 13 ], or found protective effects against stroke [ 14 ]. Dietary fiber may lower the risk of CVD, through improved glucose control and lower serum cholesterol concentration [ 15 ]. However, despite years of public health efforts, population dietary change has been slow [ 1 , 16 ]. This may reflect in part the difficulties of translating present dietary recommendations into food-based public health advice [ 17 ], and some existing recommendations are not universally echoed across countries [ 18 ]. The public have frequently been confused by apparently conflicting messages, for example about the importance of reducing saturated fat or free sugars [ 12 ], without recognizing that these nutrients frequently co-exist in foods and that the consequence may be a diet that is high in both saturated fats and free sugars and they may have synergistic effects on health. Dietary guidelines which focus on foods rather than individual nutrient recommendations could help avoid confusion and avoid inadvertent increases in one nutrient of concern at the expense of another. Despite the inclusion of some food-based recommendations in recent dietary guidelines (especially regarding fruits, vegetables, dairy), nutrient-based advice still remains the most common, often co-existing with food-based guidance, as seen in the latest release of the Dietary Guidelines for Americans 2020–2025 [ 6 ]. Increasingly, researchers have sought to characterize complex dietary patterns using either a priori (based on adherence to a specific patterns, e.g., Mediterranean diet, or a score which reflects overall dietary quality) [ 19 ] or a posteriori (based on the observed dietary intake using empirical methods such as factor analysis or principal component analysis (PCA)) [ 20 , 21 ]. Reduced rank regression (RRR) is a data-dimension reduction technique that aims to identify the combination of food groups that explain the maximum amount of variation in a set of response variables (e.g., nutrients) hypothesized to be on the causal pathway between diet and health outcomes. This approach can test a priori hypotheses of the pathophysiology of disease [ 22 ]. To our knowledge, only six longitudinal cohort studies have examined overall CVD risk and/or all-cause mortality using RRR, but all included smaller populations and none was focused in the UK (Additional file 1 : Table S1). This population-specificity is important given that dietary patterns can vary substantially even when nutrient intakes are broadly similar, owing to cultural differences in food preference. Using data from the UK Biobank study, we aimed to identify food-based dietary patterns explaining the variability in known dietary risk factors which operate through excess energy intake, such as energy density, free sugars, saturated fat, and low fiber intakes, and to investigate their association with total and fatal<|im_end|> <|im_start|>assistant Two common dietary patterns identified in British adults, which include high intakes of chocolate and confectionary, may be associated with an increased risk of cardiovascular disease and death in middle-age, according to a study published in the open access journal BMC Medicine. Carmen Piernas, the corresponding author said: "Cardiovascular disease is one of the main causes of death and disability in the UK and poor diet is a major contributor to this. The most common dietary guidelines are based on the nutrients found in foods rather than foods themselves and this can be confusing for the public. Our findings help identify specific foods and beverages that are commonly eaten in Britain and that may increase the risk of cardiovascular disease and mortality." Researchers from the University of Oxford, UK identified two diets that were associated with an increased risk of cardiovascular disease and death in middle-age in Britain. The first was high in chocolate, confectionary, butter and white bread and low in fresh fruit and vegetables. The second was high in sugar-sweetened beverages, fruit juice, chocolate, confectionary, table sugar and preserves and low in butter and higher-fat cheese. The researchers found that those whose diet included higher amounts of chocolate, confectionary, butter and white bread, were more likely to be male, younger, experiencing economic deprivation, current smokers, less physically active, living with obesity or have hypertension compared to those whose diet did not include high amounts of these foods. In this group, individuals who were younger than 60 years old or living with overweight or obesity had a higher risk of cardiovascular disease than individuals who were older than 60 years or not living with overweight or obesity. Those whose diet was high in sugar-sweetened beverages, fruit juice and preserves were found to have an increased risk for cardiovascular disease and mortality, even though they also tended to be physically active and less likely to be current smokers or living with obesity, hypertension, diabetes or high cholesterol, than those who did not eat this diet. Women, individuals who were younger than 60 years old or who lived with obesity in particular had a higher risk of cardiovascular disease, if they consumed a diet high in these foods. To examine the effects of diet on the risk of cardiovascular disease and mortality, the authors analysed data collected from 116,806 adults from England, Scotland and Wales who were recruited to the UK Biobank between 2006 and 2010. Participants were aged between 37 and 73 years old, with an average age of 56 years old. Participants reported the food they ate during the previous 24 hours on between two and five occasions. The researchers then identified the nutrients and food groups eaten by participants. The incidence of cardiovascular disease and mortality was calculated using hospital admission and death registry records until 2017 and 2020, respectively. The authors caution that the observational nature of the study does not allow for conclusions about a causal relationship between diet, cardiovascular disease and mortality. Additionally, as dietary data was taken from individual 24 hour assessments rather than a continuous period of time, it may not be representative of participants' lifetime diets. Future research could investigate the potential reasons for the associations between the two diets investigated in this study and cardiovascular disease and mortality. Carmen Piernas said: "Our research suggests that eating less chocolate, confectionery, butter, low-fibre bread, sugar-sweetened beverages, fruit juice, table sugar and preserves could be associated with a lower risk of cardiovascular disease or death during middle-age. This is consistent with previous research which has suggested that eating foods that contain less sugar and fewer calories may be associated with a lower risk of cardiovascular disease. The findings of this study could be used to create food-based dietary advice that could help people eat more healthily and reduce their risk of cardiovascular disease." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Spin manipulation in a semiconductor offers a new paradigm for device operation beyond Moore's law. Ferromagnetic metals are ideal contacts for spin injection and detection, but the intervening tunnel barrier required to accommodate the large difference in conductivity introduces defects, trapped charge and material interdiffusion, which severely compromise performance. Here, we show that single-layer graphene successfully circumvents the classic issue of conductivity mismatch between a metal and a semiconductor for electrical spin injection and detection, providing a highly uniform, chemically inert and thermally robust tunnel barrier. We demonstrate electrical generation and detection of spin accumulation in silicon above room temperature, and show that the contact resistance–area products are two to three orders of magnitude lower than those achieved with oxide tunnel barriers on silicon substrates with identical doping levels. Our results identify a new route to low resistance–area product spin-polarized contacts, a key requirement for semiconductor spintronic devices that rely on two-terminal magnetoresistance, including spin-based transistors, logic and memory. Main The spin angular momentum of an electron has been identified as a potential new state variable in semiconductor device operation for use beyond Moore's law 1 , 2 , 3 , and new paradigms for spin-based device operation have been proposed and modelled 4 , 5 , 6 , 7 , 8 . Ferromagnetic metals, which exhibit intrinsically spin-polarized electron populations, high Curie temperatures and low coercive fields, are seemingly ideal candidates as contacts for electrical injection and detection of spin currents in the semiconductor channel. However, the large difference in conductivity between metal and semiconductor makes this impossible 9 , 10 , 11 . A tunnel barrier between the ferromagnetic metal and the semiconductor has been identified as a potential solution to this problem 9 , 10 , 11 , and extensive effort has therefore been directed towards developing appropriate tunnel barriers for spin contacts. Most work has focused on a reverse-biased ferromagnetic Schottky barrier 12 , 13 or an insulating oxide layer such as Al 2 O 3 or MgO with a ferromagnetic metal contact 14 , 15 , 16 , 17 . For example, we have recently shown that SiO 2 , an oxide widely used in the electronics industry, serves as an excellent spin tunnel barrier in ferromagnetic metal/SiO 2 /Si structures 18 , although the oxide thickness required to achieve a good spin signal resulted in high contact resistance–area products. An ideal tunnel barrier should exhibit the following key material characteristics: a uniform and planar habit with well-controlled thickness, minimal defect/trapped charge density, a low resistance–area product for minimal power consumption, and compatibility with both the ferromagnetic metal and the semiconductor of choice, ensuring minimal diffusion to/from the surrounding materials at the temperatures required for device processing. Metal Schottky barriers and oxide layers are susceptible to interdiffusion, interface defects and trapped charge, which have been shown to compromise spin injection/transport/detection. Ferromagnetic metals readily form silicides even at room temperature 19 , and diffusion of the ferromagnetic species into the silicon creates magnetic scattering sites, limiting spin diffusion lengths and spin lifetimes in the silicon. Even a well developed and widely utilized oxide such as SiO 2 is known to have defects and trapped or mobile charge, which limit both charge and spin-based performance. Such approaches also result in contacts with high resistance–area products, and previous work has shown that smaller resistance–area products within a window of values are essential for efficient spin injection/detection 11 , 20 , in addition to the more obvious benefit of reduced power consumption. Graphene as a tunnel barrier Graphene, an atomically thin honeycomb lattice of carbon, offers a compelling alternative. Although it is very conductive in plane 21 , 22 , it exhibits poor conductivity perpendicular to the plane 23 . Its sp 2 bonding results in a highly uniform, defect-free layer that is chemically inert, thermally robust, and essentially impervious to diffusion 24 . We have recently demonstrated that single-layer graphene can be used as a tunnel barrier between two metals in a magnetic tunnel junction, albeit with modest tunnel magnetoresistance 25 . Here, we show that a ferromagnetic metal/monolayer graphene contact serves as a spin-polarized tunnel barrier contact that successfully circumvents the classic metal/semiconductor conductivity mismatch issue for electrical spin injection into a semiconductor, and enables one to achieve contact resistance–area products that fall within the critical window of values required for practical devices 11 , 20 . We demonstrate electrical injection and detection of spin accumulation in silicon above room temperature, and show that the corresponding spin lifetimes correlate with the silicon donor concentration, confirming that the spin accumulation measured occurs in the silicon and not in the graphene or interface trap states. The resistance–area products are three orders of magnitude lower than those achieved with oxide tunnel barrier contacts on silicon substrates with identical doping levels. These results enable the realization of semiconductor spintronic devices such as spin-based transistors, logic and memory that rely on local magnetoresistance 4 , 5 , 6 , 7 . Graphene was grown by low-pressure chemical vapour deposition (CVD) within copper foil ‘enclosures’ according to ref. 26 , and transferred onto hydrogen-passivated n-type silicon (001) substrates (electron density n = 6 × 10 19 and 1 × 10 19 cm −3 ). Raman spectroscopy confirmed that the graphene was of high quality with minimal defects 27 . During device fabrication, care was taken to isolate the conducting edges 28 of the graphene by burying them in a layer of sputter-deposited Si 3 N 4 ( Fig. 1 ). Ni 80 Fe 20 was then sputter-deposited onto the graphene through vias in the Si 3 N 4 , defining the spin-polarized contacts, followed by another layer of Si 3 N 4 , and then electron-beam evaporation of ohmic Ti/Au contacts and bond pads. A schematic of the devices is provided in Fig. 1 a,b. Electrical measurements were performed in a cryogen-free cryostat and electromagnet set-up using a three-terminal configuration, as depicted in Fig. 1 a and described in the following. Further", "role": "user" }, { "content": "(Phys.org)—Scientists at the Naval Research Laboratory have demonstrated that graphene, a single layer of carbon atoms in a honeycomb lattice, can serve as a low resistance spin-polarized tunnel barrier contact which successfully enables spin injection/detection in silicon from a ferromagnetic metal. The graphene provides a highly uniform, chemically inert and thermally robust tunnel barrier free of defects and trap states which plague oxide barriers. This discovery clears an important hurdle to the development of future semiconductor spintronic devices, that is, devices which rely on manipulating the electron's spin rather than its charge for low-power, high-speed information processing beyond the traditional size scaling of Moore's Law. The research results are reported in a paper published in Nature Nanotechnology on September 30, 2012. Ferromagnetic metals, such as iron or permalloy, have intrinsically spin-polarized electron populations (more \"spin-up\" electrons than \"spin-down\", see figure), and are thus ideal contacts for injection and detection of spin in a semiconductor. An intervening tunnel barrier is required to avoid saturation of both semiconductor spin channels by the much larger metal conductivity - this would otherwise result in no net spin polarization in the semiconductor. However, the oxide barriers typically used (such as Al2O3 or MgO) introduce defects, trapped charge and interdiffusion, and have resistances, which are too high - all of these factors severely impact the performance. To solve this problem, the NRL research team, led by Dr. Berend Jonker, used single layer graphene as the tunnel barrier. This novel approach utilizes a defect resistant, chemically inert and stable material with well-controlled thickness to achieve a low resistance spin contact compatible with both the ferromagnetic metal and semiconductor of choice. These qualities insure minimal diffusion to/ and from the surrounding materials at temperatures required for device manufacturing. The research team used this approach to demonstrate electrical generation and detection of spin accumulation in silicon above room temperature, and showed that the contact resistance-area products are 100 to 1000 times lower than achieved with oxide tunnel barriers on silicon substrates with identical doping levels. These results identify a new route to low resistance-area product spin-polarized contacts, a key requirement for semiconductor spintronic devices that rely upon two-terminal magnetoresistance, including spin-based transistors, logic and memory, explains NRL's Dr. Berend Jonker. In looking to the future, the NRL team suggests that the use of multilayer graphene in such structures may provide much higher values of the tunnel spin polarization due to band structure derived spin filtering effects which have been predicted for selected ferromagnetic metal / multi-layer graphene structures. This increase would improve the performance of semiconductor spintronic devices by providing higher signal to noise ratios and corresponding operating speeds, advancing the techological applications of silicon spintronics. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Spin manipulation in a semiconductor offers a new paradigm for device operation beyond Moore's law. Ferromagnetic metals are ideal contacts for spin injection and detection, but the intervening tunnel barrier required to accommodate the large difference in conductivity introduces defects, trapped charge and material interdiffusion, which severely compromise performance. Here, we show that single-layer graphene successfully circumvents the classic issue of conductivity mismatch between a metal and a semiconductor for electrical spin injection and detection, providing a highly uniform, chemically inert and thermally robust tunnel barrier. We demonstrate electrical generation and detection of spin accumulation in silicon above room temperature, and show that the contact resistance–area products are two to three orders of magnitude lower than those achieved with oxide tunnel barriers on silicon substrates with identical doping levels. Our results identify a new route to low resistance–area product spin-polarized contacts, a key requirement for semiconductor spintronic devices that rely on two-terminal magnetoresistance, including spin-based transistors, logic and memory. Main The spin angular momentum of an electron has been identified as a potential new state variable in semiconductor device operation for use beyond Moore's law 1 , 2 , 3 , and new paradigms for spin-based device operation have been proposed and modelled 4 , 5 , 6 , 7 , 8 . Ferromagnetic metals, which exhibit intrinsically spin-polarized electron populations, high Curie temperatures and low coercive fields, are seemingly ideal candidates as contacts for electrical injection and detection of spin currents in the semiconductor channel. However, the large difference in conductivity between metal and semiconductor makes this impossible 9 , 10 , 11 . A tunnel barrier between the ferromagnetic metal and the semiconductor has been identified as a potential solution to this problem 9 , 10 , 11 , and extensive effort has therefore been directed towards developing appropriate tunnel barriers for spin contacts. Most work has focused on a reverse-biased ferromagnetic Schottky barrier 12 , 13 or an insulating oxide layer such as Al 2 O 3 or MgO with a ferromagnetic metal contact 14 , 15 , 16 , 17 . For example, we have recently shown that SiO 2 , an oxide widely used in the electronics industry, serves as an excellent spin tunnel barrier in ferromagnetic metal/SiO 2 /Si structures 18 , although the oxide thickness required to achieve a good spin signal resulted in high contact resistance–area products. An ideal tunnel barrier should exhibit the following key material characteristics: a uniform and planar habit with well-controlled thickness, minimal defect/trapped charge density, a low resistance–area product for minimal power consumption, and compatibility with both the ferromagnetic metal and the semiconductor of choice, ensuring minimal diffusion to/from the surrounding materials at the temperatures required for device processing. Metal Schottky barriers and oxide layers are susceptible to interdiffusion, interface defects and trapped charge, which have been shown to compromise spin injection/transport/detection. Ferromagnetic metals readily form silicides even at room temperature 19 , and diffusion of the ferromagnetic species into the silicon creates magnetic scattering sites, limiting spin diffusion lengths and spin lifetimes in the silicon. Even a well developed and widely utilized oxide such as SiO 2 is known to have defects and trapped or mobile charge, which limit both charge and spin-based performance. Such approaches also result in contacts with high resistance–area products, and previous work has shown that smaller resistance–area products within a window of values are essential for efficient spin injection/detection 11 , 20 , in addition to the more obvious benefit of reduced power consumption. Graphene as a tunnel barrier Graphene, an atomically thin honeycomb lattice of carbon, offers a compelling alternative. Although it is very conductive in plane 21 , 22 , it exhibits poor conductivity perpendicular to the plane 23 . Its sp 2 bonding results in a highly uniform, defect-free layer that is chemically inert, thermally robust, and essentially impervious to diffusion 24 . We have recently demonstrated that single-layer graphene can be used as a tunnel barrier between two metals in a magnetic tunnel junction, albeit with modest tunnel magnetoresistance 25 . Here, we show that a ferromagnetic metal/monolayer graphene contact serves as a spin-polarized tunnel barrier contact that successfully circumvents the classic metal/semiconductor conductivity mismatch issue for electrical spin injection into a semiconductor, and enables one to achieve contact resistance–area products that fall within the critical window of values required for practical devices 11 , 20 . We demonstrate electrical injection and detection of spin accumulation in silicon above room temperature, and show that the corresponding spin lifetimes correlate with the silicon donor concentration, confirming that the spin accumulation measured occurs in the silicon and not in the graphene or interface trap states. The resistance–area products are three orders of magnitude lower than those achieved with oxide tunnel barrier contacts on silicon substrates with identical doping levels. These results enable the realization of semiconductor spintronic devices such as spin-based transistors, logic and memory that rely on local magnetoresistance 4 , 5 , 6 , 7 . Graphene was grown by low-pressure chemical vapour deposition (CVD) within copper foil ‘enclosures’ according to ref. 26 , and transferred onto hydrogen-passivated n-type silicon (001) substrates (electron density n = 6 × 10 19 and 1 × 10 19 cm −3 ). Raman spectroscopy confirmed that the graphene was of high quality with minimal defects 27 . During device fabrication, care was taken to isolate the conducting edges 28 of the graphene by burying them in a layer of sputter-deposited Si 3 N 4 ( Fig. 1 ). Ni 80 Fe 20 was then sputter-deposited onto the graphene through vias in the Si 3 N 4 , defining the spin-polarized contacts, followed by another layer of Si 3 N 4 , and then electron-beam evaporation of ohmic Ti/Au contacts and bond pads. A schematic of the devices is provided in Fig. 1 a,b. Electrical measurements were performed in a cryogen-free cryostat and electromagnet set-up using a three-terminal configuration, as depicted in Fig. 1 a and described in the following. Further<|im_end|> <|im_start|>assistant (Phys.org)—Scientists at the Naval Research Laboratory have demonstrated that graphene, a single layer of carbon atoms in a honeycomb lattice, can serve as a low resistance spin-polarized tunnel barrier contact which successfully enables spin injection/detection in silicon from a ferromagnetic metal. The graphene provides a highly uniform, chemically inert and thermally robust tunnel barrier free of defects and trap states which plague oxide barriers. This discovery clears an important hurdle to the development of future semiconductor spintronic devices, that is, devices which rely on manipulating the electron's spin rather than its charge for low-power, high-speed information processing beyond the traditional size scaling of Moore's Law. The research results are reported in a paper published in Nature Nanotechnology on September 30, 2012. Ferromagnetic metals, such as iron or permalloy, have intrinsically spin-polarized electron populations (more "spin-up" electrons than "spin-down", see figure), and are thus ideal contacts for injection and detection of spin in a semiconductor. An intervening tunnel barrier is required to avoid saturation of both semiconductor spin channels by the much larger metal conductivity - this would otherwise result in no net spin polarization in the semiconductor. However, the oxide barriers typically used (such as Al2O3 or MgO) introduce defects, trapped charge and interdiffusion, and have resistances, which are too high - all of these factors severely impact the performance. To solve this problem, the NRL research team, led by Dr. Berend Jonker, used single layer graphene as the tunnel barrier. This novel approach utilizes a defect resistant, chemically inert and stable material with well-controlled thickness to achieve a low resistance spin contact compatible with both the ferromagnetic metal and semiconductor of choice. These qualities insure minimal diffusion to/ and from the surrounding materials at temperatures required for device manufacturing. The research team used this approach to demonstrate electrical generation and detection of spin accumulation in silicon above room temperature, and showed that the contact resistance-area products are 100 to 1000 times lower than achieved with oxide tunnel barriers on silicon substrates with identical doping levels. These results identify a new route to low resistance-area product spin-polarized contacts, a key requirement for semiconductor spintronic devices that rely upon two-terminal magnetoresistance, including spin-based transistors, logic and memory, explains NRL's Dr. Berend Jonker. In looking to the future, the NRL team suggests that the use of multilayer graphene in such structures may provide much higher values of the tunnel spin polarization due to band structure derived spin filtering effects which have been predicted for selected ferromagnetic metal / multi-layer graphene structures. This increase would improve the performance of semiconductor spintronic devices by providing higher signal to noise ratios and corresponding operating speeds, advancing the techological applications of silicon spintronics. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Torque sensors such as the torsion balance enabled the first determination of the gravitational constant by Henri Cavendish 1 and the discovery of Coulomb’s law. Torque sensors are also widely used in studying small-scale magnetism 2 , 3 , the Casimir effect 4 and other applications 5 . Great effort has been made to improve the torque detection sensitivity by nanofabrication and cryogenic cooling. Until now, the most sensitive torque sensor has achieved a remarkable sensitivity of 2.9 × 10 −24 N m Hz −1/2 at millikelvin temperatures in a dilution refrigerator 6 . Here, we show a torque sensor reaching sensitivity of (4.2 ± 1.2) × 10 −27 N m Hz −1/2 at room temperature. It is created by an optically levitated nanoparticle in vacuum. Our system does not require complex nanofabrication. Moreover, we drive a nanoparticle to rotate at a record high speed beyond 5 GHz (300 billion r.p.m.). Our calculations show that this system will be able to detect the long sought after vacuum friction 7 , 8 , 9 , 10 near a surface under realistic conditions. The optically levitated nanorotor will also have applications in studying nanoscale magnetism 2 , 3 and the quantum geometric phase 11 . Main Recent developments in levitated optomechanics provide a new paradigm for sensing and precision measurements 12 , 13 , 14 . Recently, the centre-of-mass motion of an optically levitated nanoparticle in vacuum was cooled to microkelvin temperatures 15 . Experimental control of the rotation 16 , 17 , 18 , 19 , 20 , 21 , torsional vibration 18 , 22 and precession 23 of a levitated nanoparticle in vacuum have also been demonstrated. A levitated nanoparticle has been used to study nonequilibrium thermodynamics at small scales 24 , 25 , 26 , 27 and demonstrate force sensing at the zeptonewton scale 13 . It was proposed that an optically levitated nonspherical nanoparticle in vacuum would be an ultrasensitive torque sensor 22 and could study anisotropic surface interactions 28 . While optically levitated torque sensors have attracted a lot of interest 17 , 18 , 23 , an experimental demonstration of a torque sensitivity better than that of the state-of-the-art nanofabricated torque sensor (10 −24 N m Hz −1/2 ) (ref. 6 ) has not been reported. In this experiment, we optically trap a silica nanoparticle (a nanosphere or a nanodumbbell) in a vacuum chamber using a tightly focused 1,550-nm laser (Fig. 1 ). The polarization of the trapping laser is controlled with a quarter waveplate. An additional 1,020-nm laser is used to apply an external torque that will be measured. The trapping laser passes a collimation lens and is guided to balanced photodetectors that monitor the rotational, torsional and centre-of-mass motions of the levitated nanoparticle. When the nanoparticle rotates, it changes the polarization of the trapping laser slightly, which is monitored with a balanced photodetector after a polarizing beam splitter (Fig. 1a ). The signal of the balanced detector is sent to a spectrum analyser to measure the rotation frequency. Fig. 1: Experimental schematic and rotation spectra of an optically levitated nanoparticle. a , A silica nanoparticle (NP) is levitated in vacuum with a 500-mW, 1,550-nm laser tightly focused by an objective lens (OBJ) with a numerical aperture of 0.85. An additional 1,020-nm laser is used to apply an external torque on the nanoparticle. The polarization of each laser is controlled with a quarter waveplate ( \$\\lambda\$ /4). After the collimation lens, the trapping laser is directed to detectors for monitoring the motion of the trapped nanoparticle. DM, dichroic mirror; \$\\lambda\$ /2, half waveplate; PBS, polarizing beam splitter; and DET, balanced photodetector. Inset: scanning electron microscope images of a silica nanosphere (left) and a silica nanodumbbell (right). The scale bar is 200 nm for both images. b , A measured PSD of the rotation of an optically levitated nanoparticle at \$1{0}^{-4}\$ torr. The frequency of the PSD peak is twice the rotation frequency of the nanoparticle. c , A spectrogram (time trace) of the rotation PSD of an optically levitated nanoparticle recorded for 100 s. The first vertical line corresponds to the PSD shown in b . a.u., arbitrary units. Source data Full size image Once a nanoparticle is trapped in a linearly polarized 1,550-nm laser, we collect the power spectral density (PSD) signals of its motion at 10 torr to verify its geometry 18 . Figure 2a shows the PSDs of the motion of a nanosphere. The ratio of the damping rates in directions perpendicular and parallel to the electric field of the laser is measured to be \$1.02\\pm 0.01\$ , which is in reasonable agreement with the expected value of one for a sphere. There is no observable torsional peak for the nanosphere. On the other hand, the PSD of a nanodumbbell has a clear torsional peak as shown in Fig. 2b . The measured damping ratio is \$1.23\\pm 0.02\$ for this nanodumbbell, which is comparable with the expected value of 1.27 (ref. 18 ). Fig. 2: Vibration and rotation of optically levitated silica nanoparticles. a , b , PSDs of the motions of a silica nanosphere ( a ) and a nanodumbbell ( b ) trapped by a linearly polarized laser at 10 torr. The ratios of the damping rates in directions perpendicular ( \$y\$ ) and parallel ( \$x\$ ) to the electric field of the laser are \$1.02\\pm 0.01\$ and \$1.23\\pm 0.02\$ for the nanosphere ( a ) and nanodumbbell ( b ), respectively. Also, an additional torsional peak appears for the nanodumbbell that does not show for the nanosphere. The \$z\$ axis is parallel to the propagating direction of the laser. c , The rotation frequencies of a nanodumbbell (blue squares) and a silica nanosphere (green circles) in a circularly polarized optical tweezer as a function of the air pressure. The solid lines show the \$1/p\$ dependence of the rotation frequencies, where \$p\$ is the air pressure. The diameters of the nanosphere and the nanodumbbell are about 150 nm.", "role": "user" }, { "content": "A team of physicists at Purdue University has built the most sensitive torque measuring device ever. In their paper published in the journal Nature Nanotechnology, the team describes their new device and outline how it might be used. Torque is a twisting force that often leads to rotation. Devices built to measure torque in a system take many forms and come in many sizes. In recent years, scientists have been working on ways to downsize torque sensors with the goal of measuring very small amounts of torque. Tiny devices that use nanofabrication and cryogenic cooling have been developed to study such things as the Casimir effect and small-scale magnetism. Prior to this new effort, the most sensitive torque sensor had achieved a sensitivity of 2.9 × 10−24 N m Hz−1/2 at millikelvin temperatures. The team at Purdue set themselves the goal of breaking that record. The new device consisted of a silica nanoparticle suspended inside of a vacuum chamber by a 500-mW, 1,550-nm laser beam. The team applied torque to the nanoparticle by firing a pulsating, circularly polarized 1,020-nm laser beam at it for 100 seconds at a time. The researchers used a quarter waveplate to control polarization. The rotating waves in the electromagnet beam imparted a twisting action on the nanoparticle, making it spin at 300 billion rpm—the fastest man-made rotor ever built. The team was able to measure the amount of torque in the device by measuring how much the particle's spin speed changed during the on and off cycles using an optical sensor. The researchers point out that their system, unlike others being developed, did not require intricate nanofabrication. Using the device, the researchers were able to measure torque to a quadrillionth of a newton-meter—making it approximately 700 times as sensitive as the previous record holder. They claim that their device will be the first to measure vacuum friction—in which quantum mechanics suggests an object spinning in a vacuum experiences drag due to electromagnetic fields that constantly appear and disappear. The team also claims that the device could be used for nanoscale magnetism research and for studying the quantum geometric phase. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Torque sensors such as the torsion balance enabled the first determination of the gravitational constant by Henri Cavendish 1 and the discovery of Coulomb’s law. Torque sensors are also widely used in studying small-scale magnetism 2 , 3 , the Casimir effect 4 and other applications 5 . Great effort has been made to improve the torque detection sensitivity by nanofabrication and cryogenic cooling. Until now, the most sensitive torque sensor has achieved a remarkable sensitivity of 2.9 × 10 −24 N m Hz −1/2 at millikelvin temperatures in a dilution refrigerator 6 . Here, we show a torque sensor reaching sensitivity of (4.2 ± 1.2) × 10 −27 N m Hz −1/2 at room temperature. It is created by an optically levitated nanoparticle in vacuum. Our system does not require complex nanofabrication. Moreover, we drive a nanoparticle to rotate at a record high speed beyond 5 GHz (300 billion r.p.m.). Our calculations show that this system will be able to detect the long sought after vacuum friction 7 , 8 , 9 , 10 near a surface under realistic conditions. The optically levitated nanorotor will also have applications in studying nanoscale magnetism 2 , 3 and the quantum geometric phase 11 . Main Recent developments in levitated optomechanics provide a new paradigm for sensing and precision measurements 12 , 13 , 14 . Recently, the centre-of-mass motion of an optically levitated nanoparticle in vacuum was cooled to microkelvin temperatures 15 . Experimental control of the rotation 16 , 17 , 18 , 19 , 20 , 21 , torsional vibration 18 , 22 and precession 23 of a levitated nanoparticle in vacuum have also been demonstrated. A levitated nanoparticle has been used to study nonequilibrium thermodynamics at small scales 24 , 25 , 26 , 27 and demonstrate force sensing at the zeptonewton scale 13 . It was proposed that an optically levitated nonspherical nanoparticle in vacuum would be an ultrasensitive torque sensor 22 and could study anisotropic surface interactions 28 . While optically levitated torque sensors have attracted a lot of interest 17 , 18 , 23 , an experimental demonstration of a torque sensitivity better than that of the state-of-the-art nanofabricated torque sensor (10 −24 N m Hz −1/2 ) (ref. 6 ) has not been reported. In this experiment, we optically trap a silica nanoparticle (a nanosphere or a nanodumbbell) in a vacuum chamber using a tightly focused 1,550-nm laser (Fig. 1 ). The polarization of the trapping laser is controlled with a quarter waveplate. An additional 1,020-nm laser is used to apply an external torque that will be measured. The trapping laser passes a collimation lens and is guided to balanced photodetectors that monitor the rotational, torsional and centre-of-mass motions of the levitated nanoparticle. When the nanoparticle rotates, it changes the polarization of the trapping laser slightly, which is monitored with a balanced photodetector after a polarizing beam splitter (Fig. 1a ). The signal of the balanced detector is sent to a spectrum analyser to measure the rotation frequency. Fig. 1: Experimental schematic and rotation spectra of an optically levitated nanoparticle. a , A silica nanoparticle (NP) is levitated in vacuum with a 500-mW, 1,550-nm laser tightly focused by an objective lens (OBJ) with a numerical aperture of 0.85. An additional 1,020-nm laser is used to apply an external torque on the nanoparticle. The polarization of each laser is controlled with a quarter waveplate ( $\lambda$ /4). After the collimation lens, the trapping laser is directed to detectors for monitoring the motion of the trapped nanoparticle. DM, dichroic mirror; $\lambda$ /2, half waveplate; PBS, polarizing beam splitter; and DET, balanced photodetector. Inset: scanning electron microscope images of a silica nanosphere (left) and a silica nanodumbbell (right). The scale bar is 200 nm for both images. b , A measured PSD of the rotation of an optically levitated nanoparticle at $1{0}^{-4}$ torr. The frequency of the PSD peak is twice the rotation frequency of the nanoparticle. c , A spectrogram (time trace) of the rotation PSD of an optically levitated nanoparticle recorded for 100 s. The first vertical line corresponds to the PSD shown in b . a.u., arbitrary units. Source data Full size image Once a nanoparticle is trapped in a linearly polarized 1,550-nm laser, we collect the power spectral density (PSD) signals of its motion at 10 torr to verify its geometry 18 . Figure 2a shows the PSDs of the motion of a nanosphere. The ratio of the damping rates in directions perpendicular and parallel to the electric field of the laser is measured to be $1.02\pm 0.01$ , which is in reasonable agreement with the expected value of one for a sphere. There is no observable torsional peak for the nanosphere. On the other hand, the PSD of a nanodumbbell has a clear torsional peak as shown in Fig. 2b . The measured damping ratio is $1.23\pm 0.02$ for this nanodumbbell, which is comparable with the expected value of 1.27 (ref. 18 ). Fig. 2: Vibration and rotation of optically levitated silica nanoparticles. a , b , PSDs of the motions of a silica nanosphere ( a ) and a nanodumbbell ( b ) trapped by a linearly polarized laser at 10 torr. The ratios of the damping rates in directions perpendicular ( $y$ ) and parallel ( $x$ ) to the electric field of the laser are $1.02\pm 0.01$ and $1.23\pm 0.02$ for the nanosphere ( a ) and nanodumbbell ( b ), respectively. Also, an additional torsional peak appears for the nanodumbbell that does not show for the nanosphere. The $z$ axis is parallel to the propagating direction of the laser. c , The rotation frequencies of a nanodumbbell (blue squares) and a silica nanosphere (green circles) in a circularly polarized optical tweezer as a function of the air pressure. The solid lines show the $1/p$ dependence of the rotation frequencies, where $p$ is the air pressure. The diameters of the nanosphere and the nanodumbbell are about 150 nm.<|im_end|> <|im_start|>assistant A team of physicists at Purdue University has built the most sensitive torque measuring device ever. In their paper published in the journal Nature Nanotechnology, the team describes their new device and outline how it might be used. Torque is a twisting force that often leads to rotation. Devices built to measure torque in a system take many forms and come in many sizes. In recent years, scientists have been working on ways to downsize torque sensors with the goal of measuring very small amounts of torque. Tiny devices that use nanofabrication and cryogenic cooling have been developed to study such things as the Casimir effect and small-scale magnetism. Prior to this new effort, the most sensitive torque sensor had achieved a sensitivity of 2.9 × 10−24 N m Hz−1/2 at millikelvin temperatures. The team at Purdue set themselves the goal of breaking that record. The new device consisted of a silica nanoparticle suspended inside of a vacuum chamber by a 500-mW, 1,550-nm laser beam. The team applied torque to the nanoparticle by firing a pulsating, circularly polarized 1,020-nm laser beam at it for 100 seconds at a time. The researchers used a quarter waveplate to control polarization. The rotating waves in the electromagnet beam imparted a twisting action on the nanoparticle, making it spin at 300 billion rpm—the fastest man-made rotor ever built. The team was able to measure the amount of torque in the device by measuring how much the particle's spin speed changed during the on and off cycles using an optical sensor. The researchers point out that their system, unlike others being developed, did not require intricate nanofabrication. Using the device, the researchers were able to measure torque to a quadrillionth of a newton-meter—making it approximately 700 times as sensitive as the previous record holder. They claim that their device will be the first to measure vacuum friction—in which quantum mechanics suggests an object spinning in a vacuum experiences drag due to electromagnetic fields that constantly appear and disappear. The team also claims that the device could be used for nanoscale magnetism research and for studying the quantum geometric phase. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Hippocampal place cells represent the cellular substrate of episodic memory. Place cell ensembles reorganize to support learning but must also maintain stable representations to facilitate memory recall. Despite extensive research, the learning-related role of place cell dynamics in health and disease remains elusive. Using chronic two-photon Ca 2+ imaging in hippocampal area CA1 of wild-type and Df(16)A +/− mice, an animal model of 22q11.2 deletion syndrome, one of the most common genetic risk factors for cognitive dysfunction and schizophrenia, we found that goal-oriented learning in wild-type mice was supported by stable spatial maps and robust remapping of place fields toward the goal location. Df(16)A +/− mice showed a significant learning deficit accompanied by reduced spatial map stability and the absence of goal-directed place cell reorganization. These results expand our understanding of the hippocampal ensemble dynamics supporting cognitive flexibility and demonstrate their importance in a model of 22q11.2-associated cognitive dysfunction. Main Episodic memory, the encoding of personal experience organized in space and time, is a fundamental aspect of cognition 1 . Episodic memory dysfunctions are highly debilitating symptoms of various neurological, cognitive and psychiatric disorders, including schizophrenia (SCZ) 2 . Cognitive deficits in general appear to be the strongest predictor of SCZ patients' functional outcomes 3 ; however, neural circuit dynamics supporting episodic memory and the manner in which they fail in SCZ remains poorly understood. To this end, we studied a well characterized animal model of cognitive dysfunction and SCZ, the Df(16)A +/− mouse model of the 22q11.2 deletion syndrome (22q11.2DS) 4 . The well documented role of the hippocampus in episodic and spatial memory 1 , 5 , 6 , 7 , combined with morphological and functional alterations of the hippocampus in SCZ patients 8 , 9 , collectively points to a central role of this brain area in the pathophysiology of cognitive memory deficits in SCZ 10 . In particular, physiological and morphological alterations have been reported specifically in area CA1—the hippocampal output node—in SCZ patients 11 , suggesting a potentially primary role for this area in disease pathophysiology. Principal cells throughout the hippocampus are selectively active in specific locations within an environment (place cells) 12 . Place cells collectively form cognitive maps representing spatial components of episodic memories 6 , 13 , the long-term stability of which is a widely posited prerequisite for reliable learning 14 , 15 , 16 , 17 , 18 . Place cell map stability is affected by attentional and task demands, and place cell maps also incorporate goal-related information during learning 15 , 19 , 20 , 21 , 22 , 23 , 24 , 25 . In particular, reorganizing place cell maps to enrich goal locations was found to predict memory performance 26 . Therefore, monitoring place cell ensemble dynamics during goal-directed learning may provide a tractable entry point for understanding how episodic memory deficits arise from genetic mutations associated with SCZ. Two-photon Ca 2+ imaging in awake mice during head-fixed behaviors allows for the chronic recording of physiological activity from individual place cells, as well as their ensemble activity as a whole. By tracking the activity of place cell populations in Df(16)A +/− mice and wild-type (WT) littermates through each phase of a goal-oriented learning task, we identified specific aspects of place cell map stability that evolved with learning, as well as alterations in the stability and plasticity of these cognitive maps in the mutant mice. Our findings highlight reduced stability and impaired goal-directed reorganization of hippocampal place cells as fundamental components of 22q11.2-deletion-linked cognitive dysfunction. Results Df(16)A +/− mice are impaired in a head-fixed goal-oriented learning task upon changes in both context and reward location To facilitate chronic recording from hippocampal CA1 place cells during learning, we designed a head-fixed variation of goal-oriented learning (GOL; Fig. 1a,b and Online Methods ) tasks that have been previously used in freely moving rodents 26 , allowing for chronic two-photon functional Ca 2+ imaging. Our task consisted of three sessions per day, with 3 days (d) for each of three conditions (27 total sessions per mouse). In Condition I, mice learned a single fixed reward location, then remembered that location while the environmental context and local cues were altered (Online Methods ) in Condition II, and the reward was moved in Condition III. Figure 1: Differences in learning performance between Df(16)A +/− and WT mice in GOL task. ( a ) The three conditions of the GOL task. Mice spend 3 d in each condition. Contexts A and A′ are composed of different auditory, visual, olfactory and tactile cues (Online Methods ), varied between Condition I and Condition II. The location of the hidden reward (blue circles, Rew 1 and Rew 2) is switched between Condition II and Condition III. Water-deprived mice trained to run on a linear treadmill were introduced to a novel environmental context (Context A) consisting of a feature-rich fabric belt and specific background with nonspatial odor, tones and blinking light patterns (Context A) on the first day of the experiment. Operant water rewards were available at a single unmarked location on the belt (Rew 1 in Conditions I and II; Rew 2 in Condition III); if the mouse licked in the correct location they received a water reward, but no water was administered if they did not lick in the reward location or if they licked outside the reward location (Condition I, 3 d and 3 sessions per d). The time of each lick as well as the position of the mouse on the treadmill were recorded both to determine when to deliver water rewards and to provide a readout of learning. To test the ability of mice to adjust to changes in the task conditions, mice were exposed to an altered context (Context A′: same sequence of belt materials, shuffled local cues, different nonspatial odor, tone and light; Online Methods ), while maintaining the same reward location relative to the belt fabric sequence (Condition II, 3 d and 3 sessions per d). During the last part", "role": "user" }, { "content": "A team of Columbia scientists has found that disruptions to the brain's center for spatial navigation—its internal GPS—result in some of the severe memory deficits seen in schizophrenia. The new study in mouse models of the disorder marks the first time that schizophrenia's effects have been observed in the behavior of living animals—and at the level of individual brain cells—with such high-resolution, precision and clarity. The findings offer a promising entry point for attacking a near-universal and debilitating symptom of schizophrenia, memory deficits, which has thus far withstood all forms of treatment. The results of this study were published today in Nature Neuroscience. \"An almost intractably complex disorder, schizophrenia is nearly impossible to fully treat—in large part because it acts as two disorders in one,\" said Joseph Gogos, MD, PhD, a principal investigator at Columbia's Mortimer B. Zuckerman Mind Brain Behavior Institute and the paper's co-senior author. \"On one hand, you have paranoia, hallucinations and delusions; while on the other you have severe memory deficits. Antipsychotic drugs, which treat the first class of symptoms, are entirely ineffective when dealing with the second. The reasons for this are simple: we do not yet understand what happens in the brains of schizophrenia patients. Cracking schizophrenia's code must therefore start with deciphering its biological origins, says Dr. Gogos, who is also professor of physiology, cellular biophysics and neuroscience at Columbia University Medical Center (CUMC). This has led to a recent focus on the memory impairments that are so common among schizophrenia patients. In this new study, Dr. Gogos teamed up with Attila Losonczy, MD, PhD, a fellow Zuckerman Institute principal investigator, to investigate episodic memory, which is severely impaired in cases of schizophrenia. \"Episodic memory is the brain's repository of information about the past; a way of traveling backwards to recall a specific moment in time,\" said Dr. Losonczy, who was also a senior author. \"This type of memory is critical for learning about and functioning in everyday life.\" For this study, the team focused on a brain region called CA1, located in the hippocampus, which plays a role in both navigation and in episodic memory. Physical alterations to CA1 have been previously reported among schizophrenia patients. CA1 is home to place cells, which collectively form internal maps in the brain critical for navigating one's present surroundings. The CA1 place cells also encode the spatial aspects of episodic memories, such as where you were when you last saw your best friend, or the place your parents always kept the holiday decorations. Video showing neuronal activity during memory formation in the brain of a mouse genetically modified to mimic schizophrenia. Credit: Jeffrey Zaremba/Losonczy Lab/Columbia's Zuckerman Institute \"Recent advances in imaging technologies now give us the power to watch the activity of hundreds of place cells in the CA1 in real time while an animal forms and recalls memories,\" said Dr. Losonczy, who is also an associate professor of neuroscience at CUMC. \"We developed experiments to record CA1 activity in mice that were genetically modified to mimic schizophrenia, and compared them to normal, healthy mice.\" The researchers placed both groups of animals on a treadmill under a high-resolution, two-photon microscope, where they were exposed to a variety of sights, sounds and smells (including a water reward placed at unmarked locations on the treadmill). These experiments were designed to test the animals' ability to navigate a new environment, remember how to navigate a familiar one and adapt quickly when that environment was altered. The two groups of mice showed striking differences in behavior and in cell activity. While both groups could successfully navigate a new environment, the schizophrenia-like mice had more trouble remembering familiar environments from day to day, as well as adapting when aspects of that environment changed. By simultaneously tracking the animals' place cells via the two-photon microscope, the team spotted the difference. \"When the healthy mice approached something familiar, such as water, their place cells fired with increasing intensity, and then quieted down as the animals moved away,\" explained Dr. Losonczy. \"And when we moved the location of the water, and gave the animals a chance to relearn where it was, the activity of their place cells reflected the new location.\" But the brains of the schizophrenia-like mice were different. Their place cells did not shift when the water reward was moved. The brain cells' lack of adaptability, the scientists argue, could reflect a key and more general mechanism of memory deficits in schizophrenia. It could also represent a new target for drug intervention. \"These studies are helping to build an understanding of a disorder that has remained a biological mystery,\" said Dr. Gogos. \"By pinpointing schizophrenia's many causes, we are opening up multiple points of intervention to slow, halt and even prevent the disorder—which stands to dramatically improve the lives of patients and their families.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Hippocampal place cells represent the cellular substrate of episodic memory. Place cell ensembles reorganize to support learning but must also maintain stable representations to facilitate memory recall. Despite extensive research, the learning-related role of place cell dynamics in health and disease remains elusive. Using chronic two-photon Ca 2+ imaging in hippocampal area CA1 of wild-type and Df(16)A +/− mice, an animal model of 22q11.2 deletion syndrome, one of the most common genetic risk factors for cognitive dysfunction and schizophrenia, we found that goal-oriented learning in wild-type mice was supported by stable spatial maps and robust remapping of place fields toward the goal location. Df(16)A +/− mice showed a significant learning deficit accompanied by reduced spatial map stability and the absence of goal-directed place cell reorganization. These results expand our understanding of the hippocampal ensemble dynamics supporting cognitive flexibility and demonstrate their importance in a model of 22q11.2-associated cognitive dysfunction. Main Episodic memory, the encoding of personal experience organized in space and time, is a fundamental aspect of cognition 1 . Episodic memory dysfunctions are highly debilitating symptoms of various neurological, cognitive and psychiatric disorders, including schizophrenia (SCZ) 2 . Cognitive deficits in general appear to be the strongest predictor of SCZ patients' functional outcomes 3 ; however, neural circuit dynamics supporting episodic memory and the manner in which they fail in SCZ remains poorly understood. To this end, we studied a well characterized animal model of cognitive dysfunction and SCZ, the Df(16)A +/− mouse model of the 22q11.2 deletion syndrome (22q11.2DS) 4 . The well documented role of the hippocampus in episodic and spatial memory 1 , 5 , 6 , 7 , combined with morphological and functional alterations of the hippocampus in SCZ patients 8 , 9 , collectively points to a central role of this brain area in the pathophysiology of cognitive memory deficits in SCZ 10 . In particular, physiological and morphological alterations have been reported specifically in area CA1—the hippocampal output node—in SCZ patients 11 , suggesting a potentially primary role for this area in disease pathophysiology. Principal cells throughout the hippocampus are selectively active in specific locations within an environment (place cells) 12 . Place cells collectively form cognitive maps representing spatial components of episodic memories 6 , 13 , the long-term stability of which is a widely posited prerequisite for reliable learning 14 , 15 , 16 , 17 , 18 . Place cell map stability is affected by attentional and task demands, and place cell maps also incorporate goal-related information during learning 15 , 19 , 20 , 21 , 22 , 23 , 24 , 25 . In particular, reorganizing place cell maps to enrich goal locations was found to predict memory performance 26 . Therefore, monitoring place cell ensemble dynamics during goal-directed learning may provide a tractable entry point for understanding how episodic memory deficits arise from genetic mutations associated with SCZ. Two-photon Ca 2+ imaging in awake mice during head-fixed behaviors allows for the chronic recording of physiological activity from individual place cells, as well as their ensemble activity as a whole. By tracking the activity of place cell populations in Df(16)A +/− mice and wild-type (WT) littermates through each phase of a goal-oriented learning task, we identified specific aspects of place cell map stability that evolved with learning, as well as alterations in the stability and plasticity of these cognitive maps in the mutant mice. Our findings highlight reduced stability and impaired goal-directed reorganization of hippocampal place cells as fundamental components of 22q11.2-deletion-linked cognitive dysfunction. Results Df(16)A +/− mice are impaired in a head-fixed goal-oriented learning task upon changes in both context and reward location To facilitate chronic recording from hippocampal CA1 place cells during learning, we designed a head-fixed variation of goal-oriented learning (GOL; Fig. 1a,b and Online Methods ) tasks that have been previously used in freely moving rodents 26 , allowing for chronic two-photon functional Ca 2+ imaging. Our task consisted of three sessions per day, with 3 days (d) for each of three conditions (27 total sessions per mouse). In Condition I, mice learned a single fixed reward location, then remembered that location while the environmental context and local cues were altered (Online Methods ) in Condition II, and the reward was moved in Condition III. Figure 1: Differences in learning performance between Df(16)A +/− and WT mice in GOL task. ( a ) The three conditions of the GOL task. Mice spend 3 d in each condition. Contexts A and A′ are composed of different auditory, visual, olfactory and tactile cues (Online Methods ), varied between Condition I and Condition II. The location of the hidden reward (blue circles, Rew 1 and Rew 2) is switched between Condition II and Condition III. Water-deprived mice trained to run on a linear treadmill were introduced to a novel environmental context (Context A) consisting of a feature-rich fabric belt and specific background with nonspatial odor, tones and blinking light patterns (Context A) on the first day of the experiment. Operant water rewards were available at a single unmarked location on the belt (Rew 1 in Conditions I and II; Rew 2 in Condition III); if the mouse licked in the correct location they received a water reward, but no water was administered if they did not lick in the reward location or if they licked outside the reward location (Condition I, 3 d and 3 sessions per d). The time of each lick as well as the position of the mouse on the treadmill were recorded both to determine when to deliver water rewards and to provide a readout of learning. To test the ability of mice to adjust to changes in the task conditions, mice were exposed to an altered context (Context A′: same sequence of belt materials, shuffled local cues, different nonspatial odor, tone and light; Online Methods ), while maintaining the same reward location relative to the belt fabric sequence (Condition II, 3 d and 3 sessions per d). During the last part<|im_end|> <|im_start|>assistant A team of Columbia scientists has found that disruptions to the brain's center for spatial navigation—its internal GPS—result in some of the severe memory deficits seen in schizophrenia. The new study in mouse models of the disorder marks the first time that schizophrenia's effects have been observed in the behavior of living animals—and at the level of individual brain cells—with such high-resolution, precision and clarity. The findings offer a promising entry point for attacking a near-universal and debilitating symptom of schizophrenia, memory deficits, which has thus far withstood all forms of treatment. The results of this study were published today in Nature Neuroscience. "An almost intractably complex disorder, schizophrenia is nearly impossible to fully treat—in large part because it acts as two disorders in one," said Joseph Gogos, MD, PhD, a principal investigator at Columbia's Mortimer B. Zuckerman Mind Brain Behavior Institute and the paper's co-senior author. "On one hand, you have paranoia, hallucinations and delusions; while on the other you have severe memory deficits. Antipsychotic drugs, which treat the first class of symptoms, are entirely ineffective when dealing with the second. The reasons for this are simple: we do not yet understand what happens in the brains of schizophrenia patients. Cracking schizophrenia's code must therefore start with deciphering its biological origins, says Dr. Gogos, who is also professor of physiology, cellular biophysics and neuroscience at Columbia University Medical Center (CUMC). This has led to a recent focus on the memory impairments that are so common among schizophrenia patients. In this new study, Dr. Gogos teamed up with Attila Losonczy, MD, PhD, a fellow Zuckerman Institute principal investigator, to investigate episodic memory, which is severely impaired in cases of schizophrenia. "Episodic memory is the brain's repository of information about the past; a way of traveling backwards to recall a specific moment in time," said Dr. Losonczy, who was also a senior author. "This type of memory is critical for learning about and functioning in everyday life." For this study, the team focused on a brain region called CA1, located in the hippocampus, which plays a role in both navigation and in episodic memory. Physical alterations to CA1 have been previously reported among schizophrenia patients. CA1 is home to place cells, which collectively form internal maps in the brain critical for navigating one's present surroundings. The CA1 place cells also encode the spatial aspects of episodic memories, such as where you were when you last saw your best friend, or the place your parents always kept the holiday decorations. Video showing neuronal activity during memory formation in the brain of a mouse genetically modified to mimic schizophrenia. Credit: Jeffrey Zaremba/Losonczy Lab/Columbia's Zuckerman Institute "Recent advances in imaging technologies now give us the power to watch the activity of hundreds of place cells in the CA1 in real time while an animal forms and recalls memories," said Dr. Losonczy, who is also an associate professor of neuroscience at CUMC. "We developed experiments to record CA1 activity in mice that were genetically modified to mimic schizophrenia, and compared them to normal, healthy mice." The researchers placed both groups of animals on a treadmill under a high-resolution, two-photon microscope, where they were exposed to a variety of sights, sounds and smells (including a water reward placed at unmarked locations on the treadmill). These experiments were designed to test the animals' ability to navigate a new environment, remember how to navigate a familiar one and adapt quickly when that environment was altered. The two groups of mice showed striking differences in behavior and in cell activity. While both groups could successfully navigate a new environment, the schizophrenia-like mice had more trouble remembering familiar environments from day to day, as well as adapting when aspects of that environment changed. By simultaneously tracking the animals' place cells via the two-photon microscope, the team spotted the difference. "When the healthy mice approached something familiar, such as water, their place cells fired with increasing intensity, and then quieted down as the animals moved away," explained Dr. Losonczy. "And when we moved the location of the water, and gave the animals a chance to relearn where it was, the activity of their place cells reflected the new location." But the brains of the schizophrenia-like mice were different. Their place cells did not shift when the water reward was moved. The brain cells' lack of adaptability, the scientists argue, could reflect a key and more general mechanism of memory deficits in schizophrenia. It could also represent a new target for drug intervention. "These studies are helping to build an understanding of a disorder that has remained a biological mystery," said Dr. Gogos. "By pinpointing schizophrenia's many causes, we are opening up multiple points of intervention to slow, halt and even prevent the disorder—which stands to dramatically improve the lives of patients and their families." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The circadian clock imposes daily rhythms in cell proliferation, metabolism, inflammation and DNA damage response 1 , 2 . Perturbations of these processes are hallmarks of cancer 3 and chronic circadian rhythm disruption predisposes individuals to tumour development 1 , 4 . This raises the hypothesis that pharmacological modulation of the circadian machinery may be an effective therapeutic strategy for combating cancer. REV-ERBs, the nuclear hormone receptors REV-ERBα (also known as NR1D1) and REV-ERBβ (also known as NR1D2), are essential components of the circadian clock 5 , 6 . Here we show that two agonists of REV-ERBs—SR9009 and SR9011—are specifically lethal to cancer cells and oncogene-induced senescent cells, including melanocytic naevi, and have no effect on the viability of normal cells or tissues. The anticancer activity of SR9009 and SR9011 affects a number of oncogenic drivers (such as HRAS, BRAF, PIK3CA and others) and persists in the absence of p53 and under hypoxic conditions. The regulation of autophagy and de novo lipogenesis by SR9009 and SR9011 has a critical role in evoking an apoptotic response in malignant cells. Notably, the selective anticancer properties of these REV-ERB agonists impair glioblastoma growth in vivo and improve survival without causing overt toxicity in mice. These results indicate that pharmacological modulation of circadian regulators is an effective antitumour strategy, identifying a class of anticancer agents with a wide therapeutic window. We propose that REV-ERB agonists are inhibitors of autophagy and de novo lipogenesis, with selective activity towards malignant and benign neoplasms. Main The cell-autonomous circadian clock pleiotropically coordinates a complex network of physiological processes 1 . In both mice and humans, disruption of circadian rhythms increases cancer incidence 1 , 7 . Given the unique ability of the circadian clock to directly control several pathways that are crucial for tumorigenesis 2 , 8 , 9 , 10 , 11 , pharmacological modulation of circadian components may offer promising selective anticancer strategies. REV-ERBs are haem-binding circadian clock components 6 , 12 , 13 that act as repressors of processes involved in tumorigenesis, including metabolism 5 , 14 , 15 , proliferation 16 and inflammation 2 . Binding to tetrapyrrole haem enhances the repressive function of REV-ERBs 13 . The development of the pyrrole derivatives SR9009 and SR9011 14 as specific agonists of REV-ERBs, with potent in vivo activity, prompted us to investigate whether pharmacological activation of these circadian repressors affects cancer cell viability by restraining pathways that are aberrantly activated in cancer. SR9009 had a cytotoxic effect on cancer cells derived from a range of tumour types, namely brain cancer, leukaemia, breast cancer, colon cancer and melanoma ( Fig. 1a, d, g, j, o ). SR9011 displayed similar cytotoxic properties against the same cancer cell lines ( Extended Data Fig. 1a–j ). Notably, SR9009 and SR9011 are effective against tumour cell lines that harbour a range of oncogenic drivers, including HRAS, KRAS, BRAF, PTEN deficiency and β-catenin ( Fig. 1 , Extended Data Fig. 1 ), but have little or no toxic effect on normal cells at comparable concentrations ( Fig. 1a, b , Extended Data Fig. 1a, b ). Therefore, the antitumour activity of REV-ERB agonists is not limited to a single oncogenic driver, but is instead effective against a broad spectrum of tumorigenic pathways. Figure 1: SR9009 is selectively lethal in cancer cell lines driven by different oncogenic signalling. a , SR9009 treatment is cytotoxic specifically in cancer cells (72 h). One-way ANOVA. n indicates biological replicates: astrocytes, n = 12 (mock), n = 12 (2.5 μM), n = 12 (5 μM), n = 15 (10 μM), n = 18 (20 μM); astrocytomas, n = 8 (mock), n = 9 (2.5 μM), n = 10 (5 μM), n = 11 (10 μM) and n = 6 (20 μM), * P = 0.037; and brain-tumour-initiating cells (BTICs), n = 10 (mock), n = 9 (2.5 μM), n = 9 (5 μM), n = 15 (10 μM) and n = 18 (20 μM), * ***P < 0.0001. b , SR9009 treatment impairs the viability of BJ-ELR, but not BJ, cells (proliferation assay, 7 days, 20 μM). LT/ST, large T antigen, small T antigen. c , Expression of REV-ERBs in BJ and BJ-ELR cells; quantitative PCR with reverse transcription (qRT–PCR), n = 3 biologically independent samples, two-tailed Mann–Whitney test. Expression of mRNA shown relative to housekeeper RPLP0 . d , Jurkat cell viability is reduced by SR9009; n = 12 biological replicates, 72 h 20 μM, one-tailed Mann–Whitney test, ****P < 0.0001. e , f , Immunostaining ( e ) and quantification ( f ) of cleaved caspase 3 (Cl. Casp. 3) and TUNEL assays (72 h, 20 μM); in f , n = 5 (mock) and 6 (SR9009) biologically independent samples, one-tailed Mann–Whitney test, cleaved caspase 3 assay, ** P = 0.0022; TUNEL assay, ** P = 0.0022. g , Breast cancer cell line MCF-7 viability is reduced by SR9009; n = 12 (mock) or 8 (SR9009) biological replicates, 72 h 20 μM, one-tailed Mann–Whitney test, ****P < 0.0001. h , i , Immunostaining ( h ) and quantification ( i ) of cleaved caspase 3 and TUNEL assays (72 h, 20 μM). In i , n = 5 biologically independent samples, one-tailed Mann–Whitney test; cleaved caspase 3 assay, ** P = 0.004; TUNEL assay, ** P = 0.004. j , Colon cancer cell line HCT116 viability is reduced by SR9009; n = 8 biological replicates, water-soluble tetrazolium salt (WST-1) assay, 72 h, one-tailed Mann–Whitney test, ****P < 0.0001. k , l , Induction of apoptosis is shown by cleaved caspase 3 and TUNEL staining ( k , 72 h, 20 μM); for quantification in l , n = 8 (mock) or 5 (SR9009) biologically independent samples, one-tailed Mann–Whitney test; cleaved caspase 3 assay, *** P = 0.0008; TUNEL assay ** P = 0.0021. m – o , Prolonged SR9009 treatment eradicates cancer cells (7 days, 20 μM), but does not affect cells that express NR1D1 and NR1D2 shRNA. shNS, non-silencing shRNA. p ,", "role": "user" }, { "content": "Salk researchers have discovered how to curb the growth of cancer cells by blocking the cells' access to certain nutrients. The approach, detailed in a new paper published today in Nature, took advantage of knowledge on how healthy cells use a 24-hour cycle to regulate the production of nutrients and was tested on glioblastoma brain tumors in mice. \"When we block access to these resources, cancer cells starve to death but normal cells are already used to this constraint so they're not affected,\" says Satchidananda Panda, a professor in the Salk Institute's Regulatory Biology Laboratory and lead author of the paper. The circadian cycle, the intrinsic clock that exists in all living things, is known to help control when individual cells produce and use nutrients, among many other functions. Scientists previously discovered that proteins known as REV-ERBα and REV-ERBβ are responsible for turning on and off cells' ability to synthesize fats, as well as their ability to recycle materials—a process called autophagy—throughout the day. In healthy cells, fat synthesis and autophagy are allowed to occur for about 12 hours a day when REV-ERB protein levels remain low. The rest of the time, higher levels of the REV-ERB proteins block the processes so that the cells are not flooded with excessive fat synthesis and recycled nutrients. In the past, researchers developed compounds to activate REV-ERBs in the hopes of stopping fat synthesis to treat certain metabolic diseases. Panda and his colleagues wondered whether activating REV-ERBs would slow cancer growth, since cancer cells heavily rely on the products of both fat synthesis and autophagy to grow. \"While current cancer research was investigating established cancer hallmarks/characteristic we decided to explore something completely new,\" says Research Associate Gabriele Sulli, the paper's first and co-corresponding author. \"Given the importance of the circadian clock in the regulation of many cellular and physiological processes we hypothesize that targeting the circadian clock with drugs may open the way to novel anticancer strategies. This study is very exciting because it sheds light on a new uncharacterized way to treat cancer with very limited toxicity.\" Adds Panda, \"We've always thought about ways to stop cancer cells from dividing. But once they divide, they also have to grow before they can divide again, and to grow they need all these raw materials that are normally in short supply. So cancer cells devise strategies to escape the daily constraints of the circadian clock.\" Salk researchers discover how to curb the growth of cancer cells by activating their biological clocks. Credit: Salk Institute Although cancer cells contain REV-ERB proteins, somehow they remain inactive. Panda's team used two REV-ERB activators that had already been developed—SR9009 and SR9011—in studies on a variety of cancer cells, including those from T cell leukemia, breast cancer, colorectal cancer, melanoma and glioblastoma. In each cell line, treatment with the REV-ERB activators was enough to kill the cells. The same treatment on healthy cells had no effect. \"Activating REV-ERBs seemed to work in all the types of cancer we tried,\" says Panda. \"That makes sense because irrespective of where or how a cancer started, all cancer cells need more nutrients and more recycled materials to build new cells.\" Panda then went on to test the drugs on a new mouse model of glioblastoma recently developed by Inder Verma, a professor in the Salk Institute's Laboratory of Genetics. Once again, the REV-ERB activators were successful at killing cancer cells and stopping tumor growth but seemed not to affect the rest of the mice's cells. Verma says the findings are not only exciting because they point toward existing REV-ERB activators as potential cancer drugs, but also because they help shine light on the importance of the link between the circadian cycle, metabolism and cancer. \"These are all fundamental elements required by all living cells,\" says Verma. \"By affecting REV-ERBs, you get to the heart of how cells grow and proliferate, but there are lots of other ways to get at this as well.\" Verma says his group is planning follow-up studies on how, exactly, the REV-ERB activators alter metabolism, as well as whether they may affect the metabolism of bacteria in the microbiome, the collection of microbes that live in the gut. Panda's team is hoping to study the role of other circadian cycle genes and proteins in cancer. Panda, Verma and coauthor Alan Saghatelian, also a Salk professor, are all members of the Salk Cancer Center, a National Cancer Institute–designated basic research cancer center. Other researchers on the study were Amy Rommel and Matthew J. Kolar of the Salk Institute; Xiaojie Wang and Maksim V. Plikus of the University of California, Irvine; and Francesca Puca of The University of Texas MD Anderson Cancer Center. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The circadian clock imposes daily rhythms in cell proliferation, metabolism, inflammation and DNA damage response 1 , 2 . Perturbations of these processes are hallmarks of cancer 3 and chronic circadian rhythm disruption predisposes individuals to tumour development 1 , 4 . This raises the hypothesis that pharmacological modulation of the circadian machinery may be an effective therapeutic strategy for combating cancer. REV-ERBs, the nuclear hormone receptors REV-ERBα (also known as NR1D1) and REV-ERBβ (also known as NR1D2), are essential components of the circadian clock 5 , 6 . Here we show that two agonists of REV-ERBs—SR9009 and SR9011—are specifically lethal to cancer cells and oncogene-induced senescent cells, including melanocytic naevi, and have no effect on the viability of normal cells or tissues. The anticancer activity of SR9009 and SR9011 affects a number of oncogenic drivers (such as HRAS, BRAF, PIK3CA and others) and persists in the absence of p53 and under hypoxic conditions. The regulation of autophagy and de novo lipogenesis by SR9009 and SR9011 has a critical role in evoking an apoptotic response in malignant cells. Notably, the selective anticancer properties of these REV-ERB agonists impair glioblastoma growth in vivo and improve survival without causing overt toxicity in mice. These results indicate that pharmacological modulation of circadian regulators is an effective antitumour strategy, identifying a class of anticancer agents with a wide therapeutic window. We propose that REV-ERB agonists are inhibitors of autophagy and de novo lipogenesis, with selective activity towards malignant and benign neoplasms. Main The cell-autonomous circadian clock pleiotropically coordinates a complex network of physiological processes 1 . In both mice and humans, disruption of circadian rhythms increases cancer incidence 1 , 7 . Given the unique ability of the circadian clock to directly control several pathways that are crucial for tumorigenesis 2 , 8 , 9 , 10 , 11 , pharmacological modulation of circadian components may offer promising selective anticancer strategies. REV-ERBs are haem-binding circadian clock components 6 , 12 , 13 that act as repressors of processes involved in tumorigenesis, including metabolism 5 , 14 , 15 , proliferation 16 and inflammation 2 . Binding to tetrapyrrole haem enhances the repressive function of REV-ERBs 13 . The development of the pyrrole derivatives SR9009 and SR9011 14 as specific agonists of REV-ERBs, with potent in vivo activity, prompted us to investigate whether pharmacological activation of these circadian repressors affects cancer cell viability by restraining pathways that are aberrantly activated in cancer. SR9009 had a cytotoxic effect on cancer cells derived from a range of tumour types, namely brain cancer, leukaemia, breast cancer, colon cancer and melanoma ( Fig. 1a, d, g, j, o ). SR9011 displayed similar cytotoxic properties against the same cancer cell lines ( Extended Data Fig. 1a–j ). Notably, SR9009 and SR9011 are effective against tumour cell lines that harbour a range of oncogenic drivers, including HRAS, KRAS, BRAF, PTEN deficiency and β-catenin ( Fig. 1 , Extended Data Fig. 1 ), but have little or no toxic effect on normal cells at comparable concentrations ( Fig. 1a, b , Extended Data Fig. 1a, b ). Therefore, the antitumour activity of REV-ERB agonists is not limited to a single oncogenic driver, but is instead effective against a broad spectrum of tumorigenic pathways. Figure 1: SR9009 is selectively lethal in cancer cell lines driven by different oncogenic signalling. a , SR9009 treatment is cytotoxic specifically in cancer cells (72 h). One-way ANOVA. n indicates biological replicates: astrocytes, n = 12 (mock), n = 12 (2.5 μM), n = 12 (5 μM), n = 15 (10 μM), n = 18 (20 μM); astrocytomas, n = 8 (mock), n = 9 (2.5 μM), n = 10 (5 μM), n = 11 (10 μM) and n = 6 (20 μM), * P = 0.037; and brain-tumour-initiating cells (BTICs), n = 10 (mock), n = 9 (2.5 μM), n = 9 (5 μM), n = 15 (10 μM) and n = 18 (20 μM), * ***P < 0.0001. b , SR9009 treatment impairs the viability of BJ-ELR, but not BJ, cells (proliferation assay, 7 days, 20 μM). LT/ST, large T antigen, small T antigen. c , Expression of REV-ERBs in BJ and BJ-ELR cells; quantitative PCR with reverse transcription (qRT–PCR), n = 3 biologically independent samples, two-tailed Mann–Whitney test. Expression of mRNA shown relative to housekeeper RPLP0 . d , Jurkat cell viability is reduced by SR9009; n = 12 biological replicates, 72 h 20 μM, one-tailed Mann–Whitney test, ****P < 0.0001. e , f , Immunostaining ( e ) and quantification ( f ) of cleaved caspase 3 (Cl. Casp. 3) and TUNEL assays (72 h, 20 μM); in f , n = 5 (mock) and 6 (SR9009) biologically independent samples, one-tailed Mann–Whitney test, cleaved caspase 3 assay, ** P = 0.0022; TUNEL assay, ** P = 0.0022. g , Breast cancer cell line MCF-7 viability is reduced by SR9009; n = 12 (mock) or 8 (SR9009) biological replicates, 72 h 20 μM, one-tailed Mann–Whitney test, ****P < 0.0001. h , i , Immunostaining ( h ) and quantification ( i ) of cleaved caspase 3 and TUNEL assays (72 h, 20 μM). In i , n = 5 biologically independent samples, one-tailed Mann–Whitney test; cleaved caspase 3 assay, ** P = 0.004; TUNEL assay, ** P = 0.004. j , Colon cancer cell line HCT116 viability is reduced by SR9009; n = 8 biological replicates, water-soluble tetrazolium salt (WST-1) assay, 72 h, one-tailed Mann–Whitney test, ****P < 0.0001. k , l , Induction of apoptosis is shown by cleaved caspase 3 and TUNEL staining ( k , 72 h, 20 μM); for quantification in l , n = 8 (mock) or 5 (SR9009) biologically independent samples, one-tailed Mann–Whitney test; cleaved caspase 3 assay, *** P = 0.0008; TUNEL assay ** P = 0.0021. m – o , Prolonged SR9009 treatment eradicates cancer cells (7 days, 20 μM), but does not affect cells that express NR1D1 and NR1D2 shRNA. shNS, non-silencing shRNA. p ,<|im_end|> <|im_start|>assistant Salk researchers have discovered how to curb the growth of cancer cells by blocking the cells' access to certain nutrients. The approach, detailed in a new paper published today in Nature, took advantage of knowledge on how healthy cells use a 24-hour cycle to regulate the production of nutrients and was tested on glioblastoma brain tumors in mice. "When we block access to these resources, cancer cells starve to death but normal cells are already used to this constraint so they're not affected," says Satchidananda Panda, a professor in the Salk Institute's Regulatory Biology Laboratory and lead author of the paper. The circadian cycle, the intrinsic clock that exists in all living things, is known to help control when individual cells produce and use nutrients, among many other functions. Scientists previously discovered that proteins known as REV-ERBα and REV-ERBβ are responsible for turning on and off cells' ability to synthesize fats, as well as their ability to recycle materials—a process called autophagy—throughout the day. In healthy cells, fat synthesis and autophagy are allowed to occur for about 12 hours a day when REV-ERB protein levels remain low. The rest of the time, higher levels of the REV-ERB proteins block the processes so that the cells are not flooded with excessive fat synthesis and recycled nutrients. In the past, researchers developed compounds to activate REV-ERBs in the hopes of stopping fat synthesis to treat certain metabolic diseases. Panda and his colleagues wondered whether activating REV-ERBs would slow cancer growth, since cancer cells heavily rely on the products of both fat synthesis and autophagy to grow. "While current cancer research was investigating established cancer hallmarks/characteristic we decided to explore something completely new," says Research Associate Gabriele Sulli, the paper's first and co-corresponding author. "Given the importance of the circadian clock in the regulation of many cellular and physiological processes we hypothesize that targeting the circadian clock with drugs may open the way to novel anticancer strategies. This study is very exciting because it sheds light on a new uncharacterized way to treat cancer with very limited toxicity." Adds Panda, "We've always thought about ways to stop cancer cells from dividing. But once they divide, they also have to grow before they can divide again, and to grow they need all these raw materials that are normally in short supply. So cancer cells devise strategies to escape the daily constraints of the circadian clock." Salk researchers discover how to curb the growth of cancer cells by activating their biological clocks. Credit: Salk Institute Although cancer cells contain REV-ERB proteins, somehow they remain inactive. Panda's team used two REV-ERB activators that had already been developed—SR9009 and SR9011—in studies on a variety of cancer cells, including those from T cell leukemia, breast cancer, colorectal cancer, melanoma and glioblastoma. In each cell line, treatment with the REV-ERB activators was enough to kill the cells. The same treatment on healthy cells had no effect. "Activating REV-ERBs seemed to work in all the types of cancer we tried," says Panda. "That makes sense because irrespective of where or how a cancer started, all cancer cells need more nutrients and more recycled materials to build new cells." Panda then went on to test the drugs on a new mouse model of glioblastoma recently developed by Inder Verma, a professor in the Salk Institute's Laboratory of Genetics. Once again, the REV-ERB activators were successful at killing cancer cells and stopping tumor growth but seemed not to affect the rest of the mice's cells. Verma says the findings are not only exciting because they point toward existing REV-ERB activators as potential cancer drugs, but also because they help shine light on the importance of the link between the circadian cycle, metabolism and cancer. "These are all fundamental elements required by all living cells," says Verma. "By affecting REV-ERBs, you get to the heart of how cells grow and proliferate, but there are lots of other ways to get at this as well." Verma says his group is planning follow-up studies on how, exactly, the REV-ERB activators alter metabolism, as well as whether they may affect the metabolism of bacteria in the microbiome, the collection of microbes that live in the gut. Panda's team is hoping to study the role of other circadian cycle genes and proteins in cancer. Panda, Verma and coauthor Alan Saghatelian, also a Salk professor, are all members of the Salk Cancer Center, a National Cancer Institute–designated basic research cancer center. Other researchers on the study were Amy Rommel and Matthew J. Kolar of the Salk Institute; Xiaojie Wang and Maksim V. Plikus of the University of California, Irvine; and Francesca Puca of The University of Texas MD Anderson Cancer Center. <|im_end|>

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2,739

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The visual system has developed to transform an undifferentiated and continuous flow of information into discrete and manageable representations, and this ability rests primarily on the uninterrupted nature of the input. Here we explore the impact of altering how visual information is accumulated over time by assessing how intermittent vision influences memory retention. Previous work has shown that intermittent, or stroboscopic, visual training (i.e., practicing while only experiencing snapshots of vision) can enhance visual–motor control and visual cognition, yet many questions remain unanswered about the mechanisms that are altered. In the present study, we used a partial-report memory paradigm to assess the possible changes in visual memory following training under stroboscopic conditions. In Experiment 1 , the memory task was completed before and immediately after a training phase, wherein participants engaged in physical activities (e.g., playing catch) while wearing either specialized stroboscopic eyewear or transparent control eyewear. In Experiment 2 , an additional group of participants underwent the same stroboscopic protocol but were delayed 24 h between training and assessment, so as to measure retention. In comparison to the control group, both stroboscopic groups (immediate and delayed retest) revealed enhanced retention of information in short-term memory, leading to better recall at longer stimulus-to-cue delays (640–2,560 ms). These results demonstrate that training under stroboscopic conditions has the capacity to enhance some aspects of visual memory, that these faculties generalize beyond the specific tasks that were trained, and that trained improvements can be maintained for at least a day. Working on a manuscript? Avoid the common mistakes Exposing an organism to an altered visual environment often results in modifications to the visual system of the organism (e.g., Blake & Hirsch, 1975 ; Webster, Mizokami, & Webster, 2007 ). As humans, our typical visual experiences begin with a continuous and uninterrupted flow of incoming information, and our visual system has developed the ability to transform this information into a seamless and continuous perceptual experience of motion and form. What would happen if the stream of input to the visual system were altered to only allow successive glimpses of the world? Intermittent, or stroboscopic, vision provides an interesting manipulation because it interrupts the normal flow of visual information, and therefore reduces the feedback that is available to guide movements as they are carried out. For example, imagine trying to catch a ball while in a stroboscopic environment. Because you cannot see continuously, you are forced to extrapolate between discrete visual samples to correctly judge the ball’s trajectory. If the stroboscopic rate is sufficiently fast, visual feedback is frequent, and catching the ball is not complicated. However, as the rate decreases, more time passes between visual samples, and essential visual information is lost. Under these conditions, trying to catch a thrown ball becomes quite difficult. When placed in a stroboscopic environment, one must adjust to perform visual tasks adequately, and several possible mechanistic changes could be made. For example, individuals may seek to compensate for their lack of continuous vision by preferentially storing information in visual memory to facilitate perception and/or motor control. This need for compensation suggests that stroboscopic environments may offer an especially powerful research tool for studying visual processing and the interplay between vision and motor actions. Previous research has used intermittent visual experience to study what aspects of sight are important for regulating perceptual–motor performance, such as during driving (Senders et al., 1967 ), one-handed catching (Lyons, Fontaine, & Elliot, 1997 ), or manual aiming (Elliott, Chua, & Pollock, 1994 ). More recently, training in a stroboscopic environment was shown to enhance visual sensitivity in a number of “low-level” perceptual domains, including foveal motion sensitivity and transient attentional selectivity (Appelbaum et al., 2011 ). For example, participants who practiced physical activities under stroboscopic conditions were more accurate afterward at reporting briefly presented stimuli in a dual-task setting than were matched controls who performed the same physical activities under full-vision conditions. Similarly, improvements in anticipatory timing have been observed after stroboscopic training (Smith & Mitroff, under review), and professional ice hockey players have been found to improve in their on-ice skills after stroboscopic training (Mitroff et al., under review). While not all aspects of visual cognition tested in these studies were altered by stroboscopic training (suggesting that the observed effects were not solely due to motivational differences; see the Discussion section), the findings above indicate that experience with stroboscopic vision can enhance some aspects of perception and visual–motor control. In the present study, we expanded upon these research findings to investigate the hypothesis that stroboscopic vision may force individuals to more robustly engage visual memory for successful motor planning (e.g., through greater retention of motion samples in order to estimate motion trajectories), and that this increased engagement may lead to enhancements in the early stages of visual memory. In particular, we focused here on the interplay between visual sensory memory and visual short-term memory. Visual sensory memory, also called “iconic memory” (Neisser, 1967 ), refers to the very brief, precategorical, representation of a visual stimulus that persists following the disappearance of that item (Coltheart, 1980 ; Gegenfurtner & Sperling, 1993 ; Sperling, 1960 ). This initial, short-lived, and high-capacity system is accessible for several hundred milliseconds and has been shown to be a critical component of motor planning (Elliott et al., 1990 , 1994 ). In the second stage of memory, “visual short-term memory,” a subset of the elements contained in the initial sensory buffer are amplified and sustained for a short period, thereby creating a more durable memory store (Chun & Potter, 1995 ; Hoffman, 1979 ). This second stage has been shown to depend on top-down factors, such as attention (e.g., Awh, Vogel, & Oh, 2006 ; Cowan & Morey, 2006 ), and to be susceptible to training-based plasticity and learning (Berry et al., 2010 ; Klingberg, 2010 ; Westerberg et al., 2007 ). To assess possible effects on visual memory due to stroboscopic experiences, participants in the present study either completed an experimental condition, in which they trained", "role": "user" }, { "content": "Stroboscopic training, performing a physical activity while using eyewear that simulates a strobe-like experience, has been found to increase visual short-term memory retention, and the effects last for 24 hours. Participants in a Duke University study engaged in physical activities, such as playing catch, while using either specialized eyewear that limits vision to only brief snapshots or while using eyewear with clear lenses that provides uninterrupted vision. Participants from the Duke community, including varsity athletes, completed a computer-based visual memory test before and after the physical activities. The study found that participants who trained with the strobe eyewear gained a boost in visual memory abilities. Participants completed a memory test that required them to note the identity of eight letters of the alphabet that were briefly displayed on a computer screen. After a variable delay, participants were asked to recall one of the eight letters. On easy-level trials, the recall prompt came immediately after the letters disappeared, but on more difficult trials, the prompt came as late as 2.5 seconds following the display. Because participants did not know which letter they would be asked to recall, they had to retain all of the items in memory. \"Humans have a memory buffer in their brain that keeps information alive for a certain short-lived period,\" said Greg Appelbaum, assistant professor of psychiatry at Duke and first author of the study. \"Wearing the strobe eyewear during the physical training seemed to boost the ability to retain information in this buffer.\" The strobe eyewear disrupts vision by only allowing the user to see glimpses of the world. Users must adjust their visual processing in order to perform normally, and this adjustment produces a lingering benefit: once participants removed the strobe eyewear, there was an observed boost in their visual memory retention that was found to still be active 24 hours later. Earlier work by Appelbaum and the project's senior researcher, Stephen Mitroff, had shown that stroboscopic training improves visual perception, including the ability to detect subtle motion cues and the processing of briefly presented visual information. Yet the earlier study had not determined how long the benefits might last. \"Our earlier work on stroboscopic training showed that it can improve perceptual abilities, but we don't know exactly how,\" said Mitroff, associate professor of psychology and neuroscience and member of the Duke Institute for Brain Sciences. \"This project takes a big step by showing that these improved perceptual abilities are driven, at least in part, by improvements in visual memory.\" \"Improving human cognition is an important goal with so many benefits,\" said Appelbaum, also a member of the Duke Institute for Brain Sciences. \"Interestingly, our findings demonstrate one way in which visual experience has the capacity to improve cognition.\" Participants for the study came from the 2010-2011 Duke University men's and women's varsity soccer teams, Duke's 2010-2011 men's basketball team and members of the general university community. Mitroff reported that participants had little or no trouble with the stroboscopic training, and several participants later returned to inquire about how they could be involved as research assistants. The research was supported by Nike SPARQ Sensory Performance, which designed the eyewear and is marketing it as Nike SPARQ Vapor Strobe. The study appeared online July 19 in Attention, Perception, & Psychophysics. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The visual system has developed to transform an undifferentiated and continuous flow of information into discrete and manageable representations, and this ability rests primarily on the uninterrupted nature of the input. Here we explore the impact of altering how visual information is accumulated over time by assessing how intermittent vision influences memory retention. Previous work has shown that intermittent, or stroboscopic, visual training (i.e., practicing while only experiencing snapshots of vision) can enhance visual–motor control and visual cognition, yet many questions remain unanswered about the mechanisms that are altered. In the present study, we used a partial-report memory paradigm to assess the possible changes in visual memory following training under stroboscopic conditions. In Experiment 1 , the memory task was completed before and immediately after a training phase, wherein participants engaged in physical activities (e.g., playing catch) while wearing either specialized stroboscopic eyewear or transparent control eyewear. In Experiment 2 , an additional group of participants underwent the same stroboscopic protocol but were delayed 24 h between training and assessment, so as to measure retention. In comparison to the control group, both stroboscopic groups (immediate and delayed retest) revealed enhanced retention of information in short-term memory, leading to better recall at longer stimulus-to-cue delays (640–2,560 ms). These results demonstrate that training under stroboscopic conditions has the capacity to enhance some aspects of visual memory, that these faculties generalize beyond the specific tasks that were trained, and that trained improvements can be maintained for at least a day. Working on a manuscript? Avoid the common mistakes Exposing an organism to an altered visual environment often results in modifications to the visual system of the organism (e.g., Blake & Hirsch, 1975 ; Webster, Mizokami, & Webster, 2007 ). As humans, our typical visual experiences begin with a continuous and uninterrupted flow of incoming information, and our visual system has developed the ability to transform this information into a seamless and continuous perceptual experience of motion and form. What would happen if the stream of input to the visual system were altered to only allow successive glimpses of the world? Intermittent, or stroboscopic, vision provides an interesting manipulation because it interrupts the normal flow of visual information, and therefore reduces the feedback that is available to guide movements as they are carried out. For example, imagine trying to catch a ball while in a stroboscopic environment. Because you cannot see continuously, you are forced to extrapolate between discrete visual samples to correctly judge the ball’s trajectory. If the stroboscopic rate is sufficiently fast, visual feedback is frequent, and catching the ball is not complicated. However, as the rate decreases, more time passes between visual samples, and essential visual information is lost. Under these conditions, trying to catch a thrown ball becomes quite difficult. When placed in a stroboscopic environment, one must adjust to perform visual tasks adequately, and several possible mechanistic changes could be made. For example, individuals may seek to compensate for their lack of continuous vision by preferentially storing information in visual memory to facilitate perception and/or motor control. This need for compensation suggests that stroboscopic environments may offer an especially powerful research tool for studying visual processing and the interplay between vision and motor actions. Previous research has used intermittent visual experience to study what aspects of sight are important for regulating perceptual–motor performance, such as during driving (Senders et al., 1967 ), one-handed catching (Lyons, Fontaine, & Elliot, 1997 ), or manual aiming (Elliott, Chua, & Pollock, 1994 ). More recently, training in a stroboscopic environment was shown to enhance visual sensitivity in a number of “low-level” perceptual domains, including foveal motion sensitivity and transient attentional selectivity (Appelbaum et al., 2011 ). For example, participants who practiced physical activities under stroboscopic conditions were more accurate afterward at reporting briefly presented stimuli in a dual-task setting than were matched controls who performed the same physical activities under full-vision conditions. Similarly, improvements in anticipatory timing have been observed after stroboscopic training (Smith & Mitroff, under review), and professional ice hockey players have been found to improve in their on-ice skills after stroboscopic training (Mitroff et al., under review). While not all aspects of visual cognition tested in these studies were altered by stroboscopic training (suggesting that the observed effects were not solely due to motivational differences; see the Discussion section), the findings above indicate that experience with stroboscopic vision can enhance some aspects of perception and visual–motor control. In the present study, we expanded upon these research findings to investigate the hypothesis that stroboscopic vision may force individuals to more robustly engage visual memory for successful motor planning (e.g., through greater retention of motion samples in order to estimate motion trajectories), and that this increased engagement may lead to enhancements in the early stages of visual memory. In particular, we focused here on the interplay between visual sensory memory and visual short-term memory. Visual sensory memory, also called “iconic memory” (Neisser, 1967 ), refers to the very brief, precategorical, representation of a visual stimulus that persists following the disappearance of that item (Coltheart, 1980 ; Gegenfurtner & Sperling, 1993 ; Sperling, 1960 ). This initial, short-lived, and high-capacity system is accessible for several hundred milliseconds and has been shown to be a critical component of motor planning (Elliott et al., 1990 , 1994 ). In the second stage of memory, “visual short-term memory,” a subset of the elements contained in the initial sensory buffer are amplified and sustained for a short period, thereby creating a more durable memory store (Chun & Potter, 1995 ; Hoffman, 1979 ). This second stage has been shown to depend on top-down factors, such as attention (e.g., Awh, Vogel, & Oh, 2006 ; Cowan & Morey, 2006 ), and to be susceptible to training-based plasticity and learning (Berry et al., 2010 ; Klingberg, 2010 ; Westerberg et al., 2007 ). To assess possible effects on visual memory due to stroboscopic experiences, participants in the present study either completed an experimental condition, in which they trained<|im_end|> <|im_start|>assistant Stroboscopic training, performing a physical activity while using eyewear that simulates a strobe-like experience, has been found to increase visual short-term memory retention, and the effects last for 24 hours. Participants in a Duke University study engaged in physical activities, such as playing catch, while using either specialized eyewear that limits vision to only brief snapshots or while using eyewear with clear lenses that provides uninterrupted vision. Participants from the Duke community, including varsity athletes, completed a computer-based visual memory test before and after the physical activities. The study found that participants who trained with the strobe eyewear gained a boost in visual memory abilities. Participants completed a memory test that required them to note the identity of eight letters of the alphabet that were briefly displayed on a computer screen. After a variable delay, participants were asked to recall one of the eight letters. On easy-level trials, the recall prompt came immediately after the letters disappeared, but on more difficult trials, the prompt came as late as 2.5 seconds following the display. Because participants did not know which letter they would be asked to recall, they had to retain all of the items in memory. "Humans have a memory buffer in their brain that keeps information alive for a certain short-lived period," said Greg Appelbaum, assistant professor of psychiatry at Duke and first author of the study. "Wearing the strobe eyewear during the physical training seemed to boost the ability to retain information in this buffer." The strobe eyewear disrupts vision by only allowing the user to see glimpses of the world. Users must adjust their visual processing in order to perform normally, and this adjustment produces a lingering benefit: once participants removed the strobe eyewear, there was an observed boost in their visual memory retention that was found to still be active 24 hours later. Earlier work by Appelbaum and the project's senior researcher, Stephen Mitroff, had shown that stroboscopic training improves visual perception, including the ability to detect subtle motion cues and the processing of briefly presented visual information. Yet the earlier study had not determined how long the benefits might last. "Our earlier work on stroboscopic training showed that it can improve perceptual abilities, but we don't know exactly how," said Mitroff, associate professor of psychology and neuroscience and member of the Duke Institute for Brain Sciences. "This project takes a big step by showing that these improved perceptual abilities are driven, at least in part, by improvements in visual memory." "Improving human cognition is an important goal with so many benefits," said Appelbaum, also a member of the Duke Institute for Brain Sciences. "Interestingly, our findings demonstrate one way in which visual experience has the capacity to improve cognition." Participants for the study came from the 2010-2011 Duke University men's and women's varsity soccer teams, Duke's 2010-2011 men's basketball team and members of the general university community. Mitroff reported that participants had little or no trouble with the stroboscopic training, and several participants later returned to inquire about how they could be involved as research assistants. The research was supported by Nike SPARQ Sensory Performance, which designed the eyewear and is marketing it as Nike SPARQ Vapor Strobe. The study appeared online July 19 in Attention, Perception, & Psychophysics. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Climate change is leading to widespread elevational shifts thought to increase species extinction risk in mountains. We integrate digital elevation models with a metric of human pressure to examine changes in the amount of intact land area available for species undergoing elevational range shifts in all major mountain ranges globally ( n = 1010). Nearly 60% of mountainous area is under intense human pressure, predominantly at low elevations and mountain bases. Consequently, upslope range shifts generally resulted in modeled species at lower elevations expanding into areas of lower human pressure and, due to complex topography, encountering more intact land area relative to their starting position. Such gains were often attenuated at high elevations as land-use constraints diminished and topographic constraints increased. Integrating patterns of topography and human pressure is essential for accurate species vulnerability assessments under climate change, as priorities for protecting, connecting, and restoring mountain landscapes may otherwise be misguided. Introduction Climate change is causing widespread elevational range shifts in plant and animal species in mountainous regions 1 , 2 , 3 , 4 , 5 , 6 . Such elevational range shifts are often thought to be associated with an increased risk of extinction as topographic constraints impose significant reductions in the amount of area available for species following range shifts 7 , 8 . However, owing to complex topography in mountain ranges, such topographic constraints can occur at virtually any position along elevational gradients 9 . For instance, topographic constraints are roughly uniform along elevations in mountain ranges with unimodal declines in surface area (‘pyramid’ mountains), such as the European Alps, whereas they are greatest at high elevations in mountain ranges with mid-elevation peaks of surface area (‘diamond’ mountains), such as the Rocky Mountains of North America 9 . Few studies account for topographic patterns using high-resolution data, which could lead to inaccurate expectations of where species may experience range contractions following climate change 10 . Another limitation in many approaches to forecasting changes in available area for species persistence under climate change involves accounting for how human pressures limit species distributions and movement required to shift their range to adapt to change 11 . Human pressure on montane landscapes is predominantly through resource extraction, infrastructure development, and habitat conversion. Indeed, habitat conversion for agriculture, pasture, and cropland is extensive in mountainous regions 12 , is a leading driver of biodiversity loss globally 13 , and is often expected to exacerbate the negative effects of climate change 14 . However, because human pressure is typically biased towards low elevations 15 and protection towards high elevations in mountain ranges globally 16 , higher elevation lands could provide refuge from human activities 11 , 15 . Ultimately, accurate assessments of changes in habitable area for species undergoing upslope range shifts rely on integrating fine-scale topography with current land use patterns. Predictions of area changes due to upslope movement under climate change may be inaccurate when omitting high-resolution topography in assessments 17 , 18 , 19 . While mountainous regions are generally considered well-protected 16 , 20 , there is significant variation in protection across continents and ecoregions 21 , and even greater variation across individual mountain ranges 16 , the spatial scale most aligned with typical montane species distributions 22 . Moreover, many of these regions have faced increasing pressure from human populations over recent decades 23 , including within protected areas 24 . Consequently, population responses and threats to extinction arising from elevational range shifts will likely be highly context specific and potentially deviate from expectations derived from considerations of topographic constraints or habitat availability in isolation. Despite the recognized importance of topography and land-use in constraining species distributions 11 , to date there has been no global assessment of how these two factors combined alter the availability of intact land area for species undergoing elevational range shifts in mountain ranges. We addressed this need by evaluating the elevational distributions of total and intact land area for 1010 global mountain ranges. Here, we adopt the definition of mountain ranges used by the Global Mountain Biodiversity Assessment 25 and use the term ‘intact’ to refer to areas that are not under intense human pressure that can negatively impact species persistence (see also sections “Results” and “Methods”). We followed existing approaches to classify mountain range topography to one of four mountain topography classes (pyramid, diamond, hourglass, and inverse pyramid) based on the statistical properties of area-elevation distributions for total area 9 . We then reclassified mountain ranges based only on intact area, i.e., areas not under intense human pressure, by applying a threshold 24 to the human footprint index (HFI), a spatially explicit map of weighted cumulative threat that combines eight separate direct threats from anthropogenic activities: croplands, pastures, roads, railways, navigable waterways, human population density, nighttime lights, and the built environment, circa 2009 26 (Supplementary Fig. 1 ; see section “Methods”). We then modeled range shifts on all mountain ranges for an extensive set of hypothetical species based on expected temperature changes from a suite of general circulation models (GCMs) under two warming scenarios, assuming species could occupy all available land area in one case and that they would be restricted only to intact land area in a second case. Our approach enabled us to quantify how interactions between topography and current patterns of human pressure potentially influence the amount of intact area available for species following range shifts across the full array of elevations for all the world’s mountain ranges. Results Global patterns of human pressure over elevation Human pressure in mountain ranges has resulted in 57% of all mountainous land being considered under intense human pressure (Supplementary Fig. 1 ). For roughly 24% of ranges (239 of 1010), the entire land area is under intense human pressure (Fig. 1b ). The average elevation of peak human pressure in mountain ranges occurred at ~1210 m (range −75 to 6550 m; Supplementary Fig. 2 ). While human pressure is generally highest at low elevations and declines with elevation,", "role": "user" }, { "content": "A new WCS-led study reveals that mountain-dwelling species fleeing warming temperatures by retreating to higher elevations may find refuge from reduced human pressure. A new study published in Nature Communications by scientists at WCS, the University of California, Berkeley, and the United States Forest Service shows that nearly 60 percent of all mountainous area is under intense human pressure. Most of the pressure is at low elevations and mountain bases, which tend to be easier places for people to live, grow food, and build roads. The scientists then used climate models to make predictions about how species would move under climate change. Based on their predictions, they found that species tend to move to higher elevations, and that these higher elevations tend to have more intact land for species because there is less human pressure. Without factoring in human pressure, the authors warn that conservation actions may be misguided. Factoring in human pressure reveals the true 'shape' of a mountain for species that are restricted to intact landscapes, which are often the species of greatest conservation concern. Here, the 'true shape' refers to how much land area is potentially available as habitat for a species as it moves up in elevation, not simply how much total land area is available. The true shape can reveal where species will tend to lose versus gain intact land area as they shift under climate change: the elevations where species are expected to lose area represent the priority zones for conservation. Mountains are home to over 85 percent of the world's amphibians, birds, and mammals, making them global conservation priorities. But mountain-dwelling species are at risk from human activities, such as agriculture, livestock grazing, and development that reduce their habitat, and climate change that threatens to push species upslope as they struggle to find tolerable temperatures. \"Species are adapted to certain temperature conditions. As temperatures warm in mountains, scientists have documented species moving to higher elevations to maintain the same temperatures,\" said Paul Elsen, a WCS Climate Adaptation Scientist and lead author of the study. \"This was always seen as a problem, because species would have less land area and less habitat to occupy at high elevations. But what we found is that as species move upslope, they tend to move away from areas that are already under intense human pressure and into areas with reduced human pressure. As a result, they can occupy more intact land area, even if the total amount of land area declines.\" The authors combined several global databases to make their assessments: high-resolution digital elevation models gave a picture about how much surface area is available at different elevations. The Human Footprint Index provided information on pressure from human activities. Global climate models projected how temperatures are likely to change by the late 21st century. The authors then used computer simulations to place hundreds of thousands of hypothetical 'species' across all mountain ranges at different elevations and then predicted how they would shift their ranges based on climate projections. For each simulation, they compared the amount of area the species had to begin with to the amount they would have after the range shift under climate change. Said Elsen: \"We were surprised to find that many species had more intact land area available after the range shift compared to when they started.\" The results suggest that many species in mountain ranges may have more intact land area available in the future if they track warming temperatures to higher slopes, though there were exceptions. \"Our results offer a glimmer of hope for montane species under climate change,\" Elsen said. \"Montane species are still facing tremendous human pressure, especially at low elevations, but we have the opportunity now to protect intact habitats at higher elevations to give these species the best possible chance going forward.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Climate change is leading to widespread elevational shifts thought to increase species extinction risk in mountains. We integrate digital elevation models with a metric of human pressure to examine changes in the amount of intact land area available for species undergoing elevational range shifts in all major mountain ranges globally ( n = 1010). Nearly 60% of mountainous area is under intense human pressure, predominantly at low elevations and mountain bases. Consequently, upslope range shifts generally resulted in modeled species at lower elevations expanding into areas of lower human pressure and, due to complex topography, encountering more intact land area relative to their starting position. Such gains were often attenuated at high elevations as land-use constraints diminished and topographic constraints increased. Integrating patterns of topography and human pressure is essential for accurate species vulnerability assessments under climate change, as priorities for protecting, connecting, and restoring mountain landscapes may otherwise be misguided. Introduction Climate change is causing widespread elevational range shifts in plant and animal species in mountainous regions 1 , 2 , 3 , 4 , 5 , 6 . Such elevational range shifts are often thought to be associated with an increased risk of extinction as topographic constraints impose significant reductions in the amount of area available for species following range shifts 7 , 8 . However, owing to complex topography in mountain ranges, such topographic constraints can occur at virtually any position along elevational gradients 9 . For instance, topographic constraints are roughly uniform along elevations in mountain ranges with unimodal declines in surface area (‘pyramid’ mountains), such as the European Alps, whereas they are greatest at high elevations in mountain ranges with mid-elevation peaks of surface area (‘diamond’ mountains), such as the Rocky Mountains of North America 9 . Few studies account for topographic patterns using high-resolution data, which could lead to inaccurate expectations of where species may experience range contractions following climate change 10 . Another limitation in many approaches to forecasting changes in available area for species persistence under climate change involves accounting for how human pressures limit species distributions and movement required to shift their range to adapt to change 11 . Human pressure on montane landscapes is predominantly through resource extraction, infrastructure development, and habitat conversion. Indeed, habitat conversion for agriculture, pasture, and cropland is extensive in mountainous regions 12 , is a leading driver of biodiversity loss globally 13 , and is often expected to exacerbate the negative effects of climate change 14 . However, because human pressure is typically biased towards low elevations 15 and protection towards high elevations in mountain ranges globally 16 , higher elevation lands could provide refuge from human activities 11 , 15 . Ultimately, accurate assessments of changes in habitable area for species undergoing upslope range shifts rely on integrating fine-scale topography with current land use patterns. Predictions of area changes due to upslope movement under climate change may be inaccurate when omitting high-resolution topography in assessments 17 , 18 , 19 . While mountainous regions are generally considered well-protected 16 , 20 , there is significant variation in protection across continents and ecoregions 21 , and even greater variation across individual mountain ranges 16 , the spatial scale most aligned with typical montane species distributions 22 . Moreover, many of these regions have faced increasing pressure from human populations over recent decades 23 , including within protected areas 24 . Consequently, population responses and threats to extinction arising from elevational range shifts will likely be highly context specific and potentially deviate from expectations derived from considerations of topographic constraints or habitat availability in isolation. Despite the recognized importance of topography and land-use in constraining species distributions 11 , to date there has been no global assessment of how these two factors combined alter the availability of intact land area for species undergoing elevational range shifts in mountain ranges. We addressed this need by evaluating the elevational distributions of total and intact land area for 1010 global mountain ranges. Here, we adopt the definition of mountain ranges used by the Global Mountain Biodiversity Assessment 25 and use the term ‘intact’ to refer to areas that are not under intense human pressure that can negatively impact species persistence (see also sections “Results” and “Methods”). We followed existing approaches to classify mountain range topography to one of four mountain topography classes (pyramid, diamond, hourglass, and inverse pyramid) based on the statistical properties of area-elevation distributions for total area 9 . We then reclassified mountain ranges based only on intact area, i.e., areas not under intense human pressure, by applying a threshold 24 to the human footprint index (HFI), a spatially explicit map of weighted cumulative threat that combines eight separate direct threats from anthropogenic activities: croplands, pastures, roads, railways, navigable waterways, human population density, nighttime lights, and the built environment, circa 2009 26 (Supplementary Fig. 1 ; see section “Methods”). We then modeled range shifts on all mountain ranges for an extensive set of hypothetical species based on expected temperature changes from a suite of general circulation models (GCMs) under two warming scenarios, assuming species could occupy all available land area in one case and that they would be restricted only to intact land area in a second case. Our approach enabled us to quantify how interactions between topography and current patterns of human pressure potentially influence the amount of intact area available for species following range shifts across the full array of elevations for all the world’s mountain ranges. Results Global patterns of human pressure over elevation Human pressure in mountain ranges has resulted in 57% of all mountainous land being considered under intense human pressure (Supplementary Fig. 1 ). For roughly 24% of ranges (239 of 1010), the entire land area is under intense human pressure (Fig. 1b ). The average elevation of peak human pressure in mountain ranges occurred at ~1210 m (range −75 to 6550 m; Supplementary Fig. 2 ). While human pressure is generally highest at low elevations and declines with elevation,<|im_end|> <|im_start|>assistant A new WCS-led study reveals that mountain-dwelling species fleeing warming temperatures by retreating to higher elevations may find refuge from reduced human pressure. A new study published in Nature Communications by scientists at WCS, the University of California, Berkeley, and the United States Forest Service shows that nearly 60 percent of all mountainous area is under intense human pressure. Most of the pressure is at low elevations and mountain bases, which tend to be easier places for people to live, grow food, and build roads. The scientists then used climate models to make predictions about how species would move under climate change. Based on their predictions, they found that species tend to move to higher elevations, and that these higher elevations tend to have more intact land for species because there is less human pressure. Without factoring in human pressure, the authors warn that conservation actions may be misguided. Factoring in human pressure reveals the true 'shape' of a mountain for species that are restricted to intact landscapes, which are often the species of greatest conservation concern. Here, the 'true shape' refers to how much land area is potentially available as habitat for a species as it moves up in elevation, not simply how much total land area is available. The true shape can reveal where species will tend to lose versus gain intact land area as they shift under climate change: the elevations where species are expected to lose area represent the priority zones for conservation. Mountains are home to over 85 percent of the world's amphibians, birds, and mammals, making them global conservation priorities. But mountain-dwelling species are at risk from human activities, such as agriculture, livestock grazing, and development that reduce their habitat, and climate change that threatens to push species upslope as they struggle to find tolerable temperatures. "Species are adapted to certain temperature conditions. As temperatures warm in mountains, scientists have documented species moving to higher elevations to maintain the same temperatures," said Paul Elsen, a WCS Climate Adaptation Scientist and lead author of the study. "This was always seen as a problem, because species would have less land area and less habitat to occupy at high elevations. But what we found is that as species move upslope, they tend to move away from areas that are already under intense human pressure and into areas with reduced human pressure. As a result, they can occupy more intact land area, even if the total amount of land area declines." The authors combined several global databases to make their assessments: high-resolution digital elevation models gave a picture about how much surface area is available at different elevations. The Human Footprint Index provided information on pressure from human activities. Global climate models projected how temperatures are likely to change by the late 21st century. The authors then used computer simulations to place hundreds of thousands of hypothetical 'species' across all mountain ranges at different elevations and then predicted how they would shift their ranges based on climate projections. For each simulation, they compared the amount of area the species had to begin with to the amount they would have after the range shift under climate change. Said Elsen: "We were surprised to find that many species had more intact land area available after the range shift compared to when they started." The results suggest that many species in mountain ranges may have more intact land area available in the future if they track warming temperatures to higher slopes, though there were exceptions. "Our results offer a glimmer of hope for montane species under climate change," Elsen said. "Montane species are still facing tremendous human pressure, especially at low elevations, but we have the opportunity now to protect intact habitats at higher elevations to give these species the best possible chance going forward." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Autism spectrum disorder (ASD) affects 2% of children, and is characterized by impaired social and communication skills together with repetitive, stereotypic behavior. The pathophysiology of ASD is complex due to genetic and environmental heterogeneity, complicating the development of therapies and making diagnosis challenging. Growing genetic evidence supports a role of disrupted Ca 2+ signaling in ASD. Here, we report that patient-derived fibroblasts from three monogenic models of ASD—fragile X and tuberous sclerosis TSC1 and TSC2 syndromes—display depressed Ca 2+ release through inositol trisphosphate receptors (IP 3 Rs). This was apparent in Ca 2+ signals evoked by G protein-coupled receptors and by photoreleased IP 3 at the levels of both global and local elementary Ca 2+ events, suggesting fundamental defects in IP 3 R channel activity in ASD. Given the ubiquitous involvement of IP 3 R-mediated Ca 2+ signaling in neuronal excitability, synaptic plasticity, gene expression and neurodevelopment, we propose dysregulated IP 3 R signaling as a nexus where genes altered in ASD converge to exert their deleterious effect. These findings highlight potential pharmaceutical targets, and identify Ca 2+ screening in skin fibroblasts as a promising technique for early detection of individuals susceptible to ASD. Introduction Autism spectrum disorder (ASD) is a complex heterogeneous disorder 1 , 2 , 3 , 4 with a poorly defined etiology 5 , 6 , 7 , 8 and diagnosis criteria that are strictly clinical because there are as yet no objective biomarkers of the disorder. 9 , 10 Its high heritability, however, suggests a strong genetic component, 8 and a wealth of genetic data now implicate a host of genes encoding ion channels and associated intracellular Ca 2+ signaling proteins in the molecular architecture of ASD, 5 , 6 , 7 , 8 placing Ca 2+ homeostasis at a central node. Cytosolic Ca 2+ homeostasis involves ion flux from intracellular organellar stores, as well as transport across the plasma membrane. Diseases of the intracellular organelles are an emerging area of medicine. Several prototypes are already well-developed for neurogenetic diseases of mitochondria and the lysosomes, 11 , 12 , 13 , 14 and increasing evidence implicates the endoplasmic reticulum (ER). 15 Ca 2+ release from the ER through inositol trisphosphate receptors (IP 3 Rs) has been shown to be altered in cognitive disorders including Alzheimer’s 16 , 17 and Huntington’s diseases, 18 and IP 3 Rs have recently been identified among the genes affected by rare de novo copy number variants in ASD patients. 19 In neurons, IP 3 R-mediated Ca 2+ release is involved in crucial functions—including synaptic plasticity and memory, 20 , 21 neuronal excitability, 22 , 23 neurotransmitter release, 24 , 25 axon growth 26 and long-term changes in gene expression 27 —highlighting the central integrating position played by IP 3 Rs. 28 Ca 2+ release is activated in response to the second messenger IP 3 , which is produced on stimulation of G protein-coupled receptors (GPCRs) 29 and tyrosine kinase-linked 30 cell surface receptors. The specificity of the resulting cellular responses is ensured by an exquisite temporo-spatial patterning of cytosolic Ca 2+ signals. 31 , 32 Opening of the IP 3 R channel requires not only IP 3 , but also binding of Ca 2+ to receptor sites on the cytosolic face. This leads to biphasic regulation, such that small elevations of cytosolic Ca 2+ induce channel opening, whereas larger elevations cause inactivation. 33 The positive feedback by Ca 2+ (Ca 2+ -induced Ca 2+ release; CICR), may remain restricted to individual or clustered IP 3 Rs, producing local Ca 2+ signals known, respectively, as Ca 2+ blips and puffs, 34 or may propagate throughout the cell as a saltatory wave by successive cycles of Ca 2+ diffusion and CICR. Thus, IP 3 -mediated Ca 2+ signaling represents a hierarchy of Ca 2+ events of differing magnitudes. 35 , 36 The spatial patterning it orchestrates is critical to proper cellular function, and we hypothesize that disruptions in the magnitude and organization of neuronal Ca 2+ signals may contribute to the pathogenesis of ASD. Our understanding of the etiology of ASD 8 , 9 , 37 has been greatly advanced by studies of syndromic forms of ASD caused by rare single gene mutations. Fragile X (FXS) is the most common monogenic cause of ASD, 38 and is a widely used and well-characterized model of ASD. 37 , 39 It results from silencing of the fragile X mental retardation ( FMR1) gene and absence of its corresponding protein, the FXS mental retardation protein (FMRP). Tuberous sclerosis (TS) is a syndrome caused by dominant mutations in one of two genes, hamartin ( TSC1 ) or tuberin ( TSC2 ), causing ASD-like behaviors, seizures, intellectual disability and characteristic brain and skin lesions. Here, we used primary, untransformed skin fibroblasts derived from patients with FXS and TS to evaluate ASD-associated functional deficits in IP 3 -mediated Ca 2+ signaling. The physiology of IP 3 signaling in fibroblasts has been extensively characterized, 40 , 41 , 42 providing a validated and convenient model for the study of Ca 2+ signaling in ASD, with the further advantage that cell lines are readily obtained as clinical samples from both disease and matched control patient populations. Moreover, identification of disease-specific signaling defects in skin cells have potential as biomarkers for diagnostic purposes, much as is now routine in other organelle diseases, such as Tay–Sachs and Niemann–Pick diseases, 43 , 44 and through which novel therapies for these diseases have emerged. 45 Our results demonstrate that IP 3 -mediated Ca 2+ signals are significantly depressed in fibroblasts from both FXS and TS patients and, by resolving signals at the single-channel level, we provide evidence of fundamental defects in IP 3 R channel activity in ASD. We thus propose dysregulated IP 3 R signaling as a nexus where genes altered in ASD converge to exert their deleterious effect. Materials and methods Materials The membrane-permeant caged IP 3 analog ci-IP 3 /PM (D-2,3-O-Isopropylidene-6-O-(2-nitro-4,5-dimethoxy)benzyl-myo-Inositol 1,4,5-trisphosphate-Hexakis (propionoxymethyl) Ester) was obtained from SiChem (Bremen, Germany),", "role": "user" }, { "content": "By identifying a key signaling defect within a specific membrane structure in all cells, University of California, Irvine researchers believe, they have found both a possible reliable biomarker for diagnosing certain forms of autism and a potential therapeutic target. Dr. J. Jay Gargus, Ian Parker and colleagues at the UCI Center for Autism Research & Translation examined skin biopsies of patients with three very different genetic types of the disorder (fragile X syndrome and tuberous sclerosis 1 and 2). They discovered that a cellular calcium signaling process involving the inositol trisphosphate receptor was very much altered. This IP3R functional defect was located in the endoplasmic reticulum, which is among the specialized membrane compartments in cells called organelles, and may underpin cognitive impairments - and possibly digestive and immune problems - associated with autism. \"We believe this finding will be another arrow in the quiver for early and accurate diagnoses of autism spectrum disorders,\" said Gargus, director of the Center for Autism Research & Translation and professor of pediatrics and physiology & biophysics. \"Equally exciting, it also presents a target of a molecular class already well-established to be useful for drug discovery.\" Study results appear online in Translational Psychiatry, a Nature publication. Autism spectrum disorder is a range of complex neurodevelopmental disorders affecting 2 percent of U.S. children. The social and economic burden of ASD is enormous, currently estimated at more than $66 billion per year in the U.S. alone. Drug development has proven problematic due to the limited understanding of the underlying causes of ASD, as demonstrated by the recent failure of several much anticipated drug trials. There are also no current, reliable diagnostic biomarkers for ASD. Genetic research has identified hundreds of genes that are involved, which impedes diagnosis and, ultimately, drug development. There simply may be too many targets, each with too small an effect. Many of these genes associated with ASD, however, have been found to be part of the same signaling pathway, and multiple defects in this pathway may converge to produce a large functional change. The UCI scientists detected such a convergence in the IP3R calcium channel in an organelle called the endoplasmic reticulum. Organelles are membrane structures within cells with specialized cellular functions. According to Gargus, diseases of the organelles, such as the ER, are an emerging field in medicine, with several well-recognized neurological ailments linked to two other ones, the mitochondria and lysosomes. The IP3R controls the release of calcium from the ER. In the brain, calcium is used to communicate information within and between neurons, and it activates a host of other cell functions, including ones regulating learning and memory, neuronal excitability and neurotransmitter release - areas known to be dysfunctional in ASD. \"We propose that the proper function of this channel and its signaling pathway is critical for normal performance of neurons and that this signaling pathway represents a key 'hub' in the pathogenesis of ASD,\" said Parker, a fellow of London's Royal Society and UCI professor of neurobiology & behavior, who studies cellular calcium signaling. To see if IP3R function is altered across the autism spectrum, clinical researchers at the Center for Autism & Neurodevelopmental Disorders - which is affiliated with the Center for Autism Research & Translation - are currently expanding the study and have begun to examine children with and without typical ASD for the same signaling abnormalities. These patients undergo complete behavioral diagnostic testing, and sophisticated EEG, sleep and biochemical studies are performed. This includes the sequencing of their entire genome. Also, skin cell samples are cultured and made available to lab-based researchers for functional assays. In the area of drug discovery, scientists at the Center for Autism Research & Translation continue to probe the IP3R channel, specifically how it regulates the level of neuron excitability. The brains of people who have autism show signs of hyperexcitability, which is also seen in epilepsy, a disorder increasingly found to be associated with ASD. Cells from individuals who have autism exhibit depressed levels of calcium signaling, and this might explain why these patients experience this hyperexcitability. By restoring the release of calcium from the IP3R, the researchers believe, they can apply a \"brake\" on this activity. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Autism spectrum disorder (ASD) affects 2% of children, and is characterized by impaired social and communication skills together with repetitive, stereotypic behavior. The pathophysiology of ASD is complex due to genetic and environmental heterogeneity, complicating the development of therapies and making diagnosis challenging. Growing genetic evidence supports a role of disrupted Ca 2+ signaling in ASD. Here, we report that patient-derived fibroblasts from three monogenic models of ASD—fragile X and tuberous sclerosis TSC1 and TSC2 syndromes—display depressed Ca 2+ release through inositol trisphosphate receptors (IP 3 Rs). This was apparent in Ca 2+ signals evoked by G protein-coupled receptors and by photoreleased IP 3 at the levels of both global and local elementary Ca 2+ events, suggesting fundamental defects in IP 3 R channel activity in ASD. Given the ubiquitous involvement of IP 3 R-mediated Ca 2+ signaling in neuronal excitability, synaptic plasticity, gene expression and neurodevelopment, we propose dysregulated IP 3 R signaling as a nexus where genes altered in ASD converge to exert their deleterious effect. These findings highlight potential pharmaceutical targets, and identify Ca 2+ screening in skin fibroblasts as a promising technique for early detection of individuals susceptible to ASD. Introduction Autism spectrum disorder (ASD) is a complex heterogeneous disorder 1 , 2 , 3 , 4 with a poorly defined etiology 5 , 6 , 7 , 8 and diagnosis criteria that are strictly clinical because there are as yet no objective biomarkers of the disorder. 9 , 10 Its high heritability, however, suggests a strong genetic component, 8 and a wealth of genetic data now implicate a host of genes encoding ion channels and associated intracellular Ca 2+ signaling proteins in the molecular architecture of ASD, 5 , 6 , 7 , 8 placing Ca 2+ homeostasis at a central node. Cytosolic Ca 2+ homeostasis involves ion flux from intracellular organellar stores, as well as transport across the plasma membrane. Diseases of the intracellular organelles are an emerging area of medicine. Several prototypes are already well-developed for neurogenetic diseases of mitochondria and the lysosomes, 11 , 12 , 13 , 14 and increasing evidence implicates the endoplasmic reticulum (ER). 15 Ca 2+ release from the ER through inositol trisphosphate receptors (IP 3 Rs) has been shown to be altered in cognitive disorders including Alzheimer’s 16 , 17 and Huntington’s diseases, 18 and IP 3 Rs have recently been identified among the genes affected by rare de novo copy number variants in ASD patients. 19 In neurons, IP 3 R-mediated Ca 2+ release is involved in crucial functions—including synaptic plasticity and memory, 20 , 21 neuronal excitability, 22 , 23 neurotransmitter release, 24 , 25 axon growth 26 and long-term changes in gene expression 27 —highlighting the central integrating position played by IP 3 Rs. 28 Ca 2+ release is activated in response to the second messenger IP 3 , which is produced on stimulation of G protein-coupled receptors (GPCRs) 29 and tyrosine kinase-linked 30 cell surface receptors. The specificity of the resulting cellular responses is ensured by an exquisite temporo-spatial patterning of cytosolic Ca 2+ signals. 31 , 32 Opening of the IP 3 R channel requires not only IP 3 , but also binding of Ca 2+ to receptor sites on the cytosolic face. This leads to biphasic regulation, such that small elevations of cytosolic Ca 2+ induce channel opening, whereas larger elevations cause inactivation. 33 The positive feedback by Ca 2+ (Ca 2+ -induced Ca 2+ release; CICR), may remain restricted to individual or clustered IP 3 Rs, producing local Ca 2+ signals known, respectively, as Ca 2+ blips and puffs, 34 or may propagate throughout the cell as a saltatory wave by successive cycles of Ca 2+ diffusion and CICR. Thus, IP 3 -mediated Ca 2+ signaling represents a hierarchy of Ca 2+ events of differing magnitudes. 35 , 36 The spatial patterning it orchestrates is critical to proper cellular function, and we hypothesize that disruptions in the magnitude and organization of neuronal Ca 2+ signals may contribute to the pathogenesis of ASD. Our understanding of the etiology of ASD 8 , 9 , 37 has been greatly advanced by studies of syndromic forms of ASD caused by rare single gene mutations. Fragile X (FXS) is the most common monogenic cause of ASD, 38 and is a widely used and well-characterized model of ASD. 37 , 39 It results from silencing of the fragile X mental retardation ( FMR1) gene and absence of its corresponding protein, the FXS mental retardation protein (FMRP). Tuberous sclerosis (TS) is a syndrome caused by dominant mutations in one of two genes, hamartin ( TSC1 ) or tuberin ( TSC2 ), causing ASD-like behaviors, seizures, intellectual disability and characteristic brain and skin lesions. Here, we used primary, untransformed skin fibroblasts derived from patients with FXS and TS to evaluate ASD-associated functional deficits in IP 3 -mediated Ca 2+ signaling. The physiology of IP 3 signaling in fibroblasts has been extensively characterized, 40 , 41 , 42 providing a validated and convenient model for the study of Ca 2+ signaling in ASD, with the further advantage that cell lines are readily obtained as clinical samples from both disease and matched control patient populations. Moreover, identification of disease-specific signaling defects in skin cells have potential as biomarkers for diagnostic purposes, much as is now routine in other organelle diseases, such as Tay–Sachs and Niemann–Pick diseases, 43 , 44 and through which novel therapies for these diseases have emerged. 45 Our results demonstrate that IP 3 -mediated Ca 2+ signals are significantly depressed in fibroblasts from both FXS and TS patients and, by resolving signals at the single-channel level, we provide evidence of fundamental defects in IP 3 R channel activity in ASD. We thus propose dysregulated IP 3 R signaling as a nexus where genes altered in ASD converge to exert their deleterious effect. Materials and methods Materials The membrane-permeant caged IP 3 analog ci-IP 3 /PM (D-2,3-O-Isopropylidene-6-O-(2-nitro-4,5-dimethoxy)benzyl-myo-Inositol 1,4,5-trisphosphate-Hexakis (propionoxymethyl) Ester) was obtained from SiChem (Bremen, Germany),<|im_end|> <|im_start|>assistant By identifying a key signaling defect within a specific membrane structure in all cells, University of California, Irvine researchers believe, they have found both a possible reliable biomarker for diagnosing certain forms of autism and a potential therapeutic target. Dr. J. Jay Gargus, Ian Parker and colleagues at the UCI Center for Autism Research & Translation examined skin biopsies of patients with three very different genetic types of the disorder (fragile X syndrome and tuberous sclerosis 1 and 2). They discovered that a cellular calcium signaling process involving the inositol trisphosphate receptor was very much altered. This IP3R functional defect was located in the endoplasmic reticulum, which is among the specialized membrane compartments in cells called organelles, and may underpin cognitive impairments - and possibly digestive and immune problems - associated with autism. "We believe this finding will be another arrow in the quiver for early and accurate diagnoses of autism spectrum disorders," said Gargus, director of the Center for Autism Research & Translation and professor of pediatrics and physiology & biophysics. "Equally exciting, it also presents a target of a molecular class already well-established to be useful for drug discovery." Study results appear online in Translational Psychiatry, a Nature publication. Autism spectrum disorder is a range of complex neurodevelopmental disorders affecting 2 percent of U.S. children. The social and economic burden of ASD is enormous, currently estimated at more than $66 billion per year in the U.S. alone. Drug development has proven problematic due to the limited understanding of the underlying causes of ASD, as demonstrated by the recent failure of several much anticipated drug trials. There are also no current, reliable diagnostic biomarkers for ASD. Genetic research has identified hundreds of genes that are involved, which impedes diagnosis and, ultimately, drug development. There simply may be too many targets, each with too small an effect. Many of these genes associated with ASD, however, have been found to be part of the same signaling pathway, and multiple defects in this pathway may converge to produce a large functional change. The UCI scientists detected such a convergence in the IP3R calcium channel in an organelle called the endoplasmic reticulum. Organelles are membrane structures within cells with specialized cellular functions. According to Gargus, diseases of the organelles, such as the ER, are an emerging field in medicine, with several well-recognized neurological ailments linked to two other ones, the mitochondria and lysosomes. The IP3R controls the release of calcium from the ER. In the brain, calcium is used to communicate information within and between neurons, and it activates a host of other cell functions, including ones regulating learning and memory, neuronal excitability and neurotransmitter release - areas known to be dysfunctional in ASD. "We propose that the proper function of this channel and its signaling pathway is critical for normal performance of neurons and that this signaling pathway represents a key 'hub' in the pathogenesis of ASD," said Parker, a fellow of London's Royal Society and UCI professor of neurobiology & behavior, who studies cellular calcium signaling. To see if IP3R function is altered across the autism spectrum, clinical researchers at the Center for Autism & Neurodevelopmental Disorders - which is affiliated with the Center for Autism Research & Translation - are currently expanding the study and have begun to examine children with and without typical ASD for the same signaling abnormalities. These patients undergo complete behavioral diagnostic testing, and sophisticated EEG, sleep and biochemical studies are performed. This includes the sequencing of their entire genome. Also, skin cell samples are cultured and made available to lab-based researchers for functional assays. In the area of drug discovery, scientists at the Center for Autism Research & Translation continue to probe the IP3R channel, specifically how it regulates the level of neuron excitability. The brains of people who have autism show signs of hyperexcitability, which is also seen in epilepsy, a disorder increasingly found to be associated with ASD. Cells from individuals who have autism exhibit depressed levels of calcium signaling, and this might explain why these patients experience this hyperexcitability. By restoring the release of calcium from the IP3R, the researchers believe, they can apply a "brake" on this activity. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Haematopoietic stem cells (HSCs) maintain lifelong blood production and increase blood cell numbers in response to chronic and acute injury. However, the mechanism(s) by which inflammatory insults are communicated to HSCs and their consequences for HSC activity remain largely unknown. Here, we demonstrate that interleukin-1 (IL-1), which functions as a key pro-inflammatory ‘emergency’ signal, directly accelerates cell division and myeloid differentiation of HSCs through precocious activation of a PU.1-dependent gene program. Although this effect is essential for rapid myeloid recovery following acute injury to the bone marrow, chronic IL-1 exposure restricts HSC lineage output, severely erodes HSC self-renewal capacity, and primes IL-1-exposed HSCs to fail massive replicative challenges such as transplantation. Importantly, these damaging effects are transient and fully reversible on IL-1 withdrawal. Our results identify a critical regulatory circuit that tailors HSC responses to acute needs, and is likely to underlie deregulated blood homeostasis in chronic inflammation conditions. Main All lineages of haematopoietic cells, including those of the immune system, arise from a rare population of self-renewing HSCs residing in the bone marrow (BM) of adult mammals 1 . Blood production by HSCs is regulated by the concerted action of cell-intrinsic transcription factors such as PU.1 and GATA-1, and cell-extrinsic determinants produced by the stromal and haematopoietic components of the BM niche, which together regulate HSC self-renewal and specify lineage commitment 2 , 3 . Although normally maintained in a largely quiescent or dormant state, most HSCs can be rapidly activated to proliferate and differentiate in response to acute needs such as regenerative challenges including myeloablation and transplantation, and physiological insults that induce an inflammatory state 4 , 5 , 6 . Inflammation is a critical physiological process that mediates host defence against invading pathogens, injury and other insults, and is characterized by rapid mobilization and overproduction of specialized immune cells, particularly myeloid cells 7 . Inflammation is communicated to the haematopoietic system, and HSCs in particular, either by direct sensing through Toll-like receptors (TLRs), or indirectly through a series of pro-inflammatory cytokines 8 , 9 , 10 . In particular, interferons (IFNs), both type-I (IFN-α/β) and type-II (IFN-γ), and tumour necrosis factor alpha (TNFα) directly impact HSC fate during an inflammatory response 11 , 12 , 13 , 14 and drive HSC specification during embryonic development 15 , 16 . Pro-inflammatory cytokines are therefore exciting new regulators of HSC function 17 , with much remaining to be understood regarding how inflammatory insults tailor blood production under homeostatic and disease conditions. Interleukin-1 (IL-1) was the first interleukin identified and is the founding member of a group of 11 cytokines (the IL-1 family), with a central role in responses to infections or sterile insults 18 , 19 . IL-1 consists of two related genes ( Il1a and Il1b ) with distinct regulation but similar biological activities 18 , which bind a broadly expressed surface receptor (IL-1R) and trigger downstream transcriptional responses through the adaptor protein MyD88 and a broad range of signalling pathways including NF-κB, p38 MAPK, JNK and AP-1 (ref. 20 ). IL-1 is a key ‘emergency’ signal that rapidly activates host defence and repair in many tissues, including the blood system, but also drives tissue dysfunction in the context of chronic inflammation and autoimmune diseases 7 , 19 . Acute IL-1 signalling is associated with increased myeloid cell production both in culture and in vivo in response to infection, irradiation or myeloablative chemotherapy 21 , 22 , 23 , 24 . Many of the inflammatory disease conditions associated with chronic IL-1 production such as rheumatoid arthritis, obesity and type-2 diabetes also feature severe haematological complications, including overproduction of tissue-damaging myeloid cells, loss of naive lymphoid cell production and chronic anaemia 25 , 26 , 27 . However, the mechanism by which IL-1 contributes to deregulated blood output in these conditions, and the functional consequences of both acute and chronic IL-1 exposure on HSC fate, is largely unknown. RESULTS IL-1 accelerates HSC differentiation To investigate IL-1 effects, we isolated HSCs (Lin − c-Kit + Sca-1 + Flk2 − CD48 − CD150 + ; Supplementary Fig. 1a ) from wild-type mice and monitored their expansion in liquid culture with or without (±) IL-1α or IL-1β (25 ng ml −1 ). Notably, HSCs cultured with IL-1 differentiated and expanded significantly faster than untreated HSCs over an 8-day period ( Fig. 1a ), which seemed to result from faster division rates as measured by carboxyfluorescein succinimidyl ester (CFSE) dilution assay after 60 h ( Fig. 1b ). To confirm accelerated cell division in HSC cultures, we used an automated single-cell tracking approach to continuously monitor cell division over a 6-day period ( Fig. 1c ) 28 . Remarkably, although the timing of the exit from quiescence first division seemed relatively unaffected in IL-1-treated HSCs, the kinetics of the subsequent differentiation divisions were significantly compressed ( Fig. 1d, e ). This effect was specific to HSCs, as expansion, survival and proliferation were unchanged in IL-1-treated granulocyte/macrophage progenitors (GMPs: Lin − c-Kit + Sca-1 − CD34 + FcγR + ) and multipotent progenitors (MPPs), including myeloid-biased MPP2 (Lin − c-Kit + Sca-1 + Flk2 − CD48 + CD150 + ) and MPP3 (Lin − c-Kit + Sca-1 + Flk2 − CD48 + CD150 − ) or lymphoid-primed MPP4 (Lin − c-Kit + Sca-1 + Flk2 + ) 29 , 30 , which all express IL-1R at similar levels to HSCs ( Supplementary Fig. 1a–e ). These results indicate that IL-1 specifically targets HSCs and accelerates their division kinetics. Figure 1: IL-1 accelerates HSC differentiation along the myeloid lineage. ( a ) Representative expansion in liquid culture ( n = 3 biological replicates per group). ( b ) CFSE dilution assays after 60 h. Data represent one of two replicate experiments. Grey histogram shows −IL-1β HSCs at 24 h. ( c – e ) Continuous single-cell tracking experiments ( n = 47 and 51 HSCs per group): experimental design ( c ), single-cell pedigrees of median division times ( d ), and box plot", "role": "user" }, { "content": "A study published today in the journal Nature Cell Biology shows that chronic exposure to an inflammatory \"emergency\" signal, interleukin-1, causes blood-forming bone marrow stem cells to produce cells needed to fight infection and repair injury, but at the expense of their own ability to self-renew and maintain a healthy blood system. This results in overproduction of aggressive immune cells capable of severely damaging tissues. Elevated interleukin-1 (IL-1) accompanies the chronic inflammation associated with human conditions including obesity, diabetes and autoimmune disorders. The imbalance of blood system cell types can result in inefficient oxygen delivery, immunodeficiency, and could predispose the development of cancer. \"Inflammation evolved to function for very short periods of time, marshaling resources to fight infections and repair damaged tissue. However, over long periods of time, these conditions become very toxic,\" says Eric M. Pietras, PhD, investigator at the University of Colorado Cancer Center and assistant professor at the CU School of Medicine Blood Cancer & BMT Program. Pietras performed the work as a postdoctoral researcher in the lab of Emmanuelle Passegué, PhD, professor at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at the University of California San Francisco. IL-1 is a cytokine long understood to be an essential signal the immune system uses to recruit and activate inflammatory cells needed to protect from and repair acute occurrences of infection or injury. However, elevated levels of IL-1 are a feature of chronic inflammation, as is commonly seen in aging, and with a number of disease conditions including obesity and type 2 diabetes, which are associated with Western diet and lifestyle. \"If you're working under a constant state of emergency, you become stressed and less effective. I think of blood stem cells in the same way,\" Pietras says. While blood-forming stem cells, also termed hematopoietic stem cells (or HSCs), are usually dormant in the bone marrow, \"waking\" occasionally to maintain proper blood levels in healthy individuals, Pietras and colleagues show that, \"these cells are also exquisitely sensitive to changes in their environment and react accordingly.\" Specifically, HSCs are sensitive to the amount of IL-1 they encounter, and go to work creating \"first responder\" myeloid cells needed to fight what they recognize as a crisis of infection or injury. If the IL-1 signal doesn't end, HSCs continue making these cells but at the expense of their ability to regenerate themselves and correctly build the rest of the blood system. \"They're receiving a signal telling them they need to keep building myeloid cells and as a result they don't make the other blood cells you need. You can end up with too few red blood cells, reducing the body's ability to deliver oxygen to cells. Or we see decreased production of new lymphoid cells, leaving the system potentially immunodeficient. These are all common features of chronically inflamed and even aged blood systems,\" Pietras says. Another major question was whether these effects are reversible, in other words, once an HSC has \"learned\" to overproduce myeloid cells, can it just as readily unlearn this function? The question has major implications for patient care, for example in the case of bone marrow stem cell transplant. For many years, bone marrow transplant has been used to treat leukemias by removing a patient's blood system and replacing it with that of a compatible donor. However, \"Our results show that not only should we be looking for markers of blood system compatibility, but we may also want to explore whether a potential donor's stem cells have been exposed to inflammation and may not be as effective at rebuilding the patient's blood system,\" Pietras says. \"Likewise, the presence of inflammation in the individual receiving the bone marrow could also be an important factor in how well the stem cells regenerate a new blood system once they are transplanted.\" Pietras also points out increased interest in \"autologous\" stem cell transplants to potentially treat autoimmune diseases and multiple myeloma, another type of leukemia. In this technique, a patient's healthy blood stem cells are removed and expanded. Components of the blood system responsible for the disease condition are killed and then the patient's original stem cells are reinfused and encouraged to regrow a new blood system. However, this approach would not be ideal if the original blood stem cells retained \"injuries\" that left them predisposed toward building a blood system that is imbalanced by the insult of chronic inflammation. To test the durability of the IL-1 insult to HSCs following chronic inflammation, Pietras treated mice for 20 days with IL-1 and then took it away for several weeks to see if the HSCs recovered. \"Our data suggest that it is possible to turn back the clock and reverse the effects of chronic inflammation on blood stem cells, perhaps using therapies already available in the clinic to block inflammatory signals such as IL-1,\" Pietras says. \"Of course, we don't yet know on a human scale how long it takes a stem cell to 'remember' these insults. It may be that after a longer period of exposure to IL-1, these changes become more fixed.\" Overall, the study demonstrates for the first time that blood stem cells adapt to meet what they recognize as the body's needs, and that chronic inflammation can act like a thumb on the scale, implying a need that does not really exist. \"For decades we have recognized the importance of these bone marrow stem cells in dealing with crisis while also maintaining the stability of the blood system. Now we show that conditions in the rest of the body can have profound implications for how stem cells behave, both in the blood and likely in many other tissues as well,\" Pietras says. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Haematopoietic stem cells (HSCs) maintain lifelong blood production and increase blood cell numbers in response to chronic and acute injury. However, the mechanism(s) by which inflammatory insults are communicated to HSCs and their consequences for HSC activity remain largely unknown. Here, we demonstrate that interleukin-1 (IL-1), which functions as a key pro-inflammatory ‘emergency’ signal, directly accelerates cell division and myeloid differentiation of HSCs through precocious activation of a PU.1-dependent gene program. Although this effect is essential for rapid myeloid recovery following acute injury to the bone marrow, chronic IL-1 exposure restricts HSC lineage output, severely erodes HSC self-renewal capacity, and primes IL-1-exposed HSCs to fail massive replicative challenges such as transplantation. Importantly, these damaging effects are transient and fully reversible on IL-1 withdrawal. Our results identify a critical regulatory circuit that tailors HSC responses to acute needs, and is likely to underlie deregulated blood homeostasis in chronic inflammation conditions. Main All lineages of haematopoietic cells, including those of the immune system, arise from a rare population of self-renewing HSCs residing in the bone marrow (BM) of adult mammals 1 . Blood production by HSCs is regulated by the concerted action of cell-intrinsic transcription factors such as PU.1 and GATA-1, and cell-extrinsic determinants produced by the stromal and haematopoietic components of the BM niche, which together regulate HSC self-renewal and specify lineage commitment 2 , 3 . Although normally maintained in a largely quiescent or dormant state, most HSCs can be rapidly activated to proliferate and differentiate in response to acute needs such as regenerative challenges including myeloablation and transplantation, and physiological insults that induce an inflammatory state 4 , 5 , 6 . Inflammation is a critical physiological process that mediates host defence against invading pathogens, injury and other insults, and is characterized by rapid mobilization and overproduction of specialized immune cells, particularly myeloid cells 7 . Inflammation is communicated to the haematopoietic system, and HSCs in particular, either by direct sensing through Toll-like receptors (TLRs), or indirectly through a series of pro-inflammatory cytokines 8 , 9 , 10 . In particular, interferons (IFNs), both type-I (IFN-α/β) and type-II (IFN-γ), and tumour necrosis factor alpha (TNFα) directly impact HSC fate during an inflammatory response 11 , 12 , 13 , 14 and drive HSC specification during embryonic development 15 , 16 . Pro-inflammatory cytokines are therefore exciting new regulators of HSC function 17 , with much remaining to be understood regarding how inflammatory insults tailor blood production under homeostatic and disease conditions. Interleukin-1 (IL-1) was the first interleukin identified and is the founding member of a group of 11 cytokines (the IL-1 family), with a central role in responses to infections or sterile insults 18 , 19 . IL-1 consists of two related genes ( Il1a and Il1b ) with distinct regulation but similar biological activities 18 , which bind a broadly expressed surface receptor (IL-1R) and trigger downstream transcriptional responses through the adaptor protein MyD88 and a broad range of signalling pathways including NF-κB, p38 MAPK, JNK and AP-1 (ref. 20 ). IL-1 is a key ‘emergency’ signal that rapidly activates host defence and repair in many tissues, including the blood system, but also drives tissue dysfunction in the context of chronic inflammation and autoimmune diseases 7 , 19 . Acute IL-1 signalling is associated with increased myeloid cell production both in culture and in vivo in response to infection, irradiation or myeloablative chemotherapy 21 , 22 , 23 , 24 . Many of the inflammatory disease conditions associated with chronic IL-1 production such as rheumatoid arthritis, obesity and type-2 diabetes also feature severe haematological complications, including overproduction of tissue-damaging myeloid cells, loss of naive lymphoid cell production and chronic anaemia 25 , 26 , 27 . However, the mechanism by which IL-1 contributes to deregulated blood output in these conditions, and the functional consequences of both acute and chronic IL-1 exposure on HSC fate, is largely unknown. RESULTS IL-1 accelerates HSC differentiation To investigate IL-1 effects, we isolated HSCs (Lin − c-Kit + Sca-1 + Flk2 − CD48 − CD150 + ; Supplementary Fig. 1a ) from wild-type mice and monitored their expansion in liquid culture with or without (±) IL-1α or IL-1β (25 ng ml −1 ). Notably, HSCs cultured with IL-1 differentiated and expanded significantly faster than untreated HSCs over an 8-day period ( Fig. 1a ), which seemed to result from faster division rates as measured by carboxyfluorescein succinimidyl ester (CFSE) dilution assay after 60 h ( Fig. 1b ). To confirm accelerated cell division in HSC cultures, we used an automated single-cell tracking approach to continuously monitor cell division over a 6-day period ( Fig. 1c ) 28 . Remarkably, although the timing of the exit from quiescence first division seemed relatively unaffected in IL-1-treated HSCs, the kinetics of the subsequent differentiation divisions were significantly compressed ( Fig. 1d, e ). This effect was specific to HSCs, as expansion, survival and proliferation were unchanged in IL-1-treated granulocyte/macrophage progenitors (GMPs: Lin − c-Kit + Sca-1 − CD34 + FcγR + ) and multipotent progenitors (MPPs), including myeloid-biased MPP2 (Lin − c-Kit + Sca-1 + Flk2 − CD48 + CD150 + ) and MPP3 (Lin − c-Kit + Sca-1 + Flk2 − CD48 + CD150 − ) or lymphoid-primed MPP4 (Lin − c-Kit + Sca-1 + Flk2 + ) 29 , 30 , which all express IL-1R at similar levels to HSCs ( Supplementary Fig. 1a–e ). These results indicate that IL-1 specifically targets HSCs and accelerates their division kinetics. Figure 1: IL-1 accelerates HSC differentiation along the myeloid lineage. ( a ) Representative expansion in liquid culture ( n = 3 biological replicates per group). ( b ) CFSE dilution assays after 60 h. Data represent one of two replicate experiments. Grey histogram shows −IL-1β HSCs at 24 h. ( c – e ) Continuous single-cell tracking experiments ( n = 47 and 51 HSCs per group): experimental design ( c ), single-cell pedigrees of median division times ( d ), and box plot<|im_end|> <|im_start|>assistant A study published today in the journal Nature Cell Biology shows that chronic exposure to an inflammatory "emergency" signal, interleukin-1, causes blood-forming bone marrow stem cells to produce cells needed to fight infection and repair injury, but at the expense of their own ability to self-renew and maintain a healthy blood system. This results in overproduction of aggressive immune cells capable of severely damaging tissues. Elevated interleukin-1 (IL-1) accompanies the chronic inflammation associated with human conditions including obesity, diabetes and autoimmune disorders. The imbalance of blood system cell types can result in inefficient oxygen delivery, immunodeficiency, and could predispose the development of cancer. "Inflammation evolved to function for very short periods of time, marshaling resources to fight infections and repair damaged tissue. However, over long periods of time, these conditions become very toxic," says Eric M. Pietras, PhD, investigator at the University of Colorado Cancer Center and assistant professor at the CU School of Medicine Blood Cancer & BMT Program. Pietras performed the work as a postdoctoral researcher in the lab of Emmanuelle Passegué, PhD, professor at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at the University of California San Francisco. IL-1 is a cytokine long understood to be an essential signal the immune system uses to recruit and activate inflammatory cells needed to protect from and repair acute occurrences of infection or injury. However, elevated levels of IL-1 are a feature of chronic inflammation, as is commonly seen in aging, and with a number of disease conditions including obesity and type 2 diabetes, which are associated with Western diet and lifestyle. "If you're working under a constant state of emergency, you become stressed and less effective. I think of blood stem cells in the same way," Pietras says. While blood-forming stem cells, also termed hematopoietic stem cells (or HSCs), are usually dormant in the bone marrow, "waking" occasionally to maintain proper blood levels in healthy individuals, Pietras and colleagues show that, "these cells are also exquisitely sensitive to changes in their environment and react accordingly." Specifically, HSCs are sensitive to the amount of IL-1 they encounter, and go to work creating "first responder" myeloid cells needed to fight what they recognize as a crisis of infection or injury. If the IL-1 signal doesn't end, HSCs continue making these cells but at the expense of their ability to regenerate themselves and correctly build the rest of the blood system. "They're receiving a signal telling them they need to keep building myeloid cells and as a result they don't make the other blood cells you need. You can end up with too few red blood cells, reducing the body's ability to deliver oxygen to cells. Or we see decreased production of new lymphoid cells, leaving the system potentially immunodeficient. These are all common features of chronically inflamed and even aged blood systems," Pietras says. Another major question was whether these effects are reversible, in other words, once an HSC has "learned" to overproduce myeloid cells, can it just as readily unlearn this function? The question has major implications for patient care, for example in the case of bone marrow stem cell transplant. For many years, bone marrow transplant has been used to treat leukemias by removing a patient's blood system and replacing it with that of a compatible donor. However, "Our results show that not only should we be looking for markers of blood system compatibility, but we may also want to explore whether a potential donor's stem cells have been exposed to inflammation and may not be as effective at rebuilding the patient's blood system," Pietras says. "Likewise, the presence of inflammation in the individual receiving the bone marrow could also be an important factor in how well the stem cells regenerate a new blood system once they are transplanted." Pietras also points out increased interest in "autologous" stem cell transplants to potentially treat autoimmune diseases and multiple myeloma, another type of leukemia. In this technique, a patient's healthy blood stem cells are removed and expanded. Components of the blood system responsible for the disease condition are killed and then the patient's original stem cells are reinfused and encouraged to regrow a new blood system. However, this approach would not be ideal if the original blood stem cells retained "injuries" that left them predisposed toward building a blood system that is imbalanced by the insult of chronic inflammation. To test the durability of the IL-1 insult to HSCs following chronic inflammation, Pietras treated mice for 20 days with IL-1 and then took it away for several weeks to see if the HSCs recovered. "Our data suggest that it is possible to turn back the clock and reverse the effects of chronic inflammation on blood stem cells, perhaps using therapies already available in the clinic to block inflammatory signals such as IL-1," Pietras says. "Of course, we don't yet know on a human scale how long it takes a stem cell to 'remember' these insults. It may be that after a longer period of exposure to IL-1, these changes become more fixed." Overall, the study demonstrates for the first time that blood stem cells adapt to meet what they recognize as the body's needs, and that chronic inflammation can act like a thumb on the scale, implying a need that does not really exist. "For decades we have recognized the importance of these bone marrow stem cells in dealing with crisis while also maintaining the stability of the blood system. Now we show that conditions in the rest of the body can have profound implications for how stem cells behave, both in the blood and likely in many other tissues as well," Pietras says. <|im_end|>

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2,739

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Understanding genomic functions requires site-specific manipulation of loci via efficient protein effector targeting systems. However, few approaches for targeted manipulation of the epigenome are available in plants. Here, we adapt the dCas9-SunTag system to engineer targeted gene activation and DNA methylation in Arabidopsis . We demonstrate that a dCas9-SunTag system utilizing the transcriptional activator VP64 drives robust and specific activation of several loci, including protein coding genes and transposable elements, in diverse chromatin contexts. In addition, we present a CRISPR-based methylation targeting system for plants, utilizing a SunTag system with the catalytic domain of the Nicotiana tabacum DRM methyltransferase, which efficiently targets DNA methylation to specific loci, including the FWA promoter, triggering a developmental phenotype, and the SUPERMAN promoter. These SunTag systems represent valuable tools for the site-specific manipulation of plant epigenomes. Introduction Gene transcription, and thus function, can be controlled in trans , via the binding of transcription factors to promoters, or in cis , via epigenetic modifications. Functional analyses of plant genomes have relied mainly on the indirect reactivation of genes or transposable elements (TEs) through the use of mutants 1 . However, the biological outcomes of these manipulations represent an aggregate view of gene expression changes. Examining epigenetic regulation of gene expression, such as by DNA methylation, faces similar issues, where indirect and widespread changes in epigenetic mutants complicate the exploration of locus-specific effects. Mutant analysis, hairpin-mediated targeting of small interfering RNAs (siRNAs), and zinc-finger-mediated targeting have been used to assess the function of genes and DNA methylation in plants 1 , 2 , 3 . For example, fusion of a zinc-finger protein to the RNA-directed DNA methylation effector SUVH9 enabled methylation of the Arabidopsis FWA promoter 3 . The fwa-4 ( fwa ) epiallele in Arabidopsis plants displays a loss of FWA promoter methylation, leading to FWA activation and a late flowering phenotype 3 . SUVH9-mediated de novo methylation of the FWA promoter in fwa plants restored FWA silencing and an early flowering phenotype 3 , indicating that promoter methylation was sufficient to regulate FWA expression. Although zinc-finger fusions are an effective tool, they are laborious to design, difficult to verify, and often display broad, off-target binding activity 4 . CRISPR-Cas approaches enable targeted manipulation of specific loci 5 . Synthetic transcriptional activators, for instance consisting of deactivated versions of Cas9 (dCas9) fused to transcriptional activation domains, can specifically activate genes in both plants and mammals 6 , 7 , 8 , 9 , 10 , 11 , 12 . Several other CRISPR-Cas9-based activation systems, such as the synergistic activation mediator (SAM) as well as a hybrid VP64-p65-Rta (VPR) activator, have been developed to further enhance dCas9-mediated transcriptional upregulation as well as to recruit multiple protein effectors 13 , 14 . The dCas9-SunTag-VP64 system is a potent transcriptional activator in mammalian cell lines 15 , 16 . This system consists of two modules: dCas9 fused to tandem GCN4 peptide repeats, and a single chain variable fragment (scFv) GCN4 antibody fused to superfolder-GFP (sfGFP) and VP64. Thus, multiple copies of the VP64 transcriptional activator associate with the GCN4 repeats and are recruited to a specific locus via dCas9/guide RNAs. This method has been adapted for site-specific DNA demethylation in mammals and plants, and for DNA methylation in mammals 17 , 18 , 19 . DNA methylation in plants exists in three different nucleotide contexts: CG, CHG, and CHH (where H = A, T, or C) 20 . Maintenance methylation is controlled by several pathways in Arabidopsis : CG methylation is maintained by DNA METHYLTRANSFERASE 1 (MET1), a homolog of DNMT1; CHG methylation is maintained by CHROMOMETHYLASE 3 (CMT3), a plant specific methyltransferase; and much of the CHH methylation is maintained by DOMAINS REARRANGED METHYLTRANSFERASE 2 (DRM2)-a homologue of DNMT3 methyltransferases-through the RNA-directed DNA methylation (RdDM) pathway. While DRM2 is responsible for CHH maintenance methylation in short euchromatic regions, short TEs, and the edges of long TEs, CHROMOMETHYLASE 2 (CMT2) is responsible for CHH methylation in pericentromeric heterochromatin and the bodies of long TEs 21 , 22 . RdDM is also responsible for de novo methylation of all three sequence contexts 20 , 23 . Here, we have developed CRISPR-Cas9-SunTag-based targeting systems to site-specifically and efficiently manipulate gene methylation and expression in plants. We modified the SunTag system to recruit multiple copies of a methylation effector or of VP64 to distinct loci. Using the previously characterized Nicotiana tabacum DRM methyltransferase catalytic domain as our methylation effector 24 , we found that SunTag NtDRMcd effectively targets methylation to specific loci. Importantly, at the FWA locus, this methylated state remains meiotically heritable through multiple generations in the absence of the targeting transgene. Results Targeted transcriptional activation of the FWA locus We previously adapted the SunTag system for site-specific DNA demethylation in plants by targeting the human TET1 catalytic domain to Arabidopsis loci 18 . To generate a transcriptional activator system, we used the Arabidopsis UBIQUITIN10 ( UBQ10 ) promoter to drive the expression of dCas9-10 × GCN4 and of scFv-sfGFP-VP64 (Supplementary Fig. 1a ). Additionally, we added an SV40-type NLS to the scFv module to ensure proper nuclear import in plants. Imaging of the roots of T2 transgenic Arabidopsis plants expressing the SunTag VP64 construct showed clear nuclear localization of the antibody module (Supplementary Fig. 1b). In addition, dCas9-10 × GCN4 was stably expressed in T2 Arabidopsis plants (Supplementary Fig. 1c). To test whether this system activates gene expression, we targeted the DNA methylated and silent FWA gene in Arabidopsis wild-type (Col-0) plants 25 . We observed ectopic activation of FWA in numerous T1 lines containing a single guide RNA (gRNA4) that targets FWA , but not in control lines that lack a guide (nog) or that lack VP64 (Supplementary Fig. 2a, b ). Strong activation of FWA was also observed in the next generation T2 plants (Supplementary Fig. 2b,c ). RNA-seq of T2 gRNA4 plants confirmed that FWA was robustly upregulated (Fig. 1a and Supplementary Fig. 2d ). In addition to gRNA4, we tested a guide (gRNA17) that", "role": "user" }, { "content": "UCLA biologist Steve Jacobsen's research has the potential to have a significant impact on the improvement of crops. Jacobsen, who is a professor of molecular, cell and developmental biology, specializes in plant epigenetics—the study of how a gene's function can change without changes to the DNA sequence—and his research could lead to more resilient crops. \"Epigenetic science has many applications, with one of the most promising areas being agriculture,\" said Jacobsen, an investigator of the Howard Hughes Medical Institute. Jacobsen is also scientific co-founder of the company Inari, which has licensed plant breeding patents he developed at UCLA. Inari is a plant-breeding company that equips crops to be more resilient to climate change, and is enhancing plant breeding by tapping natural genetic diversity. Decades of intensive breeding for desirable characteristics, such as higher yield or resistance to specific diseases, has increased our food supply, but has also led to genetic uniformity in many crops. In some cases, this means the loss of natural resistance to disease compared with their more genetically diverse wild relatives. This loss could leave our food supply vulnerable to future stressors, including those induced by climate change, at a time when the global population is projected to see considerable growth. Inari is working to discover and re-introduce these genes, so crops can exhibit natural resilience while meeting the nutritional demands of a growing worldwide population. The company has introduced the world's first seed foundry as part of its mission to revolutionize the seed industry. The agreement provides Inari with new ways to improve plant performance by tapping natural genetic diversity, and provides access to technology that influences a plant's genes without altering its genetic code. \"Discoveries that take place in our laboratories directly help solve global issues, and the fragility of the food system has been an issue of concern for some time now,\" said Roger Wakimoto, UCLA vice chancellor for research. \"Through Inari, we're able to apply high-impact research and scientific techniques to the private sector and watch the benefits unfold.\" Inari is currently developing its first wave of commercial crop varieties, including corn, soy and wheat. \"Collaboration and partnerships drive change that addresses the critical problems we face globally in agriculture,\" said Ponsi Trivisvavet, CEO of Inari. \"Licensing this technology from UCLA provides us with a robust new approach that strengthens our efforts to create a winning food system.\" Jacobsen's epigenetics research, which was funded in part by the Bill & Melinda Gates Foundation, was published online Feb. 7 in the journal Cell, and published today in the journal Nature Communications. These research papers from Jacobsen's laboratory, along with earlier research from his laboratory, describe the inner workings of epigenetic pathways in plants, and describe tools that allow for \"precise changes in gene expression through modulation of epigenetics,\" Jacobsen said. The Cell research describes, among other scientific issues, various proteins in the plant Arabidopsis, and how they can be used to target DNA methylation. Jacobsen's research team explains in detail exactly how specific biological pathways work. (DNA methylation is a process by which a methyl group is added to DNA, and is important in regulating genes) The Nature Communications paper describes the development of a system based on CRISPR—a powerful tool for editing DNA sequences at specific locations and modifying the functions of genes— to target methylation and gene silencing in a much more precise way than ever before and describes a system for targeting the activation of genes using a CRISPR system. A paper by Jacobsen's laboratory published in in the journal PNAS in 2018 describes another scientific tool, also based on a CRISPR system, to target the precise removal of DNA methylation at a gene, which causes the gene to be activated. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Understanding genomic functions requires site-specific manipulation of loci via efficient protein effector targeting systems. However, few approaches for targeted manipulation of the epigenome are available in plants. Here, we adapt the dCas9-SunTag system to engineer targeted gene activation and DNA methylation in Arabidopsis . We demonstrate that a dCas9-SunTag system utilizing the transcriptional activator VP64 drives robust and specific activation of several loci, including protein coding genes and transposable elements, in diverse chromatin contexts. In addition, we present a CRISPR-based methylation targeting system for plants, utilizing a SunTag system with the catalytic domain of the Nicotiana tabacum DRM methyltransferase, which efficiently targets DNA methylation to specific loci, including the FWA promoter, triggering a developmental phenotype, and the SUPERMAN promoter. These SunTag systems represent valuable tools for the site-specific manipulation of plant epigenomes. Introduction Gene transcription, and thus function, can be controlled in trans , via the binding of transcription factors to promoters, or in cis , via epigenetic modifications. Functional analyses of plant genomes have relied mainly on the indirect reactivation of genes or transposable elements (TEs) through the use of mutants 1 . However, the biological outcomes of these manipulations represent an aggregate view of gene expression changes. Examining epigenetic regulation of gene expression, such as by DNA methylation, faces similar issues, where indirect and widespread changes in epigenetic mutants complicate the exploration of locus-specific effects. Mutant analysis, hairpin-mediated targeting of small interfering RNAs (siRNAs), and zinc-finger-mediated targeting have been used to assess the function of genes and DNA methylation in plants 1 , 2 , 3 . For example, fusion of a zinc-finger protein to the RNA-directed DNA methylation effector SUVH9 enabled methylation of the Arabidopsis FWA promoter 3 . The fwa-4 ( fwa ) epiallele in Arabidopsis plants displays a loss of FWA promoter methylation, leading to FWA activation and a late flowering phenotype 3 . SUVH9-mediated de novo methylation of the FWA promoter in fwa plants restored FWA silencing and an early flowering phenotype 3 , indicating that promoter methylation was sufficient to regulate FWA expression. Although zinc-finger fusions are an effective tool, they are laborious to design, difficult to verify, and often display broad, off-target binding activity 4 . CRISPR-Cas approaches enable targeted manipulation of specific loci 5 . Synthetic transcriptional activators, for instance consisting of deactivated versions of Cas9 (dCas9) fused to transcriptional activation domains, can specifically activate genes in both plants and mammals 6 , 7 , 8 , 9 , 10 , 11 , 12 . Several other CRISPR-Cas9-based activation systems, such as the synergistic activation mediator (SAM) as well as a hybrid VP64-p65-Rta (VPR) activator, have been developed to further enhance dCas9-mediated transcriptional upregulation as well as to recruit multiple protein effectors 13 , 14 . The dCas9-SunTag-VP64 system is a potent transcriptional activator in mammalian cell lines 15 , 16 . This system consists of two modules: dCas9 fused to tandem GCN4 peptide repeats, and a single chain variable fragment (scFv) GCN4 antibody fused to superfolder-GFP (sfGFP) and VP64. Thus, multiple copies of the VP64 transcriptional activator associate with the GCN4 repeats and are recruited to a specific locus via dCas9/guide RNAs. This method has been adapted for site-specific DNA demethylation in mammals and plants, and for DNA methylation in mammals 17 , 18 , 19 . DNA methylation in plants exists in three different nucleotide contexts: CG, CHG, and CHH (where H = A, T, or C) 20 . Maintenance methylation is controlled by several pathways in Arabidopsis : CG methylation is maintained by DNA METHYLTRANSFERASE 1 (MET1), a homolog of DNMT1; CHG methylation is maintained by CHROMOMETHYLASE 3 (CMT3), a plant specific methyltransferase; and much of the CHH methylation is maintained by DOMAINS REARRANGED METHYLTRANSFERASE 2 (DRM2)-a homologue of DNMT3 methyltransferases-through the RNA-directed DNA methylation (RdDM) pathway. While DRM2 is responsible for CHH maintenance methylation in short euchromatic regions, short TEs, and the edges of long TEs, CHROMOMETHYLASE 2 (CMT2) is responsible for CHH methylation in pericentromeric heterochromatin and the bodies of long TEs 21 , 22 . RdDM is also responsible for de novo methylation of all three sequence contexts 20 , 23 . Here, we have developed CRISPR-Cas9-SunTag-based targeting systems to site-specifically and efficiently manipulate gene methylation and expression in plants. We modified the SunTag system to recruit multiple copies of a methylation effector or of VP64 to distinct loci. Using the previously characterized Nicotiana tabacum DRM methyltransferase catalytic domain as our methylation effector 24 , we found that SunTag NtDRMcd effectively targets methylation to specific loci. Importantly, at the FWA locus, this methylated state remains meiotically heritable through multiple generations in the absence of the targeting transgene. Results Targeted transcriptional activation of the FWA locus We previously adapted the SunTag system for site-specific DNA demethylation in plants by targeting the human TET1 catalytic domain to Arabidopsis loci 18 . To generate a transcriptional activator system, we used the Arabidopsis UBIQUITIN10 ( UBQ10 ) promoter to drive the expression of dCas9-10 × GCN4 and of scFv-sfGFP-VP64 (Supplementary Fig. 1a ). Additionally, we added an SV40-type NLS to the scFv module to ensure proper nuclear import in plants. Imaging of the roots of T2 transgenic Arabidopsis plants expressing the SunTag VP64 construct showed clear nuclear localization of the antibody module (Supplementary Fig. 1b). In addition, dCas9-10 × GCN4 was stably expressed in T2 Arabidopsis plants (Supplementary Fig. 1c). To test whether this system activates gene expression, we targeted the DNA methylated and silent FWA gene in Arabidopsis wild-type (Col-0) plants 25 . We observed ectopic activation of FWA in numerous T1 lines containing a single guide RNA (gRNA4) that targets FWA , but not in control lines that lack a guide (nog) or that lack VP64 (Supplementary Fig. 2a, b ). Strong activation of FWA was also observed in the next generation T2 plants (Supplementary Fig. 2b,c ). RNA-seq of T2 gRNA4 plants confirmed that FWA was robustly upregulated (Fig. 1a and Supplementary Fig. 2d ). In addition to gRNA4, we tested a guide (gRNA17) that<|im_end|> <|im_start|>assistant UCLA biologist Steve Jacobsen's research has the potential to have a significant impact on the improvement of crops. Jacobsen, who is a professor of molecular, cell and developmental biology, specializes in plant epigenetics—the study of how a gene's function can change without changes to the DNA sequence—and his research could lead to more resilient crops. "Epigenetic science has many applications, with one of the most promising areas being agriculture," said Jacobsen, an investigator of the Howard Hughes Medical Institute. Jacobsen is also scientific co-founder of the company Inari, which has licensed plant breeding patents he developed at UCLA. Inari is a plant-breeding company that equips crops to be more resilient to climate change, and is enhancing plant breeding by tapping natural genetic diversity. Decades of intensive breeding for desirable characteristics, such as higher yield or resistance to specific diseases, has increased our food supply, but has also led to genetic uniformity in many crops. In some cases, this means the loss of natural resistance to disease compared with their more genetically diverse wild relatives. This loss could leave our food supply vulnerable to future stressors, including those induced by climate change, at a time when the global population is projected to see considerable growth. Inari is working to discover and re-introduce these genes, so crops can exhibit natural resilience while meeting the nutritional demands of a growing worldwide population. The company has introduced the world's first seed foundry as part of its mission to revolutionize the seed industry. The agreement provides Inari with new ways to improve plant performance by tapping natural genetic diversity, and provides access to technology that influences a plant's genes without altering its genetic code. "Discoveries that take place in our laboratories directly help solve global issues, and the fragility of the food system has been an issue of concern for some time now," said Roger Wakimoto, UCLA vice chancellor for research. "Through Inari, we're able to apply high-impact research and scientific techniques to the private sector and watch the benefits unfold." Inari is currently developing its first wave of commercial crop varieties, including corn, soy and wheat. "Collaboration and partnerships drive change that addresses the critical problems we face globally in agriculture," said Ponsi Trivisvavet, CEO of Inari. "Licensing this technology from UCLA provides us with a robust new approach that strengthens our efforts to create a winning food system." Jacobsen's epigenetics research, which was funded in part by the Bill & Melinda Gates Foundation, was published online Feb. 7 in the journal Cell, and published today in the journal Nature Communications. These research papers from Jacobsen's laboratory, along with earlier research from his laboratory, describe the inner workings of epigenetic pathways in plants, and describe tools that allow for "precise changes in gene expression through modulation of epigenetics," Jacobsen said. The Cell research describes, among other scientific issues, various proteins in the plant Arabidopsis, and how they can be used to target DNA methylation. Jacobsen's research team explains in detail exactly how specific biological pathways work. (DNA methylation is a process by which a methyl group is added to DNA, and is important in regulating genes) The Nature Communications paper describes the development of a system based on CRISPR—a powerful tool for editing DNA sequences at specific locations and modifying the functions of genes— to target methylation and gene silencing in a much more precise way than ever before and describes a system for targeting the activation of genes using a CRISPR system. A paper by Jacobsen's laboratory published in in the journal PNAS in 2018 describes another scientific tool, also based on a CRISPR system, to target the precise removal of DNA methylation at a gene, which causes the gene to be activated. <|im_end|>

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2,364

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract High-throughput computational imaging requires efficient processing algorithms to retrieve multi-dimensional and multi-scale information. In computational phase imaging, phase retrieval (PR) is required to reconstruct both amplitude and phase in complex space from intensity-only measurements. The existing PR algorithms suffer from the tradeoff among low computational complexity, robustness to measurement noise and strong generalization on different modalities. In this work, we report an efficient large-scale phase retrieval technique termed as LPR . It extends the plug-and-play generalized-alternating-projection framework from real space to nonlinear complex space. The alternating projection solver and enhancing neural network are respectively derived to tackle the measurement formation and statistical prior regularization. This framework compensates the shortcomings of each operator, so as to realize high-fidelity phase retrieval with low computational complexity and strong generalization. We applied the technique for a series of computational phase imaging modalities including coherent diffraction imaging, coded diffraction pattern imaging, and Fourier ptychographic microscopy. Extensive simulations and experiments validate that the technique outperforms the existing PR algorithms with as much as 17dB enhancement on signal-to-noise ratio, and more than one order-of-magnitude increased running efficiency. Besides, we for the first time demonstrate ultra-large-scale phase retrieval at the 8K level ( 7680\\times 4320 7680\\times 4320 pixels) in minute-level time. Peer Review reports 1 Introduction Wide field of view and high resolution are both desirable for various imaging applications, such as medical imaging [ 1 , 2 , 3 , 4 ] and remote sensing [ 5 ], providing multi-dimensional and multi-scale target information. As the recent development of computational imaging, large-scale detection has been widely employed in a variety of computational imaging modalities [ 3 , 4 , 6 , 7 ]. These computational imaging techniques largely extend the spatial-bandwidth product (SBP) [ 8 ] of optical systems from million scale to billion scale. As an example, the SBP of the real-time, ultra-large-scale, high-resolution (RUSH) platform [ 4 ] and the Fourier ptychographic microscopy (FPM) [ 3 ] have reached to as high as 10 8 –10 9 . Such a large amount of data poses a great challenge for post software processing. Therefore, large-scale processing algorithms with low computational complexity and high fidelity are of great significance for those imaging and perception applications in various dimensions [ 9 ]. In computational phase imaging, phase retrieval (PR) is required to reconstruct both amplitude and phase in complex space from intensity-only measurements. This problem originates from the limitation of the low response speed of photodetectors that impedes direct acquisition of light wavefront. Mathematically, the underlying goal of PR is to estimate an unknown complex-field signal from the intensity-only measurements of its complex-valued transformation, which is described as \\begin{aligned} {I}=|{\\varvec{A}} u|^2+\\omega , \\end{aligned} \\begin{aligned} {I}=|{\\varvec{A}} u|^2+\\omega , \\end{aligned} (1) where u is the underlying signal to be recovered \\left( u \\in {\\mathbb {C}}^{n \\times 1}\\right) \\left( u \\in {\\mathbb {C}}^{n \\times 1}\\right) , I contains the intensity-only measurements \\left( I \\in {\\mathbb {R}}^{m \\times 1}\\right) \\left( I \\in {\\mathbb {R}}^{m \\times 1}\\right) , {\\varvec{A}} {\\varvec{A}} represents measurement matrix \\left( {\\varvec{A}} \\in {\\mathbb {R}}^{m \\times n} \\text{ or } {\\mathbb {C}}^{m \\times n}\\right) \\left( {\\varvec{A}} \\in {\\mathbb {R}}^{m \\times n} \\text{ or } {\\mathbb {C}}^{m \\times n}\\right) , and \\omega \\omega stands for measurement noise. Phase retrieval has been widely applied in plenty fields such as astronomy, crystallography, electron microscopy and optics [ 10 ]. It solves various nonlinear inverse problems in optical imaging, such as coherent diffraction imaging [ 11 ] (CDI), coded diffraction pattern imaging [ 12 ] (CDP), Fourier ptychographic microscopy [ 3 ] (FPM) and imaging through scattering medium [ 13 ]. In the past few decades, different phase retrieval algorithms have been developed. Gerchberg and Saxton pioneered the earliest alternating projection (AP) algorithm in the 1970s [ 14 ], which was then extended by Fienup et al. with several variants [ 15 ]. Due to its strong generalization ability, AP has been widely employed in multiple phase imaging models. Nevertheless, it is sensitive to measurement noise, suffering from poor noise robustness. Afterwards, researchers introduced optimization into PR, deriving a series of semi-definite programming (SDP) based algorithms [ 16 , 17 ] and Wirtinger flow (WF) based algorithms [ 18 , 19 , 20 ]. These techniques enhance robustness to measurement noise, but they require high computational complexity and high sampling rate, making them inapplicable for large-scale phase retrieval. Although the sparsity prior of natural images in transformed domains can be incorporated as an additional constraint to lower sampling rate [ 21 , 22 ], it further increases computational complexity. Although these algorithms can theoretically employ patch-wise [ 23 ] and parallel strategies to deal with large-scale data, such a manner leads to a heavier load of memory requirement. In the last few years, the booming deep learning (DL) technique has also been introduced for phase retrieval [ 24 ]. Following the large-scale training framework, the DL strategy outperforms the above traditional PR techniques with higher fidelity. However, it provides poor generalization that each suits only for specific models, such as holography [ 24 ] and FPM [ 25 ]. For different models and even different system parameters, the deep neural network requires to be retrained with new large-scale data sets. Recently, the prDeep technique [ 26 ] integrates iterative optimization and deep learning together, enabling to benefit from respective advantages. However, prDeep cannot recover complex-domain signals, leading to limited applications in practice. To sum, despite of different workflows, the above existing PR algorithms suffer from the tradeoff among low computational complexity, robustness to measurement noise and strong generalization, making them inapplicable for general large-scale phase retrieval. In this work, we report an efficient large-scale phase retrieval technique termed as LPR , as sketched in Fig. 1 . It builds on the plug-and-play (PNP) [ 27 ] optimization framework, and extends the efficient generalized-alternating-projection (GAP) [ 9 , 28 , 29 ] strategy from real space to nonlinear. The complex-field PNP-GAP scheme ensures strong generalization of LPR on various imaging modalities, and outperforms the", "role": "user" }, { "content": "Wide field of view and high resolution are both desirable for imaging applications, providing multi-dimensional and multi-scale target information. As the recent development of phase imaging, large-scale detection has been widely employed in a variety of imaging modalities, which largely extends the spatial-bandwidth product (SBP) of optical systems from million scale to billion scale. Such a large amount of data poses a great challenge for post phase retrieval (PR) processing. Therefore, large-scale PR technique with low computational complexity and high fidelity are of great significance for those imaging and perception applications in various dimensions. However, the existing PR algorithms suffer from the tradeoff among low computational complexity, robustness to measurement noise and strong generalization, making them inapplicable for general large-scale phase retrieval. In a newly published research article in eLight, a team of scientists, led by Professor Jun Zhang from Beijing Institute of Technology, China have developed an efficient large-scale phase retrieval technique for realizing high-fidelity complex-domain phase imaging. They combine the conventional optimization algorithm with the deep learning technique and realize low computational complexity, robustness to measurement noise and strong generalization. They compare the reported method with the existing PR methods on three imaging modalities, including coherent diffraction imaging (CDI), coded diffraction pattern imaging (CDP) and Fourier ptychographic microscopy (FPM). The results confirm that compared to the alternating projection (AP) algorithm, the reported technique is robust to measurement noise with as much as 17dB enhancement on signal-to-noise ratio. Compared with the optimization-based algorithms, the running time is significantly reduced by more than one order of magnitude. Besides, they for the first time demonstrate ultra-large-scale phase retrieval at the 8K level in minute-level time. The reported PR technique builds on the plug-and-play (PNP) optimization framework, and extends the efficient generalized-alternating-projection (GAP) strategy from real space to nonlinear space. These scientists summarize the characters of their technique: \"The complex-field PNP-GAP scheme ensures strong generalization of our technique on various imaging modalities, and outperforms the conventional PNP techniques with fewer auxiliary variables, lower computational complexity and faster convergence.\" \"Under GAP framework, the phase retrieval problem is decomposed with two sub-problems. We introduced an alternating projection solver and an enhancing neural network respectively to solve the two sub-problems. These two solvers compensate the shortcomings of each other, allowing the optimization to bypass the poor generalization of deep learning and poor noise robustness of AP. \"Benefiting from the flexible optimization framework, our technique is able to introduce the best solvers in the future to update itself. Besides, it is interesting to investigate the influence of employing other image enhancing solvers such as super-resolution neural network, deblurring network and distortion removal network. This may open new insights for phase retrieval with further boosted quality,\" the scientists write. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract High-throughput computational imaging requires efficient processing algorithms to retrieve multi-dimensional and multi-scale information. In computational phase imaging, phase retrieval (PR) is required to reconstruct both amplitude and phase in complex space from intensity-only measurements. The existing PR algorithms suffer from the tradeoff among low computational complexity, robustness to measurement noise and strong generalization on different modalities. In this work, we report an efficient large-scale phase retrieval technique termed as LPR . It extends the plug-and-play generalized-alternating-projection framework from real space to nonlinear complex space. The alternating projection solver and enhancing neural network are respectively derived to tackle the measurement formation and statistical prior regularization. This framework compensates the shortcomings of each operator, so as to realize high-fidelity phase retrieval with low computational complexity and strong generalization. We applied the technique for a series of computational phase imaging modalities including coherent diffraction imaging, coded diffraction pattern imaging, and Fourier ptychographic microscopy. Extensive simulations and experiments validate that the technique outperforms the existing PR algorithms with as much as 17dB enhancement on signal-to-noise ratio, and more than one order-of-magnitude increased running efficiency. Besides, we for the first time demonstrate ultra-large-scale phase retrieval at the 8K level ( 7680\times 4320 7680\times 4320 pixels) in minute-level time. Peer Review reports 1 Introduction Wide field of view and high resolution are both desirable for various imaging applications, such as medical imaging [ 1 , 2 , 3 , 4 ] and remote sensing [ 5 ], providing multi-dimensional and multi-scale target information. As the recent development of computational imaging, large-scale detection has been widely employed in a variety of computational imaging modalities [ 3 , 4 , 6 , 7 ]. These computational imaging techniques largely extend the spatial-bandwidth product (SBP) [ 8 ] of optical systems from million scale to billion scale. As an example, the SBP of the real-time, ultra-large-scale, high-resolution (RUSH) platform [ 4 ] and the Fourier ptychographic microscopy (FPM) [ 3 ] have reached to as high as 10 8 –10 9 . Such a large amount of data poses a great challenge for post software processing. Therefore, large-scale processing algorithms with low computational complexity and high fidelity are of great significance for those imaging and perception applications in various dimensions [ 9 ]. In computational phase imaging, phase retrieval (PR) is required to reconstruct both amplitude and phase in complex space from intensity-only measurements. This problem originates from the limitation of the low response speed of photodetectors that impedes direct acquisition of light wavefront. Mathematically, the underlying goal of PR is to estimate an unknown complex-field signal from the intensity-only measurements of its complex-valued transformation, which is described as \begin{aligned} {I}=|{\varvec{A}} u|^2+\omega , \end{aligned} \begin{aligned} {I}=|{\varvec{A}} u|^2+\omega , \end{aligned} (1) where u is the underlying signal to be recovered \left( u \in {\mathbb {C}}^{n \times 1}\right) \left( u \in {\mathbb {C}}^{n \times 1}\right) , I contains the intensity-only measurements \left( I \in {\mathbb {R}}^{m \times 1}\right) \left( I \in {\mathbb {R}}^{m \times 1}\right) , {\varvec{A}} {\varvec{A}} represents measurement matrix \left( {\varvec{A}} \in {\mathbb {R}}^{m \times n} \text{ or } {\mathbb {C}}^{m \times n}\right) \left( {\varvec{A}} \in {\mathbb {R}}^{m \times n} \text{ or } {\mathbb {C}}^{m \times n}\right) , and \omega \omega stands for measurement noise. Phase retrieval has been widely applied in plenty fields such as astronomy, crystallography, electron microscopy and optics [ 10 ]. It solves various nonlinear inverse problems in optical imaging, such as coherent diffraction imaging [ 11 ] (CDI), coded diffraction pattern imaging [ 12 ] (CDP), Fourier ptychographic microscopy [ 3 ] (FPM) and imaging through scattering medium [ 13 ]. In the past few decades, different phase retrieval algorithms have been developed. Gerchberg and Saxton pioneered the earliest alternating projection (AP) algorithm in the 1970s [ 14 ], which was then extended by Fienup et al. with several variants [ 15 ]. Due to its strong generalization ability, AP has been widely employed in multiple phase imaging models. Nevertheless, it is sensitive to measurement noise, suffering from poor noise robustness. Afterwards, researchers introduced optimization into PR, deriving a series of semi-definite programming (SDP) based algorithms [ 16 , 17 ] and Wirtinger flow (WF) based algorithms [ 18 , 19 , 20 ]. These techniques enhance robustness to measurement noise, but they require high computational complexity and high sampling rate, making them inapplicable for large-scale phase retrieval. Although the sparsity prior of natural images in transformed domains can be incorporated as an additional constraint to lower sampling rate [ 21 , 22 ], it further increases computational complexity. Although these algorithms can theoretically employ patch-wise [ 23 ] and parallel strategies to deal with large-scale data, such a manner leads to a heavier load of memory requirement. In the last few years, the booming deep learning (DL) technique has also been introduced for phase retrieval [ 24 ]. Following the large-scale training framework, the DL strategy outperforms the above traditional PR techniques with higher fidelity. However, it provides poor generalization that each suits only for specific models, such as holography [ 24 ] and FPM [ 25 ]. For different models and even different system parameters, the deep neural network requires to be retrained with new large-scale data sets. Recently, the prDeep technique [ 26 ] integrates iterative optimization and deep learning together, enabling to benefit from respective advantages. However, prDeep cannot recover complex-domain signals, leading to limited applications in practice. To sum, despite of different workflows, the above existing PR algorithms suffer from the tradeoff among low computational complexity, robustness to measurement noise and strong generalization, making them inapplicable for general large-scale phase retrieval. In this work, we report an efficient large-scale phase retrieval technique termed as LPR , as sketched in Fig. 1 . It builds on the plug-and-play (PNP) [ 27 ] optimization framework, and extends the efficient generalized-alternating-projection (GAP) [ 9 , 28 , 29 ] strategy from real space to nonlinear. The complex-field PNP-GAP scheme ensures strong generalization of LPR on various imaging modalities, and outperforms the<|im_end|> <|im_start|>assistant Wide field of view and high resolution are both desirable for imaging applications, providing multi-dimensional and multi-scale target information. As the recent development of phase imaging, large-scale detection has been widely employed in a variety of imaging modalities, which largely extends the spatial-bandwidth product (SBP) of optical systems from million scale to billion scale. Such a large amount of data poses a great challenge for post phase retrieval (PR) processing. Therefore, large-scale PR technique with low computational complexity and high fidelity are of great significance for those imaging and perception applications in various dimensions. However, the existing PR algorithms suffer from the tradeoff among low computational complexity, robustness to measurement noise and strong generalization, making them inapplicable for general large-scale phase retrieval. In a newly published research article in eLight, a team of scientists, led by Professor Jun Zhang from Beijing Institute of Technology, China have developed an efficient large-scale phase retrieval technique for realizing high-fidelity complex-domain phase imaging. They combine the conventional optimization algorithm with the deep learning technique and realize low computational complexity, robustness to measurement noise and strong generalization. They compare the reported method with the existing PR methods on three imaging modalities, including coherent diffraction imaging (CDI), coded diffraction pattern imaging (CDP) and Fourier ptychographic microscopy (FPM). The results confirm that compared to the alternating projection (AP) algorithm, the reported technique is robust to measurement noise with as much as 17dB enhancement on signal-to-noise ratio. Compared with the optimization-based algorithms, the running time is significantly reduced by more than one order of magnitude. Besides, they for the first time demonstrate ultra-large-scale phase retrieval at the 8K level in minute-level time. The reported PR technique builds on the plug-and-play (PNP) optimization framework, and extends the efficient generalized-alternating-projection (GAP) strategy from real space to nonlinear space. These scientists summarize the characters of their technique: "The complex-field PNP-GAP scheme ensures strong generalization of our technique on various imaging modalities, and outperforms the conventional PNP techniques with fewer auxiliary variables, lower computational complexity and faster convergence." "Under GAP framework, the phase retrieval problem is decomposed with two sub-problems. We introduced an alternating projection solver and an enhancing neural network respectively to solve the two sub-problems. These two solvers compensate the shortcomings of each other, allowing the optimization to bypass the poor generalization of deep learning and poor noise robustness of AP. "Benefiting from the flexible optimization framework, our technique is able to introduce the best solvers in the future to update itself. Besides, it is interesting to investigate the influence of employing other image enhancing solvers such as super-resolution neural network, deblurring network and distortion removal network. This may open new insights for phase retrieval with further boosted quality," the scientists write. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Ingested food and water stimulate sensory systems in the oropharyngeal and gastrointestinal areas before absorption 1 , 2 . These sensory signals modulate brain appetite circuits in a feed-forward manner 3 , 4 , 5 . Emerging evidence suggests that osmolality sensing in the gut rapidly inhibits thirst neurons upon water intake. Nevertheless, it remains unclear how peripheral sensory neurons detect visceral osmolality changes, and how they modulate thirst. Here we use optical and electrical recording combined with genetic approaches to visualize osmolality responses from sensory ganglion neurons. Gut hypotonic stimuli activate a dedicated vagal population distinct from mechanical-, hypertonic- or nutrient-sensitive neurons. We demonstrate that hypotonic responses are mediated by vagal afferents innervating the hepatic portal area (HPA), through which most water and nutrients are absorbed. Eliminating sensory inputs from this area selectively abolished hypotonic but not mechanical responses in vagal neurons. Recording from forebrain thirst neurons and behavioural analyses show that HPA-derived osmolality signals are required for feed-forward thirst satiation and drinking termination. Notably, HPA-innervating vagal afferents do not sense osmolality itself. Instead, these responses are mediated partly by vasoactive intestinal peptide secreted after water ingestion. Together, our results reveal visceral hypoosmolality as an important vagal sensory modality, and that intestinal osmolality change is translated into hormonal signals to regulate thirst circuit activity through the HPA pathway. Main Communication between the periphery and the brain serves as a critical component of appetite induction and satiation. All major circuits for hunger, thirst and sodium appetite receive pre-absorptive feed-forward satiation signals after nutrient ingestion through multiple sensory systems 3 , 4 , 6 , 7 , 8 , 9 , 10 . Forebrain lamina terminalis (LT) is the interoceptive brain area that regulates thirst and fluid intake. Recent studies have shown that thirst neurons in the LT are rapidly inhibited by liquid gulping signals from the upper digestive tract and osmolality signals from the gut 6 , 11 , 12 , 13 . Gut osmolality responses in sensory ganglia Multiple visceral afferent pathways are involved in gut osmolality sensing. Dorsal root ganglion (DRG) neurons are sensitive to hypotonic stimuli through a transient receptor potential (TRP) channel, possibly contributing to blood pressure regulation 14 , 15 . Another line of studies using vagotomy has demonstrated that normal water intake is disrupted without the functioning vagus nerve 12 , 16 , 17 , 18 . Despite these functional implications, osmolality responses in peripheral sensory ganglia have not been directly examined and characterized in vivo. Moreover, because sensory afferents innervate multiple organs of the gut, specific sensory sites for osmolality detection remain elusive. Here we exploit in vivo optical recording from peripheral sensory ganglia and central thirst circuits to examine the representation of visceral hypotonic stimuli. We show that the vagal signalling through the HPA, a combined area of the hepatic portal vein (HPV) and liver hilus, has a critical role in transmitting osmolality information from gut to brain to modulate thirst. To examine visceral osmolality responses, we performed recording from vagal and DRG neurons that carry the majority of gut sensory information. First, we recorded vagus nerve activity by in vivo electrophysiology combined with intestinal perfusion (Fig. 1a , Extended Data Fig. 1a ). Multiple stimuli activated the vagus nerve, including acidic solutions, liquid diet (Ensure) and mechanical distension 1 , 19 , 20 (Fig. 1b , Extended Data Fig. 1b ). Robust activation was also observed by intestinal water infusion. These responses were dose-dependent, as lower osmolality caused larger vagal activity (Fig. 1c ) but flow rate did not affect response amplitude (Fig. 1d , Extended Data Fig. 1c ). Next, we examined osmolality responses in the spinal pathway. We placed a gradient index (GRIN) lens on a thoracic DRG (T12 or T13), where gut signals are most abundantly represented (Extended Data Fig. 1d ). Calcium dynamics of individual neurons were then visualized in Slc17a6-cre ;Ai96 mice (Extended Data Fig. 1e ). While we observed calcium activity by intestinal infusion of water, nutrients or acid, these responses were sparse compared to robust tactile responses, and not precisely induced at the stimulus onset (Extended Data Fig. 1f ). Fig. 1: The vagus nerve responds to visceral osmolality changes. a , Diagram of electrophysiological recording of the vagus nerve. Electrical nerve activity was monitored during intestinal stimulation. b , Representative vagus nerve responses to intestinal infusion of isotonic saline, water, NaCl (1 M), acetic acid (4%), Ensure and intestinal distension (representative responses from 8 mice for saline and water, and from 6 mice for other stimuli). c , Dose dependence of osmolality responses. Representative integrated responses to 0–150 mM NaCl solutions (left) and quantification of responses (right) ( n = 6 mice). d , Water response at different flow rates. Faster flow rate induced shorter latency but did not affect peak response amplitude (representative responses from 5 mice). Blue shaded areas denote infusion periods. AUC, area under the curve. *P < 0.05, **P < 0.01, ***P < 0.001; Kruskal–Wallis test (with Dunn’s post test). Data are mean ± s.e.m. Source data Full size image Given the robust and time-locked responses in the vagus nerve, we next investigated how osmolality signals are represented by individual neurons. To achieve this, we genetically expressed GCaMP6s ( Slc17a6-cre ;Ai96 line) in vagal sensory neurons and performed imaging with confocal microscopy (Fig. 2a ). We found that a subset of gut-innervating vagal neurons were consistently activated upon intestinal water infusion (Extended Data Fig. 2a, b ). Hypo-osmotic, hyper-osmotic and glucose infusion for an extended period (2 min) activated large fractions of vagal neurons. Notably, nearly half of these neurons responded to multiple nutrients, which may reflect a combination of sensory nutrient detection and post-absorptive physiological changes as illustrated previously 19 , 21 (Fig. 2b ). To selectively visualize rapid sensory detection of osmolality, we used a short stimulation paradigm (20 s) (Extended Data Fig. 2c ). With this stimulation scheme, hypotonic responses were largely segregated from hypertonic, glucose and distension responses (Fig. 2c , Extended Data Fig.", "role": "user" }, { "content": "Drinking a glass of water is often sufficient to quench thirst after exercising. But while the sensation of thirst may be satiated after just a few minutes of drinking, the process of rehydration actually takes around half an hour. The delay occurs because the brain receives signals that you drank water before the body is fully rehydrated based on the detection and measurement of osmolality levels in the gut. Osmolality represents the concentration of dissolved materials including sodium and glucose. The laboratory of Caltech biologist Yuki Oka has worked to learn more about the gut-to-brain osmolality signaling that regulates thirst, and now his team has discovered the major sensory pathway that mediates this process. Oka, professor of biology, Chen Scholar, and Heritage Medical Research Institute Investigator; and his lab collaborated on the research with the lab of David Anderson, Seymour Benzer Professor of Biology and Howard Hughes Medical Institute Investigator. Anderson is the Tianqiao and Chrissy Chen Institute for Neuroscience Leadership Chair and director of the Tianqiao and Chrissy Chen Institute for Neuroscience at Caltech, of which Oka is also an affiliated faculty member. A paper describing the study appears in the journal Nature on January 26. Blood has high osmolality when our bodies are dehydrated, which triggers the feeling of thirst. But because of the time delay between when we feel quenched and when the body is fully rehydrated, the gut must sense osmolality changes before they happen in the bloodstream, and it must send this information to the brain. Once we ingest food and water, nutrients are absorbed from the intestine to the liver through the specialized blood vessel called the portal vein. During this absorption event, osmolality signals are also detected by sensory neurons in the gut. In the research, led by postdoctoral scholar Takako Ichiki and graduate student Tongtong Wang, the team examined how the gut communicates this information to the brain to indicate thirst or satiation. There are two major sensory pathways from the gut to the brain: the spinal (dorsal root ganglia, or DRG) and vagal pathways. In this study, Ichiki used genetically engineered mice to visualize neural activation patterns in these two pathways. She then systematically monitored DRG and vagal neurons in response to infusions of water, salt, or sugar into the mouse intestine that mimic normal nutrient ingestion. The team found that the vagal neurons, but not spinal neurons, are strongly activated upon osmolality changes in the gut. In fact, distinct subsets of neurons were active in response to the different liquids. The next question was: What part of the gut sends the osmolality information to the brain? The team examined the hepatic portal area (HPA), a major blood vessel running through the gut responsible for absorbing the vast majority of nutrients from the intestine and carrying them to the liver. They found that vagal nerves innervating the HPA indeed carry osmolality signals. Severing a specific vagal nerve branch to the HPA eliminated the ability of vagal neurons to respond to changes in osmolality. The team further investigated whether vagal nerves directly or indirectly sense osmolality changes in the gut. They found that, in response to osmolality changes in the intestine, one particular peptide, the vasoactive intestinal peptide, or VIP, is secreted into the portal vein, which in turn activates vagus nerves in the HPA area. This explains how the gut translates physical osmolality changes into hormonal signals that encode osmolality changes. \"We have discovered the beginning of a pathway, the HPA-to-brain axis,\" says Oka, who is also a New York Stem Cell Foundation Investigator. \"The details of all of the connections and molecular mechanisms are still to be determined.\" Additional future research will examine the connections between the vagal neurons in the body and the regions of the brain known to control thirst. In previous work, Oka lab researchers identified so-called thirst neurons within the brain's subfornical organ (SFO) region. When animals are thirsty, these neurons are highly active; drinking water rapidly calms them down. But the SFO thirst neurons are not directly connected to any gut neurons, so the team aims to figure out how changes in osmolality are communicated to the SFO thirst neurons. \"There is still so much that we don't know about how the nervous system controls basic functions, like thirst and satiety,\" says Karen David, Ph.D., program director at the National Institute of Neurological Disorders and Stroke. \"This study shows how approaches supported by the BRAIN Initiative are being used to uncover how brain circuits handle this important sensory information.\" The paper is titled \"Sensory representation and detection mechanisms of gut osmolality change.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Ingested food and water stimulate sensory systems in the oropharyngeal and gastrointestinal areas before absorption 1 , 2 . These sensory signals modulate brain appetite circuits in a feed-forward manner 3 , 4 , 5 . Emerging evidence suggests that osmolality sensing in the gut rapidly inhibits thirst neurons upon water intake. Nevertheless, it remains unclear how peripheral sensory neurons detect visceral osmolality changes, and how they modulate thirst. Here we use optical and electrical recording combined with genetic approaches to visualize osmolality responses from sensory ganglion neurons. Gut hypotonic stimuli activate a dedicated vagal population distinct from mechanical-, hypertonic- or nutrient-sensitive neurons. We demonstrate that hypotonic responses are mediated by vagal afferents innervating the hepatic portal area (HPA), through which most water and nutrients are absorbed. Eliminating sensory inputs from this area selectively abolished hypotonic but not mechanical responses in vagal neurons. Recording from forebrain thirst neurons and behavioural analyses show that HPA-derived osmolality signals are required for feed-forward thirst satiation and drinking termination. Notably, HPA-innervating vagal afferents do not sense osmolality itself. Instead, these responses are mediated partly by vasoactive intestinal peptide secreted after water ingestion. Together, our results reveal visceral hypoosmolality as an important vagal sensory modality, and that intestinal osmolality change is translated into hormonal signals to regulate thirst circuit activity through the HPA pathway. Main Communication between the periphery and the brain serves as a critical component of appetite induction and satiation. All major circuits for hunger, thirst and sodium appetite receive pre-absorptive feed-forward satiation signals after nutrient ingestion through multiple sensory systems 3 , 4 , 6 , 7 , 8 , 9 , 10 . Forebrain lamina terminalis (LT) is the interoceptive brain area that regulates thirst and fluid intake. Recent studies have shown that thirst neurons in the LT are rapidly inhibited by liquid gulping signals from the upper digestive tract and osmolality signals from the gut 6 , 11 , 12 , 13 . Gut osmolality responses in sensory ganglia Multiple visceral afferent pathways are involved in gut osmolality sensing. Dorsal root ganglion (DRG) neurons are sensitive to hypotonic stimuli through a transient receptor potential (TRP) channel, possibly contributing to blood pressure regulation 14 , 15 . Another line of studies using vagotomy has demonstrated that normal water intake is disrupted without the functioning vagus nerve 12 , 16 , 17 , 18 . Despite these functional implications, osmolality responses in peripheral sensory ganglia have not been directly examined and characterized in vivo. Moreover, because sensory afferents innervate multiple organs of the gut, specific sensory sites for osmolality detection remain elusive. Here we exploit in vivo optical recording from peripheral sensory ganglia and central thirst circuits to examine the representation of visceral hypotonic stimuli. We show that the vagal signalling through the HPA, a combined area of the hepatic portal vein (HPV) and liver hilus, has a critical role in transmitting osmolality information from gut to brain to modulate thirst. To examine visceral osmolality responses, we performed recording from vagal and DRG neurons that carry the majority of gut sensory information. First, we recorded vagus nerve activity by in vivo electrophysiology combined with intestinal perfusion (Fig. 1a , Extended Data Fig. 1a ). Multiple stimuli activated the vagus nerve, including acidic solutions, liquid diet (Ensure) and mechanical distension 1 , 19 , 20 (Fig. 1b , Extended Data Fig. 1b ). Robust activation was also observed by intestinal water infusion. These responses were dose-dependent, as lower osmolality caused larger vagal activity (Fig. 1c ) but flow rate did not affect response amplitude (Fig. 1d , Extended Data Fig. 1c ). Next, we examined osmolality responses in the spinal pathway. We placed a gradient index (GRIN) lens on a thoracic DRG (T12 or T13), where gut signals are most abundantly represented (Extended Data Fig. 1d ). Calcium dynamics of individual neurons were then visualized in Slc17a6-cre ;Ai96 mice (Extended Data Fig. 1e ). While we observed calcium activity by intestinal infusion of water, nutrients or acid, these responses were sparse compared to robust tactile responses, and not precisely induced at the stimulus onset (Extended Data Fig. 1f ). Fig. 1: The vagus nerve responds to visceral osmolality changes. a , Diagram of electrophysiological recording of the vagus nerve. Electrical nerve activity was monitored during intestinal stimulation. b , Representative vagus nerve responses to intestinal infusion of isotonic saline, water, NaCl (1 M), acetic acid (4%), Ensure and intestinal distension (representative responses from 8 mice for saline and water, and from 6 mice for other stimuli). c , Dose dependence of osmolality responses. Representative integrated responses to 0–150 mM NaCl solutions (left) and quantification of responses (right) ( n = 6 mice). d , Water response at different flow rates. Faster flow rate induced shorter latency but did not affect peak response amplitude (representative responses from 5 mice). Blue shaded areas denote infusion periods. AUC, area under the curve. *P < 0.05, **P < 0.01, ***P < 0.001; Kruskal–Wallis test (with Dunn’s post test). Data are mean ± s.e.m. Source data Full size image Given the robust and time-locked responses in the vagus nerve, we next investigated how osmolality signals are represented by individual neurons. To achieve this, we genetically expressed GCaMP6s ( Slc17a6-cre ;Ai96 line) in vagal sensory neurons and performed imaging with confocal microscopy (Fig. 2a ). We found that a subset of gut-innervating vagal neurons were consistently activated upon intestinal water infusion (Extended Data Fig. 2a, b ). Hypo-osmotic, hyper-osmotic and glucose infusion for an extended period (2 min) activated large fractions of vagal neurons. Notably, nearly half of these neurons responded to multiple nutrients, which may reflect a combination of sensory nutrient detection and post-absorptive physiological changes as illustrated previously 19 , 21 (Fig. 2b ). To selectively visualize rapid sensory detection of osmolality, we used a short stimulation paradigm (20 s) (Extended Data Fig. 2c ). With this stimulation scheme, hypotonic responses were largely segregated from hypertonic, glucose and distension responses (Fig. 2c , Extended Data Fig.<|im_end|> <|im_start|>assistant Drinking a glass of water is often sufficient to quench thirst after exercising. But while the sensation of thirst may be satiated after just a few minutes of drinking, the process of rehydration actually takes around half an hour. The delay occurs because the brain receives signals that you drank water before the body is fully rehydrated based on the detection and measurement of osmolality levels in the gut. Osmolality represents the concentration of dissolved materials including sodium and glucose. The laboratory of Caltech biologist Yuki Oka has worked to learn more about the gut-to-brain osmolality signaling that regulates thirst, and now his team has discovered the major sensory pathway that mediates this process. Oka, professor of biology, Chen Scholar, and Heritage Medical Research Institute Investigator; and his lab collaborated on the research with the lab of David Anderson, Seymour Benzer Professor of Biology and Howard Hughes Medical Institute Investigator. Anderson is the Tianqiao and Chrissy Chen Institute for Neuroscience Leadership Chair and director of the Tianqiao and Chrissy Chen Institute for Neuroscience at Caltech, of which Oka is also an affiliated faculty member. A paper describing the study appears in the journal Nature on January 26. Blood has high osmolality when our bodies are dehydrated, which triggers the feeling of thirst. But because of the time delay between when we feel quenched and when the body is fully rehydrated, the gut must sense osmolality changes before they happen in the bloodstream, and it must send this information to the brain. Once we ingest food and water, nutrients are absorbed from the intestine to the liver through the specialized blood vessel called the portal vein. During this absorption event, osmolality signals are also detected by sensory neurons in the gut. In the research, led by postdoctoral scholar Takako Ichiki and graduate student Tongtong Wang, the team examined how the gut communicates this information to the brain to indicate thirst or satiation. There are two major sensory pathways from the gut to the brain: the spinal (dorsal root ganglia, or DRG) and vagal pathways. In this study, Ichiki used genetically engineered mice to visualize neural activation patterns in these two pathways. She then systematically monitored DRG and vagal neurons in response to infusions of water, salt, or sugar into the mouse intestine that mimic normal nutrient ingestion. The team found that the vagal neurons, but not spinal neurons, are strongly activated upon osmolality changes in the gut. In fact, distinct subsets of neurons were active in response to the different liquids. The next question was: What part of the gut sends the osmolality information to the brain? The team examined the hepatic portal area (HPA), a major blood vessel running through the gut responsible for absorbing the vast majority of nutrients from the intestine and carrying them to the liver. They found that vagal nerves innervating the HPA indeed carry osmolality signals. Severing a specific vagal nerve branch to the HPA eliminated the ability of vagal neurons to respond to changes in osmolality. The team further investigated whether vagal nerves directly or indirectly sense osmolality changes in the gut. They found that, in response to osmolality changes in the intestine, one particular peptide, the vasoactive intestinal peptide, or VIP, is secreted into the portal vein, which in turn activates vagus nerves in the HPA area. This explains how the gut translates physical osmolality changes into hormonal signals that encode osmolality changes. "We have discovered the beginning of a pathway, the HPA-to-brain axis," says Oka, who is also a New York Stem Cell Foundation Investigator. "The details of all of the connections and molecular mechanisms are still to be determined." Additional future research will examine the connections between the vagal neurons in the body and the regions of the brain known to control thirst. In previous work, Oka lab researchers identified so-called thirst neurons within the brain's subfornical organ (SFO) region. When animals are thirsty, these neurons are highly active; drinking water rapidly calms them down. But the SFO thirst neurons are not directly connected to any gut neurons, so the team aims to figure out how changes in osmolality are communicated to the SFO thirst neurons. "There is still so much that we don't know about how the nervous system controls basic functions, like thirst and satiety," says Karen David, Ph.D., program director at the National Institute of Neurological Disorders and Stroke. "This study shows how approaches supported by the BRAIN Initiative are being used to uncover how brain circuits handle this important sensory information." The paper is titled "Sensory representation and detection mechanisms of gut osmolality change." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Empirical and theoretical studies suggest that marine species respond to ocean warming by shifting ranges poleward and/or into deeper depths. However, future distributional patterns of deep-sea organisms, which comprise the largest ecosystem of Earth, remain poorly known. We explore potential horizontal range shifts of benthic shallow-water and deep-sea Crustacea due to climatic changes within the remainder of the century, and discuss the results in light of species-specific traits related to invasiveness. Using a maximum entropy approach, we estimated the direction and magnitude of distributional shifts for 94 species belonging to 12 orders of benthic marine crustaceans, projected to the years 2050 and 2100. Distance, direction, and species richness shifts between climate zones were estimated conservatively, by considering only areas suitable, non-extrapolative, and adjacent to the currently known distributions. Our hypothesis is that species will present poleward range-shifts, based on results of previous studies. Results reveal idiosyncratic and species-specific responses, with prevailing poleward shifts and a decline of species richness at mid-latitudes, while more frequent shifts between temperate to polar regions were recovered. Shallow-water species are expected to shift longer distances than deep-sea species. Net gain of suitability is slightly higher than the net loss for shallow-water species, while for deep-sea species, the net loss is higher than the gain in all scenarios. Our estimates can be viewed as a set of hypotheses for future analytical and empirical studies, and will be useful in planning and executing strategic interventions and developing conservation strategies. Working on a manuscript? Avoid the common mistakes 1 Introduction Empirical and theoretical studies suggest that marine species respond to ocean warming by shifting ranges poleward and/or into deeper depths (Poloczanska et al. 2013 ; Saeedi et al. 2017 ; Pinsky et al. 2019 ; Lenoir et al. 2020 ; Chaudhary et al. 2021 ). Moreover, in association with human activities (e.g., aquaculture and maritime trade), changes in ocean temperatures have aided expansion and settlement of species into places that would otherwise be inaccessible. This leads to geographic shifts and unprecedented rates of non-native species settlement, representing a significant threat to ecosystem function (Molnar et al. 2008 ; Ojaveer et al. 2015 ; Chan et al. 2019 ). Deep-sea ecosystems, which have long been thought to be extremely stable in terms of physico-chemical conditions, have shown growing evidence that they also may experience abrupt changes and climate-driven temperature shifts (Danovaro et al. 2001 , 2004 ), putting the most extensive ecosystem on Earth and its largest reservoir of biomass in danger (Sweetman et al. 2017 ; Folkersen et al. 2018 ). However, studies on the potential effects of climatic changes and species range shifts on this marine ecosystem remain scarce, and the effects on ecosystem functioning and potential biodiversity gain or loss remain almost completely unknown (Danovaro et al. 2001 ; Hoegh-Guldberg and Poloczanska 2017 ). Crustaceans are one of the most dominant taxa of both shallow-water and deep-sea communities (Saeedi et al. 2019a , b ; Saeedi and Brandt 2020 ). They are also among the most successful groups of aquatic alien invaders in the ocean, with life history, behavioral and physiological traits that favor a high rate of establishment and success as invasive species (Karatayev et al. 2009 ; Hänfling et al. 2011 ). Their impacts are often substantial due to the complex trophic role of many of these species, leading to cascading effects throughout invaded ecosystems, resulting in fast spread and costly management and/or eradication measures (Thresher and Kuris 2004 ). Therefore, the early detection of climate-driven range shifts and prompt implementation of appropriate management strategies are crucial (Fogarty et al. 2017 ). The application of environmental matching approaches, of which a key concept is the linkage of species distributions and environmental conditions, can assist in the exploration and forecasting of species range shifts in response to changing environments (Jiménez-Valverde et al. 2011 ; Hänfling et al. 2011 ). Insights gained from such analyses can help elucidate current patterns and provide a first approximation of distributional patterns of marine biodiversity due to anthropogenic climate change (Cheung et al. 2016 ; Robinson et al. 2017 ). Concerning marine crustacean fauna, so far, environmental matching has been seldom applied within the context of climate change and its potential impacts on future distribution patterns (Poloczanska et al. 2013 ; Melo-Merino et al. 2020 ; Lenoir et al. 2020 ). Limited by the high cost and logistical and technological limitations in sampling, the marine realm does not allow easy definition of the full spatial distribution of many marine species, and there are large taxonomic biases in the study of species/diversity spatial patterns (Reygondeau 2019 ). The few macroecological studies on marine crustaceans have focused on distributional patterns of economically relevant, well-studied species, and have been restricted to well-sampled geographical locations (i.e., North Sea and other coast of the Atlantic continental shelf; Neumann et al. 2013 ; Melo-Merino et al. 2020 ; Lenoir et al. 2020 ). Fortunately, in recent years, distributional, demographic, genetic and climatic data have become increasingly available digitally through global initiatives, such as the Ocean Biodiversity Information System (OBIS, ). As a result, unprecedented possibilities to search for general patterns and mechanisms in the global distribution of marine biodiversity have been created (Wüest et al. 2019 ). To fill the knowledge gap regarding future climatic change effects on the marine crustacean fauna, and to provide an initial assessment of climate-related horizontal distributional shifts for crustacean species, in this study we use a correlative maximum entropy approach. We estimate the direction and magnitude of potential climate-related range shifts of 94 shallow-water and deep-sea crustacean species representing 12 orders, to both 2050 and 2100, for two representative concentration pathway emission scenarios (RCP 2.6 and 8.5). In addition, we discuss our results in light of species-specific traits that could characterize invasiveness. We hypothesize that both shallow water and deep-sea crustacean species will follow trends seen in other marine organisms by shifting their distribution ranges poleward. Our estimations can be viewed as a set of hypotheses for future analytical", "role": "user" }, { "content": "Senckenberg scientists from Frankfurt and Müncheberg, together with a US-American colleague, have modeled the future distribution patterns of marine crustaceans for the years 2050 and 2100. In their study, published in the journal Climatic Change, they conclude that animals living in water depths above 500 meters will move northward as a result of climate change. In contrast, crustaceans found at depths below 500 meters will spread southward in the future. To this end, the team analyzed data from 94 crustacean species assuming two possible scenarios from the Intergovernmental Panel on Climate Change (IPCC) report—an increase in global mean ocean temperature by either one or by 4.8 degrees Celsius by 2100. The study is part of the Beneficial project regarding the biogeography of the Northwest Pacific fauna. The baseline study will help to estimate the extent of invasions of non-native species to the Arctic Ocean under the rapid global climate change. Crustaceans are one of the most dominant animal groups in both shallow-water and deep-sea communities worldwide. Various studies suggest that crustaceans are shifting their ranges toward the poles or to greater depths as the oceans become warmer. \"However, this assumption mainly applies to shallow-water organisms,\" explains Dr. Marianna Simões of the Senckenberg German Entomological Institute in Müncheberg. \"On the other hand, it remains unexplored how global climate change affects the distribution of deep-sea communities and whether there is a difference here compared to the shallow-water fauna—even though the deep sea is the largest ecosystem on Earth.\" Simões, her Senckenberg colleagues Angelika Brandt and Hanieh Saeedi, and Marlon Cobos of the University of Kansas therefore analyzed more than 12,500 distribution records of 94 globally distributed, ground-dwelling crustacean species from 12 orders and developed climatic models predicting for their distribution in 2050 and 2100. \"We wanted to know how global climate change might influence the distribution and abundance of marine crustacean species within the reminder of the century. To do this, we used two Intergovernmental Panel on Climate Change (IPCC) scenarios for global mean ocean temperatures: An increase by one or by 4.8 degrees Celsius by 2050 and 2100, respectively,\" adds Simões. In addition to the possible horizontal distributional shifts of shallow-water and deep-sea benthic crustaceans, the researchers also discuss species-specific traits in their study that may lead to dispersal into new habitats—the so-called \"invasion potential.\" Crustaceans such as Tecticeps leucophthalmus Gurjanova, 1936 are one of the most dominant groups of animals worldwide in shallow water as well as deep-sea communities. Credit: Anna Lavrenteva Considering all factors, according to the modeling, crustaceans living in shallow water could relocate an average of 431 kilometers away from their original habitats by 2050 with a temperature increase of one degree Celsius, and 620 kilometers with an increase of 4.8 degrees Celsius. Projecting the data to 2100, the shifts estimations are between 435 and 1300 kilometers, respectively. \"Deep-sea species, on the other hand, are not predicted to move as far. By 2050, we predict a distance of about 90 kilometers at one degree of warming, and 110 kilometers at 4.8 degrees. By 2100, this still amounts to a potential distribution shift of 130 and 180 kilometers, respectively,\" says Simões. There are exceptions here, too: For the shrimp species Thor paschalis (Heller, 1861), the researchers predict a horizontal distribution shift by 3715 kilometers for 2050, with a water temperature increase of only one degree. \"What surprised us most, however, was the direction in which the crustaceans move,\" says Simões. \"The species we studied that live above a depth of 500 meters migrate northward. Crustaceans below that level move to the south.\" A decrease in species richness in temperate climates and a potential increase in species richness in polar regions could be the result of this event. \"However, not all species can adapt to changing environmental conditions,\" says Simões. \"As anthropogenic disturbances such as fishing, marine mining, oil drilling, or warming and acidification of marine ecosystems increase, so does the pressure on deep-sea fauna. Although our study only covers about 0.3 percent of the total crustacean diversity, our results can help us to better understand the future magnitude of changes affecting the deep-sea life, allowing us to implement appropriate conservation measures.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Empirical and theoretical studies suggest that marine species respond to ocean warming by shifting ranges poleward and/or into deeper depths. However, future distributional patterns of deep-sea organisms, which comprise the largest ecosystem of Earth, remain poorly known. We explore potential horizontal range shifts of benthic shallow-water and deep-sea Crustacea due to climatic changes within the remainder of the century, and discuss the results in light of species-specific traits related to invasiveness. Using a maximum entropy approach, we estimated the direction and magnitude of distributional shifts for 94 species belonging to 12 orders of benthic marine crustaceans, projected to the years 2050 and 2100. Distance, direction, and species richness shifts between climate zones were estimated conservatively, by considering only areas suitable, non-extrapolative, and adjacent to the currently known distributions. Our hypothesis is that species will present poleward range-shifts, based on results of previous studies. Results reveal idiosyncratic and species-specific responses, with prevailing poleward shifts and a decline of species richness at mid-latitudes, while more frequent shifts between temperate to polar regions were recovered. Shallow-water species are expected to shift longer distances than deep-sea species. Net gain of suitability is slightly higher than the net loss for shallow-water species, while for deep-sea species, the net loss is higher than the gain in all scenarios. Our estimates can be viewed as a set of hypotheses for future analytical and empirical studies, and will be useful in planning and executing strategic interventions and developing conservation strategies. Working on a manuscript? Avoid the common mistakes 1 Introduction Empirical and theoretical studies suggest that marine species respond to ocean warming by shifting ranges poleward and/or into deeper depths (Poloczanska et al. 2013 ; Saeedi et al. 2017 ; Pinsky et al. 2019 ; Lenoir et al. 2020 ; Chaudhary et al. 2021 ). Moreover, in association with human activities (e.g., aquaculture and maritime trade), changes in ocean temperatures have aided expansion and settlement of species into places that would otherwise be inaccessible. This leads to geographic shifts and unprecedented rates of non-native species settlement, representing a significant threat to ecosystem function (Molnar et al. 2008 ; Ojaveer et al. 2015 ; Chan et al. 2019 ). Deep-sea ecosystems, which have long been thought to be extremely stable in terms of physico-chemical conditions, have shown growing evidence that they also may experience abrupt changes and climate-driven temperature shifts (Danovaro et al. 2001 , 2004 ), putting the most extensive ecosystem on Earth and its largest reservoir of biomass in danger (Sweetman et al. 2017 ; Folkersen et al. 2018 ). However, studies on the potential effects of climatic changes and species range shifts on this marine ecosystem remain scarce, and the effects on ecosystem functioning and potential biodiversity gain or loss remain almost completely unknown (Danovaro et al. 2001 ; Hoegh-Guldberg and Poloczanska 2017 ). Crustaceans are one of the most dominant taxa of both shallow-water and deep-sea communities (Saeedi et al. 2019a , b ; Saeedi and Brandt 2020 ). They are also among the most successful groups of aquatic alien invaders in the ocean, with life history, behavioral and physiological traits that favor a high rate of establishment and success as invasive species (Karatayev et al. 2009 ; Hänfling et al. 2011 ). Their impacts are often substantial due to the complex trophic role of many of these species, leading to cascading effects throughout invaded ecosystems, resulting in fast spread and costly management and/or eradication measures (Thresher and Kuris 2004 ). Therefore, the early detection of climate-driven range shifts and prompt implementation of appropriate management strategies are crucial (Fogarty et al. 2017 ). The application of environmental matching approaches, of which a key concept is the linkage of species distributions and environmental conditions, can assist in the exploration and forecasting of species range shifts in response to changing environments (Jiménez-Valverde et al. 2011 ; Hänfling et al. 2011 ). Insights gained from such analyses can help elucidate current patterns and provide a first approximation of distributional patterns of marine biodiversity due to anthropogenic climate change (Cheung et al. 2016 ; Robinson et al. 2017 ). Concerning marine crustacean fauna, so far, environmental matching has been seldom applied within the context of climate change and its potential impacts on future distribution patterns (Poloczanska et al. 2013 ; Melo-Merino et al. 2020 ; Lenoir et al. 2020 ). Limited by the high cost and logistical and technological limitations in sampling, the marine realm does not allow easy definition of the full spatial distribution of many marine species, and there are large taxonomic biases in the study of species/diversity spatial patterns (Reygondeau 2019 ). The few macroecological studies on marine crustaceans have focused on distributional patterns of economically relevant, well-studied species, and have been restricted to well-sampled geographical locations (i.e., North Sea and other coast of the Atlantic continental shelf; Neumann et al. 2013 ; Melo-Merino et al. 2020 ; Lenoir et al. 2020 ). Fortunately, in recent years, distributional, demographic, genetic and climatic data have become increasingly available digitally through global initiatives, such as the Ocean Biodiversity Information System (OBIS, ). As a result, unprecedented possibilities to search for general patterns and mechanisms in the global distribution of marine biodiversity have been created (Wüest et al. 2019 ). To fill the knowledge gap regarding future climatic change effects on the marine crustacean fauna, and to provide an initial assessment of climate-related horizontal distributional shifts for crustacean species, in this study we use a correlative maximum entropy approach. We estimate the direction and magnitude of potential climate-related range shifts of 94 shallow-water and deep-sea crustacean species representing 12 orders, to both 2050 and 2100, for two representative concentration pathway emission scenarios (RCP 2.6 and 8.5). In addition, we discuss our results in light of species-specific traits that could characterize invasiveness. We hypothesize that both shallow water and deep-sea crustacean species will follow trends seen in other marine organisms by shifting their distribution ranges poleward. Our estimations can be viewed as a set of hypotheses for future analytical<|im_end|> <|im_start|>assistant Senckenberg scientists from Frankfurt and Müncheberg, together with a US-American colleague, have modeled the future distribution patterns of marine crustaceans for the years 2050 and 2100. In their study, published in the journal Climatic Change, they conclude that animals living in water depths above 500 meters will move northward as a result of climate change. In contrast, crustaceans found at depths below 500 meters will spread southward in the future. To this end, the team analyzed data from 94 crustacean species assuming two possible scenarios from the Intergovernmental Panel on Climate Change (IPCC) report—an increase in global mean ocean temperature by either one or by 4.8 degrees Celsius by 2100. The study is part of the Beneficial project regarding the biogeography of the Northwest Pacific fauna. The baseline study will help to estimate the extent of invasions of non-native species to the Arctic Ocean under the rapid global climate change. Crustaceans are one of the most dominant animal groups in both shallow-water and deep-sea communities worldwide. Various studies suggest that crustaceans are shifting their ranges toward the poles or to greater depths as the oceans become warmer. "However, this assumption mainly applies to shallow-water organisms," explains Dr. Marianna Simões of the Senckenberg German Entomological Institute in Müncheberg. "On the other hand, it remains unexplored how global climate change affects the distribution of deep-sea communities and whether there is a difference here compared to the shallow-water fauna—even though the deep sea is the largest ecosystem on Earth." Simões, her Senckenberg colleagues Angelika Brandt and Hanieh Saeedi, and Marlon Cobos of the University of Kansas therefore analyzed more than 12,500 distribution records of 94 globally distributed, ground-dwelling crustacean species from 12 orders and developed climatic models predicting for their distribution in 2050 and 2100. "We wanted to know how global climate change might influence the distribution and abundance of marine crustacean species within the reminder of the century. To do this, we used two Intergovernmental Panel on Climate Change (IPCC) scenarios for global mean ocean temperatures: An increase by one or by 4.8 degrees Celsius by 2050 and 2100, respectively," adds Simões. In addition to the possible horizontal distributional shifts of shallow-water and deep-sea benthic crustaceans, the researchers also discuss species-specific traits in their study that may lead to dispersal into new habitats—the so-called "invasion potential." Crustaceans such as Tecticeps leucophthalmus Gurjanova, 1936 are one of the most dominant groups of animals worldwide in shallow water as well as deep-sea communities. Credit: Anna Lavrenteva Considering all factors, according to the modeling, crustaceans living in shallow water could relocate an average of 431 kilometers away from their original habitats by 2050 with a temperature increase of one degree Celsius, and 620 kilometers with an increase of 4.8 degrees Celsius. Projecting the data to 2100, the shifts estimations are between 435 and 1300 kilometers, respectively. "Deep-sea species, on the other hand, are not predicted to move as far. By 2050, we predict a distance of about 90 kilometers at one degree of warming, and 110 kilometers at 4.8 degrees. By 2100, this still amounts to a potential distribution shift of 130 and 180 kilometers, respectively," says Simões. There are exceptions here, too: For the shrimp species Thor paschalis (Heller, 1861), the researchers predict a horizontal distribution shift by 3715 kilometers for 2050, with a water temperature increase of only one degree. "What surprised us most, however, was the direction in which the crustaceans move," says Simões. "The species we studied that live above a depth of 500 meters migrate northward. Crustaceans below that level move to the south." A decrease in species richness in temperate climates and a potential increase in species richness in polar regions could be the result of this event. "However, not all species can adapt to changing environmental conditions," says Simões. "As anthropogenic disturbances such as fishing, marine mining, oil drilling, or warming and acidification of marine ecosystems increase, so does the pressure on deep-sea fauna. Although our study only covers about 0.3 percent of the total crustacean diversity, our results can help us to better understand the future magnitude of changes affecting the deep-sea life, allowing us to implement appropriate conservation measures." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Objectives To identify factors predicting maternal sex steroid hormone concentrations in early pregnancy. Methods The Infant Development and the Environment Study recruited healthy pregnant women from academic medical centers in four US cities. Gold standard liquid chromatography–tandem mass spectrometry was used to measure maternal sex steroids concentrations (total testosterone [TT], free testosterone [FT], estrone [E1], estradiol [E2], and estriol [E3] concentrations) in serum samples from 548 women carrying singletons (median = 11.7 weeks gestation). Women completed questionnaires on demographic and lifestyle characteristics. Results In multivariable linear regression analyses, hormone concentrations varied in relation to maternal age, body mass index (BMI), race, and parity. Older mothers had significantly lower levels of most hormones; for every year increase in maternal age, there was a 1–2% decrease in E1, E2, TT, and FT. By contrast, each unit increase in maternal BMI was associated 1–2% lower estrogen (E1, E2, E3) levels, but 1–2% higher androgen (TT, FT) concentrations. Hormone concentrations were 4–18% lower among parous women, and for each year elapsed since last birth, TT and FT were 1–2% higher (no difference in estrogens). Androgen concentrations were 18–30% higher among Black women compared to women of other races. Fetal sex, maternal stress, and lifestyle factors (including alcohol and tobacco use) were not related to maternal steroid concentrations. Conclusions for Practice Maternal demographic factors predict sex steroid hormone concentrations during pregnancy, which is important given increasing evidence that the prenatal endocrine environment shapes future risk of chronic disease for both mother and offspring. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Significance What is already known on this topic? Although numerous studies have examined variation in maternal hormones during pregnancy, most have had notable limitations. These limitations include small sample sizes, and demographically homogeneous populations, use of outdated or suboptimal analytic techniques for hormone measurement. What does this study add? Using gold-standard analytic techniques in a large, diverse sample, we demonstrate that maternal sex steroid profiles during pregnancy vary in relation to maternal age, body mass index (BMI), race, and parity. This work confirms and extends the previous literature on this topic. Introduction Health begins in utero, and there is tremendous interest in better understanding how early development contributes to our later health and disease risk. Early research relied upon size at birth as a crude proxy for the in utero environment, but the field has since expanded to examine a wide range of materno-feto-placental biomarkers that may confer—or protect against—future disease risk in the child. The prenatal hormonal milieu has been an area of particular interest given long-standing hypotheses that excess fetal exposure to estrogens and/or androgens may play a role in future risk of reproductive cancers (Schooling et al. 2016 ). Additionally, recent studies link putative biomarkers of the prenatal hormonal milieu, including anogenital distance and digit ratios, to adult outcomes including polycystic ovary syndrome (PCOS) (Wu et al. 2017 ), endometriosis (Mendiola et al. 2016 ), prostate cancer (Mendes et al. 2016 ), and semen quality (Mendiola et al. 2011 ). Characterizing sex steroid concentrations during pregnancy may also yield important insights into the mother’s own future risk of disease including breast (Troisi et al. 2008 ; Arslan et al. 2006 ) and ovarian cancer (Chen et al. 2011 ). Given the important downstream health outcomes believed to be associated with the prenatal endocrine milieu, characterizing natural variation in hormone levels during pregnancy and identifying factors contributing to that variation is important. Indeed, since the 1980s, over a dozen studies have examined prenatal hormone levels in the context of maternal and infant characteristics. However the study population, sample size, timing of sample collection, laboratory techniques, and steroid hormones measured have varied considerably. For example, although many believe that the endocrine environment during early pregnancy is arguably of greatest concern with respect to subsequent disease risk in the fetus (given the rapid cell differentiation, proliferation, and organogenesis that occurs during this period), timing of biospecimen collection for hormone measurement has ranged from early pregnancy through umbilical cord blood collection at delivery. The vast majority of these studies have relied upon immunoassays (including chemiluminescent-, electrochemiluminescent-, and radioimmunoassays) which are relatively cheap, easy, and quick to perform (Troisi et al. 2003 , 2008 ; Caanen et al. 2016 ; Jarvela et al. 2012 ; Bremme et al. 1990 ; Lagerstrom et al. 1990 ; Lagiou et al. 2014 ; O’Leary et al. 1991 ; Steier et al. 2002 ). However in immunoassay, there is potential for the antibodies to cross-react with multiple hormones due to non-specific binding of steroids to the antibody (for example both dehydroepiandrosterone sulphate [DHEAS] and testosterone) (Middle 2007 ), as well as with synthetic steroids (Krasowski et al. 2014 ; Tejada et al. 1998 ). This non-specificity may account for the higher serum sex steroid levels in pregnant women found in some studies using immunoassay e.g. (Zhang et al. 2005 ) compared to studies using LC/MS–MS (Toriola et al. 2011 ). Perhaps the greatest concern is that immunoassay does not offer adequate sensitivity to measure hormones that are present in very low concentrations, such as testosterone in women (Rosner et al. 2007 ). Newer methods like liquid chromatography–tandem mass spectrometry (LC–MS/MS), are more expensive and labor intensive, but offer greater sensitivity and specificity for steroid measurement and are therefore the current gold standard (French 2016 ). To date, only one large study has examined maternal determinants of sex steroid concentrations in early pregnancy using the preferred LC–MS/MS method. Toriola et al. ( 2011 ) measured a panel of steroid hormones (testosterone, androstenedione, estradiol [E2], progesterone, and 17-hydroxyprogesterone) in 1343 women who provided samples for a large Finnish biorepository, finding that parity, smoking, maternal age, and fetal sex predicted maternal steroid levels measured at median 11 weeks gestation (Toriola et al. 2011 ). Here, we seek to extend this work in a more diverse, US pregnancy cohort. Our objective was to identify sociodemographic predictors of early pregnancy maternal serum sex steroid concentrations, including total", "role": "user" }, { "content": "Hormone concentrations during early fetal development—that may affect the child's development and increase the mother's risk for breast and ovarian cancer years later—are significantly affected by maternal age, body mass index and race rather than lifestyle, according to a Rutgers study. The findings appear in Maternal and Child Health Journal. The researchers looked at the concentrations of estrogens and testosterone in 548 healthy women in the first trimester of pregnancy in relation to their lifestyle to better understand what drives elevated sex hormones during fetal development. \"Hormones in early development play a key role in human health and disease risk. Since we are unable to directly measure hormones in fetuses as they are developing, the next best way is to study the mother's hormones since they can be transferred to the fetus,\" said Emily Barrett, an associate professor at Rutgers School of Public Health and a faculty member at Rutgers Environmental and Occupational Health Sciences Institute. Previous studies have suggested that excess fetal exposure to estrogens and androgens, which are male sex hormones such as testosterone, may play a role in future risk of reproductive cancers and other conditions such as polycystic ovary syndrome, endometriosis, prostate cancer and semen quality in the infant. In the new study, researchers recruited women during early pregnancy and collected a blood sample to measure hormones. The participants completed questionnaires with items on demographics as well as lifestyle factors, including their alcohol or tobacco use, and stressors in their lives Most of the women were white, married, well-educated and had an average age of 31. Less than 5 percent drank alcohol and less than 8 percent smoked. The researchers found that older mothers and women who had previously given birth had lower estrogen and testosterone levels. They also found that heavier women had lower estrogen levels, but higher testosterone levels than leaner women. Confirming results from previous work, they found that black women had higher testosterone levels than women of other races, a difference that may help to explain health disparities in reproductive cancers and other hormone-sensitive diseases. According to the Centers for Disease Control and Prevention, black women and white women get breast cancer at about the same rate, but black women die from breast cancer at a higher rate than white women. The study found no variation in maternal hormone concentrations in relation to fetal sex, stressful life events during pregnancy or lifestyle factors such as smoking and alcohol use, suggesting that hormone concentrations were not influenced by maternal behaviors or the gender of the fetus. \"Characterizing sex steroid concentrations during pregnancy may yield important insights into the mother's own future risk of disease as high levels of exposure to estrogen have been shown to increase the risk for breast and ovarian cancer later on,\" said Barrett, whose research focuses on prenatal exposure to endocrine disruptors, agents which interfere with the normal activity of hormones in the body. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Objectives To identify factors predicting maternal sex steroid hormone concentrations in early pregnancy. Methods The Infant Development and the Environment Study recruited healthy pregnant women from academic medical centers in four US cities. Gold standard liquid chromatography–tandem mass spectrometry was used to measure maternal sex steroids concentrations (total testosterone [TT], free testosterone [FT], estrone [E1], estradiol [E2], and estriol [E3] concentrations) in serum samples from 548 women carrying singletons (median = 11.7 weeks gestation). Women completed questionnaires on demographic and lifestyle characteristics. Results In multivariable linear regression analyses, hormone concentrations varied in relation to maternal age, body mass index (BMI), race, and parity. Older mothers had significantly lower levels of most hormones; for every year increase in maternal age, there was a 1–2% decrease in E1, E2, TT, and FT. By contrast, each unit increase in maternal BMI was associated 1–2% lower estrogen (E1, E2, E3) levels, but 1–2% higher androgen (TT, FT) concentrations. Hormone concentrations were 4–18% lower among parous women, and for each year elapsed since last birth, TT and FT were 1–2% higher (no difference in estrogens). Androgen concentrations were 18–30% higher among Black women compared to women of other races. Fetal sex, maternal stress, and lifestyle factors (including alcohol and tobacco use) were not related to maternal steroid concentrations. Conclusions for Practice Maternal demographic factors predict sex steroid hormone concentrations during pregnancy, which is important given increasing evidence that the prenatal endocrine environment shapes future risk of chronic disease for both mother and offspring. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Significance What is already known on this topic? Although numerous studies have examined variation in maternal hormones during pregnancy, most have had notable limitations. These limitations include small sample sizes, and demographically homogeneous populations, use of outdated or suboptimal analytic techniques for hormone measurement. What does this study add? Using gold-standard analytic techniques in a large, diverse sample, we demonstrate that maternal sex steroid profiles during pregnancy vary in relation to maternal age, body mass index (BMI), race, and parity. This work confirms and extends the previous literature on this topic. Introduction Health begins in utero, and there is tremendous interest in better understanding how early development contributes to our later health and disease risk. Early research relied upon size at birth as a crude proxy for the in utero environment, but the field has since expanded to examine a wide range of materno-feto-placental biomarkers that may confer—or protect against—future disease risk in the child. The prenatal hormonal milieu has been an area of particular interest given long-standing hypotheses that excess fetal exposure to estrogens and/or androgens may play a role in future risk of reproductive cancers (Schooling et al. 2016 ). Additionally, recent studies link putative biomarkers of the prenatal hormonal milieu, including anogenital distance and digit ratios, to adult outcomes including polycystic ovary syndrome (PCOS) (Wu et al. 2017 ), endometriosis (Mendiola et al. 2016 ), prostate cancer (Mendes et al. 2016 ), and semen quality (Mendiola et al. 2011 ). Characterizing sex steroid concentrations during pregnancy may also yield important insights into the mother’s own future risk of disease including breast (Troisi et al. 2008 ; Arslan et al. 2006 ) and ovarian cancer (Chen et al. 2011 ). Given the important downstream health outcomes believed to be associated with the prenatal endocrine milieu, characterizing natural variation in hormone levels during pregnancy and identifying factors contributing to that variation is important. Indeed, since the 1980s, over a dozen studies have examined prenatal hormone levels in the context of maternal and infant characteristics. However the study population, sample size, timing of sample collection, laboratory techniques, and steroid hormones measured have varied considerably. For example, although many believe that the endocrine environment during early pregnancy is arguably of greatest concern with respect to subsequent disease risk in the fetus (given the rapid cell differentiation, proliferation, and organogenesis that occurs during this period), timing of biospecimen collection for hormone measurement has ranged from early pregnancy through umbilical cord blood collection at delivery. The vast majority of these studies have relied upon immunoassays (including chemiluminescent-, electrochemiluminescent-, and radioimmunoassays) which are relatively cheap, easy, and quick to perform (Troisi et al. 2003 , 2008 ; Caanen et al. 2016 ; Jarvela et al. 2012 ; Bremme et al. 1990 ; Lagerstrom et al. 1990 ; Lagiou et al. 2014 ; O’Leary et al. 1991 ; Steier et al. 2002 ). However in immunoassay, there is potential for the antibodies to cross-react with multiple hormones due to non-specific binding of steroids to the antibody (for example both dehydroepiandrosterone sulphate [DHEAS] and testosterone) (Middle 2007 ), as well as with synthetic steroids (Krasowski et al. 2014 ; Tejada et al. 1998 ). This non-specificity may account for the higher serum sex steroid levels in pregnant women found in some studies using immunoassay e.g. (Zhang et al. 2005 ) compared to studies using LC/MS–MS (Toriola et al. 2011 ). Perhaps the greatest concern is that immunoassay does not offer adequate sensitivity to measure hormones that are present in very low concentrations, such as testosterone in women (Rosner et al. 2007 ). Newer methods like liquid chromatography–tandem mass spectrometry (LC–MS/MS), are more expensive and labor intensive, but offer greater sensitivity and specificity for steroid measurement and are therefore the current gold standard (French 2016 ). To date, only one large study has examined maternal determinants of sex steroid concentrations in early pregnancy using the preferred LC–MS/MS method. Toriola et al. ( 2011 ) measured a panel of steroid hormones (testosterone, androstenedione, estradiol [E2], progesterone, and 17-hydroxyprogesterone) in 1343 women who provided samples for a large Finnish biorepository, finding that parity, smoking, maternal age, and fetal sex predicted maternal steroid levels measured at median 11 weeks gestation (Toriola et al. 2011 ). Here, we seek to extend this work in a more diverse, US pregnancy cohort. Our objective was to identify sociodemographic predictors of early pregnancy maternal serum sex steroid concentrations, including total<|im_end|> <|im_start|>assistant Hormone concentrations during early fetal development—that may affect the child's development and increase the mother's risk for breast and ovarian cancer years later—are significantly affected by maternal age, body mass index and race rather than lifestyle, according to a Rutgers study. The findings appear in Maternal and Child Health Journal. The researchers looked at the concentrations of estrogens and testosterone in 548 healthy women in the first trimester of pregnancy in relation to their lifestyle to better understand what drives elevated sex hormones during fetal development. "Hormones in early development play a key role in human health and disease risk. Since we are unable to directly measure hormones in fetuses as they are developing, the next best way is to study the mother's hormones since they can be transferred to the fetus," said Emily Barrett, an associate professor at Rutgers School of Public Health and a faculty member at Rutgers Environmental and Occupational Health Sciences Institute. Previous studies have suggested that excess fetal exposure to estrogens and androgens, which are male sex hormones such as testosterone, may play a role in future risk of reproductive cancers and other conditions such as polycystic ovary syndrome, endometriosis, prostate cancer and semen quality in the infant. In the new study, researchers recruited women during early pregnancy and collected a blood sample to measure hormones. The participants completed questionnaires with items on demographics as well as lifestyle factors, including their alcohol or tobacco use, and stressors in their lives Most of the women were white, married, well-educated and had an average age of 31. Less than 5 percent drank alcohol and less than 8 percent smoked. The researchers found that older mothers and women who had previously given birth had lower estrogen and testosterone levels. They also found that heavier women had lower estrogen levels, but higher testosterone levels than leaner women. Confirming results from previous work, they found that black women had higher testosterone levels than women of other races, a difference that may help to explain health disparities in reproductive cancers and other hormone-sensitive diseases. According to the Centers for Disease Control and Prevention, black women and white women get breast cancer at about the same rate, but black women die from breast cancer at a higher rate than white women. The study found no variation in maternal hormone concentrations in relation to fetal sex, stressful life events during pregnancy or lifestyle factors such as smoking and alcohol use, suggesting that hormone concentrations were not influenced by maternal behaviors or the gender of the fetus. "Characterizing sex steroid concentrations during pregnancy may yield important insights into the mother's own future risk of disease as high levels of exposure to estrogen have been shown to increase the risk for breast and ovarian cancer later on," said Barrett, whose research focuses on prenatal exposure to endocrine disruptors, agents which interfere with the normal activity of hormones in the body. <|im_end|>

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2,056

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Since the original work on Bose–Einstein condensation 1 , 2 , the use of quantum degenerate gases of atoms has enabled the quantum emulation of important systems in condensed matter and nuclear physics, as well as the study of many-body states that have no analogue in other fields of physics 3 . Ultracold molecules in the micro- and nanokelvin regimes are expected to bring powerful capabilities to quantum emulation 4 and quantum computing 5 , owing to their rich internal degrees of freedom compared to atoms, and to facilitate precision measurement and the study of quantum chemistry 6 . Quantum gases of ultracold atoms can be created using collision-based cooling schemes such as evaporative cooling, but thermalization and collisional cooling have not yet been realized for ultracold molecules. Other techniques, such as the use of supersonic jets and cryogenic buffer gases, have reached temperatures limited to above 10 millikelvin 7 , 8 . Here we show cooling of NaLi molecules to micro- and nanokelvin temperatures through collisions with ultracold Na atoms, with both molecules and atoms prepared in their stretched hyperfine spin states. We find a lower bound on the ratio of elastic to inelastic molecule–atom collisions that is greater than 50—large enough to support sustained collisional cooling. By employing two stages of evaporation, we increase the phase-space density of the molecules by a factor of 20, achieving temperatures as low as 220 nanokelvin. The favourable collisional properties of the Na–NaLi system could enable the creation of deeply quantum degenerate dipolar molecules and raises the possibility of using stretched spin states in the cooling of other molecules. Main The full potential of ultracold atoms was not realized until the advent of collision-based cooling methods such as evaporative and sympathetic cooling. Although atomic systems have been recently used to demonstrate laser cooling to quantum degeneracy, these schemes still require collisional thermalization 9 , 10 . Therefore, many efforts have been made over the past 15 years 11 to achieve collisional cooling of ultracold molecules. Buffer gas cooling 8 cannot achieve temperatures below 100 mK owing to the rapidly diminishing vapour pressure of buffer gases at such temperatures. Supersonic expansion 7 can produce temperatures around 100 mK. Controlled collisions in crossed molecular beams 12 can decrease the laboratory-frame velocity of particles while narrowing the velocity distribution. However, this technique has not been demonstrated below about 500 mK. Merged supersonic beams can be used to study collisions at energies equivalent to a temperature of 10 mK (ref. 13 ). Cooling below 100 mK calls for trapping molecules in magnetic or electrostatic traps and for good collisional properties (that is, a ratio of elastic to inelastic collisions much greater than 1). Such traps require preparing molecules in weak-field seeking states, which are never the absolute ground state, allowing inelastic state-changing collisions to eject the cold molecules from the trap. A variety of systems have been proposed for evaporative or sympathetic cooling of molecules 11 , 14 , 15 , 16 , 17 , 18 . So far, elastic collisions have been observed clearly in O 2 at temperatures below 1 K (ref. 19 ) and possibly in OH radicals around 10 mK (ref. 20 corrects an earlier report 21 ). In the O 2 case, inelastic collisions prevent thermalization and collisional cooling. In recent years, the assembly of molecules from ultracold atoms 22 and the direct laser cooling of molecules 23 , 24 , 25 , 26 have both expanded to new molecules and temperature regimes. These techniques have achieved molecular systems at temperatures less than 100 mK, raising the challenge of collisional cooling in the micro- and nanokelvin regimes. Optical traps enable trapping of the absolute ground state, which removes the concern of state-changing collisions. However, collisional cooling in the absolute ground state of chemically stable systems has not yet been realized 27 . By contrast, chemically stable molecular species have shown anomalously high inelastic loss rates that preclude collisional cooling, possibly owing to collision complex formation 28 or interactions with optical trapping beams 29 . In this study we observe sympathetic cooling of rovibrational ground-state triplet 23 Na 6 Li molecules by 23 Na atoms, both of which are prepared in their upper stretched hyperfine spin states (that is, states with both nuclear and electronic spins aligned along the direction of the magnetic bias field). Although sympathetic cooling of one atomic species by another has been observed in various ultracold atomic mixtures 30 , triplet NaLi was considered unlikely to have sufficiently good collisional properties to support such cooling. NaLi has energetically allowed chemical reactions, even in the electronic ground state (that is, a singlet state), and the triplet state has an electronic excitation energy of 0.8 eV or 10,000 K. Furthermore, theoretical studies on various systems have explored the possibility of suppressing inelastic collisions and reactions by spin polarization, giving pessimistic predictions for triplet molecules and more favourable ones for doublet molecules 17 , 31 , 32 , 33 , 34 . Nonetheless, here we report clear thermalization and sympathetic cooling of triplet NaLi to 220 nK. We observe 20-fold increases of phase-space density (PSD), opening the possibility of collisional cooling to deep quantum degeneracy. Our experimental setup is summarized in Fig. 1 . Similarly to our previous work 35 , 36 , we produce about 3.0 × 10 4 NaLi molecules in the rovibrational ground state of the triplet potential using a mixture of Na and Li atoms (further details in Methods). We also prepare about 1.0 × 10 5 Na atoms in the upper stretched hyperfine state (in the low-field basis, | F , m F ⟩ = |2, 2 ⟩ , where F and m F are the hyperfine and magnetic quantum numbers, respectively) in a one-dimensional (1D) optical lattice formed by 1,596-nm light. Owing to the differential polarizability at 1,596 nm, molecules feel a deeper trapping potential than atoms. This results in a sudden increase of the potential energy as atoms associate and form molecules (see", "role": "user" }, { "content": "For years, scientists have looked for ways to cool molecules down to ultracold temperatures, at which point the molecules should slow to a crawl, allowing scientists to precisely control their quantum behavior. This could enable researchers to use molecules as complex bits for quantum computing, tuning individual molecules like tiny knobs to carry out multiple streams of calculations at a time. While scientists have super-cooled atoms, doing the same for molecules, which are more complex in their behavior and structure, has proven to be a much bigger challenge. Now MIT physicists have found a way to cool molecules of sodium lithium down to 200 billionths of a Kelvin, just a hair above absolute zero. They did so by applying a technique called collisional cooling, in which they immersed molecules of cold sodium lithium in a cloud of even colder sodium atoms. The ultracold atoms acted as a refrigerant to cool the molecules even further. Collisional cooling is a standard technique used to cool down atoms using other, colder atoms. And for more than a decade, researchers have attempted to supercool a number of different molecules using collisional cooling, only to find that when molecules collided with atoms, they exchanged energy in such a way that the molecules were heated or destroyed in the process, called \"bad\" collisions. In their own experiments, the MIT researchers found that if sodium lithium molecules and sodium atoms were made to spin in the same way, they could avoid self-destructing, and instead engaged in \"good\" collisions, where the atoms took away the molecules' energy, in the form of heat. The team used precise control of magnetic fields and an intricate system of lasers to choreograph the spin and the rotational motion of the molecules. As result, the atom-molecule mixture had a high ratio of good-to-bad collisions and was cooled down from 2 microkelvins to 220 nanokelvins. \"Collisional cooling has been the workhorse for cooling atoms,\" adds Nobel Prize laureate Wolfgang Ketterle, the John D. Arthur professor of physics at MIT. \"I wasn't convinced that our scheme would work, but since we didn't know for sure, we had to try it. We know now that it works for cooling sodium lithium molecules. Whether it will work for other classes of molecules remains to be seen.\" Their findings, published in the journal Nature, mark the first time researchers have successfully used collisional cooling to cool molecules down to nanokelvin temperatures. Ketterle's coauthors on the paper are lead author Hyungmok Son, a graduate student in Harvard University's Department of Physics, along with MIT physics graduate student Juliana Park, and Alan Jamison, a professor of physics at the University of Waterloo and visiting scientist in MIT's Research Laboratory of Electronics. Reaching ultralow temperatures In the past, scientists found that when they tried to cool molecules down to ultracold temperatures by surrounding them with even colder atoms, the particles collided such that the atoms imparted extra energy or rotation to the molecules, sending them flying out of the trap, or self-destructing all together by chemical reactions. The MIT researchers wondered whether molecules and atoms, having the same spin, could avoid this effect, and remain ultracold and stable as a result. They looked to test their idea with sodium lithium, a \"diatomic\" molecule that Ketterle's group experiments with regularly, consisting of one lithium and one sodium atom. \"Sodium lithium molecules are quite different from other molecules people have tried,\" Jamison says. \"Many folks expected those differences would make cooling even less likely to work. However, we had a feeling these differences could be an advantage instead of a detriment.\" The researchers fine-tuned a system of more than 20 laser beams and various magnetic fields to trap and cool atoms of sodium and lithium in a vacuum chamber, down to about 2 microkelvins—a temperature Son says is optimal for the atoms to bond together as sodium lithium molecules. Once the researchers were able to produce enough molecules, they shone laser beams of specific frequencies and polarizations to control the quantum state of the molecules and carefully tuned microwave fields to make atoms spin in the same way as the molecules. \"Then we make the refrigerator colder and colder,\" says Son, referring to the sodium atoms that surround the cloud of the newly formed molecules. \"We lower the power of the trapping laser, making the optical trap looser and looser, which brings the temperature of sodium atoms down, and further cools the molecules, to 200 billionths of a kelvin.\" The group observed that the molecules were able to remain at these ultracold temperatures for up to one second. \"In our world, a second is very long,\" Ketterle says. \"What you want to do with these molecules is quantum computation and exploring new materials, which all can be done in small fractions of a second.\" If the team can get sodium lithium molecules to be about five times colder than what they have so far achieved, they will have reached a so-called quantum degenerate regime where individual molecules become indistinguishable and their collective behavior is controlled by quantum mechanics. Son and his colleagues have some ideas for how to achieve this, which will involve months of work in optimizing their setup, as well as acquiring a new laser to integrate into their setup. \"Our work will lead to discussion in our community why collisional cooling has worked for us but not for others,\" Son says \"Perhaps we will soon have predictions how other molecules could be cooled in this way.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Since the original work on Bose–Einstein condensation 1 , 2 , the use of quantum degenerate gases of atoms has enabled the quantum emulation of important systems in condensed matter and nuclear physics, as well as the study of many-body states that have no analogue in other fields of physics 3 . Ultracold molecules in the micro- and nanokelvin regimes are expected to bring powerful capabilities to quantum emulation 4 and quantum computing 5 , owing to their rich internal degrees of freedom compared to atoms, and to facilitate precision measurement and the study of quantum chemistry 6 . Quantum gases of ultracold atoms can be created using collision-based cooling schemes such as evaporative cooling, but thermalization and collisional cooling have not yet been realized for ultracold molecules. Other techniques, such as the use of supersonic jets and cryogenic buffer gases, have reached temperatures limited to above 10 millikelvin 7 , 8 . Here we show cooling of NaLi molecules to micro- and nanokelvin temperatures through collisions with ultracold Na atoms, with both molecules and atoms prepared in their stretched hyperfine spin states. We find a lower bound on the ratio of elastic to inelastic molecule–atom collisions that is greater than 50—large enough to support sustained collisional cooling. By employing two stages of evaporation, we increase the phase-space density of the molecules by a factor of 20, achieving temperatures as low as 220 nanokelvin. The favourable collisional properties of the Na–NaLi system could enable the creation of deeply quantum degenerate dipolar molecules and raises the possibility of using stretched spin states in the cooling of other molecules. Main The full potential of ultracold atoms was not realized until the advent of collision-based cooling methods such as evaporative and sympathetic cooling. Although atomic systems have been recently used to demonstrate laser cooling to quantum degeneracy, these schemes still require collisional thermalization 9 , 10 . Therefore, many efforts have been made over the past 15 years 11 to achieve collisional cooling of ultracold molecules. Buffer gas cooling 8 cannot achieve temperatures below 100 mK owing to the rapidly diminishing vapour pressure of buffer gases at such temperatures. Supersonic expansion 7 can produce temperatures around 100 mK. Controlled collisions in crossed molecular beams 12 can decrease the laboratory-frame velocity of particles while narrowing the velocity distribution. However, this technique has not been demonstrated below about 500 mK. Merged supersonic beams can be used to study collisions at energies equivalent to a temperature of 10 mK (ref. 13 ). Cooling below 100 mK calls for trapping molecules in magnetic or electrostatic traps and for good collisional properties (that is, a ratio of elastic to inelastic collisions much greater than 1). Such traps require preparing molecules in weak-field seeking states, which are never the absolute ground state, allowing inelastic state-changing collisions to eject the cold molecules from the trap. A variety of systems have been proposed for evaporative or sympathetic cooling of molecules 11 , 14 , 15 , 16 , 17 , 18 . So far, elastic collisions have been observed clearly in O 2 at temperatures below 1 K (ref. 19 ) and possibly in OH radicals around 10 mK (ref. 20 corrects an earlier report 21 ). In the O 2 case, inelastic collisions prevent thermalization and collisional cooling. In recent years, the assembly of molecules from ultracold atoms 22 and the direct laser cooling of molecules 23 , 24 , 25 , 26 have both expanded to new molecules and temperature regimes. These techniques have achieved molecular systems at temperatures less than 100 mK, raising the challenge of collisional cooling in the micro- and nanokelvin regimes. Optical traps enable trapping of the absolute ground state, which removes the concern of state-changing collisions. However, collisional cooling in the absolute ground state of chemically stable systems has not yet been realized 27 . By contrast, chemically stable molecular species have shown anomalously high inelastic loss rates that preclude collisional cooling, possibly owing to collision complex formation 28 or interactions with optical trapping beams 29 . In this study we observe sympathetic cooling of rovibrational ground-state triplet 23 Na 6 Li molecules by 23 Na atoms, both of which are prepared in their upper stretched hyperfine spin states (that is, states with both nuclear and electronic spins aligned along the direction of the magnetic bias field). Although sympathetic cooling of one atomic species by another has been observed in various ultracold atomic mixtures 30 , triplet NaLi was considered unlikely to have sufficiently good collisional properties to support such cooling. NaLi has energetically allowed chemical reactions, even in the electronic ground state (that is, a singlet state), and the triplet state has an electronic excitation energy of 0.8 eV or 10,000 K. Furthermore, theoretical studies on various systems have explored the possibility of suppressing inelastic collisions and reactions by spin polarization, giving pessimistic predictions for triplet molecules and more favourable ones for doublet molecules 17 , 31 , 32 , 33 , 34 . Nonetheless, here we report clear thermalization and sympathetic cooling of triplet NaLi to 220 nK. We observe 20-fold increases of phase-space density (PSD), opening the possibility of collisional cooling to deep quantum degeneracy. Our experimental setup is summarized in Fig. 1 . Similarly to our previous work 35 , 36 , we produce about 3.0 × 10 4 NaLi molecules in the rovibrational ground state of the triplet potential using a mixture of Na and Li atoms (further details in Methods). We also prepare about 1.0 × 10 5 Na atoms in the upper stretched hyperfine state (in the low-field basis, | F , m F ⟩ = |2, 2 ⟩ , where F and m F are the hyperfine and magnetic quantum numbers, respectively) in a one-dimensional (1D) optical lattice formed by 1,596-nm light. Owing to the differential polarizability at 1,596 nm, molecules feel a deeper trapping potential than atoms. This results in a sudden increase of the potential energy as atoms associate and form molecules (see<|im_end|> <|im_start|>assistant For years, scientists have looked for ways to cool molecules down to ultracold temperatures, at which point the molecules should slow to a crawl, allowing scientists to precisely control their quantum behavior. This could enable researchers to use molecules as complex bits for quantum computing, tuning individual molecules like tiny knobs to carry out multiple streams of calculations at a time. While scientists have super-cooled atoms, doing the same for molecules, which are more complex in their behavior and structure, has proven to be a much bigger challenge. Now MIT physicists have found a way to cool molecules of sodium lithium down to 200 billionths of a Kelvin, just a hair above absolute zero. They did so by applying a technique called collisional cooling, in which they immersed molecules of cold sodium lithium in a cloud of even colder sodium atoms. The ultracold atoms acted as a refrigerant to cool the molecules even further. Collisional cooling is a standard technique used to cool down atoms using other, colder atoms. And for more than a decade, researchers have attempted to supercool a number of different molecules using collisional cooling, only to find that when molecules collided with atoms, they exchanged energy in such a way that the molecules were heated or destroyed in the process, called "bad" collisions. In their own experiments, the MIT researchers found that if sodium lithium molecules and sodium atoms were made to spin in the same way, they could avoid self-destructing, and instead engaged in "good" collisions, where the atoms took away the molecules' energy, in the form of heat. The team used precise control of magnetic fields and an intricate system of lasers to choreograph the spin and the rotational motion of the molecules. As result, the atom-molecule mixture had a high ratio of good-to-bad collisions and was cooled down from 2 microkelvins to 220 nanokelvins. "Collisional cooling has been the workhorse for cooling atoms," adds Nobel Prize laureate Wolfgang Ketterle, the John D. Arthur professor of physics at MIT. "I wasn't convinced that our scheme would work, but since we didn't know for sure, we had to try it. We know now that it works for cooling sodium lithium molecules. Whether it will work for other classes of molecules remains to be seen." Their findings, published in the journal Nature, mark the first time researchers have successfully used collisional cooling to cool molecules down to nanokelvin temperatures. Ketterle's coauthors on the paper are lead author Hyungmok Son, a graduate student in Harvard University's Department of Physics, along with MIT physics graduate student Juliana Park, and Alan Jamison, a professor of physics at the University of Waterloo and visiting scientist in MIT's Research Laboratory of Electronics. Reaching ultralow temperatures In the past, scientists found that when they tried to cool molecules down to ultracold temperatures by surrounding them with even colder atoms, the particles collided such that the atoms imparted extra energy or rotation to the molecules, sending them flying out of the trap, or self-destructing all together by chemical reactions. The MIT researchers wondered whether molecules and atoms, having the same spin, could avoid this effect, and remain ultracold and stable as a result. They looked to test their idea with sodium lithium, a "diatomic" molecule that Ketterle's group experiments with regularly, consisting of one lithium and one sodium atom. "Sodium lithium molecules are quite different from other molecules people have tried," Jamison says. "Many folks expected those differences would make cooling even less likely to work. However, we had a feeling these differences could be an advantage instead of a detriment." The researchers fine-tuned a system of more than 20 laser beams and various magnetic fields to trap and cool atoms of sodium and lithium in a vacuum chamber, down to about 2 microkelvins—a temperature Son says is optimal for the atoms to bond together as sodium lithium molecules. Once the researchers were able to produce enough molecules, they shone laser beams of specific frequencies and polarizations to control the quantum state of the molecules and carefully tuned microwave fields to make atoms spin in the same way as the molecules. "Then we make the refrigerator colder and colder," says Son, referring to the sodium atoms that surround the cloud of the newly formed molecules. "We lower the power of the trapping laser, making the optical trap looser and looser, which brings the temperature of sodium atoms down, and further cools the molecules, to 200 billionths of a kelvin." The group observed that the molecules were able to remain at these ultracold temperatures for up to one second. "In our world, a second is very long," Ketterle says. "What you want to do with these molecules is quantum computation and exploring new materials, which all can be done in small fractions of a second." If the team can get sodium lithium molecules to be about five times colder than what they have so far achieved, they will have reached a so-called quantum degenerate regime where individual molecules become indistinguishable and their collective behavior is controlled by quantum mechanics. Son and his colleagues have some ideas for how to achieve this, which will involve months of work in optimizing their setup, as well as acquiring a new laser to integrate into their setup. "Our work will lead to discussion in our community why collisional cooling has worked for us but not for others," Son says "Perhaps we will soon have predictions how other molecules could be cooled in this way." <|im_end|>

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539, 369, 3885, 1359, 12103, 2795, 330, 32576, 584, 690, 5246, 617, 20492, 1268, 1023, 35715, 1436, 387, 65410, 304, 420, 1648, 1210, 220, 128257, 198 ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Background Maternal obesity and high gestational weight gain (GWG) disproportionally affect low-income populations and may be associated with child neurodevelopment in a sex-specific manner. We examined sex-specific associations between prepregnancy BMI, GWG, and child neurodevelopment at age 7. Methods Data are from a prospective low-income cohort of African American and Dominican women ( n = 368; 44.8% male offspring) enrolled during the second half of pregnancy from 1998 to 2006. Neurodevelopment was measured using the Wechsler Intelligence Scale for Children (WISC-IV) at approximately child age 7. Linear regression estimated associations between prepregnancy BMI, GWG, and child outcomes, adjusting for race/ethnicity, marital status, gestational age at delivery, maternal education, maternal IQ and child age. Results Overweight affected 23.9% of mothers and obesity affected 22.6%. At age 7, full-scale IQ was higher among girls (99.7 ± 11.6) compared to boys (96.9 ± 13.3). Among boys, but not girls, prepregnancy overweight and obesity were associated with lower full-scale IQ scores [overweight β: − 7.1, 95% CI: (− 12.1, − 2.0); obesity β: − 5.7, 95% CI: (− 10.7, − 0.7)]. GWG was not associated with full-scale IQ in either sex. Conclusions Prepregnancy overweight and obesity were associated with lower IQ among boys, but not girls, at 7 years. These findings are important considering overweight and obesity prevalence and the long-term implications of early cognitive development. Peer Review reports Background Low-income, urban children are at higher risk of not achieving their developmental potential [ 1 , 2 , 3 ]. Furthermore, low-income, multiethnic populations are disproportionally affected by adverse prenatal factors, such as excessive maternal adiposity and high gestational weight gain (GWG) [ 4 , 5 ]. Prior studies suggest that prepregnancy body mass index (BMI) and/or GWG may be negatively associated with cognitive development in early and mid-childhood [ 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ]; however, these associations have not been examined in a low-income, multiethnic urban population. Fetal development depends on maternal nutrition status, but the systemic inflammation, metabolic stress, and hormonal perturbations that accompany excess adiposity may adversely affect placental function and fetal development at critical phases [ 15 , 16 , 17 ]. While child sex is a determinant of behavior and cognition, and evidence suggests that boys and girls respond differently to adverse exposures (e.g., poverty, stress, prenatal lead exposure [ 18 , 19 ]), the interplay among maternal BMI and/or GWG, child sex and cognitive development is poorly understood. We recently reported differences in associations of maternal prepregnancy BMI and child development by sex in our cohort at age 3; specifically we found that maternal obesity was associated with lower psychomotor development index scores in boys, but not girls [ 20 ]. Whether these sex-specific effects persist into mid-childhood remains unknown. Child growth and development are also shaped by environmental and socioeconomic factors, many of which are interrelated. Although partially heritable, child cognition may be predicted by postnatal aspects of the home environment, such as parental nurturance or environmental stimulation [ 21 , 22 ]. A more nurturing environment has the potential to temper adverse effects from other key determinants, such as limited socioeconomic resources, environmental exposures and possibly maternal excess adiposity or GWG; however, this has not been evaluated [ 12 , 23 , 24 ]. Environmental toxicant exposures, including pesticides and air pollution, are associated with child neural development [ 25 , 26 , 27 , 28 , 29 ] and have been linked to weight and fat mass gain [ 30 , 31 , 32 , 33 , 34 , 35 ]. Because pregnancy includes shifts in adipose tissue depots [ 36 ], toxicant exposure levels in utero could potentially vary by prepregnancy BMI and GWG; but it is unclear if toxicants impact associations between BMI and/or GWG and child cognition. Therefore, among low-income African American and Dominican urban children participating in the Columbia Center for Children’s Environmental Health (CCCEH) Mothers and Newborns Study, we examined whether maternal prepregnancy BMI and GWG were related to neurodevelopment at child age 7 and if associations varied by child sex. We hypothesized that maternal obesity and greater GWG would be associated with lower IQ, and that associations would be stronger among boys. Moreover, we evaluated whether a more nurturing postnatal home environment changed directions of associations. We also conducted a sensitivity analysis to evaluate whether associations observed were moderated or confounded by prenatal exposure to chlorpyrifos (CPF) and polycyclic aromatic hydrocarbons (PAH), which were previously associated with decreased child IQ in our population [ 25 , 26 ]. Methods This analysis was conducted in a subset of a cohort designed to examine the role of environmental exposures on birth outcomes. Since 1997, the CCCEH Mothers and Newborns cohort ( n = 727) has followed mother-child dyads from northern Manhattan and the South Bronx, previously described in detail [ 37 ]. From 1997 to 2006, Dominican and African American women with singleton gestations were enrolled from prenatal clinics at New York Presbyterian Medical Center and Harlem Hospital if they met eligibility criteria, including first prenatal visit < 20 weeks of gestation and no self-reported diabetes, hypertension, HIV, illicit drug use or smoking during pregnancy. An initial prenatal visit during the second or third trimester included maternal measurements and an interviewer-administered questionnaire. Self-reported prepregnancy weight, Income, marital status, exposure to environmental tobacco smoke, and prenatal distress, including demoralization (i.e. psychological stress) [ 38 ], use of public assistance, and material hardship (self-report of challenges affording food, paying utilities) [ 39 ] were assessed. Self-reported height was obtained at the prenatal visit, and measured height was obtained at postnatal follow-up visits. Maternal height data checking and cleaning in this cohort was previously described in detail [ 40 ]. After delivery, medical records were abstracted to ascertain prenatal medical history, last measured weight prior to delivery and infant birth weight. Total GWG was calculated by subtracting the last measured weight prior to delivery from the self-reported prepregnancy weight. BMI", "role": "user" }, { "content": "A mother's obesity in pregnancy can affect her child's development years down the road, according to researchers who found impaired motor skills in preschoolers and lower IQ in middle childhood for boys whose mothers were severely overweight while expecting them. A team of nutrition and environmental health researchers at The University of Texas at Austin and Columbia University found that the differences are comparable to the impact of lead exposure in early childhood. The team studied 368 mothers and their children, all from similar economic circumstances and neighborhoods, during pregnancy and when the children were 3 and 7 years of age. At age 3, the researchers measured the children's motor skills and found that maternal obesity during pregnancy was strongly associated with lower motor skills in boys. At age 7, they again measured the children and found that the boys whose mothers were overweight or obese in pregnancy had scores 5 or more points lower on full-scale IQ tests, compared with boys whose mothers had been at a normal weight. No effect was found in the girls. \"What's striking is, even using different age-appropriate developmental assessments, we found these associations in both early and middle childhood, meaning these effects persist over time,\" said Elizabeth Widen, assistant professor of nutritional sciences at UT Austin. \"These findings aren't meant to shame or scare anyone. We are just beginning to understand some of these interactions between mothers' weight and the health of their babies.\" It isn't clear why obesity in pregnancy would affect a child later, though previous research has found links between a mother's diet and cognitive development, such as higher IQ scores in kids whose mothers have more of certain fatty acids found in fish. Widen said that dietary and behavioral differences may be driving factors, or fetal development may be affected by some of the things that tend to happen in the bodies of people with too much extra weight, such as inflammation, metabolic stress, hormonal disruptions and high amounts of insulin and glucose. The researchers controlled for several factors in their analysis, including race and ethnicity, marital status, the mother's education and IQ, as well as whether the children were born prematurely or exposed to environmental irritants such as air pollution. What the pregnant mothers ate or whether they breastfed were not included in the analysis. The team also examined and accounted for the nurturing environment in a child's home in early childhood, looking at how parents interacted with their children and whether the child was provided with books and toys. A nurturing home environment was found to lessen the negative effects of obesity. \"The effect on IQ was smaller in nurturing home environments, but it was still there,\" Widen said. This is not the first study to find that boys appear to be more vulnerable in utero. A 2018 study found lower performance IQ in boys, but not girls, whose mothers were exposed to lead, and a 2019 study suggested boys whose moms had fluoride in pregnancy scored lower on an IQ assessment. Because childhood IQ is a predictor of education level, socioeconomic status and professional success later in life, the researchers said there is potential for effects to last into adulthood. Widen advised women who are obese or overweight when they become pregnant to eat a well-balanced diet that is rich in fruits and vegetables, take a prenatal vitamin, stay active and make sure to get enough fatty acids such as the kind found in fish oil. Giving children a nurturing home environment also matters, as does seeing a doctor regularly, including during pregnancy to discuss weight gain. \"Work with your doctor and talk about what is appropriate for your circumstances,\" Widen said. The families involved in the research were participating in the urban birth cohort study in New York City led by the Columbia Center for Children's Environmental Health. The study on IQ at age 7 was published today in BMC Pediatrics with co-authors Amy Nichols and Sara Dube of UT Austin; Linda Kahn of New York University; and Pam Factor-Litvak, Beverly Insel, Lori Hoepner, Virginia Rauh, Frederica Perera and Andrew Rundle of Columbia University. The same team, absent Dube and Kahn, were involved in a paper about the children at age 3, published in September in the Journal of Developmental Origins of Health and Disease. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Background Maternal obesity and high gestational weight gain (GWG) disproportionally affect low-income populations and may be associated with child neurodevelopment in a sex-specific manner. We examined sex-specific associations between prepregnancy BMI, GWG, and child neurodevelopment at age 7. Methods Data are from a prospective low-income cohort of African American and Dominican women ( n = 368; 44.8% male offspring) enrolled during the second half of pregnancy from 1998 to 2006. Neurodevelopment was measured using the Wechsler Intelligence Scale for Children (WISC-IV) at approximately child age 7. Linear regression estimated associations between prepregnancy BMI, GWG, and child outcomes, adjusting for race/ethnicity, marital status, gestational age at delivery, maternal education, maternal IQ and child age. Results Overweight affected 23.9% of mothers and obesity affected 22.6%. At age 7, full-scale IQ was higher among girls (99.7 ± 11.6) compared to boys (96.9 ± 13.3). Among boys, but not girls, prepregnancy overweight and obesity were associated with lower full-scale IQ scores [overweight β: − 7.1, 95% CI: (− 12.1, − 2.0); obesity β: − 5.7, 95% CI: (− 10.7, − 0.7)]. GWG was not associated with full-scale IQ in either sex. Conclusions Prepregnancy overweight and obesity were associated with lower IQ among boys, but not girls, at 7 years. These findings are important considering overweight and obesity prevalence and the long-term implications of early cognitive development. Peer Review reports Background Low-income, urban children are at higher risk of not achieving their developmental potential [ 1 , 2 , 3 ]. Furthermore, low-income, multiethnic populations are disproportionally affected by adverse prenatal factors, such as excessive maternal adiposity and high gestational weight gain (GWG) [ 4 , 5 ]. Prior studies suggest that prepregnancy body mass index (BMI) and/or GWG may be negatively associated with cognitive development in early and mid-childhood [ 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ]; however, these associations have not been examined in a low-income, multiethnic urban population. Fetal development depends on maternal nutrition status, but the systemic inflammation, metabolic stress, and hormonal perturbations that accompany excess adiposity may adversely affect placental function and fetal development at critical phases [ 15 , 16 , 17 ]. While child sex is a determinant of behavior and cognition, and evidence suggests that boys and girls respond differently to adverse exposures (e.g., poverty, stress, prenatal lead exposure [ 18 , 19 ]), the interplay among maternal BMI and/or GWG, child sex and cognitive development is poorly understood. We recently reported differences in associations of maternal prepregnancy BMI and child development by sex in our cohort at age 3; specifically we found that maternal obesity was associated with lower psychomotor development index scores in boys, but not girls [ 20 ]. Whether these sex-specific effects persist into mid-childhood remains unknown. Child growth and development are also shaped by environmental and socioeconomic factors, many of which are interrelated. Although partially heritable, child cognition may be predicted by postnatal aspects of the home environment, such as parental nurturance or environmental stimulation [ 21 , 22 ]. A more nurturing environment has the potential to temper adverse effects from other key determinants, such as limited socioeconomic resources, environmental exposures and possibly maternal excess adiposity or GWG; however, this has not been evaluated [ 12 , 23 , 24 ]. Environmental toxicant exposures, including pesticides and air pollution, are associated with child neural development [ 25 , 26 , 27 , 28 , 29 ] and have been linked to weight and fat mass gain [ 30 , 31 , 32 , 33 , 34 , 35 ]. Because pregnancy includes shifts in adipose tissue depots [ 36 ], toxicant exposure levels in utero could potentially vary by prepregnancy BMI and GWG; but it is unclear if toxicants impact associations between BMI and/or GWG and child cognition. Therefore, among low-income African American and Dominican urban children participating in the Columbia Center for Children’s Environmental Health (CCCEH) Mothers and Newborns Study, we examined whether maternal prepregnancy BMI and GWG were related to neurodevelopment at child age 7 and if associations varied by child sex. We hypothesized that maternal obesity and greater GWG would be associated with lower IQ, and that associations would be stronger among boys. Moreover, we evaluated whether a more nurturing postnatal home environment changed directions of associations. We also conducted a sensitivity analysis to evaluate whether associations observed were moderated or confounded by prenatal exposure to chlorpyrifos (CPF) and polycyclic aromatic hydrocarbons (PAH), which were previously associated with decreased child IQ in our population [ 25 , 26 ]. Methods This analysis was conducted in a subset of a cohort designed to examine the role of environmental exposures on birth outcomes. Since 1997, the CCCEH Mothers and Newborns cohort ( n = 727) has followed mother-child dyads from northern Manhattan and the South Bronx, previously described in detail [ 37 ]. From 1997 to 2006, Dominican and African American women with singleton gestations were enrolled from prenatal clinics at New York Presbyterian Medical Center and Harlem Hospital if they met eligibility criteria, including first prenatal visit < 20 weeks of gestation and no self-reported diabetes, hypertension, HIV, illicit drug use or smoking during pregnancy. An initial prenatal visit during the second or third trimester included maternal measurements and an interviewer-administered questionnaire. Self-reported prepregnancy weight, Income, marital status, exposure to environmental tobacco smoke, and prenatal distress, including demoralization (i.e. psychological stress) [ 38 ], use of public assistance, and material hardship (self-report of challenges affording food, paying utilities) [ 39 ] were assessed. Self-reported height was obtained at the prenatal visit, and measured height was obtained at postnatal follow-up visits. Maternal height data checking and cleaning in this cohort was previously described in detail [ 40 ]. After delivery, medical records were abstracted to ascertain prenatal medical history, last measured weight prior to delivery and infant birth weight. Total GWG was calculated by subtracting the last measured weight prior to delivery from the self-reported prepregnancy weight. BMI<|im_end|> <|im_start|>assistant A mother's obesity in pregnancy can affect her child's development years down the road, according to researchers who found impaired motor skills in preschoolers and lower IQ in middle childhood for boys whose mothers were severely overweight while expecting them. A team of nutrition and environmental health researchers at The University of Texas at Austin and Columbia University found that the differences are comparable to the impact of lead exposure in early childhood. The team studied 368 mothers and their children, all from similar economic circumstances and neighborhoods, during pregnancy and when the children were 3 and 7 years of age. At age 3, the researchers measured the children's motor skills and found that maternal obesity during pregnancy was strongly associated with lower motor skills in boys. At age 7, they again measured the children and found that the boys whose mothers were overweight or obese in pregnancy had scores 5 or more points lower on full-scale IQ tests, compared with boys whose mothers had been at a normal weight. No effect was found in the girls. "What's striking is, even using different age-appropriate developmental assessments, we found these associations in both early and middle childhood, meaning these effects persist over time," said Elizabeth Widen, assistant professor of nutritional sciences at UT Austin. "These findings aren't meant to shame or scare anyone. We are just beginning to understand some of these interactions between mothers' weight and the health of their babies." It isn't clear why obesity in pregnancy would affect a child later, though previous research has found links between a mother's diet and cognitive development, such as higher IQ scores in kids whose mothers have more of certain fatty acids found in fish. Widen said that dietary and behavioral differences may be driving factors, or fetal development may be affected by some of the things that tend to happen in the bodies of people with too much extra weight, such as inflammation, metabolic stress, hormonal disruptions and high amounts of insulin and glucose. The researchers controlled for several factors in their analysis, including race and ethnicity, marital status, the mother's education and IQ, as well as whether the children were born prematurely or exposed to environmental irritants such as air pollution. What the pregnant mothers ate or whether they breastfed were not included in the analysis. The team also examined and accounted for the nurturing environment in a child's home in early childhood, looking at how parents interacted with their children and whether the child was provided with books and toys. A nurturing home environment was found to lessen the negative effects of obesity. "The effect on IQ was smaller in nurturing home environments, but it was still there," Widen said. This is not the first study to find that boys appear to be more vulnerable in utero. A 2018 study found lower performance IQ in boys, but not girls, whose mothers were exposed to lead, and a 2019 study suggested boys whose moms had fluoride in pregnancy scored lower on an IQ assessment. Because childhood IQ is a predictor of education level, socioeconomic status and professional success later in life, the researchers said there is potential for effects to last into adulthood. Widen advised women who are obese or overweight when they become pregnant to eat a well-balanced diet that is rich in fruits and vegetables, take a prenatal vitamin, stay active and make sure to get enough fatty acids such as the kind found in fish oil. Giving children a nurturing home environment also matters, as does seeing a doctor regularly, including during pregnancy to discuss weight gain. "Work with your doctor and talk about what is appropriate for your circumstances," Widen said. The families involved in the research were participating in the urban birth cohort study in New York City led by the Columbia Center for Children's Environmental Health. The study on IQ at age 7 was published today in BMC Pediatrics with co-authors Amy Nichols and Sara Dube of UT Austin; Linda Kahn of New York University; and Pam Factor-Litvak, Beverly Insel, Lori Hoepner, Virginia Rauh, Frederica Perera and Andrew Rundle of Columbia University. The same team, absent Dube and Kahn, were involved in a paper about the children at age 3, published in September in the Journal of Developmental Origins of Health and Disease. <|im_end|>

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2,259

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Magnetoresistive effects are usually invariant on inversion of the magnetization direction. In non-centrosymmetric conductors, however, nonlinear resistive terms can give rise to a current dependence that is quadratic in the applied voltage and linear in the magnetization. Here we demonstrate that such conditions are realized in simple bilayer metal films where the spin–orbit interaction and spin-dependent scattering couple the current-induced spin accumulation to the electrical conductivity. We show that the longitudinal resistance of Ta|Co and Pt|Co bilayers changes when reversing the polarity of the current or the sign of the magnetization. This unidirectional magnetoresistance scales linearly with current density and has opposite sign in Ta and Pt, which we associate with the modification of the interface scattering potential induced by the spin Hall effect in these materials. Our results suggest a route to control the resistance and detect magnetization switching in spintronic devices using a two-terminal geometry, which applies also to heterostructures including topological insulators. Main The effects of the magnetization on the electric conductivity of metals have been studied for a long time 1 , providing understanding of fundamental phenomena associated with electron transport and magnetism as well as a multitude of applications in sensor technology. The anisotropic magnetoresistance (AMR)—the change of the resistance of a material on rotation of the magnetization—is a prominent manifestation of spin–orbit coupling and spin-dependent conductivity in bulk ferromagnets 2 , 3 . In thin-film heterostructures, the additional possibility of orienting the magnetization of stacked ferromagnetic layers parallel or antiparallel to each other gives rise to the celebrated giant magnetoresistance (GMR) effect 4 , 5 , which has played a major role in all modern developments of spintronics. Together with the early spin-injection experiments 6 , 7 , the study of GMR revealed how non-equilibrium spin accumulation at the interface between ferromagnetic (FM) and normal metal (NM) conductors governs the propagation of spin currents 8 , 9 , 10 , 11 and, ultimately, the conductivity of multilayer systems 10 , 12 . Recently, it has been shown that significant spin accumulation at a FM/NM interface can be achieved using a current-in-plane (CIP) geometry owing to the spin Hall effect (SHE) in the NM (ref. 13 ). When the FM is a metal and NM is a heavy element such as Pt or Ta, the spin accumulation is strong enough to induce magnetization reversal of nanometre-thick FM layers at current densities of the order of j = 10 7 –10 8 A cm −2 (refs 14 , 15 , 16 ). When the FM is an insulator, such as yttrium iron garnet, the SHE causes an unusual magnetoresistance associated with the back-flow of a spin current into the NM when the spin accumulation is aligned with the magnetization of the FM, which increases the conductivity of the NM due to the inverse SHE (refs 17 , 18 , 19 , 20 ). This so-called spin Hall magnetoresistance (SMR) is characterized by R y < R z ≍ R x , where R i is the resistance measured when the magnetization ( M ) is saturated parallel to i = x , y , z , and differs from the conventional AMR in polycrystalline samples, for which and R y ≍ R z < R x (ref. 3 ). In this work, we report on a magnetoresistance effect occurring in FM/NM bilayers with the NM possessing a large SHE. The effect combines features that are typical of the current-in-plane (CIP) GMR and SHE, whereby the spin accumulation induced by the SHE in the NM replaces one of the FM polarizers of a typical GMR device. Differently from GMR, however, this effect introduces a nonlinear dependence of the resistance on the current, which gives it unique unidirectional properties: the resistivity changes when reversing either the sign of the magnetization or the polarity of the current, increasing (decreasing) when the SHE-induced non-equilibrium magnetization at the FM/NM interface is oriented parallel (antiparallel) to the magnetization of the FM, as illustrated in Fig. 1a, b . We associate this phenomenon with the modulation of the FM/NM interface resistance due to the SHE-induced spin accumulation, which gives rise to a nonlinear contribution to the longitudinal conductivity that scales proportionally with the current density and has opposite sign in Pt and Ta. Contrary to the linear magnetoresistive effects, including the AMR, GMR, and SMR described above, which are even with respect to the inversion of either the current or magnetization owing to the time reversal symmetry embodied in the Onsager’s reciprocity relations, here we observe R ( j , M ) = − R ( −j , M ) = − R ( j , −M ), providing a unidirectional contribution to the magnetoresistance in simple bilayer systems. Figure 1: Illustration of the unidirectional spin Hall magnetoresistance effect and sample layout. a , Parallel alignment of the SHE-induced non-equilibrium magnetization at the FM/NM interface with the magnetization of the FM increases the resistivity of the bilayer. b , Antiparallel alignment decreases the resistivity. The arrows in a , b indicate the direction of the spin magnetic moment. c , Scanning electron micrograph of a sample and schematics of the longitudinal resistance measurements. Full size image Sample layout The samples studied in this work are Pt (1–9 nm)|Co (2.5 nm) and Ta (1–9 nm)|Co (2.5 nm) films with spontaneous in-plane magnetization, capped by 2 nm of AlO x and patterned in the shape of Hall bars of nominal length l = 20–50 μm, width w = 4–10 μm, and l / w = 4, as shown in Fig. 1c . Additional control experiments were carried out on single Co, Ta and Pt films, and Ta (1, 6 nm)|Cu (2, 4, 6 nm)|Co (2.5 nm) trilayers. To characterize the magnetic and electrical properties of these layers we performed harmonic measurements of the longitudinal resistance ( R , see Supplementary Information ) and transverse Hall resistance ( R H ; refs 16 , 21 , 22 , 23 ) as a function of a", "role": "user" }, { "content": "More than 150 years ago, William Thomson, later Lord Kelvin, discovered the magnetoresistive effect. Today, this finding enables sensors to measure the rotational speed of a car wheel, and is also used in compass navigation and robot control systems. ETH material scientists have now found a new kind of magnetoresistance that promises further insight into basic research and could one day be used for practical applications. The discovery by Pietro Gambardella, Professor for Magnetism and Interface Physics at ETH Zurich, and his team has just been published in the British scientific journal Nature Physics. However, advance publication of their work a few months ago on a science platform caused a stir among experts and has motivated other researchers to attempt similar experiments. The magnetoresistance of a conductive material normally remains the same when an electric current changes direction. \"However, a new magnetoresistive effect that we discovered changed when the electron flow was reversed,\" Gambardella explains. \"This is very unusual in metals.\" According to physical principles, these microscopic processes should remain independent of the direction of electrons in a metallic conductor. This new discovery is even more surprising considering that the first magnetoresistance effect was observed more than 150 years ago. Resistance measurements are \"among the simplest that you can do\", according to Gambardella. In the laboratory at ETH Zurich, old-style electromagnets are placed next to modern superconductors and laser instruments. One of the magnets comes from Gambardella's earlier workplace at EPFL in Lausanne; he rescued it from the trash before it was carted off for disposal. The researchers clamped samples manufactured in the laboratory in the magnets and measured the electrical resistance at different magnetisation. Sensors and read heads for hard drives Wiring of a sample for magnetoresistance measurements. Credit: Avci, Mendil and Gambardella / ETH Zurich Electrical resistance is a fundamental property of conductive materials. It indicates how well an electric current can be sent through a wire and is dependent on the magnetisation of the material. In 1856, William Thomson (later Lord Kelvin) discovered that an iron plate's electrical resistance changed depending on the direction in which the magnetisation ran. This anisotropic magnetoresistive effect (AMR) is used today in a variety of sensors; for example, it is used in cars to measure the wheel speed and the pedal and sitting position, and to control the power steering. AMR sensors are also used in cameras and in engineering and medical technology. They can even be found on Mars; the robots have more than 100 AMR sensors to control the moving parts. AMR sensors are based on thin magnetic layers in which the resistance varies by a few percent depending on whether the current is perpendicular or parallel relative to the magnetisation. French physicist Albert Fert and his German colleague Peter Grünberg discovered a much larger resistance difference of 50 percent in thin-film structures made up of alternating layers of magnetic and non-magnetic materials. For this Giant Magnetoresistive Effect (GMR), the two researchers received the Nobel Prize in Physics in 2007. The GMR effect is used today in, inter alia, magnetic field sensors and to read data on computer hard drives. Bilayers of heavy metal and ferromagnet A GMR structure typically consists of two films of ferromagnetic material, such as iron or cobalt, separated by a non-magnetic layer of copper. If the magnetisation of the iron or cobalt layer is parallel, the structure's electric resistance is small. If the orientation is anti-parallel, resistance is greater. \"We restricted ourselves to two instead of three layers,\" explains Gambardella. The researchers' structure consisted of a thin layer of heavy metal, such as platinum or tantalum, with a thin layer of iron or cobalt above. \"The very clever idea for this experiment came from one of our students, Can Onur Avci,\" says the ETH professor. With their two–layer samples, the researchers measured a normal AMR effect; as expected, the resistance changed according to the magnetisation of the ferromagnets. Surprisingly, however, they also found a new magnetoresistive effect in which the resistance depended on the direction of the electron flow. The samples' strange behaviour can be explained by the electrons' magnetic moment – the spin. In heavy metals, electrons with opposite spin are deflected in different directions. Electrons with the same spin direction therefore accumulate at the interface of the platinum or tantalum. But if a layer of iron or cobalt is placed on the heavy metal, the total electrical resistance depends on how the accumulated spin and the magnetisation of the ferromagnetic material are aligned. Small effect, big hopes The opposite deflection of the electrons with the opposite spin is called the Spin Hall effect, which is why the ETH researchers dubbed the newly discovered magnetoresistance, which depends on the direction of electron flow, Unidirectional Spin Hall Magnetoresistance. This phenomenon is similar to GMR, according to Gambardella. However, it not only involves a material's property, but is directly proportional to the amount of current flowing into the material. Nevertheless, ETH researchers warn that expectations should not be set too high: \"Our effect is very interesting for basic research, but can't yet be used in a practical way.\" The fractional differences in resistance are much too small. One day, however, customised materials may be produced in which the new magnetoresistance could be used. The researchers are thinking of semiconductors or topological insulators in which the electrons are confined at the interface of different material components and may present amplified magnetoresistances. Spintronics is the name of the field of research that flourished after the discovery of the GMR effect. Advances in this area have applications for the storage and processing of digital information, for example by storing and processing information not only based on charges but also on the spin. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Magnetoresistive effects are usually invariant on inversion of the magnetization direction. In non-centrosymmetric conductors, however, nonlinear resistive terms can give rise to a current dependence that is quadratic in the applied voltage and linear in the magnetization. Here we demonstrate that such conditions are realized in simple bilayer metal films where the spin–orbit interaction and spin-dependent scattering couple the current-induced spin accumulation to the electrical conductivity. We show that the longitudinal resistance of Ta|Co and Pt|Co bilayers changes when reversing the polarity of the current or the sign of the magnetization. This unidirectional magnetoresistance scales linearly with current density and has opposite sign in Ta and Pt, which we associate with the modification of the interface scattering potential induced by the spin Hall effect in these materials. Our results suggest a route to control the resistance and detect magnetization switching in spintronic devices using a two-terminal geometry, which applies also to heterostructures including topological insulators. Main The effects of the magnetization on the electric conductivity of metals have been studied for a long time 1 , providing understanding of fundamental phenomena associated with electron transport and magnetism as well as a multitude of applications in sensor technology. The anisotropic magnetoresistance (AMR)—the change of the resistance of a material on rotation of the magnetization—is a prominent manifestation of spin–orbit coupling and spin-dependent conductivity in bulk ferromagnets 2 , 3 . In thin-film heterostructures, the additional possibility of orienting the magnetization of stacked ferromagnetic layers parallel or antiparallel to each other gives rise to the celebrated giant magnetoresistance (GMR) effect 4 , 5 , which has played a major role in all modern developments of spintronics. Together with the early spin-injection experiments 6 , 7 , the study of GMR revealed how non-equilibrium spin accumulation at the interface between ferromagnetic (FM) and normal metal (NM) conductors governs the propagation of spin currents 8 , 9 , 10 , 11 and, ultimately, the conductivity of multilayer systems 10 , 12 . Recently, it has been shown that significant spin accumulation at a FM/NM interface can be achieved using a current-in-plane (CIP) geometry owing to the spin Hall effect (SHE) in the NM (ref. 13 ). When the FM is a metal and NM is a heavy element such as Pt or Ta, the spin accumulation is strong enough to induce magnetization reversal of nanometre-thick FM layers at current densities of the order of j = 10 7 –10 8 A cm −2 (refs 14 , 15 , 16 ). When the FM is an insulator, such as yttrium iron garnet, the SHE causes an unusual magnetoresistance associated with the back-flow of a spin current into the NM when the spin accumulation is aligned with the magnetization of the FM, which increases the conductivity of the NM due to the inverse SHE (refs 17 , 18 , 19 , 20 ). This so-called spin Hall magnetoresistance (SMR) is characterized by R y < R z ≍ R x , where R i is the resistance measured when the magnetization ( M ) is saturated parallel to i = x , y , z , and differs from the conventional AMR in polycrystalline samples, for which and R y ≍ R z < R x (ref. 3 ). In this work, we report on a magnetoresistance effect occurring in FM/NM bilayers with the NM possessing a large SHE. The effect combines features that are typical of the current-in-plane (CIP) GMR and SHE, whereby the spin accumulation induced by the SHE in the NM replaces one of the FM polarizers of a typical GMR device. Differently from GMR, however, this effect introduces a nonlinear dependence of the resistance on the current, which gives it unique unidirectional properties: the resistivity changes when reversing either the sign of the magnetization or the polarity of the current, increasing (decreasing) when the SHE-induced non-equilibrium magnetization at the FM/NM interface is oriented parallel (antiparallel) to the magnetization of the FM, as illustrated in Fig. 1a, b . We associate this phenomenon with the modulation of the FM/NM interface resistance due to the SHE-induced spin accumulation, which gives rise to a nonlinear contribution to the longitudinal conductivity that scales proportionally with the current density and has opposite sign in Pt and Ta. Contrary to the linear magnetoresistive effects, including the AMR, GMR, and SMR described above, which are even with respect to the inversion of either the current or magnetization owing to the time reversal symmetry embodied in the Onsager’s reciprocity relations, here we observe R ( j , M ) = − R ( −j , M ) = − R ( j , −M ), providing a unidirectional contribution to the magnetoresistance in simple bilayer systems. Figure 1: Illustration of the unidirectional spin Hall magnetoresistance effect and sample layout. a , Parallel alignment of the SHE-induced non-equilibrium magnetization at the FM/NM interface with the magnetization of the FM increases the resistivity of the bilayer. b , Antiparallel alignment decreases the resistivity. The arrows in a , b indicate the direction of the spin magnetic moment. c , Scanning electron micrograph of a sample and schematics of the longitudinal resistance measurements. Full size image Sample layout The samples studied in this work are Pt (1–9 nm)|Co (2.5 nm) and Ta (1–9 nm)|Co (2.5 nm) films with spontaneous in-plane magnetization, capped by 2 nm of AlO x and patterned in the shape of Hall bars of nominal length l = 20–50 μm, width w = 4–10 μm, and l / w = 4, as shown in Fig. 1c . Additional control experiments were carried out on single Co, Ta and Pt films, and Ta (1, 6 nm)|Cu (2, 4, 6 nm)|Co (2.5 nm) trilayers. To characterize the magnetic and electrical properties of these layers we performed harmonic measurements of the longitudinal resistance ( R , see Supplementary Information ) and transverse Hall resistance ( R H ; refs 16 , 21 , 22 , 23 ) as a function of a<|im_end|> <|im_start|>assistant More than 150 years ago, William Thomson, later Lord Kelvin, discovered the magnetoresistive effect. Today, this finding enables sensors to measure the rotational speed of a car wheel, and is also used in compass navigation and robot control systems. ETH material scientists have now found a new kind of magnetoresistance that promises further insight into basic research and could one day be used for practical applications. The discovery by Pietro Gambardella, Professor for Magnetism and Interface Physics at ETH Zurich, and his team has just been published in the British scientific journal Nature Physics. However, advance publication of their work a few months ago on a science platform caused a stir among experts and has motivated other researchers to attempt similar experiments. The magnetoresistance of a conductive material normally remains the same when an electric current changes direction. "However, a new magnetoresistive effect that we discovered changed when the electron flow was reversed," Gambardella explains. "This is very unusual in metals." According to physical principles, these microscopic processes should remain independent of the direction of electrons in a metallic conductor. This new discovery is even more surprising considering that the first magnetoresistance effect was observed more than 150 years ago. Resistance measurements are "among the simplest that you can do", according to Gambardella. In the laboratory at ETH Zurich, old-style electromagnets are placed next to modern superconductors and laser instruments. One of the magnets comes from Gambardella's earlier workplace at EPFL in Lausanne; he rescued it from the trash before it was carted off for disposal. The researchers clamped samples manufactured in the laboratory in the magnets and measured the electrical resistance at different magnetisation. Sensors and read heads for hard drives Wiring of a sample for magnetoresistance measurements. Credit: Avci, Mendil and Gambardella / ETH Zurich Electrical resistance is a fundamental property of conductive materials. It indicates how well an electric current can be sent through a wire and is dependent on the magnetisation of the material. In 1856, William Thomson (later Lord Kelvin) discovered that an iron plate's electrical resistance changed depending on the direction in which the magnetisation ran. This anisotropic magnetoresistive effect (AMR) is used today in a variety of sensors; for example, it is used in cars to measure the wheel speed and the pedal and sitting position, and to control the power steering. AMR sensors are also used in cameras and in engineering and medical technology. They can even be found on Mars; the robots have more than 100 AMR sensors to control the moving parts. AMR sensors are based on thin magnetic layers in which the resistance varies by a few percent depending on whether the current is perpendicular or parallel relative to the magnetisation. French physicist Albert Fert and his German colleague Peter Grünberg discovered a much larger resistance difference of 50 percent in thin-film structures made up of alternating layers of magnetic and non-magnetic materials. For this Giant Magnetoresistive Effect (GMR), the two researchers received the Nobel Prize in Physics in 2007. The GMR effect is used today in, inter alia, magnetic field sensors and to read data on computer hard drives. Bilayers of heavy metal and ferromagnet A GMR structure typically consists of two films of ferromagnetic material, such as iron or cobalt, separated by a non-magnetic layer of copper. If the magnetisation of the iron or cobalt layer is parallel, the structure's electric resistance is small. If the orientation is anti-parallel, resistance is greater. "We restricted ourselves to two instead of three layers," explains Gambardella. The researchers' structure consisted of a thin layer of heavy metal, such as platinum or tantalum, with a thin layer of iron or cobalt above. "The very clever idea for this experiment came from one of our students, Can Onur Avci," says the ETH professor. With their two–layer samples, the researchers measured a normal AMR effect; as expected, the resistance changed according to the magnetisation of the ferromagnets. Surprisingly, however, they also found a new magnetoresistive effect in which the resistance depended on the direction of the electron flow. The samples' strange behaviour can be explained by the electrons' magnetic moment – the spin. In heavy metals, electrons with opposite spin are deflected in different directions. Electrons with the same spin direction therefore accumulate at the interface of the platinum or tantalum. But if a layer of iron or cobalt is placed on the heavy metal, the total electrical resistance depends on how the accumulated spin and the magnetisation of the ferromagnetic material are aligned. Small effect, big hopes The opposite deflection of the electrons with the opposite spin is called the Spin Hall effect, which is why the ETH researchers dubbed the newly discovered magnetoresistance, which depends on the direction of electron flow, Unidirectional Spin Hall Magnetoresistance. This phenomenon is similar to GMR, according to Gambardella. However, it not only involves a material's property, but is directly proportional to the amount of current flowing into the material. Nevertheless, ETH researchers warn that expectations should not be set too high: "Our effect is very interesting for basic research, but can't yet be used in a practical way." The fractional differences in resistance are much too small. One day, however, customised materials may be produced in which the new magnetoresistance could be used. The researchers are thinking of semiconductors or topological insulators in which the electrons are confined at the interface of different material components and may present amplified magnetoresistances. Spintronics is the name of the field of research that flourished after the discovery of the GMR effect. Advances in this area have applications for the storage and processing of digital information, for example by storing and processing information not only based on charges but also on the spin. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Although interactions between the thalamus and cortex are critical for cognitive function 1 , 2 , 3 , the exact contribution of the thalamus to these interactions remains unclear. Recent studies have shown diverse connectivity patterns across the thalamus 4 , 5 , but whether this diversity translates to thalamic functions beyond relaying information to or between cortical regions 6 is unknown. Here we show, by investigating the representation of two rules used to guide attention in the mouse prefrontal cortex (PFC), that the mediodorsal thalamus sustains these representations without relaying categorical information. Specifically, mediodorsal input amplifies local PFC connectivity, enabling rule-specific neural sequences to emerge and thereby maintain rule representations. Consistent with this notion, broadly enhancing PFC excitability diminishes rule specificity and behavioural performance, whereas enhancing mediodorsal excitability improves both. Overall, our results define a previously unknown principle in neuroscience; thalamic control of functional cortical connectivity. This function, which is dissociable from categorical information relay, indicates that the thalamus has a much broader role in cognition than previously thought. Main We recorded PFC ensembles in a two-alternative forced choice (2AFC) task, in which a freely behaving mouse selected between conflicting visual and auditory stimuli based on whether one of two rules was presented, and where rule presentation was varied on a trial-by-trial basis ( Fig. 1a ). Broadband white noise was informative of trial availability, prompting trial initiation by snout-protrusion into a centrally located port. Subsequently, either low-pass (10 kHz) or high-pass (11 kHz) noise was presented for 100 ms to signal the task rules (rule 1 (low pass), attend to vision; rule 2 (high pass), attend to audition), and after a brief delay where the head position was stably maintained, the animal selected between spatially conflicting visual and auditory stimuli to receive a reward. Animals achieved a balanced and robust performance across modalities ( Extended Data Fig. 1a ) and no stereotypical behaviour, which indicates a modality or location preference, was observed during the delay. These findings suggest that animals were capable of holding the task rule ‘in mind’ and using it to map onto sensory targets. Figure 1: Task-specific sequential PFC activity maintains rule representation. a , Schematic of task design. b , Example peri-stimulus time histogram (PSTH) and rasters for neurons tuned to either attend to vision (red) or attend to audition (blue) rules. c , Examples of tuning peaks across multiple sessions. d , Task-variable information, indicates that tuned neurons ( n = 512 neurons from four mice) reflect rule information (top, green), but not movement (top, grey), whereas unturned neurons do not reflect rule information ( n = 2,727, bottom). AU, arbitrary units. e , Example spike-time cross-correlation between two neurons (50-μs bins), indicating a putative monosynaptic connection. f , Putative monosynaptic connections in same rule tuned pairs showed a significantly larger average peak. Vertical ticks indicate peak times. Opp. rule, opposite rule. g , Cumulative plot showing cross-correlation values for each pair. Kolmogorov–Smirnov test. h , Same rule tuned pairs with putative monosynaptic connections had overlapping tuning peaks. i , Raster and PSTH examples showing diminished tuning during optogenetic activation of inhibitory neurons (blue shading indicates laser on). j , Quantification of laser effects on peak sizes ( n = 94 neurons, three mice; example in Extended Data Fig. 3j ). k , l , Temporally limited optogenetic manipulations indicate that later tuning depends on earlier activity. Blue line, laser on; green line, mean; green shading, 95% confidence interval (CI); grey shading, 95% CI for the baseline. PowerPoint slide Full size image Given that prelimbic cortex 7 activity during the delay (referred to as prefrontal cortex (PFC)) is necessary for task performance 8 , we directly interrogated its neural substrates ( Extended Data Fig. 1b–d ). We found that certain PFC neurons signalled the task rule by an increase in spiking for a brief moment during the delay ( Fig. 1b ). This temporal sparseness is analogous to that observed in the primate dorsolateral PFC during task rule encoding and/or maintenance 9 . The majority of such neurons signalled only one rule, but a minority (17%) signalled both rules at different temporal offsets ( Extended Data Fig. 1e, f ). Most tuned neurons exhibited regular spiking waveforms (regular spiking, 82% of total tuned neurons; 19% of all recorded regular-spiking neurons) consistent with these neurons being pyramidal neurons. Only a minority were fast spiking (fast-spiking neurons, 18% of total tuned neurons; 11% of all fast-spiking neurons; proportion of tuned fast-spiking out of total tuned neurons versus proportion of tuned regular-spiking neurons out of total tuned neurons, P = 0.001, binomial test; Extended Data Fig. 1g and Supplementary Note 1 ). Tuned peaks tiled the entire delay ( Fig. 1c ), and tuning was independent of delay length ( Extended Data Fig. 1h ). Linear decoding 10 showed that tuned neurons encoded task rule but not movement ( Fig. 1d and Supplementary Discussion 1 ). Rule information was exclusively represented by neurons we identified as tuned, because spike trains derived from the remaining neurons (untuned) did not contain rule information (or movement, Fig. 1d (bottom) and Extended Data Fig. 1i ). As such, distinct PFC populations represent the two task rules used for sensory selection. The conclusion that these population codes reflect sensory selection rules, rather than rules directing the selection or avoidance of one sensory target, is supported by multiple findings. First, performance on trials with single-target modality presentation was identical to performance with sensory conflict ( Extended Data Fig. 2a ). Second, in sessions with sufficient errors (more than 20 trials), PFC neurons that were appropriately tuned to one rule displayed identical activity during error trials of the opposite trial type, indicating that inappropriate rule encoding was the major source of errors in this task ( Extended Data Fig. 2b, c ). To fully test this idea, we developed a four-alternative forced choice (4AFC) task ( Extended Data Fig. 2d ) in which animals separately indicated their choice for target modality type", "role": "user" }, { "content": "Long assumed to be a mere \"relay,\" an often-overlooked egg-like structure in the middle of the brain also turns out to play a pivotal role in tuning-up thinking circuity. A trio of studies in mice funded by the National Institutes of Health (NIH) are revealing that the thalamus sustains the ability to distinguish categories and hold thoughts in mind. By manipulating activity of thalamus neurons, scientists were able to control an animal's ability to remember how to find a reward. In the future, the thalamus might even become a target for interventions to reduce cognitive deficits in psychiatric disorders such as schizophrenia, researchers say. \"If the brain works like an orchestra, our results suggest the thalamus may be its conductor,\" explained Michael Halassa, M.D., Ph.D., of New York University (NYU) Langone Medical Center, a BRAINS Award grantee of the NIH's National Institute of Mental Health (NIMH), and also a grantee of the National Institute of Neurological Disorders and Stroke (NINDS). \"It helps ensembles play in-sync by boosting their functional connectivity.\" Three independent teams of investigators led by Halassa, Joshua Gordon, M.D., Ph.D., formerly of Columbia University, New York City, now NIMH director, in collaboration with Christoph Kellendonk, Ph.D. of Columbia, and Karel Svoboda, PhD, at Howard Hughes Medical Institute Janelia Research Campus, Ashburn, Virginia, in collaboration with Charles Gerfen, Ph.D., of the NIMH Intramural Research Program, report on the newfound role for the thalamus online May 3, 2017 in the journals Nature and Nature Neuroscience. The prevailing notion of the thalamus as a relay was based on its connections with parts of the brain that process inputs from the senses. But the thalamus has many connections with other parts of the brain that have yet to be explored, say the researchers. Halassa and colleagues studied communications between neurons in the mediodorsal thalamus and the prefrontal cortex in mice. Credit: Michael Halassa, M.D., Ph.D., NYU Langone Medical Center All three groups investigated a circuit that connects the mid/upper (mediodorsal) thalamus with the prefrontal cortex (PFC), the brain's thinking and decision making center. Brain imaging studies have detected decreased connectivity in this circuit in patients with schizophrenia, who often experience working memory problems. Dr. Halassa and colleagues found that neurons in the thalamus and PFC appear to talk back and forth with each other. They monitored neural activity in mice performing a task that required them to hold in mind information about categories, so that they could act on cues indicating which of two doors hid a milk reward. Optogenetically suppressing neuronal activity in the thalamus blocked the mice's ability to choose the correct door, while optogenetically stimulating thalamus neural activity improved the animals' performance on the working memory task. This confirmed a previously known role for the structure, extending it to the specialized tasks Halassa and colleagues used and demonstrating for the first time a specific role in the maintenance of information in working memory. What kind of information was the thalamus helping to maintain? The researchers found sets of neurons in the PFC that held in memory the specific category of information required in order to choose the correct door. They determined that the thalamus did not (at least in this case) relay such specific category information, but instead broadly provided amplification that was crucial in sustaining memory of the category in the PFC. It accomplished this by boosting the synchronous activity, or functional connectivity, of these sets of PFC neurons. \"Our study may have uncovered the key circuit elements underlying how the brain represents categories,\" suggested Dr. Halassa. Dr. Gordon and colleagues saw similar results when they tested how the same circuit controlled a mouse's ability to find milk in a maze. The animals had to remember whether they had turned left or right to get their reward prior to a brief delay - and do the opposite. Also using optogenetics, the study teased apart differing roles for subgroups of PFC neurons and interactions with the brain's memory hub, the hippocampus. Thalamus inputs to the PFC sustained the maintenance of working memory by stabilizing activity there during the delay. \"Top-down\" signals from the PFC back to the thalamus supported memory retrieval and taking action. Consistent with previous findings, inputs from the hippocampus, were required to encode in PFC neurons the location of the reward - analgous to the correct door in the Halassa experiment. \"Strikingly, we found two separate populations of neurons in the PFC. One encoded for spatial location and required hippocampal input; the other was active during memory maintenance and required thalamic input,\" noted Dr. Gordon. \"Our findings should have translational relevance, particularly to schizophrenia. Further study of how this circuit might go awry and cause working memory deficits holds promise for improved diagnosis and more targeted therapeutic approaches.\" In their study, the Janelia team and Dr. Gerfen similarly showed that the thalamus plays a crucial role in sustaining short-term memory, by cooperating with the cortex through bi-directional interactions. Mice needed to remember where to move after a delay of seconds, to gather a reward. In this case, the thalamus was found to be in conversation with a part of the motor cortex during planning of those movements. Neuronal electrical monitoring revealed activity in both structures, indicating that they together sustain information held in the cortex that predicted in which direction the animal would subsequently move. Optogenetic probing revealed that the conversation was bidirectional, with cortex activity dependent on thalamus and vice versa. \"Our results show that cortex circuits alone can't sustain the neural activity required to prepare for movement,\" explained Dr. Gerfen. \"It also requires reciprocal participation across multiple brain areas, including the thalamus as a critical hub in the circuit.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Although interactions between the thalamus and cortex are critical for cognitive function 1 , 2 , 3 , the exact contribution of the thalamus to these interactions remains unclear. Recent studies have shown diverse connectivity patterns across the thalamus 4 , 5 , but whether this diversity translates to thalamic functions beyond relaying information to or between cortical regions 6 is unknown. Here we show, by investigating the representation of two rules used to guide attention in the mouse prefrontal cortex (PFC), that the mediodorsal thalamus sustains these representations without relaying categorical information. Specifically, mediodorsal input amplifies local PFC connectivity, enabling rule-specific neural sequences to emerge and thereby maintain rule representations. Consistent with this notion, broadly enhancing PFC excitability diminishes rule specificity and behavioural performance, whereas enhancing mediodorsal excitability improves both. Overall, our results define a previously unknown principle in neuroscience; thalamic control of functional cortical connectivity. This function, which is dissociable from categorical information relay, indicates that the thalamus has a much broader role in cognition than previously thought. Main We recorded PFC ensembles in a two-alternative forced choice (2AFC) task, in which a freely behaving mouse selected between conflicting visual and auditory stimuli based on whether one of two rules was presented, and where rule presentation was varied on a trial-by-trial basis ( Fig. 1a ). Broadband white noise was informative of trial availability, prompting trial initiation by snout-protrusion into a centrally located port. Subsequently, either low-pass (10 kHz) or high-pass (11 kHz) noise was presented for 100 ms to signal the task rules (rule 1 (low pass), attend to vision; rule 2 (high pass), attend to audition), and after a brief delay where the head position was stably maintained, the animal selected between spatially conflicting visual and auditory stimuli to receive a reward. Animals achieved a balanced and robust performance across modalities ( Extended Data Fig. 1a ) and no stereotypical behaviour, which indicates a modality or location preference, was observed during the delay. These findings suggest that animals were capable of holding the task rule ‘in mind’ and using it to map onto sensory targets. Figure 1: Task-specific sequential PFC activity maintains rule representation. a , Schematic of task design. b , Example peri-stimulus time histogram (PSTH) and rasters for neurons tuned to either attend to vision (red) or attend to audition (blue) rules. c , Examples of tuning peaks across multiple sessions. d , Task-variable information, indicates that tuned neurons ( n = 512 neurons from four mice) reflect rule information (top, green), but not movement (top, grey), whereas unturned neurons do not reflect rule information ( n = 2,727, bottom). AU, arbitrary units. e , Example spike-time cross-correlation between two neurons (50-μs bins), indicating a putative monosynaptic connection. f , Putative monosynaptic connections in same rule tuned pairs showed a significantly larger average peak. Vertical ticks indicate peak times. Opp. rule, opposite rule. g , Cumulative plot showing cross-correlation values for each pair. Kolmogorov–Smirnov test. h , Same rule tuned pairs with putative monosynaptic connections had overlapping tuning peaks. i , Raster and PSTH examples showing diminished tuning during optogenetic activation of inhibitory neurons (blue shading indicates laser on). j , Quantification of laser effects on peak sizes ( n = 94 neurons, three mice; example in Extended Data Fig. 3j ). k , l , Temporally limited optogenetic manipulations indicate that later tuning depends on earlier activity. Blue line, laser on; green line, mean; green shading, 95% confidence interval (CI); grey shading, 95% CI for the baseline. PowerPoint slide Full size image Given that prelimbic cortex 7 activity during the delay (referred to as prefrontal cortex (PFC)) is necessary for task performance 8 , we directly interrogated its neural substrates ( Extended Data Fig. 1b–d ). We found that certain PFC neurons signalled the task rule by an increase in spiking for a brief moment during the delay ( Fig. 1b ). This temporal sparseness is analogous to that observed in the primate dorsolateral PFC during task rule encoding and/or maintenance 9 . The majority of such neurons signalled only one rule, but a minority (17%) signalled both rules at different temporal offsets ( Extended Data Fig. 1e, f ). Most tuned neurons exhibited regular spiking waveforms (regular spiking, 82% of total tuned neurons; 19% of all recorded regular-spiking neurons) consistent with these neurons being pyramidal neurons. Only a minority were fast spiking (fast-spiking neurons, 18% of total tuned neurons; 11% of all fast-spiking neurons; proportion of tuned fast-spiking out of total tuned neurons versus proportion of tuned regular-spiking neurons out of total tuned neurons, P = 0.001, binomial test; Extended Data Fig. 1g and Supplementary Note 1 ). Tuned peaks tiled the entire delay ( Fig. 1c ), and tuning was independent of delay length ( Extended Data Fig. 1h ). Linear decoding 10 showed that tuned neurons encoded task rule but not movement ( Fig. 1d and Supplementary Discussion 1 ). Rule information was exclusively represented by neurons we identified as tuned, because spike trains derived from the remaining neurons (untuned) did not contain rule information (or movement, Fig. 1d (bottom) and Extended Data Fig. 1i ). As such, distinct PFC populations represent the two task rules used for sensory selection. The conclusion that these population codes reflect sensory selection rules, rather than rules directing the selection or avoidance of one sensory target, is supported by multiple findings. First, performance on trials with single-target modality presentation was identical to performance with sensory conflict ( Extended Data Fig. 2a ). Second, in sessions with sufficient errors (more than 20 trials), PFC neurons that were appropriately tuned to one rule displayed identical activity during error trials of the opposite trial type, indicating that inappropriate rule encoding was the major source of errors in this task ( Extended Data Fig. 2b, c ). To fully test this idea, we developed a four-alternative forced choice (4AFC) task ( Extended Data Fig. 2d ) in which animals separately indicated their choice for target modality type<|im_end|> <|im_start|>assistant Long assumed to be a mere "relay," an often-overlooked egg-like structure in the middle of the brain also turns out to play a pivotal role in tuning-up thinking circuity. A trio of studies in mice funded by the National Institutes of Health (NIH) are revealing that the thalamus sustains the ability to distinguish categories and hold thoughts in mind. By manipulating activity of thalamus neurons, scientists were able to control an animal's ability to remember how to find a reward. In the future, the thalamus might even become a target for interventions to reduce cognitive deficits in psychiatric disorders such as schizophrenia, researchers say. "If the brain works like an orchestra, our results suggest the thalamus may be its conductor," explained Michael Halassa, M.D., Ph.D., of New York University (NYU) Langone Medical Center, a BRAINS Award grantee of the NIH's National Institute of Mental Health (NIMH), and also a grantee of the National Institute of Neurological Disorders and Stroke (NINDS). "It helps ensembles play in-sync by boosting their functional connectivity." Three independent teams of investigators led by Halassa, Joshua Gordon, M.D., Ph.D., formerly of Columbia University, New York City, now NIMH director, in collaboration with Christoph Kellendonk, Ph.D. of Columbia, and Karel Svoboda, PhD, at Howard Hughes Medical Institute Janelia Research Campus, Ashburn, Virginia, in collaboration with Charles Gerfen, Ph.D., of the NIMH Intramural Research Program, report on the newfound role for the thalamus online May 3, 2017 in the journals Nature and Nature Neuroscience. The prevailing notion of the thalamus as a relay was based on its connections with parts of the brain that process inputs from the senses. But the thalamus has many connections with other parts of the brain that have yet to be explored, say the researchers. Halassa and colleagues studied communications between neurons in the mediodorsal thalamus and the prefrontal cortex in mice. Credit: Michael Halassa, M.D., Ph.D., NYU Langone Medical Center All three groups investigated a circuit that connects the mid/upper (mediodorsal) thalamus with the prefrontal cortex (PFC), the brain's thinking and decision making center. Brain imaging studies have detected decreased connectivity in this circuit in patients with schizophrenia, who often experience working memory problems. Dr. Halassa and colleagues found that neurons in the thalamus and PFC appear to talk back and forth with each other. They monitored neural activity in mice performing a task that required them to hold in mind information about categories, so that they could act on cues indicating which of two doors hid a milk reward. Optogenetically suppressing neuronal activity in the thalamus blocked the mice's ability to choose the correct door, while optogenetically stimulating thalamus neural activity improved the animals' performance on the working memory task. This confirmed a previously known role for the structure, extending it to the specialized tasks Halassa and colleagues used and demonstrating for the first time a specific role in the maintenance of information in working memory. What kind of information was the thalamus helping to maintain? The researchers found sets of neurons in the PFC that held in memory the specific category of information required in order to choose the correct door. They determined that the thalamus did not (at least in this case) relay such specific category information, but instead broadly provided amplification that was crucial in sustaining memory of the category in the PFC. It accomplished this by boosting the synchronous activity, or functional connectivity, of these sets of PFC neurons. "Our study may have uncovered the key circuit elements underlying how the brain represents categories," suggested Dr. Halassa. Dr. Gordon and colleagues saw similar results when they tested how the same circuit controlled a mouse's ability to find milk in a maze. The animals had to remember whether they had turned left or right to get their reward prior to a brief delay - and do the opposite. Also using optogenetics, the study teased apart differing roles for subgroups of PFC neurons and interactions with the brain's memory hub, the hippocampus. Thalamus inputs to the PFC sustained the maintenance of working memory by stabilizing activity there during the delay. "Top-down" signals from the PFC back to the thalamus supported memory retrieval and taking action. Consistent with previous findings, inputs from the hippocampus, were required to encode in PFC neurons the location of the reward - analgous to the correct door in the Halassa experiment. "Strikingly, we found two separate populations of neurons in the PFC. One encoded for spatial location and required hippocampal input; the other was active during memory maintenance and required thalamic input," noted Dr. Gordon. "Our findings should have translational relevance, particularly to schizophrenia. Further study of how this circuit might go awry and cause working memory deficits holds promise for improved diagnosis and more targeted therapeutic approaches." In their study, the Janelia team and Dr. Gerfen similarly showed that the thalamus plays a crucial role in sustaining short-term memory, by cooperating with the cortex through bi-directional interactions. Mice needed to remember where to move after a delay of seconds, to gather a reward. In this case, the thalamus was found to be in conversation with a part of the motor cortex during planning of those movements. Neuronal electrical monitoring revealed activity in both structures, indicating that they together sustain information held in the cortex that predicted in which direction the animal would subsequently move. Optogenetic probing revealed that the conversation was bidirectional, with cortex activity dependent on thalamus and vice versa. "Our results show that cortex circuits alone can't sustain the neural activity required to prepare for movement," explained Dr. Gerfen. "It also requires reciprocal participation across multiple brain areas, including the thalamus as a critical hub in the circuit." <|im_end|>

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56692, 11, 386, 920, 2637, 2405, 920, 2637, 315, 1561, 4356, 3907, 320, 23923, 52, 8, 23272, 606, 13235, 5955, 11, 264, 74863, 9751, 17768, 13500, 2176, 315, 279, 84370, 596, 5165, 10181, 315, 38895, 6401, 320, 45, 1829, 39, 705, 323, 1101, 264, 13500, 2176, 315, 279, 5165, 10181, 315, 32359, 31356, 73133, 323, 70034, 320, 45, 5358, 50, 570, 330, 2181, 8779, 665, 41794, 1514, 304, 66134, 555, 56028, 872, 16003, 31357, 1210, 14853, 9678, 7411, 315, 26453, 6197, 555, 20442, 56692, 11, 40592, 26952, 11, 386, 920, 2637, 2405, 920, 2637, 34833, 315, 19326, 3907, 11, 1561, 4356, 4409, 11, 1457, 452, 1829, 39, 7690, 11, 304, 20632, 449, 95693, 735, 616, 92086, 74, 11, 2405, 920, 13, 315, 19326, 11, 323, 124298, 64705, 677, 14320, 11, 30661, 11, 520, 20462, 41411, 13235, 10181, 622, 2444, 689, 8483, 39680, 11, 14937, 22464, 11, 13286, 11, 304, 20632, 449, 15274, 20524, 31453, 11, 2405, 920, 2637, 315, 279, 452, 1829, 39, 61894, 309, 4269, 8483, 6826, 11, 1934, 389, 279, 94621, 3560, 369, 279, 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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Macrophages play critical, but opposite, roles in acute and chronic inflammation and cancer 1 , 2 , 3 , 4 , 5 . In response to pathogens or injury, inflammatory macrophages express cytokines that stimulate cytotoxic T cells, whereas macrophages in neoplastic and parasitic diseases express anti-inflammatory cytokines that induce immune suppression and may promote resistance to T cell checkpoint inhibitors 1 , 2 , 3 , 4 , 5 , 6 , 7 . Here we show that macrophage PI 3-kinase γ controls a critical switch between immune stimulation and suppression during inflammation and cancer. PI3Kγ signalling through Akt and mTor inhibits NFκB activation while stimulating C/EBPβ activation, thereby inducing a transcriptional program that promotes immune suppression during inflammation and tumour growth. By contrast, selective inactivation of macrophage PI3Kγ stimulates and prolongs NFκB activation and inhibits C/EBPβ activation, thus promoting an immunostimulatory transcriptional program that restores CD8 + T cell activation and cytotoxicity. PI3Kγ synergizes with checkpoint inhibitor therapy to promote tumour regression and increased survival in mouse models of cancer. In addition, PI3Kγ-directed, anti-inflammatory gene expression can predict survival probability in cancer patients. Our work thus demonstrates that therapeutic targeting of intracellular signalling pathways that regulate the switch between macrophage polarization states can control immune suppression in cancer and other disorders. Main We investigated the association between immune responses and survival in primary tumours from human papilloma virus (HPV) + ( n = 97) and HPV − ( n = 423) head and neck squamous cell carcinoma (HNSCC) cohorts from the Cancer Genome Atlas 8 , 9 . High expression levels of pro-inflammatory mRNAs IL12A , IL12B , IFNG and CD8A were associated with increased survival in HPV + but not HPV − cohorts, whereas high expression of IL6 was negatively associated with survival ( Extended Data Fig. 1a–e ). HPV + patients with this favourable immune expression profile ( n = 35) had 97% survival at 3 years compared with 57% survival for patients without this profile ( n = 62) ( Fig. 1a ). Similar associations were observed in lung adenocarcinoma and gastric carcinoma patients ( Extended Data Fig. 1f, g ). These results suggest that therapeutic approaches that stimulate pro-inflammatory gene expression might enhance cancer patient survival. Figure 1: PI3Kγ promotes immune suppression. a , Multivariate immune response mRNA signature in HPV + HNSCC patients. n = 97 biological replicates; P = 0.0001; log-rank test. b , mRNA expression of genes involved in the immune response in Pik3cg −/− or wild-type (WT) peritoneal macrophages. n = 3 biological replicates; * P = 0.01 ; t -test. c , Tumour volumes in wild-type, Pik3cg −/− and PI3Kγ (PI3Kγi)-inhibitor-treated mice ( n = 15 biological replicates) P < 0.05, one-sided ANOVA with Tukey’s post-hoc test. Arrow shows time of initiation of daily treatment with the PI3Kγ inhibitor. d , Tumour weight ( P = 0.000001) and number of lung metastases ( P = 0.007) in mice with PyMT spontaneous breast carcinoma (scale bar, 200 μm) in wild-type ( n = 21 biological replicates) and Pik3cg −/− ( n = 8 biological replicates) backgrounds ( t -test). e , MHCII expression in wild-type or Pik3cg −/− TAMs. n = 3 biological replicates; P = 0.01 for both lung and breast tissue, as analysed by t -test. f , Fold change of mRNA expression in tumours and tumour-derived CD11b + cells from Pik3cg −/− and PI3Kγ-inhibitor-treated mice. n = 5 biological replicates; P < 0.01; t -test. g , Heat map of median-centred mRNA expression of genes involved in the immune response in tumours from wild-type and Pik3cg −/− mice. n = 3 biological replicates; P = 0.01; t -test. All experiments were performed two or more times. b , d , e , Data are shown as mean ± s.e.m. PowerPoint slide Source data Full size image We hypothesized that macrophage signalling pathways, such as those regulated by the class IB isoform PI3Kγ, might control the switch between immune stimulation and suppression in inflammation and cancer. PI3Kγ is abundantly expressed in myeloid cells but not in cancer cells 10 , 11 , 12 , 13 ( Extended Data Fig. 1h ) and promotes myeloid cell trafficking during inflammation and cancer 12 , 13 , 14 , 15 , 16 . Mice lacking PI3Kγ ( Pik3cg −/− ) had exaggerated, macrophage-mediated pro-inflammatory responses upon exposure to pathogenic stimuli ( Fig. 1b and Extended Data Fig. 1i–k ), suggesting that PI3Kγ inhibits macrophage inflammatory responses and might also do so in the tumour microenvironment. Mice lacking PI3Kγ and mice that were treated with PI3Kγ antagonists (TG100-115 (ref. 13 ) or IPI-549 (ref. 17 )) exhibited significantly ( P < 0.05, one-way ANOVA with Tukey’s post-hoc test) suppressed growth of implanted HPV + (MEER, mouse HPV + HNSCC cell line) and HPV − (SCCVII, mouse HPV − HNSCC cell line) HNSCC, lung carcinoma (LLC), and breast carcinoma (PyMT) tumours ( Fig. 1c and Extended Data Fig. 1l ). PI3Kγ inhibition did not directly affect the growth or survival of tumour cells, which do not express the kinase 13 , 14 , 15 , 16 ( Extended Data Fig. 1h, m ). PI3Kγ inhibition suppressed long-term growth and metastasis of spontaneous breast tumours, extended survival of mice with orthotopic breast tumours and enhanced the sensitivity of tumours to the nucleoside analogue gemcitabine ( Fig. 1d and Extended Data Fig. 1n–q ). Although PI3Kγ inhibition did not affect the accumulation of CD11b + –Gr1 − –F4/80 + tumour-associated macrophages (TAMs) in tumours ( Extended Data Fig. 2a–f ), it enhanced the expression of major histocompatibility complex class II (MHCII) and pro-inflammatory cytokines and inhibited the expression of immune-suppressive factors in tumours and TAMs, indicating that PI3Kγ controls the TAM switch between immune suppression and immune stimulation ( Fig. 1e–g and Extended Data Figs 2g–j , 3a–f ). To determine whether PI3Kγ directly regulates macrophage polarization, we analysed mRNA and protein expression in primary mouse macrophages stimulated in vitro with basal medium containing", "role": "user" }, { "content": "Researchers at University of California San Diego School of Medicine and Moores Cancer Center have identified a strategy to maximize the effectiveness of anti-cancer immune therapy. The researchers identified a molecular switch that controls immune suppression, opening the possibility to further improving and refining emerging immunotherapies that boost the body's own abilities to fight diseases ranging from cancer to Alzheimer's and Crohn's disease. The findings are published in the September 19 online issue of Nature. \"Immunotherapies, such as T cell checkpoint inhibitors, are showing great promise in early treatments and trials, but they are not universally effective,\" said Judith A. Varner, PhD, professor in the Departments of Pathology and Medicine at UC San Diego School of Medicine. \"We have identified a new method to boost the effectiveness of current immune therapy. Our findings also improve our understanding of key mechanisms that control cancer immune suppression and could lead to the development of more effective immunotherapies.\" When confronted by pathogens, injury or disease, the initial response of the body's immune system comes in the form of macrophages, a type of white blood cell that express pro-inflammatory proteins called cytokines that, in turn, activate T cells, another immune cell, to attack the health threat. The macrophages then switch gears to express other cytokines that dampen T cell activation, stimulating tissue repair. In chronic inflammatory diseases such as Alzheimer's and Crohn's, however, macrophages associated with the malignancy continue to produce pro-inflammatory cytokines and other substances that kill or transform normal cells. In cancer, highly abundant microphages express anti-inflammatory cytokines that induce immune suppression, effectively stopping the healing process. In the Nature paper, Varner and colleagues pinpoint a key, suspected player: an enzyme in macrophages called PI-3 kinase gamma (PI3Ky). In mouse studies, they found that macrophage PI3Ky signaling promotes immune suppression by inhibiting activation of anti-tumor T cells. Blocking PI3Ky activated the immune response and significantly suppressed growth of implanted tumors in animal models. It also boosted sensitivity of some tumors to existing anti-cancer drugs and synergized with existing immune therapy to eradicate tumors. Varner and her colleagues at the Moores Cancer Center also identified a molecular signature of immune suppression and response in mice and cancer patients that may be used to track the effectiveness of immunotherapy. \"Recently developed cancer immunotherapeutics, including T cell checkpoint inhibitors and vaccines, have shown encouraging results in stimulating the body's own adaptive immune response,\" said co-author Ezra Cohen, MD, who heads the cancer immunotherapy program at Moores Cancer Center. \"But they are effective only on a subset of patients, probably because they do not alter the profoundly immunosuppressive microenvironment created by tumor-associated macrophages. Our work offers a strategy to maximize patient responses to immune therapy and to eradicate tumors. \" The Nature paper builds upon other work by Varner and colleagues. In a paper first published online in May in Cancer Discovery, Varner's team reported that blocking PI3Ky in tumor-associated macrophages stimulated the immune response and inhibited tumor cell invasion, metastasis and fibrotic scarring caused by pancreatic ductal adenocarcinoma (PDAC) in animal models. In humans, PDAC is the most common malignancy of the pancreas It's aggressive and difficult to treat. Though only the 12th most common type of cancer in the United States, pancreatic cancer is the fourth most common cause of cancer-related death. \"PDAC has one of the worst 5-year survival rates of all solid tumors, so new treatment strategies are urgently needed,\" said Megan M. Kaneda, PhD, an assistant project scientist in Varner's lab and collaborator on all of the papers. In a December 2015 paper published online in Cancer Discovery, Varner and colleagues described animal studies that revealed how disrupting cross-talk between B cells (another type of immune cell) and tumor-associated macrophages inhibited PDAC growth and improved responsiveness to standard-of-care chemotherapy. Specifically, that research team, which included scientists in San Francisco, Oregon and Switzerland, reported that inhibiting Bruton tyrosine kinase, an enzyme that plays a crucial role in B cell and macrophage functions, restored T cell-dependent anti-tumor immune response. In other words, it reactivated the natural, adaptive immune response in tested mice. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Macrophages play critical, but opposite, roles in acute and chronic inflammation and cancer 1 , 2 , 3 , 4 , 5 . In response to pathogens or injury, inflammatory macrophages express cytokines that stimulate cytotoxic T cells, whereas macrophages in neoplastic and parasitic diseases express anti-inflammatory cytokines that induce immune suppression and may promote resistance to T cell checkpoint inhibitors 1 , 2 , 3 , 4 , 5 , 6 , 7 . Here we show that macrophage PI 3-kinase γ controls a critical switch between immune stimulation and suppression during inflammation and cancer. PI3Kγ signalling through Akt and mTor inhibits NFκB activation while stimulating C/EBPβ activation, thereby inducing a transcriptional program that promotes immune suppression during inflammation and tumour growth. By contrast, selective inactivation of macrophage PI3Kγ stimulates and prolongs NFκB activation and inhibits C/EBPβ activation, thus promoting an immunostimulatory transcriptional program that restores CD8 + T cell activation and cytotoxicity. PI3Kγ synergizes with checkpoint inhibitor therapy to promote tumour regression and increased survival in mouse models of cancer. In addition, PI3Kγ-directed, anti-inflammatory gene expression can predict survival probability in cancer patients. Our work thus demonstrates that therapeutic targeting of intracellular signalling pathways that regulate the switch between macrophage polarization states can control immune suppression in cancer and other disorders. Main We investigated the association between immune responses and survival in primary tumours from human papilloma virus (HPV) + ( n = 97) and HPV − ( n = 423) head and neck squamous cell carcinoma (HNSCC) cohorts from the Cancer Genome Atlas 8 , 9 . High expression levels of pro-inflammatory mRNAs IL12A , IL12B , IFNG and CD8A were associated with increased survival in HPV + but not HPV − cohorts, whereas high expression of IL6 was negatively associated with survival ( Extended Data Fig. 1a–e ). HPV + patients with this favourable immune expression profile ( n = 35) had 97% survival at 3 years compared with 57% survival for patients without this profile ( n = 62) ( Fig. 1a ). Similar associations were observed in lung adenocarcinoma and gastric carcinoma patients ( Extended Data Fig. 1f, g ). These results suggest that therapeutic approaches that stimulate pro-inflammatory gene expression might enhance cancer patient survival. Figure 1: PI3Kγ promotes immune suppression. a , Multivariate immune response mRNA signature in HPV + HNSCC patients. n = 97 biological replicates; P = 0.0001; log-rank test. b , mRNA expression of genes involved in the immune response in Pik3cg −/− or wild-type (WT) peritoneal macrophages. n = 3 biological replicates; * P = 0.01 ; t -test. c , Tumour volumes in wild-type, Pik3cg −/− and PI3Kγ (PI3Kγi)-inhibitor-treated mice ( n = 15 biological replicates) P < 0.05, one-sided ANOVA with Tukey’s post-hoc test. Arrow shows time of initiation of daily treatment with the PI3Kγ inhibitor. d , Tumour weight ( P = 0.000001) and number of lung metastases ( P = 0.007) in mice with PyMT spontaneous breast carcinoma (scale bar, 200 μm) in wild-type ( n = 21 biological replicates) and Pik3cg −/− ( n = 8 biological replicates) backgrounds ( t -test). e , MHCII expression in wild-type or Pik3cg −/− TAMs. n = 3 biological replicates; P = 0.01 for both lung and breast tissue, as analysed by t -test. f , Fold change of mRNA expression in tumours and tumour-derived CD11b + cells from Pik3cg −/− and PI3Kγ-inhibitor-treated mice. n = 5 biological replicates; P < 0.01; t -test. g , Heat map of median-centred mRNA expression of genes involved in the immune response in tumours from wild-type and Pik3cg −/− mice. n = 3 biological replicates; P = 0.01; t -test. All experiments were performed two or more times. b , d , e , Data are shown as mean ± s.e.m. PowerPoint slide Source data Full size image We hypothesized that macrophage signalling pathways, such as those regulated by the class IB isoform PI3Kγ, might control the switch between immune stimulation and suppression in inflammation and cancer. PI3Kγ is abundantly expressed in myeloid cells but not in cancer cells 10 , 11 , 12 , 13 ( Extended Data Fig. 1h ) and promotes myeloid cell trafficking during inflammation and cancer 12 , 13 , 14 , 15 , 16 . Mice lacking PI3Kγ ( Pik3cg −/− ) had exaggerated, macrophage-mediated pro-inflammatory responses upon exposure to pathogenic stimuli ( Fig. 1b and Extended Data Fig. 1i–k ), suggesting that PI3Kγ inhibits macrophage inflammatory responses and might also do so in the tumour microenvironment. Mice lacking PI3Kγ and mice that were treated with PI3Kγ antagonists (TG100-115 (ref. 13 ) or IPI-549 (ref. 17 )) exhibited significantly ( P < 0.05, one-way ANOVA with Tukey’s post-hoc test) suppressed growth of implanted HPV + (MEER, mouse HPV + HNSCC cell line) and HPV − (SCCVII, mouse HPV − HNSCC cell line) HNSCC, lung carcinoma (LLC), and breast carcinoma (PyMT) tumours ( Fig. 1c and Extended Data Fig. 1l ). PI3Kγ inhibition did not directly affect the growth or survival of tumour cells, which do not express the kinase 13 , 14 , 15 , 16 ( Extended Data Fig. 1h, m ). PI3Kγ inhibition suppressed long-term growth and metastasis of spontaneous breast tumours, extended survival of mice with orthotopic breast tumours and enhanced the sensitivity of tumours to the nucleoside analogue gemcitabine ( Fig. 1d and Extended Data Fig. 1n–q ). Although PI3Kγ inhibition did not affect the accumulation of CD11b + –Gr1 − –F4/80 + tumour-associated macrophages (TAMs) in tumours ( Extended Data Fig. 2a–f ), it enhanced the expression of major histocompatibility complex class II (MHCII) and pro-inflammatory cytokines and inhibited the expression of immune-suppressive factors in tumours and TAMs, indicating that PI3Kγ controls the TAM switch between immune suppression and immune stimulation ( Fig. 1e–g and Extended Data Figs 2g–j , 3a–f ). To determine whether PI3Kγ directly regulates macrophage polarization, we analysed mRNA and protein expression in primary mouse macrophages stimulated in vitro with basal medium containing<|im_end|> <|im_start|>assistant Researchers at University of California San Diego School of Medicine and Moores Cancer Center have identified a strategy to maximize the effectiveness of anti-cancer immune therapy. The researchers identified a molecular switch that controls immune suppression, opening the possibility to further improving and refining emerging immunotherapies that boost the body's own abilities to fight diseases ranging from cancer to Alzheimer's and Crohn's disease. The findings are published in the September 19 online issue of Nature. "Immunotherapies, such as T cell checkpoint inhibitors, are showing great promise in early treatments and trials, but they are not universally effective," said Judith A. Varner, PhD, professor in the Departments of Pathology and Medicine at UC San Diego School of Medicine. "We have identified a new method to boost the effectiveness of current immune therapy. Our findings also improve our understanding of key mechanisms that control cancer immune suppression and could lead to the development of more effective immunotherapies." When confronted by pathogens, injury or disease, the initial response of the body's immune system comes in the form of macrophages, a type of white blood cell that express pro-inflammatory proteins called cytokines that, in turn, activate T cells, another immune cell, to attack the health threat. The macrophages then switch gears to express other cytokines that dampen T cell activation, stimulating tissue repair. In chronic inflammatory diseases such as Alzheimer's and Crohn's, however, macrophages associated with the malignancy continue to produce pro-inflammatory cytokines and other substances that kill or transform normal cells. In cancer, highly abundant microphages express anti-inflammatory cytokines that induce immune suppression, effectively stopping the healing process. In the Nature paper, Varner and colleagues pinpoint a key, suspected player: an enzyme in macrophages called PI-3 kinase gamma (PI3Ky). In mouse studies, they found that macrophage PI3Ky signaling promotes immune suppression by inhibiting activation of anti-tumor T cells. Blocking PI3Ky activated the immune response and significantly suppressed growth of implanted tumors in animal models. It also boosted sensitivity of some tumors to existing anti-cancer drugs and synergized with existing immune therapy to eradicate tumors. Varner and her colleagues at the Moores Cancer Center also identified a molecular signature of immune suppression and response in mice and cancer patients that may be used to track the effectiveness of immunotherapy. "Recently developed cancer immunotherapeutics, including T cell checkpoint inhibitors and vaccines, have shown encouraging results in stimulating the body's own adaptive immune response," said co-author Ezra Cohen, MD, who heads the cancer immunotherapy program at Moores Cancer Center. "But they are effective only on a subset of patients, probably because they do not alter the profoundly immunosuppressive microenvironment created by tumor-associated macrophages. Our work offers a strategy to maximize patient responses to immune therapy and to eradicate tumors. " The Nature paper builds upon other work by Varner and colleagues. In a paper first published online in May in Cancer Discovery, Varner's team reported that blocking PI3Ky in tumor-associated macrophages stimulated the immune response and inhibited tumor cell invasion, metastasis and fibrotic scarring caused by pancreatic ductal adenocarcinoma (PDAC) in animal models. In humans, PDAC is the most common malignancy of the pancreas It's aggressive and difficult to treat. Though only the 12th most common type of cancer in the United States, pancreatic cancer is the fourth most common cause of cancer-related death. "PDAC has one of the worst 5-year survival rates of all solid tumors, so new treatment strategies are urgently needed," said Megan M. Kaneda, PhD, an assistant project scientist in Varner's lab and collaborator on all of the papers. In a December 2015 paper published online in Cancer Discovery, Varner and colleagues described animal studies that revealed how disrupting cross-talk between B cells (another type of immune cell) and tumor-associated macrophages inhibited PDAC growth and improved responsiveness to standard-of-care chemotherapy. Specifically, that research team, which included scientists in San Francisco, Oregon and Switzerland, reported that inhibiting Bruton tyrosine kinase, an enzyme that plays a crucial role in B cell and macrophage functions, restored T cell-dependent anti-tumor immune response. In other words, it reactivated the natural, adaptive immune response in tested mice. <|im_end|>

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2,482

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Lung cancer is the leading cause of cancer deaths, and effective treatments are urgently needed. Loss-of-function mutations in the DNA damage response kinase ATM are common in lung adenocarcinoma but directly targeting these with drugs remains challenging. Here we report that ATM loss-of-function is synthetic lethal with drugs inhibiting the central growth factor kinases MEK1/2, including the FDA-approved drug trametinib. Lung cancer cells resistant to MEK inhibition become highly sensitive upon loss of ATM both in vitro and in vivo . Mechanistically, ATM mediates crosstalk between the prosurvival MEK/ERK and AKT/mTOR pathways. ATM loss also enhances the sensitivity of KRAS- or BRAF-mutant lung cancer cells to MEK inhibition. Thus, ATM mutational status in lung cancer is a mechanistic biomarker for MEK inhibitor response, which may improve patient stratification and extend the applicability of these drugs beyond RAS and BRAF mutant tumours. Introduction Lung cancer remains the leading cause of cancer-related deaths 1 . Sequencing studies have identified the major genetic drivers in the various subtypes of lung cancer, including adenocarcinoma, the most frequent lung cancer 2 , 3 , 4 , 5 . However, only a minority of lung tumours harbour mutations in activated kinases such as EGFR, ALK, ROS1 and RET that can be targeted with specific small molecule inhibitors. Some of these (for example, gefitinib, erlotinib, crizotinib) have shown moderate success in the clinic, extending survival by several months on average 6 , 7 , 8 . However, none of these drugs provides a curative therapy in advanced disease setting due to emerging secondary resistance. The majority of lung cancer mutations, such as ATM (ataxia–telangiectasia mutated) loss-of-function mutations, which are found in 5–10% of patients, are not actionable with small-molecule inhibitors. Some of these so-called ‘undruggable’ mutations may result in vulnerabilities through synthetic lethal interactions that can be exploited with drugs 9 . The serine/threonine kinase ATM is well known for its involvement in the DNA damage response (DDR) and maintaining genome stability but it has also been implicated in other cancer-relevant processes including cell growth, metabolism and mitochondrial homeostasis 10 . The gene name is derived from the disease ataxia telangiectasia (A–T), a severe genetic disorder caused by homozygous germline mutations in the ATM gene. A–T patients are predisposed to cancer, particularly those of lymphoid origin, and ATM variants have also been associated with cancer predisposition 10 , 11 . More recently, cancer genome sequencing has revealed frequent ATM somatic mutations in a variety of solid tumours, including lung ( ∼ 10%), pancreatic ( ∼ 12%) and bladder ( ∼ 4%) cancers 2 , 4 , 5 , 12 , 13 . Interestingly, mutual exclusivity with p53 mutations in lung cancer suggests that ATM loss-of-function can partially substitute for p53 loss 5 . MEK1/2 are kinases that regulate cell proliferation and survival. MEK inhibitors are currently in clinical development for a variety of cancers, including lung cancer, with mutations specifically in the oncogene RAS or its downstream signalling components (for example, BRAF ), which occur in a large number of cancers. The first MEK inhibitor (trametinib) has recently been approved for treating BRAF mutant melanomas but in lung cancer results have not been as encouraging 14 , 15 . However, this does not rule out that MEK inhibitors (alone or in combination with other agents) are effective in a select lung cancer patient cohort. Thus, the identification of mutations that predict sensitivity to MEK inhibition, particularly a common one like ATM , remains of great interest and could have immediate clinical applications. MEK1/2 kinases have not been directly linked with DNA repair. Thus, our experiments reveal an unexpected link between growth factor signalling pathways and ATM loss, providing a strong rationale for testing MEK inhibitors in the context of ATM mutant tumours. Results A pharmacogenetic screen links ATM with MEK To search for synthetic lethal interactions between lung adenocarcinoma tumour suppressor genes and anti-cancer drugs, we employed an in vitro screening strategy using isogenic cell lines 16 , 17 . These isogenic cell lines only differ in the expression of one specific gene, thereby simplifying the interpretation of the screening hits. We employed the AALE lung bronchial epithelial cell line as a relatively benign lung cell type that has been immortalized with SV40 large T-antigen and hTERT, and can become tumourigenic upon KRAS or HRAS expression 18 . We compiled a list of 10 tumour suppressor genes (that is, APC , ATM , CDKN2A , ERBB4 , NF1 , PRKDC , PTEN , SMAD4 , SMARCA4 and STK11 ) that recur in human lung cancer based on publicly available tumour sequencing data and the Catalogue Of Somatic Mutations In Cancer (COSMIC) database 2 , 4 , 5 , 17 . As p53 and RB1 are inactive in AALE cells due to the expression of large T-antigen, these tumour suppressor genes were omitted. HRAS expressing cells were infected with validated shRNA vectors targeting each tumour suppressor gene and screened in a pooled format 16 against 106 diverse FDA-approved and experimental anti-cancer drugs ( Fig. 1a , Supplementary Fig. 1 , Supplementary Tables 1 and 2 and Supplementary Dataset 1 ). Figure 1: Chemical genetic screen reveals MEK inhibitor sensitivity of ATM-depleted cells. ( a ) Gene–drug interaction screen in AALE cells (see Methods). Synthetic lethal drug interactions are sorted based on Z -score for each indicated tumour suppressor. The interactions between ATM and AZD7762 (green circle) and PD0325901 (red circle) are indicated with black arrows. ( b ) Dose–response curve with the Chk1/2 inhibitor AZD7762. AALE cells were infected as indicated and treated with the drug for 3 days. Displayed is the relative viability that is calculated by normalizing the raw CellTiter-Glo data to the vehicle (DMSO) treated controls. Error bars indicate s.d. ( n =3). ( c ) Colony formation of AALE cells infected with ATM shRNA or control virus and treated with PD0325901 for 10 days. Shown is a representative example ( n =3). Numbers in the bottom right corners indicate quantification relative to DMSO-treated", "role": "user" }, { "content": "Lung cancer remains the leading cause of cancer-related deaths worldwide. In contrast to other tumour types, lung tumours present a high number of genomic alterations—this is a consequence of exposure to carcinogenic substances found in tobacco smoke, which is the main cause of lung cancer. About 10 percent of lung tumours carry mutations in a gene called ATM. However, there are no drugs available in the clinic to treat ATM mutant lung cancer. Using cutting-edge, high-throughput drug screens that analyse how the genetic makeup of the patient affects their response to drugs, the team of Sebastian Nijman at the Ludwig Institute for Cancer Research in Oxford made a surprising discovery—cancer cells with ATM mutations are sensitive for drugs that inhibit an enzyme called MEK. The study was published in Nature Communications. MEK is part of a biochemical pathway which is responsible for supporting proliferation and survival of the cell, while ATM plays a central role during the DNA damage response. In ATM-deficient lung cancer cells, Nijman's team found that MEK inhibition results in cells being unable to proliferate, leading to apoptosis. An unexpected finding, as MEK inhibitors have so far been approved for the treatment of a type of skin cancer but not for lung cancer. \"Normally, lung cancer cells are resistant to MEK inhibition as they activate compensatory signals,\" Ferran Fece, one of the two first authors on the study and former Ph.D. student at CeMM, explains. \"In contrast, ATM mutant cells fail to do this and subsequently cannot cope with the blocking of MEK and die. We call this type of unexpected drug sensitivity synthetic lethality.\" Michal Smida, the other shared first author on the article, adds: \"We knew that cancer mutations can lead to extreme sensitivity to some drugs. But finding these cancer Achilles' heels is very difficult as they are difficult to predict and extremely rare. We screened a large number of gene and drug combinations and got lucky.\" The study constitutes a substantial contribution for the development of a future precision medicine: ATM mutations could be used as a potential biomarker to stratify lung cancer patients to receive a MEK inhibitor. ATM is found to be mutated in 8-10 percent of lung adenocarcinomas—given that this type of tumour is among the most prevalent for both men and women worldwide, a significant number of patients could benefit from a MEK inhibitor based treatment. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Lung cancer is the leading cause of cancer deaths, and effective treatments are urgently needed. Loss-of-function mutations in the DNA damage response kinase ATM are common in lung adenocarcinoma but directly targeting these with drugs remains challenging. Here we report that ATM loss-of-function is synthetic lethal with drugs inhibiting the central growth factor kinases MEK1/2, including the FDA-approved drug trametinib. Lung cancer cells resistant to MEK inhibition become highly sensitive upon loss of ATM both in vitro and in vivo . Mechanistically, ATM mediates crosstalk between the prosurvival MEK/ERK and AKT/mTOR pathways. ATM loss also enhances the sensitivity of KRAS- or BRAF-mutant lung cancer cells to MEK inhibition. Thus, ATM mutational status in lung cancer is a mechanistic biomarker for MEK inhibitor response, which may improve patient stratification and extend the applicability of these drugs beyond RAS and BRAF mutant tumours. Introduction Lung cancer remains the leading cause of cancer-related deaths 1 . Sequencing studies have identified the major genetic drivers in the various subtypes of lung cancer, including adenocarcinoma, the most frequent lung cancer 2 , 3 , 4 , 5 . However, only a minority of lung tumours harbour mutations in activated kinases such as EGFR, ALK, ROS1 and RET that can be targeted with specific small molecule inhibitors. Some of these (for example, gefitinib, erlotinib, crizotinib) have shown moderate success in the clinic, extending survival by several months on average 6 , 7 , 8 . However, none of these drugs provides a curative therapy in advanced disease setting due to emerging secondary resistance. The majority of lung cancer mutations, such as ATM (ataxia–telangiectasia mutated) loss-of-function mutations, which are found in 5–10% of patients, are not actionable with small-molecule inhibitors. Some of these so-called ‘undruggable’ mutations may result in vulnerabilities through synthetic lethal interactions that can be exploited with drugs 9 . The serine/threonine kinase ATM is well known for its involvement in the DNA damage response (DDR) and maintaining genome stability but it has also been implicated in other cancer-relevant processes including cell growth, metabolism and mitochondrial homeostasis 10 . The gene name is derived from the disease ataxia telangiectasia (A–T), a severe genetic disorder caused by homozygous germline mutations in the ATM gene. A–T patients are predisposed to cancer, particularly those of lymphoid origin, and ATM variants have also been associated with cancer predisposition 10 , 11 . More recently, cancer genome sequencing has revealed frequent ATM somatic mutations in a variety of solid tumours, including lung ( ∼ 10%), pancreatic ( ∼ 12%) and bladder ( ∼ 4%) cancers 2 , 4 , 5 , 12 , 13 . Interestingly, mutual exclusivity with p53 mutations in lung cancer suggests that ATM loss-of-function can partially substitute for p53 loss 5 . MEK1/2 are kinases that regulate cell proliferation and survival. MEK inhibitors are currently in clinical development for a variety of cancers, including lung cancer, with mutations specifically in the oncogene RAS or its downstream signalling components (for example, BRAF ), which occur in a large number of cancers. The first MEK inhibitor (trametinib) has recently been approved for treating BRAF mutant melanomas but in lung cancer results have not been as encouraging 14 , 15 . However, this does not rule out that MEK inhibitors (alone or in combination with other agents) are effective in a select lung cancer patient cohort. Thus, the identification of mutations that predict sensitivity to MEK inhibition, particularly a common one like ATM , remains of great interest and could have immediate clinical applications. MEK1/2 kinases have not been directly linked with DNA repair. Thus, our experiments reveal an unexpected link between growth factor signalling pathways and ATM loss, providing a strong rationale for testing MEK inhibitors in the context of ATM mutant tumours. Results A pharmacogenetic screen links ATM with MEK To search for synthetic lethal interactions between lung adenocarcinoma tumour suppressor genes and anti-cancer drugs, we employed an in vitro screening strategy using isogenic cell lines 16 , 17 . These isogenic cell lines only differ in the expression of one specific gene, thereby simplifying the interpretation of the screening hits. We employed the AALE lung bronchial epithelial cell line as a relatively benign lung cell type that has been immortalized with SV40 large T-antigen and hTERT, and can become tumourigenic upon KRAS or HRAS expression 18 . We compiled a list of 10 tumour suppressor genes (that is, APC , ATM , CDKN2A , ERBB4 , NF1 , PRKDC , PTEN , SMAD4 , SMARCA4 and STK11 ) that recur in human lung cancer based on publicly available tumour sequencing data and the Catalogue Of Somatic Mutations In Cancer (COSMIC) database 2 , 4 , 5 , 17 . As p53 and RB1 are inactive in AALE cells due to the expression of large T-antigen, these tumour suppressor genes were omitted. HRAS expressing cells were infected with validated shRNA vectors targeting each tumour suppressor gene and screened in a pooled format 16 against 106 diverse FDA-approved and experimental anti-cancer drugs ( Fig. 1a , Supplementary Fig. 1 , Supplementary Tables 1 and 2 and Supplementary Dataset 1 ). Figure 1: Chemical genetic screen reveals MEK inhibitor sensitivity of ATM-depleted cells. ( a ) Gene–drug interaction screen in AALE cells (see Methods). Synthetic lethal drug interactions are sorted based on Z -score for each indicated tumour suppressor. The interactions between ATM and AZD7762 (green circle) and PD0325901 (red circle) are indicated with black arrows. ( b ) Dose–response curve with the Chk1/2 inhibitor AZD7762. AALE cells were infected as indicated and treated with the drug for 3 days. Displayed is the relative viability that is calculated by normalizing the raw CellTiter-Glo data to the vehicle (DMSO) treated controls. Error bars indicate s.d. ( n =3). ( c ) Colony formation of AALE cells infected with ATM shRNA or control virus and treated with PD0325901 for 10 days. Shown is a representative example ( n =3). Numbers in the bottom right corners indicate quantification relative to DMSO-treated<|im_end|> <|im_start|>assistant Lung cancer remains the leading cause of cancer-related deaths worldwide. In contrast to other tumour types, lung tumours present a high number of genomic alterations—this is a consequence of exposure to carcinogenic substances found in tobacco smoke, which is the main cause of lung cancer. About 10 percent of lung tumours carry mutations in a gene called ATM. However, there are no drugs available in the clinic to treat ATM mutant lung cancer. Using cutting-edge, high-throughput drug screens that analyse how the genetic makeup of the patient affects their response to drugs, the team of Sebastian Nijman at the Ludwig Institute for Cancer Research in Oxford made a surprising discovery—cancer cells with ATM mutations are sensitive for drugs that inhibit an enzyme called MEK. The study was published in Nature Communications. MEK is part of a biochemical pathway which is responsible for supporting proliferation and survival of the cell, while ATM plays a central role during the DNA damage response. In ATM-deficient lung cancer cells, Nijman's team found that MEK inhibition results in cells being unable to proliferate, leading to apoptosis. An unexpected finding, as MEK inhibitors have so far been approved for the treatment of a type of skin cancer but not for lung cancer. "Normally, lung cancer cells are resistant to MEK inhibition as they activate compensatory signals," Ferran Fece, one of the two first authors on the study and former Ph.D. student at CeMM, explains. "In contrast, ATM mutant cells fail to do this and subsequently cannot cope with the blocking of MEK and die. We call this type of unexpected drug sensitivity synthetic lethality." Michal Smida, the other shared first author on the article, adds: "We knew that cancer mutations can lead to extreme sensitivity to some drugs. But finding these cancer Achilles' heels is very difficult as they are difficult to predict and extremely rare. We screened a large number of gene and drug combinations and got lucky." The study constitutes a substantial contribution for the development of a future precision medicine: ATM mutations could be used as a potential biomarker to stratify lung cancer patients to receive a MEK inhibitor. ATM is found to be mutated in 8-10 percent of lung adenocarcinomas—given that this type of tumour is among the most prevalent for both men and women worldwide, a significant number of patients could benefit from a MEK inhibitor based treatment. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Cortical organoids are self-organizing three-dimensional cultures that model features of the developing human cerebral cortex 1 , 2 . However, the fidelity of organoid models remains unclear 3 , 4 , 5 . Here we analyse the transcriptomes of individual primary human cortical cells from different developmental periods and cortical areas. We find that cortical development is characterized by progenitor maturation trajectories, the emergence of diverse cell subtypes and areal specification of newborn neurons. By contrast, organoids contain broad cell classes, but do not recapitulate distinct cellular subtype identities and appropriate progenitor maturation. Although the molecular signatures of cortical areas emerge in organoid neurons, they are not spatially segregated. Organoids also ectopically activate cellular stress pathways, which impairs cell-type specification. However, organoid stress and subtype defects are alleviated by transplantation into the mouse cortex. Together, these datasets and analytical tools provide a framework for evaluating and improving the accuracy of cortical organoids as models of human brain development. Main Organoid models harness the natural self-assembly properties of development to produce 3D cultures from stem cells that recapitulate aspects of an endogenous organ’s structure and function. Organoids have applications in disease modelling, drug screening, and regenerative medicine. Single-cell RNA sequencing (scRNA-seq) provides a powerful method for comparing the fidelity of organoid cell types to their primary cell counterparts across tissues. In the liver and kidney, benchmarking comparisons with normally developing organs indicate that 3D culture better recapitulates primary cell types than adherent culture 6 , 7 . However, the lack of a comprehensive catalogue of cell types in the normal developing human brain and their molecular features has prevented careful evaluation of the strengths and weaknesses of cerebral organoids. In vitro models of human cortical development are particularly valuable because early events during neurogenesis and synaptogenesis may underlie neuropsychiatric disorders, and experimental access to the developing human cortex is otherwise limited. Initial studies have indicated that broad classes of cells are preserved in cortical organoid models 3 , 8 but also hint at distinctions between organoids and primary cells 4 , 9 , 10 . In particular, the extent to which spatial and temporal gradients of gene expression and cell-type maturation are recapitulated in organoids is unclear (Extended Data Fig. 1 ). Although analysis of some of the first organoid models suggested the emergence of spatial gradients 1 , 2 , 11 , we know little about the fidelity and organization of areal cell types in organoids, in part because we lack molecular cell signatures of cortical areas in the developing brain. Comparison of human cortex and organoids To evaluate the fidelity of cortical cell types in organoids, we performed high-throughput scRNA-seq of samples from the developing human cortex and cortical organoids, and compared the results with published organoid single-cell sequencing datasets. To characterize molecular features and gene-expression signatures during human cortical development, we performed scRNA-seq of dissociated cells from five cortical samples collected at 6–22 gestational weeks (GW), encompassing the period of neurogenesis. To assess cell-type differences across cortical areas, we studied primary samples from seven regions, including prefrontal (PFC), motor, parietal, somatosensory and primary visual (V1) cortices as well as hippocampus, resulting in transcriptomic data from 189,409 cells ( Methods , Fig. 1a , Supplementary Table 1 ). These primary data were compared to data from 235,121 single cells from 37 organoids (Fig. 1b ). We generated forebrain organoids by following three previously published protocols using different levels of directed differentiation to evaluate whether increased stringency in patterning signals results in more endogenous-like cellular subtypes 1 , 4 , 8 , 12 (Extended Data Fig. 2 ). To assess biological replicability, we used three induced pluripotent stem cell (PSC) lines and one embryonic stem cell line. Organoids were maintained under the same conditions, except for protocol-specific medium formulations (Extended Data Fig. 2 ), and samples were collected for immunohistochemistry and scRNA-seq after 3, 5, 8, 10, 15 and 24 weeks of differentiation to evaluate relevant cell types (Extended Data Figs. 3 , 4 ). Last, we compared our reference dataset to published organoid single-cell data generated from 276,054 cells across eight protocols, including time points from six months to a year 3 , 4 , 5 , 8 , 9 , 13 , 14 , 15 . This enabled us to extend our comparisons to later stages of differentiation (Extended Data Figs. 5 , 6 ). Fig. 1: Cell types in cortical primary and organoid samples. a , Single-cell sequencing of primary cortical cells identifies a number of cell types. These cell types are labelled in the t -distributed stochastic neighbour-embedding ( t -SNE) plot on the left, and markers of cell-type identity depict progenitors (SOX2), oRGs (HOPX), IPCs (EOMES), newborn neurons (NEUROD6), maturing neurons (SATB2) and inhibitory interneurons (DLX6-AS1). Single-cell data can be explored at b , Single-cell sequencing of cortical organoid cells generated from four different pluripotent stem cell lines and three protocols with varied levels of directed differentiation generates similar cell types to primary cortex, but the population proportions differ. The proportion of cells for each marker in each sample type are: SOX2 + (primary 15.4%, organoid 41.2%), HOPX + (primary 7.6%, organoid 4.2%), EOMES + (primary 4.1%, organoid 1.5%), NEUROD6 + (primary 51.9%, organoid 20.3%), SATB2 + (primary 32.5%, organoid 2.0%), and DLX6–AS1 + (primary 17.1%, organoid 3.5%). Full size image Impaired cell-type fidelity in organoids We identified broad cell types that corresponded to radial glia, intermediate progenitor cells (IPCs), maturing neurons and interneurons in both datasets (Fig. 1 , Supplementary Tables 2 , 3 ). In primary cortical samples, we also found clusters of microglia, oligodendrocyte precursors, mural cells and endothelial cells. Additionally, we identified previously described subtypes of radial glia, as well as a few instances of area- and layer-specific subtypes of excitatory neurons. In the primary samples, there was extensive intermixing within clusters of ages and cortical areas (Extended Data Fig. 4a ). Within our organoids, cell lines, protocols and ages also intermixed, with variation primarily resulting from differences between cell", "role": "user" }, { "content": "Brain organoids—three-dimensional balls of brain-like tissue grown in the lab, often from human stem cells—have been touted for their potential to let scientists study the formation of the brain's complex circuitry in controlled laboratory conditions. The discussion surrounding brain organoids has been effusive, with some scientists suggesting they will make it possible to rapidly develop treatments for devastating brain diseases and others warning that organoids may soon attain some form of consciousness. But a new UC San Francisco study offers a more restrained perspective, by showing that widely used organoid models fail to replicate even basic features of brain development and organization, much less the complex circuitry needed to model complex brain diseases or normal cognition. \"Some people have branded organoids as 'brains in a dish' but our data suggest this is a huge exaggeration at this point,\" said Arnold Kriegstein, MD, Ph.D., a professor of neurology in the UCSF Weill Institute for Neurosciences, John G. Bowes Distinguished Professor in Stem Cell and Tissue Biology, and director of the UCSF Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, whose lab has been a leader in the development of cerebral organoid models (see prior studies here, here and here.) \"We find that organoids do not develop the distinctive cell subtypes or regional circuit organization that characterize normal human brain circuits. Since most human brain diseases are highly specific to particular cell types and circuits in the brain, this presents a grave challenge to efforts to use organoids to accurately model these complex conditions.\" The new study, published January 29, 2020 in Nature, arose out of the lab's ongoing efforts to comprehensively map the gene expression programs that orchestrate brain development based on samples of normal human brain tissue, a project led by Kriegstein lab postdoctoral researcher Aparna Bhaduri, Ph.D. The lab aims to make a genetic atlas of human brain development available as a valuable resource for comparing normal brain development to what goes awry in developmental brain diseases such as autism. However, when another postdoctoral researcher, Madeline Andrews, Ph.D., began comparing Bhaduri's data from the developing brain to the lab's organoid models, she quickly discovered that the exquisitely organized developmental programs seen in normal brain tissue were significantly disrupted in the lab's organoids. Cerebral Organoids Fail to Develop Crucial Cell Types, Organization The researchers measured gene expression in more than 235,000 individual cells extracted from 37 different organoids (themselves generated using three different laboratory protocols and four different starting stem cell lines) and compared these gene expression patterns to what they saw in about 189,000 brain cells from a range of brain areas and developmental timepoints in normally developing human brains. This analysis revealed that instead of differentiating normally into the brain's distinctive cell types, organoid cells appeared to experience an identity crisis: expressing a mixed bag of genes normally found in very different kinds of cells. At first, the organoids developed structured \"rosettes\" of cells that resemble some features of the developing brain, but these quickly dissolved into a hodge-podge of intermingled cells. \"We were able to identify the major broad categories of cell types, but the normal diversity of subtypes—which play key role in the proper function of neural circuits—was lacking,\" Kriegstein said. To make sure these results extended to other common ways of making organoids used outside the Kriegstein lab, the researchers compared single-cell gene expression data from eight different organoid protocols published in the scientific literature (for a total of more than 276,000 individual cells) to their atlas of normal gene expression in the developing brain. In every case the published organoids showed the same lack of appropriate development into distinctive cell types as the lab had seen in their own models. \"The brain's ability to wire together different cell types into highly structured and regionally distinctive circuits is central not only to normal brain function and cognition, but it is also these highly specific circuits that go awry in different ways in brain diseases such as autism, schizophrenia, and other psychiatric and neurological disorders,\" Andrews said. \"Before we can use organoids to study these diseases and search for potential cures, we need to ensure they are actually modeling the brain circuits that are affected,\" Bhaduri added. Reducing Cellular Stress Could Improve Organoid Models In addition to their confused developmental programming, the brain organoid models all expressed abnormally high levels of cellular \"stress\" genes, which control cells' response to harmful environmental conditions such as lack of oxygen. The researchers hypothesized that this heightened cellular stress could be caused by methods used when the organoids were being grown in the lab, and might be preventing the organoids from developing proper neural cell types and regional organization. To test this hypothesis, the researchers took cells from developing organoids and implanted them into the brains of mice to eliminate stressors caused by being grown in a lab dish. In this more natural context, the organoids' cellular stress levels quickly fell to normal levels, and normal developmental programs began to reassert themselves. Conversely, when the researchers took early developing neural tissue and tried to grow it with their laboratory organoids, stress genes became more activated, and the young neurons developed the same kind of identity crisis seen in the lab's organoids. These results suggest that neuroscientists' ambitions to model complex brain organization in organoids will require a significant rethinking of how organoids are grown in the lab to try to reduce levels of cellular stress. \"Different groups have optimized how they culture organoids in lots of different ways, so the fact that we see these issues across organoids from different laboratories suggests it's probably going to take a pretty big overhaul to improve how organoids turn out,\" Andrews said. \"That's not going to be an easy task, but I'm hopeful that these results and Aparna's unique dataset of the genetic programs in the normally developing brain will point the field in the right direction.\" The authors emphasize that organoids can still be a useful tool in the many kinds of research that do not require accurately modeling specific brain circuits or their dysfunction, such as a recent paper by Bhaduri and colleagues that used organoids as a way to study the aggressive spread of glioblastoma brain cancer in a lab dish. \"But these results are pretty clear that organoids are far from reproducing a real developing brain in the lab,\" Bhaduri said. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Cortical organoids are self-organizing three-dimensional cultures that model features of the developing human cerebral cortex 1 , 2 . However, the fidelity of organoid models remains unclear 3 , 4 , 5 . Here we analyse the transcriptomes of individual primary human cortical cells from different developmental periods and cortical areas. We find that cortical development is characterized by progenitor maturation trajectories, the emergence of diverse cell subtypes and areal specification of newborn neurons. By contrast, organoids contain broad cell classes, but do not recapitulate distinct cellular subtype identities and appropriate progenitor maturation. Although the molecular signatures of cortical areas emerge in organoid neurons, they are not spatially segregated. Organoids also ectopically activate cellular stress pathways, which impairs cell-type specification. However, organoid stress and subtype defects are alleviated by transplantation into the mouse cortex. Together, these datasets and analytical tools provide a framework for evaluating and improving the accuracy of cortical organoids as models of human brain development. Main Organoid models harness the natural self-assembly properties of development to produce 3D cultures from stem cells that recapitulate aspects of an endogenous organ’s structure and function. Organoids have applications in disease modelling, drug screening, and regenerative medicine. Single-cell RNA sequencing (scRNA-seq) provides a powerful method for comparing the fidelity of organoid cell types to their primary cell counterparts across tissues. In the liver and kidney, benchmarking comparisons with normally developing organs indicate that 3D culture better recapitulates primary cell types than adherent culture 6 , 7 . However, the lack of a comprehensive catalogue of cell types in the normal developing human brain and their molecular features has prevented careful evaluation of the strengths and weaknesses of cerebral organoids. In vitro models of human cortical development are particularly valuable because early events during neurogenesis and synaptogenesis may underlie neuropsychiatric disorders, and experimental access to the developing human cortex is otherwise limited. Initial studies have indicated that broad classes of cells are preserved in cortical organoid models 3 , 8 but also hint at distinctions between organoids and primary cells 4 , 9 , 10 . In particular, the extent to which spatial and temporal gradients of gene expression and cell-type maturation are recapitulated in organoids is unclear (Extended Data Fig. 1 ). Although analysis of some of the first organoid models suggested the emergence of spatial gradients 1 , 2 , 11 , we know little about the fidelity and organization of areal cell types in organoids, in part because we lack molecular cell signatures of cortical areas in the developing brain. Comparison of human cortex and organoids To evaluate the fidelity of cortical cell types in organoids, we performed high-throughput scRNA-seq of samples from the developing human cortex and cortical organoids, and compared the results with published organoid single-cell sequencing datasets. To characterize molecular features and gene-expression signatures during human cortical development, we performed scRNA-seq of dissociated cells from five cortical samples collected at 6–22 gestational weeks (GW), encompassing the period of neurogenesis. To assess cell-type differences across cortical areas, we studied primary samples from seven regions, including prefrontal (PFC), motor, parietal, somatosensory and primary visual (V1) cortices as well as hippocampus, resulting in transcriptomic data from 189,409 cells ( Methods , Fig. 1a , Supplementary Table 1 ). These primary data were compared to data from 235,121 single cells from 37 organoids (Fig. 1b ). We generated forebrain organoids by following three previously published protocols using different levels of directed differentiation to evaluate whether increased stringency in patterning signals results in more endogenous-like cellular subtypes 1 , 4 , 8 , 12 (Extended Data Fig. 2 ). To assess biological replicability, we used three induced pluripotent stem cell (PSC) lines and one embryonic stem cell line. Organoids were maintained under the same conditions, except for protocol-specific medium formulations (Extended Data Fig. 2 ), and samples were collected for immunohistochemistry and scRNA-seq after 3, 5, 8, 10, 15 and 24 weeks of differentiation to evaluate relevant cell types (Extended Data Figs. 3 , 4 ). Last, we compared our reference dataset to published organoid single-cell data generated from 276,054 cells across eight protocols, including time points from six months to a year 3 , 4 , 5 , 8 , 9 , 13 , 14 , 15 . This enabled us to extend our comparisons to later stages of differentiation (Extended Data Figs. 5 , 6 ). Fig. 1: Cell types in cortical primary and organoid samples. a , Single-cell sequencing of primary cortical cells identifies a number of cell types. These cell types are labelled in the t -distributed stochastic neighbour-embedding ( t -SNE) plot on the left, and markers of cell-type identity depict progenitors (SOX2), oRGs (HOPX), IPCs (EOMES), newborn neurons (NEUROD6), maturing neurons (SATB2) and inhibitory interneurons (DLX6-AS1). Single-cell data can be explored at b , Single-cell sequencing of cortical organoid cells generated from four different pluripotent stem cell lines and three protocols with varied levels of directed differentiation generates similar cell types to primary cortex, but the population proportions differ. The proportion of cells for each marker in each sample type are: SOX2 + (primary 15.4%, organoid 41.2%), HOPX + (primary 7.6%, organoid 4.2%), EOMES + (primary 4.1%, organoid 1.5%), NEUROD6 + (primary 51.9%, organoid 20.3%), SATB2 + (primary 32.5%, organoid 2.0%), and DLX6–AS1 + (primary 17.1%, organoid 3.5%). Full size image Impaired cell-type fidelity in organoids We identified broad cell types that corresponded to radial glia, intermediate progenitor cells (IPCs), maturing neurons and interneurons in both datasets (Fig. 1 , Supplementary Tables 2 , 3 ). In primary cortical samples, we also found clusters of microglia, oligodendrocyte precursors, mural cells and endothelial cells. Additionally, we identified previously described subtypes of radial glia, as well as a few instances of area- and layer-specific subtypes of excitatory neurons. In the primary samples, there was extensive intermixing within clusters of ages and cortical areas (Extended Data Fig. 4a ). Within our organoids, cell lines, protocols and ages also intermixed, with variation primarily resulting from differences between cell<|im_end|> <|im_start|>assistant Brain organoids—three-dimensional balls of brain-like tissue grown in the lab, often from human stem cells—have been touted for their potential to let scientists study the formation of the brain's complex circuitry in controlled laboratory conditions. The discussion surrounding brain organoids has been effusive, with some scientists suggesting they will make it possible to rapidly develop treatments for devastating brain diseases and others warning that organoids may soon attain some form of consciousness. But a new UC San Francisco study offers a more restrained perspective, by showing that widely used organoid models fail to replicate even basic features of brain development and organization, much less the complex circuitry needed to model complex brain diseases or normal cognition. "Some people have branded organoids as 'brains in a dish' but our data suggest this is a huge exaggeration at this point," said Arnold Kriegstein, MD, Ph.D., a professor of neurology in the UCSF Weill Institute for Neurosciences, John G. Bowes Distinguished Professor in Stem Cell and Tissue Biology, and director of the UCSF Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, whose lab has been a leader in the development of cerebral organoid models (see prior studies here, here and here.) "We find that organoids do not develop the distinctive cell subtypes or regional circuit organization that characterize normal human brain circuits. Since most human brain diseases are highly specific to particular cell types and circuits in the brain, this presents a grave challenge to efforts to use organoids to accurately model these complex conditions." The new study, published January 29, 2020 in Nature, arose out of the lab's ongoing efforts to comprehensively map the gene expression programs that orchestrate brain development based on samples of normal human brain tissue, a project led by Kriegstein lab postdoctoral researcher Aparna Bhaduri, Ph.D. The lab aims to make a genetic atlas of human brain development available as a valuable resource for comparing normal brain development to what goes awry in developmental brain diseases such as autism. However, when another postdoctoral researcher, Madeline Andrews, Ph.D., began comparing Bhaduri's data from the developing brain to the lab's organoid models, she quickly discovered that the exquisitely organized developmental programs seen in normal brain tissue were significantly disrupted in the lab's organoids. Cerebral Organoids Fail to Develop Crucial Cell Types, Organization The researchers measured gene expression in more than 235,000 individual cells extracted from 37 different organoids (themselves generated using three different laboratory protocols and four different starting stem cell lines) and compared these gene expression patterns to what they saw in about 189,000 brain cells from a range of brain areas and developmental timepoints in normally developing human brains. This analysis revealed that instead of differentiating normally into the brain's distinctive cell types, organoid cells appeared to experience an identity crisis: expressing a mixed bag of genes normally found in very different kinds of cells. At first, the organoids developed structured "rosettes" of cells that resemble some features of the developing brain, but these quickly dissolved into a hodge-podge of intermingled cells. "We were able to identify the major broad categories of cell types, but the normal diversity of subtypes—which play key role in the proper function of neural circuits—was lacking," Kriegstein said. To make sure these results extended to other common ways of making organoids used outside the Kriegstein lab, the researchers compared single-cell gene expression data from eight different organoid protocols published in the scientific literature (for a total of more than 276,000 individual cells) to their atlas of normal gene expression in the developing brain. In every case the published organoids showed the same lack of appropriate development into distinctive cell types as the lab had seen in their own models. "The brain's ability to wire together different cell types into highly structured and regionally distinctive circuits is central not only to normal brain function and cognition, but it is also these highly specific circuits that go awry in different ways in brain diseases such as autism, schizophrenia, and other psychiatric and neurological disorders," Andrews said. "Before we can use organoids to study these diseases and search for potential cures, we need to ensure they are actually modeling the brain circuits that are affected," Bhaduri added. Reducing Cellular Stress Could Improve Organoid Models In addition to their confused developmental programming, the brain organoid models all expressed abnormally high levels of cellular "stress" genes, which control cells' response to harmful environmental conditions such as lack of oxygen. The researchers hypothesized that this heightened cellular stress could be caused by methods used when the organoids were being grown in the lab, and might be preventing the organoids from developing proper neural cell types and regional organization. To test this hypothesis, the researchers took cells from developing organoids and implanted them into the brains of mice to eliminate stressors caused by being grown in a lab dish. In this more natural context, the organoids' cellular stress levels quickly fell to normal levels, and normal developmental programs began to reassert themselves. Conversely, when the researchers took early developing neural tissue and tried to grow it with their laboratory organoids, stress genes became more activated, and the young neurons developed the same kind of identity crisis seen in the lab's organoids. These results suggest that neuroscientists' ambitions to model complex brain organization in organoids will require a significant rethinking of how organoids are grown in the lab to try to reduce levels of cellular stress. "Different groups have optimized how they culture organoids in lots of different ways, so the fact that we see these issues across organoids from different laboratories suggests it's probably going to take a pretty big overhaul to improve how organoids turn out," Andrews said. "That's not going to be an easy task, but I'm hopeful that these results and Aparna's unique dataset of the genetic programs in the normally developing brain will point the field in the right direction." The authors emphasize that organoids can still be a useful tool in the many kinds of research that do not require accurately modeling specific brain circuits or their dysfunction, such as a recent paper by Bhaduri and colleagues that used organoids as a way to study the aggressive spread of glioblastoma brain cancer in a lab dish. "But these results are pretty clear that organoids are far from reproducing a real developing brain in the lab," Bhaduri said. <|im_end|>

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2,798

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The regular arrangements of β-strands around a central axis in β-barrels and of α-helices in coiled coils contrast with the irregular tertiary structures of most globular proteins, and have fascinated structural biologists since they were first discovered. Simple parametric models have been used to design a wide range of α-helical coiled-coil structures, but to date there has been no success with β-barrels. Here we show that accurate de novo design of β-barrels requires considerable symmetry-breaking to achieve continuous hydrogen-bond connectivity and eliminate backbone strain. We then build ensembles of β-barrel backbone models with cavity shapes that match the fluorogenic compound DFHBI, and use a hierarchical grid-based search method to simultaneously optimize the rigid-body placement of DFHBI in these cavities and the identities of the surrounding amino acids to achieve high shape and chemical complementarity. The designs have high structural accuracy and bind and fluorescently activate DFHBI in vitro and in Escherichia coli , yeast and mammalian cells. This de novo design of small-molecule binding activity, using backbones custom-built to bind the ligand, should enable the design of increasingly sophisticated ligand-binding proteins, sensors and catalysts that are not limited by the backbone geometries available in known protein structures. Main There have been considerable recent advances in designing protein folds from scratch 1 , 2 , as well as redesigning already existing native scaffolds to bind small molecules 3 , 4 , 5 , but two outstanding unsolved challenges remain. The first is the de novo design of all-β proteins, which is complicated by the tendency of β-strands and sheets to associate intermolecularly to form amyloid-like structures if their register is not perfectly controlled 6 . The second is the design of proteins customized to bind small molecules of interest, which requires precise control over backbone and side chain geometry 5 , as well as the balancing of the often opposing requirements of protein folding and function 7 . Success in developing such methods would reduce the longstanding dependency on natural proteins by enabling protein engineers to craft new proteins optimized to bind chosen small-molecule targets, and lay a foundation for de novo design of proteins customized to catalyse specific chemical reactions. Principles for designing β-barrels β-barrels are single β-sheets that twist to form a closed structure in which the first strand is hydrogen-bonded to the last 8 . Anti-parallel β-barrels are excellent scaffolds for ligand binding, as the base of the barrel can accommodate a hydrophobic core to provide overall stability, and the top of the barrel can provide a recessed cavity for ligand binding 9 , often flanked by loops that can contribute further binding affinity and selectivity 10 . However, all β-sheet topologies are notoriously difficult to design from scratch—to our knowledge, there has been no reported success to date—although several descriptive parametric models of β-barrels have been proposed 11 , 12 , 13 . We first set out to address this challenge by parametrically generating regular arrangements of eight anti-parallel β-strands using the equations for an elliptic hyperboloid of revolution (adapted from previously published work 14 , Fig. 1a ). β-barrels are characterized by their shear number ( S )—the total shift in strand registry between the first and last strands—which determines the hydrophobic packing arrangement and the diameter of the barrel 15 , 16 ( Supplementary Methods ). We selected a shear number of S = 10 because it is difficult to achieve good core packing for S = 8 (the barrel has a smaller diameter and the C α –C β vectors point directly at each other), and S = 12 results in a cavity that is too large to fill with side chains (Extended Data Fig. 1b–d ). We generated ensembles of hyperboloids by sampling the elliptical parameters and the tilt of the generating lines with respect to the central axis around ideal values computed for S = 10, and then placed C α atoms on the hyperboloid surface (Fig. 1a , Supplementary Methods ). As found in earlier simulation work 17 , backbones generated with constant angles between strands could not achieve perfectly regular hydrogen bonding. To resolve this problem, we introduced force-field guided variation in local twist by gradient-based minimization. We selected the backbones with the most extensive inter-strand hydrogen bonding, connected the strands with short loops and carried out combinatorial sequence optimization to obtain low-energy sequences (Extended Data Fig. 1a ). Synthetic genes encoding 41 such designs were produced and the proteins were expressed in E. coli . Almost all were found to be insoluble or oligomeric; none of this first set of 41 designs were monomeric with an all-β circular dichroism spectrum (Supplementary Table 2 ). Fig. 1: Principles for designing β-barrels. a , b , Two methods for β-barrel backbone generation. a , Parametric generation of 3D backbones on the basis of the hyperboloid model. The cross-section of the barrel is controlled on the global level with parameters ( r , r A and r B ). b , Specification of residue connectivity in a 2D map and assembly of 3D backbones with Rosetta. The cross-section geometry is controlled on the local level with torsion angle bins specified for each residue. c , Incorporation of glycine kinks and β-bulges reduces Lennard–Jones repulsive interactions in β-barrels. Full backbones are shown on the left and one C β -strip is shown on the right. Top, no β-bulge, no glycine kink; middle, one glycine kink in the middle of each C β -strip, no β-bulge; bottom, one glycine kink in the middle of each C β -strip, and β-bulges placed near the β-turns. d , Blueprint used to generate a β-barrel of type (strand number n = 8; shear number S = 10) with a square cross-section suitable for ligand binding. The values of the barrel radius ( r ) and tilt of the strands ( θ ) used to place glycines are determined by the choice of n and S . The residues in the 2D blueprint (left) and the 3D", "role": "user" }, { "content": "For the first time, scientists have created, entirely from scratch, a protein capable of binding to a small target molecule. Researchers from the University of Washington School of Medicine report the advance in the Sept. 12 issue of the journal Nature. Previously, such small-molecule binding proteins have been made by altering proteins already existing in nature. That approach significantly limited the possibilities. The ability to make such proteins from scratch, or \"de novo,\" opens the way for scientists to create proteins unlike any found in nature. These proteins can be custom-designed with high precision and affinity to bind to and act on specific small molecule targets. The lead authors of the paper are Jiayi Dou and Anastassia A. Vorobieva, both senior fellows in the lab of senior author David Baker, professor of biochemistry at the UW School of Medicine and director of the Institute of Protein Design at UW Medicine. Baker is also an investigator at the Howard Hughes Medical Institute. The technique should have wide application in research, medicine and industry, according to Baker. \"The successful de novo design of custom-built proteins with small-molecule binding activity sets the stage for the creation of increasingly sophisticated binding proteins that will not have the limitations seen with proteins that have been designed by altering existing protein structures,\" he explained. To make the protein, the researchers had to achieve another first: Creating from scratch a cylinder-shaped protein called a beta-barrel. The beta-barrel structure was ideal because one end of the cylinder could be designed to stabilize the protein, while the other end could be used to create a cavity that can serve as the binding site for the target molecule. Proteins are made of long chains of amino acids. Once synthesized, these chains fold into precise shapes that allow the proteins to perform their functions. The shapes these chains assume are typically incredibly convoluted, but two regular features often occur: alpha-helices, which form when the sections chain winds around a central axis, and sheet-like structures, called beta-sheets. This clip shows the action of a laboratory-designed, fluorescence-activating beta barrel protein Credit: Institute for Protein Design/UW Medicine Beta-sheets form when two or more sections from different parts of the amino acid chain, because of folding, run side-by-side in 3-D space. These sections are \"stitched together\" by hydrogen bonds, creating a sheet-like structure. These beta-sheets, in turn, can assemble into barrel-like structures, called beta-barrels. In nature, beta-barrels proteins bind a wide range of small molecules. To design the new protein, Dou and Vorobieva used a software platform, developed in the Baker lab, called Rosetta. It can predict what shape a particular chain of amino acids will assume after synthesis and can tell how changing individual amino acids along the chain may alter that shape. This predictive power makes it possible to test out different combinations of amino acids to design a protein with the desired shape and function. To create the cavity, the researchers used a powerful new docking algorithm, called \"Rotamer Interaction Field\" (RIF), developed by William Sheffler, a senior research scientist in the Baker lab. RIF rapidly identifies all potential structures of cavities that fulfill the pre-requisites for binding specific molecules. Equipped with the new RIF docking methods, Dou, Vorobieva and Sheffler designed the beta barrels to bind a compound called DFHBI, a component similar to what is housed inside green fluorescent protein, which fluoresces when exposed to certain frequencies of light. Green fluorescent protein is routinely used in biological research to locate molecules and structures within living organism and to track their movement. Anastassia A. Vorobieva. holding her new son, with her research colleague Jiayi Dou. The two scientists led the design and testing of a beta-barrel protein that activates fluorescence. The new protein, built from scratch, is an advance in custom-designing proteins to precisely target small molecules. Credit: Institute for Protein Design/UW Medicine In their paper, the researcher demonstrate that their custom-designed protein avidly bound and activated the DFHBI compound. \"It worked in bacterial, yeast and mammalian cells,\" said Dou, \"and being half the size of green fluorescent protein should be very useful to researchers.\" Baker said that the approach will allow researchers to explore an effectively unlimited set of backbone structures with shapes customized to bind the molecule of interest. \"Equally important,\" he added, \"it greatly advances our understanding of the determinants of protein folding and binding beyond what we have learned from describing existing protein structures.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The regular arrangements of β-strands around a central axis in β-barrels and of α-helices in coiled coils contrast with the irregular tertiary structures of most globular proteins, and have fascinated structural biologists since they were first discovered. Simple parametric models have been used to design a wide range of α-helical coiled-coil structures, but to date there has been no success with β-barrels. Here we show that accurate de novo design of β-barrels requires considerable symmetry-breaking to achieve continuous hydrogen-bond connectivity and eliminate backbone strain. We then build ensembles of β-barrel backbone models with cavity shapes that match the fluorogenic compound DFHBI, and use a hierarchical grid-based search method to simultaneously optimize the rigid-body placement of DFHBI in these cavities and the identities of the surrounding amino acids to achieve high shape and chemical complementarity. The designs have high structural accuracy and bind and fluorescently activate DFHBI in vitro and in Escherichia coli , yeast and mammalian cells. This de novo design of small-molecule binding activity, using backbones custom-built to bind the ligand, should enable the design of increasingly sophisticated ligand-binding proteins, sensors and catalysts that are not limited by the backbone geometries available in known protein structures. Main There have been considerable recent advances in designing protein folds from scratch 1 , 2 , as well as redesigning already existing native scaffolds to bind small molecules 3 , 4 , 5 , but two outstanding unsolved challenges remain. The first is the de novo design of all-β proteins, which is complicated by the tendency of β-strands and sheets to associate intermolecularly to form amyloid-like structures if their register is not perfectly controlled 6 . The second is the design of proteins customized to bind small molecules of interest, which requires precise control over backbone and side chain geometry 5 , as well as the balancing of the often opposing requirements of protein folding and function 7 . Success in developing such methods would reduce the longstanding dependency on natural proteins by enabling protein engineers to craft new proteins optimized to bind chosen small-molecule targets, and lay a foundation for de novo design of proteins customized to catalyse specific chemical reactions. Principles for designing β-barrels β-barrels are single β-sheets that twist to form a closed structure in which the first strand is hydrogen-bonded to the last 8 . Anti-parallel β-barrels are excellent scaffolds for ligand binding, as the base of the barrel can accommodate a hydrophobic core to provide overall stability, and the top of the barrel can provide a recessed cavity for ligand binding 9 , often flanked by loops that can contribute further binding affinity and selectivity 10 . However, all β-sheet topologies are notoriously difficult to design from scratch—to our knowledge, there has been no reported success to date—although several descriptive parametric models of β-barrels have been proposed 11 , 12 , 13 . We first set out to address this challenge by parametrically generating regular arrangements of eight anti-parallel β-strands using the equations for an elliptic hyperboloid of revolution (adapted from previously published work 14 , Fig. 1a ). β-barrels are characterized by their shear number ( S )—the total shift in strand registry between the first and last strands—which determines the hydrophobic packing arrangement and the diameter of the barrel 15 , 16 ( Supplementary Methods ). We selected a shear number of S = 10 because it is difficult to achieve good core packing for S = 8 (the barrel has a smaller diameter and the C α –C β vectors point directly at each other), and S = 12 results in a cavity that is too large to fill with side chains (Extended Data Fig. 1b–d ). We generated ensembles of hyperboloids by sampling the elliptical parameters and the tilt of the generating lines with respect to the central axis around ideal values computed for S = 10, and then placed C α atoms on the hyperboloid surface (Fig. 1a , Supplementary Methods ). As found in earlier simulation work 17 , backbones generated with constant angles between strands could not achieve perfectly regular hydrogen bonding. To resolve this problem, we introduced force-field guided variation in local twist by gradient-based minimization. We selected the backbones with the most extensive inter-strand hydrogen bonding, connected the strands with short loops and carried out combinatorial sequence optimization to obtain low-energy sequences (Extended Data Fig. 1a ). Synthetic genes encoding 41 such designs were produced and the proteins were expressed in E. coli . Almost all were found to be insoluble or oligomeric; none of this first set of 41 designs were monomeric with an all-β circular dichroism spectrum (Supplementary Table 2 ). Fig. 1: Principles for designing β-barrels. a , b , Two methods for β-barrel backbone generation. a , Parametric generation of 3D backbones on the basis of the hyperboloid model. The cross-section of the barrel is controlled on the global level with parameters ( r , r A and r B ). b , Specification of residue connectivity in a 2D map and assembly of 3D backbones with Rosetta. The cross-section geometry is controlled on the local level with torsion angle bins specified for each residue. c , Incorporation of glycine kinks and β-bulges reduces Lennard–Jones repulsive interactions in β-barrels. Full backbones are shown on the left and one C β -strip is shown on the right. Top, no β-bulge, no glycine kink; middle, one glycine kink in the middle of each C β -strip, no β-bulge; bottom, one glycine kink in the middle of each C β -strip, and β-bulges placed near the β-turns. d , Blueprint used to generate a β-barrel of type (strand number n = 8; shear number S = 10) with a square cross-section suitable for ligand binding. The values of the barrel radius ( r ) and tilt of the strands ( θ ) used to place glycines are determined by the choice of n and S . The residues in the 2D blueprint (left) and the 3D<|im_end|> <|im_start|>assistant For the first time, scientists have created, entirely from scratch, a protein capable of binding to a small target molecule. Researchers from the University of Washington School of Medicine report the advance in the Sept. 12 issue of the journal Nature. Previously, such small-molecule binding proteins have been made by altering proteins already existing in nature. That approach significantly limited the possibilities. The ability to make such proteins from scratch, or "de novo," opens the way for scientists to create proteins unlike any found in nature. These proteins can be custom-designed with high precision and affinity to bind to and act on specific small molecule targets. The lead authors of the paper are Jiayi Dou and Anastassia A. Vorobieva, both senior fellows in the lab of senior author David Baker, professor of biochemistry at the UW School of Medicine and director of the Institute of Protein Design at UW Medicine. Baker is also an investigator at the Howard Hughes Medical Institute. The technique should have wide application in research, medicine and industry, according to Baker. "The successful de novo design of custom-built proteins with small-molecule binding activity sets the stage for the creation of increasingly sophisticated binding proteins that will not have the limitations seen with proteins that have been designed by altering existing protein structures," he explained. To make the protein, the researchers had to achieve another first: Creating from scratch a cylinder-shaped protein called a beta-barrel. The beta-barrel structure was ideal because one end of the cylinder could be designed to stabilize the protein, while the other end could be used to create a cavity that can serve as the binding site for the target molecule. Proteins are made of long chains of amino acids. Once synthesized, these chains fold into precise shapes that allow the proteins to perform their functions. The shapes these chains assume are typically incredibly convoluted, but two regular features often occur: alpha-helices, which form when the sections chain winds around a central axis, and sheet-like structures, called beta-sheets. This clip shows the action of a laboratory-designed, fluorescence-activating beta barrel protein Credit: Institute for Protein Design/UW Medicine Beta-sheets form when two or more sections from different parts of the amino acid chain, because of folding, run side-by-side in 3-D space. These sections are "stitched together" by hydrogen bonds, creating a sheet-like structure. These beta-sheets, in turn, can assemble into barrel-like structures, called beta-barrels. In nature, beta-barrels proteins bind a wide range of small molecules. To design the new protein, Dou and Vorobieva used a software platform, developed in the Baker lab, called Rosetta. It can predict what shape a particular chain of amino acids will assume after synthesis and can tell how changing individual amino acids along the chain may alter that shape. This predictive power makes it possible to test out different combinations of amino acids to design a protein with the desired shape and function. To create the cavity, the researchers used a powerful new docking algorithm, called "Rotamer Interaction Field" (RIF), developed by William Sheffler, a senior research scientist in the Baker lab. RIF rapidly identifies all potential structures of cavities that fulfill the pre-requisites for binding specific molecules. Equipped with the new RIF docking methods, Dou, Vorobieva and Sheffler designed the beta barrels to bind a compound called DFHBI, a component similar to what is housed inside green fluorescent protein, which fluoresces when exposed to certain frequencies of light. Green fluorescent protein is routinely used in biological research to locate molecules and structures within living organism and to track their movement. Anastassia A. Vorobieva. holding her new son, with her research colleague Jiayi Dou. The two scientists led the design and testing of a beta-barrel protein that activates fluorescence. The new protein, built from scratch, is an advance in custom-designing proteins to precisely target small molecules. Credit: Institute for Protein Design/UW Medicine In their paper, the researcher demonstrate that their custom-designed protein avidly bound and activated the DFHBI compound. "It worked in bacterial, yeast and mammalian cells," said Dou, "and being half the size of green fluorescent protein should be very useful to researchers." Baker said that the approach will allow researchers to explore an effectively unlimited set of backbone structures with shapes customized to bind the molecule of interest. "Equally important," he added, "it greatly advances our understanding of the determinants of protein folding and binding beyond what we have learned from describing existing protein structures." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The role of skeletal muscle in nonshivering thermogenesis (NST) is not well understood. Here we show that sarcolipin (Sln), a newly identified regulator of the sarco/endoplasmic reticulum Ca 2+ -ATPase (Serca) pump 1 , 2 , 3 , 4 , 5 , is necessary for muscle-based thermogenesis. When challenged to acute cold (4 °C), Sln −/− mice were not able to maintain their core body temperature (37 °C) and developed hypothermia. Surgical ablation of brown adipose tissue and functional knockdown of Ucp1 allowed us to highlight the role of muscle in NST. Overexpression of Sln in the Sln-null background fully restored muscle-based thermogenesis, suggesting that Sln is the basis for Serca-mediated heat production. We show that ryanodine receptor 1 (Ryr1)-mediated Ca 2+ leak is an important mechanism for Serca-activated heat generation. Here we present data to suggest that Sln can continue to interact with Serca in the presence of Ca 2+ , which can promote uncoupling of the Serca pump and cause futile cycling. We further show that loss of Sln predisposes mice to diet-induced obesity, which suggests that Sln-mediated NST is recruited during metabolic overload. These data collectively suggest that SLN is an important mediator of muscle thermogenesis and whole-body energy metabolism. Main Endothermic animals require heat production from within to maintain their core temperature. Mammals, including humans, depend on both shivering and NST mechanisms for temperature homeostasis 6 , 7 . Although muscle shivering is an immediate response to cold stress, continuous muscle shivering leads to exhaustion and muscle damage; therefore, NST mechanisms are activated in these conditions. Brown adipose tissue (BAT) is an important site of NST in most mammals 8 , 9 , 10 . Several studies have suggested that in addition to BAT, skeletal muscle has a role in NST 7 , 11 , 12 , but the molecular details of its involvement have not been completely explored. Studies conducted on heater organs (modified ocular muscle) 13 , 14 , 15 , 16 of fish have shown that continuous sarcoplasmic reticulum Ca 2+ transport (caused by an inherently leaky ryanodine receptor) has evolved for heat production without muscle contraction. Similarly, in malignant hyperthermia, mutations in Ryr1 predispose to abnormal Ca 2+ leak when exposed to anesthetic compounds. This condition elevates the amount of cytosolic Ca 2+ and results in excessive activation of Serca-mediated Ca 2+ transport and heat production 17 . However, it is not currently known to what extent the sarcoplasmic reticulum Ca 2+ transport machinery is recruited in muscle-based NST in the absence of contraction. Recent in vitro studies have suggested that Sln can increase heat production by uncoupling Serca-mediated ATP hydrolysis from Ca 2+ transport 18 , 19 . In this study, we sought to determine whether the Sln-Serca interaction is an important mechanism for muscle-based thermogenesis in vivo . The generation of the Sln −/− mouse model has been previously described 4 . Loss of Sln in this model enhances Serca activity and improves muscle function in the muscle tissues where it is expressed 4 , 20 . When housed at 22 ± 1.5 °C (mean ± range), Sln −/− mice had an optimal average core temperature of 36.8 ± 0.3 °C (mean ± s.e.m.) ( Supplementary Fig. 1a ) and surface body heat ( Fig. 1a ). Because BAT is an important contributor to NST in rodents, loss of Sln could be compensated for by BAT. Therefore, we surgically ablated intrascapular BAT (iBAT), which constitutes ≥60% of the total BAT content, in a set of wild-type (WT) and Sln −/− mice to minimize its contribution. At 22 ± 1.5 °C, removal of iBAT in WT and Sln −/− mice did not have a major effect on the core temperature ( Fig. 1a and Suplementary Fig. 1a ), physical activity ( Supplementary Fig. 1b ), oxygen consumption (VO 2 ) or respiratory exchange ratio of the mice ( Supplementary Fig. 1c,d ). These data show that Sln −/− mice can maintain an optimal core temperature at 22 ± 1.5 °C, suggesting that Sln-dependent NST is not activated under these conditions. Figure 1: Sln −/− mice are not able to maintain optimal core temperature ( ∼ 37 °C) and develop hypothermia when challenged with acute cold. ( a ) Infrared imaging of surface body heat in WT and Sln −/− mice with or without iBAT at 22 °C and 4 °C. ( b ) Core body temperature after acute cold exposure in WT and Sln −/− mice, with and without iBAT. n = 22 (WT + iBAT), n = 23 (WT – iBAT), n = 22 ( Sln −/− + iBAT), n = 27 ( Sln −/− – iBAT). ( c ) Percentage of mice reaching ERC. ( d , e ) Average drop in core temperature (Tc) during the first 2 h of 4 °C challenge in WT and Sln −/− mice first acclimatized to 22 °C ( d ) or 30 °C ( e ). ( f , g ) Oxygen consumption averaged over the first two hours of acute cold exposure in WT and Sln −/− mice first acclimatized to 22 °C ( f ) or 30 °C ( g ). * P < 0.05, ** P < 0.01, *** P < 0.001, NS, not significant as analyzed by Student's t test or one-way analysis of variance (ANOVA). All data are means ± s.e.m. Full size image To determine whether Sln is important for cold-induced thermogenesis, we exposed Sln −/− mice to acute cold (4 °C) in a temperature-controlled Comprehensive Lab Animal Monitoring System (CLAMS) module and monitored their core temperature using an infrared camera and implantable transponders. Infrared imaging of Sln −/− mice challenged to a temperature of 4 °C showed a substantial reduction in surface body heat, as determined by a switch in heat intensity from red to yellow ( Fig. 1a ). When exposed for a prolonged period (10 h) to 4 °C, the iBAT-ablated Sln −/− mice, despite their skeletal muscle shivering ( Supplementary", "role": "user" }, { "content": "(Medical Xpress)—A team of researchers working in Ohio has found evidence that suggests that the protein sarcolipin, normally a calcium regulator pump, also serves as a means of causing muscles to generate body heat independent of shivering. In their paper published in Nature Medicine, the team says their results show that energy heat derived from brown fat burning white fat stores, or muscle shivering, are not the only means the body has of keeping warm. The traditional view of thermogenesis, where energy stores are burned to keep the body warm, is that brown fat grabs resources from white fat and burns it or muscles contract and relax rhythmically producing shivering, are the only two means mammals have for maintaining warmth when it's colder outside than inside their bodies. This new research shows that there is a third way as well, and it involves the protein sarcolipin, which the researchers say, causes otherwise idle muscles to burn energy which creates heat which also helps to keep the body warm. The researchers came to this conclusion by studying the impact of brown fat, muscles and sarcolipin on heat generation in mice. First they genetically caused a small group of mice to cease producing sarcolipin, then they removed all of their brown fat. They also removed the brown fat from another small test group still able to produce sarcolipin. Afterwards, all of the mice in both groups were subjected to a 4 °C cold test environment. The mice that weren't producing sarcolipin died within ten hours, those that were, even without the aid of their brown fat, survived. This proves, the team says, that sarcolipin does indeed induce idle muscle to produce heat, enough obviously to keep mice alive in a cold cage. But there was another, perhaps even more intriguing, finding as well. The team reports that the mice that had their ability to produce sarcolipin removed tended to gain weight as well when put on a high fat diet; so much so that they grew to become 33 percent heavier than mice that continued to produce sarcolipin. This, the team says, might just have implications in the human world as it seems plausible that increased amounts of sarcolipin production might result in more energy burning and thus weight loss. That hasn't been tested yet, but it most certainly will be, both by this team and others searching for a way to help people lose weight despite inappropriate diets or limited exercise regimens. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The role of skeletal muscle in nonshivering thermogenesis (NST) is not well understood. Here we show that sarcolipin (Sln), a newly identified regulator of the sarco/endoplasmic reticulum Ca 2+ -ATPase (Serca) pump 1 , 2 , 3 , 4 , 5 , is necessary for muscle-based thermogenesis. When challenged to acute cold (4 °C), Sln −/− mice were not able to maintain their core body temperature (37 °C) and developed hypothermia. Surgical ablation of brown adipose tissue and functional knockdown of Ucp1 allowed us to highlight the role of muscle in NST. Overexpression of Sln in the Sln-null background fully restored muscle-based thermogenesis, suggesting that Sln is the basis for Serca-mediated heat production. We show that ryanodine receptor 1 (Ryr1)-mediated Ca 2+ leak is an important mechanism for Serca-activated heat generation. Here we present data to suggest that Sln can continue to interact with Serca in the presence of Ca 2+ , which can promote uncoupling of the Serca pump and cause futile cycling. We further show that loss of Sln predisposes mice to diet-induced obesity, which suggests that Sln-mediated NST is recruited during metabolic overload. These data collectively suggest that SLN is an important mediator of muscle thermogenesis and whole-body energy metabolism. Main Endothermic animals require heat production from within to maintain their core temperature. Mammals, including humans, depend on both shivering and NST mechanisms for temperature homeostasis 6 , 7 . Although muscle shivering is an immediate response to cold stress, continuous muscle shivering leads to exhaustion and muscle damage; therefore, NST mechanisms are activated in these conditions. Brown adipose tissue (BAT) is an important site of NST in most mammals 8 , 9 , 10 . Several studies have suggested that in addition to BAT, skeletal muscle has a role in NST 7 , 11 , 12 , but the molecular details of its involvement have not been completely explored. Studies conducted on heater organs (modified ocular muscle) 13 , 14 , 15 , 16 of fish have shown that continuous sarcoplasmic reticulum Ca 2+ transport (caused by an inherently leaky ryanodine receptor) has evolved for heat production without muscle contraction. Similarly, in malignant hyperthermia, mutations in Ryr1 predispose to abnormal Ca 2+ leak when exposed to anesthetic compounds. This condition elevates the amount of cytosolic Ca 2+ and results in excessive activation of Serca-mediated Ca 2+ transport and heat production 17 . However, it is not currently known to what extent the sarcoplasmic reticulum Ca 2+ transport machinery is recruited in muscle-based NST in the absence of contraction. Recent in vitro studies have suggested that Sln can increase heat production by uncoupling Serca-mediated ATP hydrolysis from Ca 2+ transport 18 , 19 . In this study, we sought to determine whether the Sln-Serca interaction is an important mechanism for muscle-based thermogenesis in vivo . The generation of the Sln −/− mouse model has been previously described 4 . Loss of Sln in this model enhances Serca activity and improves muscle function in the muscle tissues where it is expressed 4 , 20 . When housed at 22 ± 1.5 °C (mean ± range), Sln −/− mice had an optimal average core temperature of 36.8 ± 0.3 °C (mean ± s.e.m.) ( Supplementary Fig. 1a ) and surface body heat ( Fig. 1a ). Because BAT is an important contributor to NST in rodents, loss of Sln could be compensated for by BAT. Therefore, we surgically ablated intrascapular BAT (iBAT), which constitutes ≥60% of the total BAT content, in a set of wild-type (WT) and Sln −/− mice to minimize its contribution. At 22 ± 1.5 °C, removal of iBAT in WT and Sln −/− mice did not have a major effect on the core temperature ( Fig. 1a and Suplementary Fig. 1a ), physical activity ( Supplementary Fig. 1b ), oxygen consumption (VO 2 ) or respiratory exchange ratio of the mice ( Supplementary Fig. 1c,d ). These data show that Sln −/− mice can maintain an optimal core temperature at 22 ± 1.5 °C, suggesting that Sln-dependent NST is not activated under these conditions. Figure 1: Sln −/− mice are not able to maintain optimal core temperature ( ∼ 37 °C) and develop hypothermia when challenged with acute cold. ( a ) Infrared imaging of surface body heat in WT and Sln −/− mice with or without iBAT at 22 °C and 4 °C. ( b ) Core body temperature after acute cold exposure in WT and Sln −/− mice, with and without iBAT. n = 22 (WT + iBAT), n = 23 (WT – iBAT), n = 22 ( Sln −/− + iBAT), n = 27 ( Sln −/− – iBAT). ( c ) Percentage of mice reaching ERC. ( d , e ) Average drop in core temperature (Tc) during the first 2 h of 4 °C challenge in WT and Sln −/− mice first acclimatized to 22 °C ( d ) or 30 °C ( e ). ( f , g ) Oxygen consumption averaged over the first two hours of acute cold exposure in WT and Sln −/− mice first acclimatized to 22 °C ( f ) or 30 °C ( g ). * P < 0.05, ** P < 0.01, *** P < 0.001, NS, not significant as analyzed by Student's t test or one-way analysis of variance (ANOVA). All data are means ± s.e.m. Full size image To determine whether Sln is important for cold-induced thermogenesis, we exposed Sln −/− mice to acute cold (4 °C) in a temperature-controlled Comprehensive Lab Animal Monitoring System (CLAMS) module and monitored their core temperature using an infrared camera and implantable transponders. Infrared imaging of Sln −/− mice challenged to a temperature of 4 °C showed a substantial reduction in surface body heat, as determined by a switch in heat intensity from red to yellow ( Fig. 1a ). When exposed for a prolonged period (10 h) to 4 °C, the iBAT-ablated Sln −/− mice, despite their skeletal muscle shivering ( Supplementary<|im_end|> <|im_start|>assistant (Medical Xpress)—A team of researchers working in Ohio has found evidence that suggests that the protein sarcolipin, normally a calcium regulator pump, also serves as a means of causing muscles to generate body heat independent of shivering. In their paper published in Nature Medicine, the team says their results show that energy heat derived from brown fat burning white fat stores, or muscle shivering, are not the only means the body has of keeping warm. The traditional view of thermogenesis, where energy stores are burned to keep the body warm, is that brown fat grabs resources from white fat and burns it or muscles contract and relax rhythmically producing shivering, are the only two means mammals have for maintaining warmth when it's colder outside than inside their bodies. This new research shows that there is a third way as well, and it involves the protein sarcolipin, which the researchers say, causes otherwise idle muscles to burn energy which creates heat which also helps to keep the body warm. The researchers came to this conclusion by studying the impact of brown fat, muscles and sarcolipin on heat generation in mice. First they genetically caused a small group of mice to cease producing sarcolipin, then they removed all of their brown fat. They also removed the brown fat from another small test group still able to produce sarcolipin. Afterwards, all of the mice in both groups were subjected to a 4 °C cold test environment. The mice that weren't producing sarcolipin died within ten hours, those that were, even without the aid of their brown fat, survived. This proves, the team says, that sarcolipin does indeed induce idle muscle to produce heat, enough obviously to keep mice alive in a cold cage. But there was another, perhaps even more intriguing, finding as well. The team reports that the mice that had their ability to produce sarcolipin removed tended to gain weight as well when put on a high fat diet; so much so that they grew to become 33 percent heavier than mice that continued to produce sarcolipin. This, the team says, might just have implications in the human world as it seems plausible that increased amounts of sarcolipin production might result in more energy burning and thus weight loss. That hasn't been tested yet, but it most certainly will be, both by this team and others searching for a way to help people lose weight despite inappropriate diets or limited exercise regimens. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Studies have identified elevation-dependent warming trends, but investigations of such trends in fire danger are absent in the literature. Here, we demonstrate that while there have been widespread increases in fire danger across the mountainous western US from 1979 to 2020, trends were most acute at high-elevation regions above 3000 m. The greatest increase in the number of days conducive to large fires occurred at 2500–3000 m, adding 63 critical fire danger days between 1979 and 2020. This includes 22 critical fire danger days occurring outside the warm season (May–September). Furthermore, our findings indicate increased elevational synchronization of fire danger in western US mountains, which can facilitate increased geographic opportunities for ignitions and fire spread that further complicate fire management operations. We hypothesize that several physical mechanisms underpinned the observed trends, including elevationally disparate impacts of earlier snowmelt, intensified land-atmosphere feedbacks, irrigation, and aerosols, in addition to widespread warming/drying. Introduction Mountains provide a variety of ecosystem services, including supplying about 50% of freshwater globally and an even higher fraction in mountainous arid regions (e.g., 70% of runoff in the western US) 1 , 2 . Orographic temperature and precipitation gradients in montane areas facilitate stratified vegetation belts 3 , which promote local hotspots of biodiversity with a high degree of complexity that are particularly vulnerable to ecosystem changes in response to chronic (e.g., warming) and/or acute (e.g., wildfire) stressors 4 . Even small perturbations in these mountainous areas have large repercussions for hydrological and ecological processes, with cascading effects on downstream human-environmental systems 3 , 5 , 6 , 7 . A growing body of literature points to elevation-dependent trends in meteorological and land surface characteristics in montane regions of the world in response to the underlying warming signal 6 , 7 , 8 . In particular, more rapid warming of surface air temperature has been documented at higher elevations compared to that of lower elevations in many regions globally 7 , 9 . Similarly, trends in land surface temperature 10 , reference evapotranspiration 11 , snow cover and snow water equivalent 12 , 13 , and vegetation greening 14 , 15 have also been documented to vary across elevational gradients. Furthermore, elevation-dependent precipitation trends are observed in some regions, although the sign of such changes and associated mechanisms vary across studies 2 , 16 . Changes in the energy and water balance alter the fire danger level 17 , which is defined as the potential for a fire to ignite, spread and require suppression action. The literature has shown widespread increases in fire danger in many regions globally 18 , 19 , 20 , 21 , but how fire danger trends change across the elevational gradient has not been studied. Recent literature shows that atmospheric warming weakened the high-elevation flammability barrier and enabled the upslope advance of fires 22 , and facilitated high-elevation fires that are unprecedented in modern history 23 . Here we use the fire danger representation in the US National Fire Danger Rating System (NFDRS) 24 to investigate trends in fire danger across elevations. We note that NFDRS fire danger indices were empirically derived based on mathematical models of fire behavior, and they do not fully capture the energy and water balance related to fuels and fire 24 . Previous studies have linked these indices with regional burned area 25 and the growth of individual fires 26 , and they are operationally used by fire management agencies across the US 27 . We evaluated elevation-dependent trends in fire danger indices between 1979 and 2020 across 15 level III Omernik ecoregions of the western US 28 that are mountainous. We augmented this list with a variety of meteorological variables that are commonly used in fire studies 29 , 30 and posed two questions: (1) Are there elevation-dependent trends in fire danger indices across montane regions of the western US? (2) If so, do they culminate in the elevational synchronization of fire danger? We answered these questions using the gridMET dataset of daily meteorological and NFDRS variables (~4 km grid) 31 , Omernik level III ecoregions map from the US Environmental Protection Agency 28 , and the National Elevation Dataset (10 m resolution) from the US Geological Survey. We present the results of the energy release component (ERC, Fuel Model G in NFDRS 77 24 ) in the main paper and all other NFDRS indices (burning index [BI], 100-h and 1000-h dead fuel moisture—FM100 and FM1000, respectively) and meteorological variables (vapor pressure deficit [VPD], temperature, relative and specific humidity, and reference evapotranspiration) in the Supplementary Information. ERC indicates the available energy per unit area at the flame front, measuring the dryness of dead and live fuels. ERC is less directly influenced by temperature than other fire danger indices. It is, however, strongly influenced by relative humidity—which is in turn related to temperature—and precipitation. Here, we select a fuel-agnostic measure across western landscapes through a single fuel model (model G) not to conflate heterogeneity in vegetation distribution with heterogeneity in climate trends. We, however, show that general conclusions hold for other fire danger indices that are not dependent on the fuel model. Results Elevation-dependent trends in warm-season ERC All fire danger indices, as well as meteorological variables, showed marked drying/warming trends over the period of 1979–2020 in all 15 mountainous ecoregions of the western US and across all elevation bands (Fig. 1 , Supplementary Figs. S 1 –S 8 ). Temporal trends in warm-season-average (hereafter warm-season; May–September) fire danger indices were computed over 500 m elevation bands in each ecoregion using least squares linear regression (e.g., Fig. 1a ), and linear slope of trends was calculated across elevation bands (e.g., Fig. 1b ). The former indicates temporal trends in fire danger indices in each band, whereas the latter points out whether or not trends are magnified at higher elevations compared to the lower land. Fig. 1: Elevation-dependent trends in fire danger across montane ecoregions in the western US. a Temporal trends in warm-season (May–September) average energy release component", "role": "user" }, { "content": "As wildfire risk rises in the West, wildland firefighters and officials are keeping a closer eye on the high mountains—regions once considered too wet to burn. The growing fire risk in these areas became startling clear in 2020, when Colorado's East Troublesome Fire burned up and over the Continental Divide to become the state's second-largest fire on record. The following year, California's Dixie Fire became the first on record to burn across the Sierra Nevada's crest and start down the other side. We study wildfire behavior as climate scientists and engineers. In a new study published in Nature Communications, we show that fire risk has intensified in every region across the West over the past four decades, but the sharpest upward trends are in the high elevations. High mountain fires can create a cascade of risks for local ecosystems and for millions of people living farther down the mountains. Since cooler, wetter high mountain landscapes rarely burn, vegetation and dead wood can build up, so highland fires tend to be intense and uncontrollable. They can affect everything from water quality and the timing of meltwater that communities and farmers rely on, to erosion that can bring debris and mud flows. Ultimately, they can change the hydrology, ecology and geomorphology of the highlands, with complex feedback loops that can transform mountain landscapes and endanger human safety. Four decades of rising fire risk Historically, higher moisture levels and cooler temperatures created a flammability barrier in the highlands. This enabled fire managers to leave fires that move away from human settlements and up mountains to run their course without interference. Fire would hit the flammability barrier and burn out. However, our findings show that's no longer reliable as the climate warms. We analyzed fire danger trends in different elevation bands of the Western U.S. mountains from 1979 to 2020. Fire danger describes conditions that reflect the potential for a fire to ignite and spread. Over that 42-year period, rising temperatures and drying trends increased the number of critical fire danger days in every region in the U.S. West. But in the highlands, certain environmental processes, such as earlier snowmelt that allowed the earth to heat up and become drier, intensified the fire danger faster than anywhere else. It was particularly stark in high-elevation forests from about 8,200 to 9,800 feet (2,500-3,000 meters) in elevation, just above the elevation of Aspen, Colorado. We found that the high-elevation band had gained on average 63 critical fire danger days a year by 2020 compared with 1979. That included 22 days outside the traditional warm season of May to September. In previous research, we found that high-elevation fires had been advancing upslope in the West at about 25 feet (7.6 meters) per year. Credit: Mohammad Reza Alizadeh, CC BY Cascading risks for humans downstream Mountains are water towers of the world, providing 70% of the runoff that cities across the West rely on. They support millions of people who live downstream. High-elevation fires can have a significant impact on snow accumulation and meltwater, even long after they have burned out. For example, fires remove vegetation cover and tree canopies, which can shorten the amount of time the snowpack stays frozen before melting. Soot from fires also darkens the snow surface, increasing its ability to absorb the Sun's energy, which facilitates melting. Similarly, darkened land surface increases the absorption of solar radiation and heightens soil temperature after fires. The result of these changes can be spring flooding, and less water later in the summer when communities downstream are counting on it. Fire-driven tree loss also removes anchor points for the snowpack, increasing the frequency and severity of avalanches. Frequent fires in high-elevation areas can also have a significant impact on the sediment dynamics of mountain streams. The loss of tree canopy means rainfall hits the ground at a higher velocity, increasing the potential for erosion. This can trigger mudslides and increase the amount of sediment sent downstream, which in turn can affect water quality and aquatic habitats. Erosion linked to runoff after fire damage can also deepen streams to the point that excess water from storms can't spread in high-elevation meadows and recharge the groundwater; instead, they route the water quickly downstream and cause flooding. Hazards for climate-stressed species and ecosystems The highlands generally have long fire return intervals, burning once every several decades if not centuries. Since they don't burn often, their ecosystems aren't as fire-adapted as lower-elevation forests, so they may not recover as efficiently or survive repeated fires. Studies show that more frequent fires could change the type of trees that grow in the highlands or even convert them to shrubs or grasses. Wet mountain areas, with their cooler temperatures and higher precipitation, are often peppered with hot spots of biodiversity and provide refuges to various species from the warming climate. If these areas lose their tree canopies, species with small ranges that depend on cold-water mountain streams can face existential risks as more energy from the Sun heats up stream water in the absence of tree shading. While the risk is rising fastest in the high mountains, most of the West is now at increasing risk of fires. With continuing greenhouse gas emissions fueling global warming, this trend of worsening fire danger is expected to intensify further, straining firefighting resources as crews battle more blazes. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Studies have identified elevation-dependent warming trends, but investigations of such trends in fire danger are absent in the literature. Here, we demonstrate that while there have been widespread increases in fire danger across the mountainous western US from 1979 to 2020, trends were most acute at high-elevation regions above 3000 m. The greatest increase in the number of days conducive to large fires occurred at 2500–3000 m, adding 63 critical fire danger days between 1979 and 2020. This includes 22 critical fire danger days occurring outside the warm season (May–September). Furthermore, our findings indicate increased elevational synchronization of fire danger in western US mountains, which can facilitate increased geographic opportunities for ignitions and fire spread that further complicate fire management operations. We hypothesize that several physical mechanisms underpinned the observed trends, including elevationally disparate impacts of earlier snowmelt, intensified land-atmosphere feedbacks, irrigation, and aerosols, in addition to widespread warming/drying. Introduction Mountains provide a variety of ecosystem services, including supplying about 50% of freshwater globally and an even higher fraction in mountainous arid regions (e.g., 70% of runoff in the western US) 1 , 2 . Orographic temperature and precipitation gradients in montane areas facilitate stratified vegetation belts 3 , which promote local hotspots of biodiversity with a high degree of complexity that are particularly vulnerable to ecosystem changes in response to chronic (e.g., warming) and/or acute (e.g., wildfire) stressors 4 . Even small perturbations in these mountainous areas have large repercussions for hydrological and ecological processes, with cascading effects on downstream human-environmental systems 3 , 5 , 6 , 7 . A growing body of literature points to elevation-dependent trends in meteorological and land surface characteristics in montane regions of the world in response to the underlying warming signal 6 , 7 , 8 . In particular, more rapid warming of surface air temperature has been documented at higher elevations compared to that of lower elevations in many regions globally 7 , 9 . Similarly, trends in land surface temperature 10 , reference evapotranspiration 11 , snow cover and snow water equivalent 12 , 13 , and vegetation greening 14 , 15 have also been documented to vary across elevational gradients. Furthermore, elevation-dependent precipitation trends are observed in some regions, although the sign of such changes and associated mechanisms vary across studies 2 , 16 . Changes in the energy and water balance alter the fire danger level 17 , which is defined as the potential for a fire to ignite, spread and require suppression action. The literature has shown widespread increases in fire danger in many regions globally 18 , 19 , 20 , 21 , but how fire danger trends change across the elevational gradient has not been studied. Recent literature shows that atmospheric warming weakened the high-elevation flammability barrier and enabled the upslope advance of fires 22 , and facilitated high-elevation fires that are unprecedented in modern history 23 . Here we use the fire danger representation in the US National Fire Danger Rating System (NFDRS) 24 to investigate trends in fire danger across elevations. We note that NFDRS fire danger indices were empirically derived based on mathematical models of fire behavior, and they do not fully capture the energy and water balance related to fuels and fire 24 . Previous studies have linked these indices with regional burned area 25 and the growth of individual fires 26 , and they are operationally used by fire management agencies across the US 27 . We evaluated elevation-dependent trends in fire danger indices between 1979 and 2020 across 15 level III Omernik ecoregions of the western US 28 that are mountainous. We augmented this list with a variety of meteorological variables that are commonly used in fire studies 29 , 30 and posed two questions: (1) Are there elevation-dependent trends in fire danger indices across montane regions of the western US? (2) If so, do they culminate in the elevational synchronization of fire danger? We answered these questions using the gridMET dataset of daily meteorological and NFDRS variables (~4 km grid) 31 , Omernik level III ecoregions map from the US Environmental Protection Agency 28 , and the National Elevation Dataset (10 m resolution) from the US Geological Survey. We present the results of the energy release component (ERC, Fuel Model G in NFDRS 77 24 ) in the main paper and all other NFDRS indices (burning index [BI], 100-h and 1000-h dead fuel moisture—FM100 and FM1000, respectively) and meteorological variables (vapor pressure deficit [VPD], temperature, relative and specific humidity, and reference evapotranspiration) in the Supplementary Information. ERC indicates the available energy per unit area at the flame front, measuring the dryness of dead and live fuels. ERC is less directly influenced by temperature than other fire danger indices. It is, however, strongly influenced by relative humidity—which is in turn related to temperature—and precipitation. Here, we select a fuel-agnostic measure across western landscapes through a single fuel model (model G) not to conflate heterogeneity in vegetation distribution with heterogeneity in climate trends. We, however, show that general conclusions hold for other fire danger indices that are not dependent on the fuel model. Results Elevation-dependent trends in warm-season ERC All fire danger indices, as well as meteorological variables, showed marked drying/warming trends over the period of 1979–2020 in all 15 mountainous ecoregions of the western US and across all elevation bands (Fig. 1 , Supplementary Figs. S 1 –S 8 ). Temporal trends in warm-season-average (hereafter warm-season; May–September) fire danger indices were computed over 500 m elevation bands in each ecoregion using least squares linear regression (e.g., Fig. 1a ), and linear slope of trends was calculated across elevation bands (e.g., Fig. 1b ). The former indicates temporal trends in fire danger indices in each band, whereas the latter points out whether or not trends are magnified at higher elevations compared to the lower land. Fig. 1: Elevation-dependent trends in fire danger across montane ecoregions in the western US. a Temporal trends in warm-season (May–September) average energy release component<|im_end|> <|im_start|>assistant As wildfire risk rises in the West, wildland firefighters and officials are keeping a closer eye on the high mountains—regions once considered too wet to burn. The growing fire risk in these areas became startling clear in 2020, when Colorado's East Troublesome Fire burned up and over the Continental Divide to become the state's second-largest fire on record. The following year, California's Dixie Fire became the first on record to burn across the Sierra Nevada's crest and start down the other side. We study wildfire behavior as climate scientists and engineers. In a new study published in Nature Communications, we show that fire risk has intensified in every region across the West over the past four decades, but the sharpest upward trends are in the high elevations. High mountain fires can create a cascade of risks for local ecosystems and for millions of people living farther down the mountains. Since cooler, wetter high mountain landscapes rarely burn, vegetation and dead wood can build up, so highland fires tend to be intense and uncontrollable. They can affect everything from water quality and the timing of meltwater that communities and farmers rely on, to erosion that can bring debris and mud flows. Ultimately, they can change the hydrology, ecology and geomorphology of the highlands, with complex feedback loops that can transform mountain landscapes and endanger human safety. Four decades of rising fire risk Historically, higher moisture levels and cooler temperatures created a flammability barrier in the highlands. This enabled fire managers to leave fires that move away from human settlements and up mountains to run their course without interference. Fire would hit the flammability barrier and burn out. However, our findings show that's no longer reliable as the climate warms. We analyzed fire danger trends in different elevation bands of the Western U.S. mountains from 1979 to 2020. Fire danger describes conditions that reflect the potential for a fire to ignite and spread. Over that 42-year period, rising temperatures and drying trends increased the number of critical fire danger days in every region in the U.S. West. But in the highlands, certain environmental processes, such as earlier snowmelt that allowed the earth to heat up and become drier, intensified the fire danger faster than anywhere else. It was particularly stark in high-elevation forests from about 8,200 to 9,800 feet (2,500-3,000 meters) in elevation, just above the elevation of Aspen, Colorado. We found that the high-elevation band had gained on average 63 critical fire danger days a year by 2020 compared with 1979. That included 22 days outside the traditional warm season of May to September. In previous research, we found that high-elevation fires had been advancing upslope in the West at about 25 feet (7.6 meters) per year. Credit: Mohammad Reza Alizadeh, CC BY Cascading risks for humans downstream Mountains are water towers of the world, providing 70% of the runoff that cities across the West rely on. They support millions of people who live downstream. High-elevation fires can have a significant impact on snow accumulation and meltwater, even long after they have burned out. For example, fires remove vegetation cover and tree canopies, which can shorten the amount of time the snowpack stays frozen before melting. Soot from fires also darkens the snow surface, increasing its ability to absorb the Sun's energy, which facilitates melting. Similarly, darkened land surface increases the absorption of solar radiation and heightens soil temperature after fires. The result of these changes can be spring flooding, and less water later in the summer when communities downstream are counting on it. Fire-driven tree loss also removes anchor points for the snowpack, increasing the frequency and severity of avalanches. Frequent fires in high-elevation areas can also have a significant impact on the sediment dynamics of mountain streams. The loss of tree canopy means rainfall hits the ground at a higher velocity, increasing the potential for erosion. This can trigger mudslides and increase the amount of sediment sent downstream, which in turn can affect water quality and aquatic habitats. Erosion linked to runoff after fire damage can also deepen streams to the point that excess water from storms can't spread in high-elevation meadows and recharge the groundwater; instead, they route the water quickly downstream and cause flooding. Hazards for climate-stressed species and ecosystems The highlands generally have long fire return intervals, burning once every several decades if not centuries. Since they don't burn often, their ecosystems aren't as fire-adapted as lower-elevation forests, so they may not recover as efficiently or survive repeated fires. Studies show that more frequent fires could change the type of trees that grow in the highlands or even convert them to shrubs or grasses. Wet mountain areas, with their cooler temperatures and higher precipitation, are often peppered with hot spots of biodiversity and provide refuges to various species from the warming climate. If these areas lose their tree canopies, species with small ranges that depend on cold-water mountain streams can face existential risks as more energy from the Sun heats up stream water in the absence of tree shading. While the risk is rising fastest in the high mountains, most of the West is now at increasing risk of fires. With continuing greenhouse gas emissions fueling global warming, this trend of worsening fire danger is expected to intensify further, straining firefighting resources as crews battle more blazes. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The mammalian hippocampus is crucial for episodic memory formation 1 and transiently retains information for about 3–4 weeks in adult mice and longer in humans 2 . Although neuroscientists widely believe that neural synapses are elemental sites of information storage 3 , there has been no direct evidence that hippocampal synapses persist for time intervals commensurate with the duration of hippocampal-dependent memory. Here we tested the prediction that the lifetimes of hippocampal synapses match the longevity of hippocampal memory. By using time-lapse two-photon microendoscopy 4 in the CA1 hippocampal area of live mice, we monitored the turnover dynamics of the pyramidal neurons’ basal dendritic spines, postsynaptic structures whose turnover dynamics are thought to reflect those of excitatory synaptic connections 5 , 6 . Strikingly, CA1 spine turnover dynamics differed sharply from those seen previously in the neocortex 7 , 8 , 9 . Mathematical modelling revealed that the data best matched kinetic models with a single population of spines with a mean lifetime of approximately 1–2 weeks. This implies ∼ 100% turnover in ∼ 2–3 times this interval, a near full erasure of the synaptic connectivity pattern. Although N -methyl- d -aspartate (NMDA) receptor blockade stabilizes spines in the neocortex 10 , 11 , in CA1 it transiently increased the rate of spine loss and thus lowered spine density. These results reveal that adult neocortical and hippocampal pyramidal neurons have divergent patterns of spine regulation and quantitatively support the idea that the transience of hippocampal-dependent memory directly reflects the turnover dynamics of hippocampal synapses. Main The hypothesis that synaptic connectivity patterns encode information has profoundly shaped research on long-term memory. In the hippocampus, synapses in basal CA1 mainly receive inputs from hippocampal area CA3, and the CA3 → CA1 projection has been widely studied regarding its plasticity and key role in memory. As in the neocortex, dendritic spines in the hippocampus are good proxies for excitatory synapses 12 , motivating time-lapse imaging of spines as a means of monitoring synaptic turnover 7 , 8 , 9 , 10 . Previous work has illustrated in vivo imaging of CA1 spines in acute and recently also in chronic preparations 13 , 14 , 15 . We tracked spines for up to ∼ 14 weeks by combining microendoscopes of diffraction-limited resolution 14 (0.85 NA), a chronic mouse preparation for time-lapse imaging in deep brain areas 4 , and Thy1-GFP mice that express green fluorescent protein (GFP) in a sparse subset of CA1 pyramidal neurons ( Fig. 1 and Extended Data Fig. 1 ). Histological analyses confirmed that this approach induced minimal activation of glia ( Extended Data Fig. 2 ), as shown previously 4 , 16 . Figure 1: Dendritic spines are dynamic in CA1 hippocampus of the adult mouse. a , A sealed, glass guide tube implanted dorsal to CA1 allows time-lapse in vivo imaging of dendritic spines. b , A doublet microendoscope projects the laser scanning pattern onto the specimen plane in the tissue. Inset: red lines indicate optical ray trajectories. c , CA1 dendritic spines in a live Thy1-GFP mouse. d , Time-lapse image sequences. Arrowheads indicate spines that either persist across the sequence (white arrowheads), disappear midway (red), arise midway and then persist (green), arise midway and then later disappear (yellow), or disappear and then later appear at an indistinguishable location (cyan). Scale bars: 500 μm ( b , inset); 10 μm ( c ); 2 μm ( d ). PowerPoint slide Full size image A major concern was that it is not possible to distinguish two or more spines spaced within the resolution limit of two-photon microscopy. This issue is critical for studies of hippocampal spines, which are more densely packed than neocortical spines 17 . To gauge how commonly the appearances of adjacent spines merged together in optical images, we examined tissue slices from Thy1-GFP mice, using both two-photon microendoscopy and stimulated-emission depletion (STED) microscopy. STED microscopy offered super-resolution ( ∼ 70 nm full width at half maximum (FWHM) lateral resolution), an optical resolution nearly nine times finer than that of two-photon microendoscopy 14 ( ∼ 610 nm), permitting tests comparing pairs of images of the same CA1 dendrites ( Fig. 2a and Extended Data Fig. 3 ). Figure 2: A simple kinetic model is sufficient to describe CA1 pyramidal cell spine dynamics. a , Two-photon microendoscopy and STED imaging of the same dendrites in vitro. Top, two-photon images depict spines closer than the resolution limit as merged entities. Bottom, asterisks mark example visually scored spines, showing cases in which nearby spines do (right) or do not (left) merge. b , Fraction of spines ( n = 151 total) seen by two-photon imaging that were one, two or three spines as determined by STED imaging. Black bars show mean ± s.d. for 12 dendrites. c , Separations between adjacent unmerged spines and pairs of spines that appeared merged by two-photon imaging. Open grey circles mark individual results from each of n = 150 spines. Black bars show mean ± s.d. d , Example computer-simulated, time-lapse image sequence used to quantify how resolution limits impact measured spine densities and dynamics. e , Computational modelling predicts the underestimation of spine density due to the finite optical resolution. Blue diagonal line: perfect detection of all spines. Black horizontal dashed lines: typical ranges of spine densities on pyramidal cells in neocortex and hippocampus. Red data: results from visually scoring simulated images of dendrites of varying spine densities. Black curve: prediction from the scoring model using 600 nm as the minimum separation between two spines correctly distinguished. f , Modelling predicts the overestimation of spine stability due to merging of adjacent spines in resolution-limited images. Blue data: survival fraction values (mean ± s.e.m.) for actual spine turnover in computer simulations (spine density: 2.56 µm −1 ). Red data: apparent turnover for these same simulated dendrites, as scored from simulated two-photon images. Black curves: theoretical predictions for spine survival based on the scoring model. Scale bars: 1 μm ( a ); and", "role": "user" }, { "content": "Our memories are as fleeting as the brain structures that store them, or so the theory goes. When the connections – called synapses – between neurons break, the memories they hold are thought to evaporate along with them. The idea seemed good, but has been hard to test. Now a Stanford team has taken on the challenge, studying a brain region called the hippocampus, which stores \"episodic\" memories. These are the memories of events or conversations that might be forgotten over time if the memories aren't used. The challenge to studying synapses in this region is that the hippocampus is so deep and the connections so densely packed that no microscope could easily monitor the synapses' longevity. Now Mark Schnitzer, an associate professor of biology and of applied physics, has leveraged microscopy tools developed in his lab and for the first time was able to monitor the connections, called synapses, between hippocampal neurons and confirm what neuroscientists thought might be happening. In the mice he and his team studied, the connections between neurons lasted about 30 days, roughly the duration over which episodic memories are believed to stay in the mouse hippocampus. The work was published on June 22 in Nature. \"Just because the community has had a longstanding idea, that doesn't make it right,\" Schnitzer said. Now that the idea has been validated, he said, his technique could open up new areas of memory research: \"It opens the door to the next set of studies, such as memory storage in stress or disease models.\" Mobile memories When mice experience a new episode or learn a new task that requires spatial navigation, the memory is stored for about a month in a structure at the center of the brain called the hippocampus (it is stored slightly longer in people). If mice have hippocampus-disrupting surgery within a month of forming a memory – a memory of meeting a new cage-mate or navigating a maze – that memory is lost. If the disruption occurs after more than a month, then the mouse still retains the memory of a new friend or location of food. That's because the memory had been relocated to a different region of the brain, the neocortex, and is no longer susceptible to disruption in the hippocampus. \"The thought is that memories are gradually moved around the brain,\" said Schnitzer, who is also a member of Stanford Bio-X and the Stanford Neurosciences Institute. \"The neocortex is a long-term repository, whereas considerable evidence indicates that memories stay in the mouse hippocampus only about a month.\" In the past, scientists at Cold Spring Harbor Laboratory in New York and elsewhere had monitored connections between neurons in the neocortex, nearer the brain's surface and therefore visible with little disruption to the brain. They watched not the connections themselves, but the bulbous projections called spines that form connections at their tips. Watching the spines come and go serves as a proxy for knowing when excitatory connections between neurons are created and broken. Those scientists found that about half of the spines in the neocortex were permanent and the rest turned over approximately every five to 15 days. \"The interpretation was that about half the spines in the neocortex are long-term repositories for memories while others retain malleability for new memories or forgetting,\" Schnitzer said. Deep and dense If the same line of thinking held true for the hippocampus as it did for the neocortex, spines in the hipocampus should turn over roughly every 30 days along with the memories they hold. Verifying that idea had been challenging, however, because the hippocampus is deeply buried in the brain and the spines in that region are so densely packed that multiple spines can appear to merge into one. Schnitzer said there were three components to his team's ability to track spines in the hippocampus. The first was a technique he reported in 2011 that allows scientists to stably image a single neuron in a living mouse over long time periods. The next was an optical needle, called a microendoscope, that provides high-resolution images of structures deep within the brain. Even with a stable and high-resolution way of imaging neurons in the hippocampus over time, the team still faced the challenge of distinguishing when spines are gained and lost if they couldn't tell the difference between a single spine and several merged bulges. \"The ability to resolve spines in the hippocampus is right on the hairy edge of our technological capability,\" Schnitzer said. The team overcame that problem with a mathematical model that took into account the limitations of the optical resolution and how that would affect the image datasets depicting the appearances and disappearances of spines. What Schnitzer and his team found in this analysis is that the region of the hippocampus that stores episodic memories contains spines that all turn over every three to six weeks – roughly the duration of episodic memory in mice. Schnitzer said that the work confirmed a long-held idea about how the brain stores memories. Using the same techniques, scientists can now probe additional aspects of how memories are formed, remembered and eventually lost at the level of the individual connections between neurons. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The mammalian hippocampus is crucial for episodic memory formation 1 and transiently retains information for about 3–4 weeks in adult mice and longer in humans 2 . Although neuroscientists widely believe that neural synapses are elemental sites of information storage 3 , there has been no direct evidence that hippocampal synapses persist for time intervals commensurate with the duration of hippocampal-dependent memory. Here we tested the prediction that the lifetimes of hippocampal synapses match the longevity of hippocampal memory. By using time-lapse two-photon microendoscopy 4 in the CA1 hippocampal area of live mice, we monitored the turnover dynamics of the pyramidal neurons’ basal dendritic spines, postsynaptic structures whose turnover dynamics are thought to reflect those of excitatory synaptic connections 5 , 6 . Strikingly, CA1 spine turnover dynamics differed sharply from those seen previously in the neocortex 7 , 8 , 9 . Mathematical modelling revealed that the data best matched kinetic models with a single population of spines with a mean lifetime of approximately 1–2 weeks. This implies ∼ 100% turnover in ∼ 2–3 times this interval, a near full erasure of the synaptic connectivity pattern. Although N -methyl- d -aspartate (NMDA) receptor blockade stabilizes spines in the neocortex 10 , 11 , in CA1 it transiently increased the rate of spine loss and thus lowered spine density. These results reveal that adult neocortical and hippocampal pyramidal neurons have divergent patterns of spine regulation and quantitatively support the idea that the transience of hippocampal-dependent memory directly reflects the turnover dynamics of hippocampal synapses. Main The hypothesis that synaptic connectivity patterns encode information has profoundly shaped research on long-term memory. In the hippocampus, synapses in basal CA1 mainly receive inputs from hippocampal area CA3, and the CA3 → CA1 projection has been widely studied regarding its plasticity and key role in memory. As in the neocortex, dendritic spines in the hippocampus are good proxies for excitatory synapses 12 , motivating time-lapse imaging of spines as a means of monitoring synaptic turnover 7 , 8 , 9 , 10 . Previous work has illustrated in vivo imaging of CA1 spines in acute and recently also in chronic preparations 13 , 14 , 15 . We tracked spines for up to ∼ 14 weeks by combining microendoscopes of diffraction-limited resolution 14 (0.85 NA), a chronic mouse preparation for time-lapse imaging in deep brain areas 4 , and Thy1-GFP mice that express green fluorescent protein (GFP) in a sparse subset of CA1 pyramidal neurons ( Fig. 1 and Extended Data Fig. 1 ). Histological analyses confirmed that this approach induced minimal activation of glia ( Extended Data Fig. 2 ), as shown previously 4 , 16 . Figure 1: Dendritic spines are dynamic in CA1 hippocampus of the adult mouse. a , A sealed, glass guide tube implanted dorsal to CA1 allows time-lapse in vivo imaging of dendritic spines. b , A doublet microendoscope projects the laser scanning pattern onto the specimen plane in the tissue. Inset: red lines indicate optical ray trajectories. c , CA1 dendritic spines in a live Thy1-GFP mouse. d , Time-lapse image sequences. Arrowheads indicate spines that either persist across the sequence (white arrowheads), disappear midway (red), arise midway and then persist (green), arise midway and then later disappear (yellow), or disappear and then later appear at an indistinguishable location (cyan). Scale bars: 500 μm ( b , inset); 10 μm ( c ); 2 μm ( d ). PowerPoint slide Full size image A major concern was that it is not possible to distinguish two or more spines spaced within the resolution limit of two-photon microscopy. This issue is critical for studies of hippocampal spines, which are more densely packed than neocortical spines 17 . To gauge how commonly the appearances of adjacent spines merged together in optical images, we examined tissue slices from Thy1-GFP mice, using both two-photon microendoscopy and stimulated-emission depletion (STED) microscopy. STED microscopy offered super-resolution ( ∼ 70 nm full width at half maximum (FWHM) lateral resolution), an optical resolution nearly nine times finer than that of two-photon microendoscopy 14 ( ∼ 610 nm), permitting tests comparing pairs of images of the same CA1 dendrites ( Fig. 2a and Extended Data Fig. 3 ). Figure 2: A simple kinetic model is sufficient to describe CA1 pyramidal cell spine dynamics. a , Two-photon microendoscopy and STED imaging of the same dendrites in vitro. Top, two-photon images depict spines closer than the resolution limit as merged entities. Bottom, asterisks mark example visually scored spines, showing cases in which nearby spines do (right) or do not (left) merge. b , Fraction of spines ( n = 151 total) seen by two-photon imaging that were one, two or three spines as determined by STED imaging. Black bars show mean ± s.d. for 12 dendrites. c , Separations between adjacent unmerged spines and pairs of spines that appeared merged by two-photon imaging. Open grey circles mark individual results from each of n = 150 spines. Black bars show mean ± s.d. d , Example computer-simulated, time-lapse image sequence used to quantify how resolution limits impact measured spine densities and dynamics. e , Computational modelling predicts the underestimation of spine density due to the finite optical resolution. Blue diagonal line: perfect detection of all spines. Black horizontal dashed lines: typical ranges of spine densities on pyramidal cells in neocortex and hippocampus. Red data: results from visually scoring simulated images of dendrites of varying spine densities. Black curve: prediction from the scoring model using 600 nm as the minimum separation between two spines correctly distinguished. f , Modelling predicts the overestimation of spine stability due to merging of adjacent spines in resolution-limited images. Blue data: survival fraction values (mean ± s.e.m.) for actual spine turnover in computer simulations (spine density: 2.56 µm −1 ). Red data: apparent turnover for these same simulated dendrites, as scored from simulated two-photon images. Black curves: theoretical predictions for spine survival based on the scoring model. Scale bars: 1 μm ( a ); and<|im_end|> <|im_start|>assistant Our memories are as fleeting as the brain structures that store them, or so the theory goes. When the connections – called synapses – between neurons break, the memories they hold are thought to evaporate along with them. The idea seemed good, but has been hard to test. Now a Stanford team has taken on the challenge, studying a brain region called the hippocampus, which stores "episodic" memories. These are the memories of events or conversations that might be forgotten over time if the memories aren't used. The challenge to studying synapses in this region is that the hippocampus is so deep and the connections so densely packed that no microscope could easily monitor the synapses' longevity. Now Mark Schnitzer, an associate professor of biology and of applied physics, has leveraged microscopy tools developed in his lab and for the first time was able to monitor the connections, called synapses, between hippocampal neurons and confirm what neuroscientists thought might be happening. In the mice he and his team studied, the connections between neurons lasted about 30 days, roughly the duration over which episodic memories are believed to stay in the mouse hippocampus. The work was published on June 22 in Nature. "Just because the community has had a longstanding idea, that doesn't make it right," Schnitzer said. Now that the idea has been validated, he said, his technique could open up new areas of memory research: "It opens the door to the next set of studies, such as memory storage in stress or disease models." Mobile memories When mice experience a new episode or learn a new task that requires spatial navigation, the memory is stored for about a month in a structure at the center of the brain called the hippocampus (it is stored slightly longer in people). If mice have hippocampus-disrupting surgery within a month of forming a memory – a memory of meeting a new cage-mate or navigating a maze – that memory is lost. If the disruption occurs after more than a month, then the mouse still retains the memory of a new friend or location of food. That's because the memory had been relocated to a different region of the brain, the neocortex, and is no longer susceptible to disruption in the hippocampus. "The thought is that memories are gradually moved around the brain," said Schnitzer, who is also a member of Stanford Bio-X and the Stanford Neurosciences Institute. "The neocortex is a long-term repository, whereas considerable evidence indicates that memories stay in the mouse hippocampus only about a month." In the past, scientists at Cold Spring Harbor Laboratory in New York and elsewhere had monitored connections between neurons in the neocortex, nearer the brain's surface and therefore visible with little disruption to the brain. They watched not the connections themselves, but the bulbous projections called spines that form connections at their tips. Watching the spines come and go serves as a proxy for knowing when excitatory connections between neurons are created and broken. Those scientists found that about half of the spines in the neocortex were permanent and the rest turned over approximately every five to 15 days. "The interpretation was that about half the spines in the neocortex are long-term repositories for memories while others retain malleability for new memories or forgetting," Schnitzer said. Deep and dense If the same line of thinking held true for the hippocampus as it did for the neocortex, spines in the hipocampus should turn over roughly every 30 days along with the memories they hold. Verifying that idea had been challenging, however, because the hippocampus is deeply buried in the brain and the spines in that region are so densely packed that multiple spines can appear to merge into one. Schnitzer said there were three components to his team's ability to track spines in the hippocampus. The first was a technique he reported in 2011 that allows scientists to stably image a single neuron in a living mouse over long time periods. The next was an optical needle, called a microendoscope, that provides high-resolution images of structures deep within the brain. Even with a stable and high-resolution way of imaging neurons in the hippocampus over time, the team still faced the challenge of distinguishing when spines are gained and lost if they couldn't tell the difference between a single spine and several merged bulges. "The ability to resolve spines in the hippocampus is right on the hairy edge of our technological capability," Schnitzer said. The team overcame that problem with a mathematical model that took into account the limitations of the optical resolution and how that would affect the image datasets depicting the appearances and disappearances of spines. What Schnitzer and his team found in this analysis is that the region of the hippocampus that stores episodic memories contains spines that all turn over every three to six weeks – roughly the duration of episodic memory in mice. Schnitzer said that the work confirmed a long-held idea about how the brain stores memories. Using the same techniques, scientists can now probe additional aspects of how memories are formed, remembered and eventually lost at the level of the individual connections between neurons. <|im_end|>

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13688, 6500, 1355, 318, 7913, 11, 892, 2922, 7629, 2217, 8668, 1511, 311, 76498, 1268, 11175, 13693, 5536, 17303, 35776, 90816, 323, 30295, 13, 384, 1174, 93028, 61966, 56978, 279, 1234, 478, 5582, 315, 35776, 17915, 4245, 311, 279, 35326, 29393, 11175, 13, 8868, 38336, 1584, 25, 4832, 18468, 315, 682, 993, 1572, 13, 5348, 16600, 67822, 5238, 25, 14595, 21986, 315, 35776, 90816, 389, 4611, 2453, 26966, 7917, 304, 841, 511, 45692, 323, 71206, 44651, 13, 3816, 828, 25, 3135, 505, 43395, 20413, 46836, 5448, 315, 90052, 24143, 315, 29865, 35776, 90816, 13, 5348, 16029, 25, 20212, 505, 279, 20413, 1646, 1701, 220, 5067, 26807, 439, 279, 8187, 25768, 1990, 1403, 993, 1572, 12722, 39575, 13, 282, 1174, 5768, 6427, 56978, 279, 927, 478, 5582, 315, 35776, 20334, 4245, 311, 54477, 315, 24894, 993, 1572, 304, 11175, 2922, 32611, 5448, 13, 8868, 828, 25, 20237, 19983, 2819, 320, 14622, 20903, 274, 1770, 749, 6266, 369, 5150, 35776, 48639, 304, 6500, 47590, 320, 2203, 483, 17915, 25, 220, 17, 13, 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374, 1101, 264, 4562, 315, 31788, 24432, 31650, 323, 279, 31788, 32359, 2445, 12242, 10181, 13, 330, 791, 841, 511, 45692, 374, 264, 1317, 9860, 12827, 11, 20444, 24779, 6029, 15151, 430, 19459, 4822, 304, 279, 8814, 71206, 44651, 1193, 922, 264, 2305, 1210, 763, 279, 3347, 11, 14248, 520, 24062, 12531, 40282, 32184, 304, 1561, 4356, 323, 18403, 1047, 41223, 13537, 1990, 34313, 304, 279, 841, 511, 45692, 11, 87920, 279, 8271, 596, 7479, 323, 9093, 9621, 449, 2697, 44219, 311, 279, 8271, 13, 2435, 15746, 539, 279, 13537, 5694, 11, 719, 279, 46912, 788, 41579, 2663, 993, 1572, 430, 1376, 13537, 520, 872, 10631, 13, 69676, 279, 993, 1572, 2586, 323, 733, 17482, 439, 264, 13594, 369, 14392, 994, 25435, 5382, 13537, 1990, 34313, 527, 3549, 323, 11102, 13, 13266, 14248, 1766, 430, 922, 4376, 315, 279, 993, 1572, 304, 279, 841, 511, 45692, 1051, 15690, 323, 279, 2800, 6656, 927, 13489, 1475, 4330, 311, 220, 868, 2919, 13, 330, 791, 23692, 574, 430, 922, 4376, 279, 993, 1572, 304, 279, 841, 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21114, 1071, 430, 279, 990, 11007, 264, 1317, 58606, 4623, 922, 1268, 279, 8271, 10756, 19459, 13, 12362, 279, 1890, 12823, 11, 14248, 649, 1457, 22477, 5217, 13878, 315, 1268, 19459, 527, 14454, 11, 27569, 323, 9778, 5675, 520, 279, 2237, 315, 279, 3927, 13537, 1990, 34313, 13, 220, 128257, 198 ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Microscale and nanoscale mechanical resonators have recently emerged as ubiquitous devices for use in advanced technological applications, for example, in mobile communications and inertial sensors, and as novel tools for fundamental scientific endeavours. Their performance is in many cases limited by the deleterious effects of mechanical damping. In this study, we report a significant advancement towards understanding and controlling support-induced losses in generic mechanical resonators. We begin by introducing an efficient numerical solver, based on the 'phonon-tunnelling' approach, capable of predicting the design-limited damping of high-quality mechanical resonators. Further, through careful device engineering, we isolate support-induced losses and perform a rigorous experimental test of the strong geometric dependence of this loss mechanism. Our results are in excellent agreement with the theory, demonstrating the predictive power of our approach. In combination with recent progress on complementary dissipation mechanisms, our phonon-tunnelling solver represents a major step towards accurate prediction of the mechanical quality factor. Introduction Mechanical coupling of a suspended structure to its supports is a fundamental energy loss mechanism in micromechanical and nanomechanical resonators 1 . Referred to variously as clamping 2 or anchor loss 3 , this process remains significant even in devices fabricated from high-quality materials operated in vacuum and at cryogenic temperatures, and is in fact unavoidable in any non-levitating system. Although much progress has been made towards the understanding of mechanical dissipation at the microscale and nanoscale 2 , 4 , obtaining reliable predictions for the fundamental design-limited quality factor, Q , remains a major challenge while direct experimental tests are scarce 5 , 6 , 7 . At the same time, the implementation of high-quality micromechanical and nanomechanical systems is becoming increasingly important for numerous advanced technological applications in sensing and metrology, with select examples including wireless filters 3 , 8 , on-chip clocks 9 , microscopy 10 , 11 , 12 , 13 and molecular-scale mass sensing 14 , 15 , and recently for a new generation of macroscopic quantum experiments that involve mesoscopic mechanical structures 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 . Here, we introduce a finite-element-enabled numerical solver for calculating the support-induced losses of a broad range of low-loss mechanical resonators. We demonstrate the efficacy of this approach via comparison with experimental results from microfabricated devices engineered to isolate support-induced losses by allowing for a significant variation in geometry, while keeping other resonator characteristics approximately constant. The efficiency of our solver results from the use of a perturbative scheme that exploits the smallness of the contact area, specifically the recently introduced 'phonon-tunnelling' approach 24 . This results in a significant simplification over previous approaches and paves the way for CAD-based predictive design of low-loss mechanical resonators. The origins of mechanical damping in microscale and nanoscale systems have been the subject of numerous studies during the last decades, and several relevant mechanisms for the decay of acoustic mechanical excitations, that is, phonons, have been investigated 2 , 4 . These include: (i) fundamental anharmonic effects such as phonon–phonon interactions 4 , 25 , thermoelastic damping (TED) 4 , 25 , 26 , 27 , 28 and the Akhiezer effect 4 , 25 ; (ii) viscous or fluidic damping involving interactions with the surrounding atmosphere or the compression of thin fluidic layers 29 , 30 , 31 ; (iii) material losses driven by the relaxation of intrinsic or extrinsic defects in the bulk or surface of the resonator 32 , 33 , 34 , 35 , 36 , 37 for which the most commonly studied model is an environment of two-level fluctuators 38 , 39 and (iv) support-induced losses, that is, the dissipation induced by the unavoidable coupling of the resonator to the substrate 3 , 7 , 8 , 40 , 41 , which corresponds to the radiation of elastic waves into the supports 5 , 6 , 24 , 42 , 43 , 44 . This last mechanism poses a fundamental limit, as vibrations of the substrate will always be present. These various dissipation processes add incoherently such that the reciprocals of the corresponding Q -values satisfy 1/ Q tot =∑ i 1/ Q i , where i labels the different mechanisms. Thus, in a realistic setting, care must be taken to isolate the contribution under scrutiny. In contrast to all other damping mechanisms (i–iii), which exhibit various dependencies with external physical variables such as pressure and temperature, support-induced dissipation is a temperature- and scale-independent phenomenon with a strong geometric character that is present in any suspended structure. Moreover, its scale independence implies that the same analysis can be applied to both microscale and nanoscale devices. We exploit this geometric character to isolate the support-induced contribution and obtain a direct experimental test of phonon-tunnelling dissipation. The numerical solver we introduce provides a new technique to efficiently model support-induced losses for a broad class of mechanical structures. Previous approaches have relied on either the direct solution of an elastic wave radiation problem involving the substrate 6 , 7 , 42 , 43 , 44 or the simulation of a perfectly absorbing artificial boundary 5 , 41 , with systematic tests as a function of geometry limited to a few specific cases 5 , 6 , 7 . In contrast, our technique represents a substantial simplification in that it reduces the problem to the calculation of a perfectly decoupled resonator mode together with free elastic wave propagation through the substrate in the absence of the suspended structure. A key feature of our method is to combine a standard finite-element method (FEM) calculation of the resonator mode together with the use of an extended contact at the support. This allows us to treat complex geometries, taking proper account of interference effects between the radiated waves. In summary, we develop and test an efficient method for calculating the clamping loss of high- Q mechanical resonators. Our analysis includes a thorough experimental verification of this theoretical framework by employing resonators that are specifically designed to isolate the clamping-loss", "role": "user" }, { "content": "Austrian and German researchers at the University of Vienna and Technische Universitaet Muenchen have solved a long-standing problem in the design of mechanical resonators: the numerical prediction of the design-limited damping. They report their achievement, which has a broad impact on diverse fields, in the forthcoming issue of Nature Communications. The article describes both a numerical method to calculate the mechanical damping as well as a stringent test of its performance on a set of mechanical microstructures. From the wooden bars in a xylophone or the head of a drum, to the strings and sound box of a guitar or violin, musical instruments are the most familiar examples of mechanical resonators. The actual mechanical vibrations of these instruments create acoustic waves that we hear as sound. The purity of the emitted tone is intimately related to the decay of the vibration amplitude, that is, the mechanical losses of the system. A figure of merit for mechanical losses is the quality factor, simply called \"Q\", which describes the number of oscillations before the amplitude has decayed to a minute fraction of its starting value. The larger Q, the purer the tone and the longer the system will vibrate before the sound damps out. In addition to the aesthetic examples found in a concert hall, mechanical resonators have become increasingly important for a wide variety of advanced technological applications, with such diverse uses as filtering elements in wireless communications systems, timing oscillators for commercial electronics, and cutting-edge research tools which include advanced biological sensors and emerging quantum electro- and optomechanical devices. Rather than producing pleasing acoustics, these applications rely on very \"pure\" vibrations for isolating a desired signal or for monitoring minute frequency shifts in order to probe external stimuli. For many of these applications it is necessary to minimize the mechanical loss. However, it had previously remained a challenge to make numerical predictions of the attainable Q for even relatively straightforward geometries. Researchers from Vienna and Munich have now overcome this hurdle by developing a finite-element-based numerical solver that is capable of predicting the design-limited damping of almost arbitrary mechanical resonators. \"We calculate how elementary mechanical excitations, or phonons, radiate from the mechanical resonator into the supports of the device\", says Garrett Cole, Senior Researcher in the Aspelmeyer group at the University of Vienna. \"This represents a significant breakthrough in the design of such devices.\" The idea goes back to a previous work by Ignacio Wilson-Rae, physicist at the Technische Universitaet Muenchen. In collaboration with the Vienna group the team managed to come up with a numerical solution to compute this radiation in a simple manner that works on any standard PC. The predictive power of the numerical Q-solver removes the guesswork that is currently involved (e.g., trial and error prototype fabrication) in the design of resonant mechanical structures. The researchers point out that their \"Q-solver\" is scale independent and thus can be applied to a wide range of scenarios, from nanoscale devices all the way up to macroscopic systems. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Microscale and nanoscale mechanical resonators have recently emerged as ubiquitous devices for use in advanced technological applications, for example, in mobile communications and inertial sensors, and as novel tools for fundamental scientific endeavours. Their performance is in many cases limited by the deleterious effects of mechanical damping. In this study, we report a significant advancement towards understanding and controlling support-induced losses in generic mechanical resonators. We begin by introducing an efficient numerical solver, based on the 'phonon-tunnelling' approach, capable of predicting the design-limited damping of high-quality mechanical resonators. Further, through careful device engineering, we isolate support-induced losses and perform a rigorous experimental test of the strong geometric dependence of this loss mechanism. Our results are in excellent agreement with the theory, demonstrating the predictive power of our approach. In combination with recent progress on complementary dissipation mechanisms, our phonon-tunnelling solver represents a major step towards accurate prediction of the mechanical quality factor. Introduction Mechanical coupling of a suspended structure to its supports is a fundamental energy loss mechanism in micromechanical and nanomechanical resonators 1 . Referred to variously as clamping 2 or anchor loss 3 , this process remains significant even in devices fabricated from high-quality materials operated in vacuum and at cryogenic temperatures, and is in fact unavoidable in any non-levitating system. Although much progress has been made towards the understanding of mechanical dissipation at the microscale and nanoscale 2 , 4 , obtaining reliable predictions for the fundamental design-limited quality factor, Q , remains a major challenge while direct experimental tests are scarce 5 , 6 , 7 . At the same time, the implementation of high-quality micromechanical and nanomechanical systems is becoming increasingly important for numerous advanced technological applications in sensing and metrology, with select examples including wireless filters 3 , 8 , on-chip clocks 9 , microscopy 10 , 11 , 12 , 13 and molecular-scale mass sensing 14 , 15 , and recently for a new generation of macroscopic quantum experiments that involve mesoscopic mechanical structures 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 . Here, we introduce a finite-element-enabled numerical solver for calculating the support-induced losses of a broad range of low-loss mechanical resonators. We demonstrate the efficacy of this approach via comparison with experimental results from microfabricated devices engineered to isolate support-induced losses by allowing for a significant variation in geometry, while keeping other resonator characteristics approximately constant. The efficiency of our solver results from the use of a perturbative scheme that exploits the smallness of the contact area, specifically the recently introduced 'phonon-tunnelling' approach 24 . This results in a significant simplification over previous approaches and paves the way for CAD-based predictive design of low-loss mechanical resonators. The origins of mechanical damping in microscale and nanoscale systems have been the subject of numerous studies during the last decades, and several relevant mechanisms for the decay of acoustic mechanical excitations, that is, phonons, have been investigated 2 , 4 . These include: (i) fundamental anharmonic effects such as phonon–phonon interactions 4 , 25 , thermoelastic damping (TED) 4 , 25 , 26 , 27 , 28 and the Akhiezer effect 4 , 25 ; (ii) viscous or fluidic damping involving interactions with the surrounding atmosphere or the compression of thin fluidic layers 29 , 30 , 31 ; (iii) material losses driven by the relaxation of intrinsic or extrinsic defects in the bulk or surface of the resonator 32 , 33 , 34 , 35 , 36 , 37 for which the most commonly studied model is an environment of two-level fluctuators 38 , 39 and (iv) support-induced losses, that is, the dissipation induced by the unavoidable coupling of the resonator to the substrate 3 , 7 , 8 , 40 , 41 , which corresponds to the radiation of elastic waves into the supports 5 , 6 , 24 , 42 , 43 , 44 . This last mechanism poses a fundamental limit, as vibrations of the substrate will always be present. These various dissipation processes add incoherently such that the reciprocals of the corresponding Q -values satisfy 1/ Q tot =∑ i 1/ Q i , where i labels the different mechanisms. Thus, in a realistic setting, care must be taken to isolate the contribution under scrutiny. In contrast to all other damping mechanisms (i–iii), which exhibit various dependencies with external physical variables such as pressure and temperature, support-induced dissipation is a temperature- and scale-independent phenomenon with a strong geometric character that is present in any suspended structure. Moreover, its scale independence implies that the same analysis can be applied to both microscale and nanoscale devices. We exploit this geometric character to isolate the support-induced contribution and obtain a direct experimental test of phonon-tunnelling dissipation. The numerical solver we introduce provides a new technique to efficiently model support-induced losses for a broad class of mechanical structures. Previous approaches have relied on either the direct solution of an elastic wave radiation problem involving the substrate 6 , 7 , 42 , 43 , 44 or the simulation of a perfectly absorbing artificial boundary 5 , 41 , with systematic tests as a function of geometry limited to a few specific cases 5 , 6 , 7 . In contrast, our technique represents a substantial simplification in that it reduces the problem to the calculation of a perfectly decoupled resonator mode together with free elastic wave propagation through the substrate in the absence of the suspended structure. A key feature of our method is to combine a standard finite-element method (FEM) calculation of the resonator mode together with the use of an extended contact at the support. This allows us to treat complex geometries, taking proper account of interference effects between the radiated waves. In summary, we develop and test an efficient method for calculating the clamping loss of high- Q mechanical resonators. Our analysis includes a thorough experimental verification of this theoretical framework by employing resonators that are specifically designed to isolate the clamping-loss<|im_end|> <|im_start|>assistant Austrian and German researchers at the University of Vienna and Technische Universitaet Muenchen have solved a long-standing problem in the design of mechanical resonators: the numerical prediction of the design-limited damping. They report their achievement, which has a broad impact on diverse fields, in the forthcoming issue of Nature Communications. The article describes both a numerical method to calculate the mechanical damping as well as a stringent test of its performance on a set of mechanical microstructures. From the wooden bars in a xylophone or the head of a drum, to the strings and sound box of a guitar or violin, musical instruments are the most familiar examples of mechanical resonators. The actual mechanical vibrations of these instruments create acoustic waves that we hear as sound. The purity of the emitted tone is intimately related to the decay of the vibration amplitude, that is, the mechanical losses of the system. A figure of merit for mechanical losses is the quality factor, simply called "Q", which describes the number of oscillations before the amplitude has decayed to a minute fraction of its starting value. The larger Q, the purer the tone and the longer the system will vibrate before the sound damps out. In addition to the aesthetic examples found in a concert hall, mechanical resonators have become increasingly important for a wide variety of advanced technological applications, with such diverse uses as filtering elements in wireless communications systems, timing oscillators for commercial electronics, and cutting-edge research tools which include advanced biological sensors and emerging quantum electro- and optomechanical devices. Rather than producing pleasing acoustics, these applications rely on very "pure" vibrations for isolating a desired signal or for monitoring minute frequency shifts in order to probe external stimuli. For many of these applications it is necessary to minimize the mechanical loss. However, it had previously remained a challenge to make numerical predictions of the attainable Q for even relatively straightforward geometries. Researchers from Vienna and Munich have now overcome this hurdle by developing a finite-element-based numerical solver that is capable of predicting the design-limited damping of almost arbitrary mechanical resonators. "We calculate how elementary mechanical excitations, or phonons, radiate from the mechanical resonator into the supports of the device", says Garrett Cole, Senior Researcher in the Aspelmeyer group at the University of Vienna. "This represents a significant breakthrough in the design of such devices." The idea goes back to a previous work by Ignacio Wilson-Rae, physicist at the Technische Universitaet Muenchen. In collaboration with the Vienna group the team managed to come up with a numerical solution to compute this radiation in a simple manner that works on any standard PC. The predictive power of the numerical Q-solver removes the guesswork that is currently involved (e.g., trial and error prototype fabrication) in the design of resonant mechanical structures. The researchers point out that their "Q-solver" is scale independent and thus can be applied to a wide range of scenarios, from nanoscale devices all the way up to macroscopic systems. <|im_end|>

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1,944

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Two-photon microscopy has enabled high-resolution imaging of neuroactivity at depth within scattering brain tissue. However, its various realizations have not overcome the tradeoffs between speed and spatiotemporal sampling that would be necessary to enable mesoscale volumetric recording of neuroactivity at cellular resolution and speed compatible with resolving calcium transients. Here, we introduce light beads microscopy (LBM), a scalable and spatiotemporally optimal acquisition approach limited only by fluorescence lifetime, where a set of axially separated and temporally distinct foci record the entire axial imaging range near-simultaneously, enabling volumetric recording at 1.41 × 10 8 voxels per second. Using LBM, we demonstrate mesoscopic and volumetric imaging at multiple scales in the mouse cortex, including cellular-resolution recordings within ~3 × 5 × 0.5 mm volumes containing >200,000 neurons at ~5 Hz and recordings of populations of ~1 million neurons within ~5.4 × 6 × 0.5 mm volumes at ~2 Hz, as well as higher speed (9.6 Hz) subcellular-resolution volumetric recordings. LBM provides an opportunity for discovering the neurocomputations underlying cortex-wide encoding and processing of information in the mammalian brain. Main Two-photon microscopy (2pM) 1 , 2 , 3 with genetically encodable calcium indicators (GECIs) 4 , 5 , 6 has emerged as the standard technique for imaging neuronal activity at depth within scattering brain tissue. However, anatomical and functional observations suggest that complex brain functions emerge from highly parallel computation 7 , 8 in which sensory information 9 , 10 and behavioral parameters 11 , 12 are mapped onto brain-wide neuronal populations 13 , 14 , 15 , 16 at scales beyond the fields of view (FOVs) of conventional microscopes (<0.5 mm). Maximizing volumetric FOVs (v-FOVs) toward brain-wide imaging requires both mesoscopic optical access and optimal spatiotemporal sampling, such that information is obtained as fast as possible, each voxel provides information at sufficient signal-to-noise ratio (SNR), and the microscope records only the minimum amount of information necessary to resolve features of interest (for example, cell bodies) in order to devote remaining resources to imaging the largest possible volumes at time scales compatible with calcium imaging. Many 2pM platforms have demonstrated mesoscopic optical performance 17 , 18 , 19 , 20 , 21 , 22 , 23 , however in these systems, spatiotemporal sampling remains suboptimal: the high-repetition-rate lasers typically employed lead to oversampling in the lateral plane and the need for multiple pulses per pixel to improve SNR at low pulse energies. Accordingly, performance is limited to, at most, multiplane rather than volumetric performance, slow frame rates, and low SNR, particularly when imaging at depth. As we have argued previously 24 , 25 , single-pulse-per-voxel acquisition maximizes SNR per unit power delivered to the brain, and additionally, sampling at the minimum lateral density dictated by the application frees up temporal resources toward scaling the v-FOV. Another approach for scaling the v-FOV is using parallel excitation to increase the information rate. Some systems employ laterally 26 or axially 27 , 28 , 29 extended point-spread functions (PSFs) to form projections of the volume such that only two-dimensional scanning is required, whereas others excite multiple sample locations simultaneously, using spatially resolved detection to reconstitute images 30 , 31 . However, these approaches suffer from scattering-mediated crosstalk at depth, and work best for sparsely labeled samples, reducing applicability to imaging large networks. Temporal multiplexing 19 , 23 , 25 , 32 , 33 , 34 can be used to increase information throughput by scanning n copies of a single laser pulse, which are delayed in time and directed toward separate regions of the sample. For beam-to-beam delays exceeding the fluorescence lifetime (~6–7 ns for GCaMP 33 ), fluorescence at the detector can be reassigned to reconstitute the FOV scanned by each beam, resulting in an n -fold increase in data rate. However, multiplexed systems employing typical Ti:Sapphire lasers (~80 MHz repetition rate) are limited to, at most, a roughly twofold increase in data rate 19 , 23 , 32 , 33 , 34 and suffer from the oversampling inefficiencies mentioned above. Lowering laser repetition rates to the few-MHz regime can simultaneously increase the maximum possible degree of multiplexing n and improve sampling efficiency 25 . However, many multiplexing platforms require chains of beam splitters and dedicated optical paths for delaying and steering each beam, resulting in the unfavorable scaling of system complexity with increasing n 10 , 19 , 23 , 25 , 33 , 34 and leaving the majority of the interpulse timing interval unexploited 25 . Recently, multipass temporal multiplexing schemes have been demonstrated, in which beams undergo multiple round trips through a single set of components that tag the light with a specific delay and focal position in the sample corresponding to each pass through the system 35 , 36 . While using a multipass design, it is in principle possible to achieve higher degrees of multiplicity at a reduced optical complexity, but current realizations either exhibit a fundamentally limited potential for an increase in multiplicity 36 or are inconsistent with one-pulse-per-voxel excitation 10 , 35 , 37 . Here we demonstrate LBM: a high-speed optical acquisition technique for mesoscopic and volumetric 2pM. In LBM, the microscope scans a set of axially separated and temporally distinct foci (‘beads’) as opposed to a single focus (Fig. 1a ). The beads record information throughout the entire depth range of the sample (~500 μm) within the deadtime between subsequent pulses of the laser (~200 ns), thus LBM can probe entire volumes within the time it takes to scan a single plane. Furthermore, by using efficient spatial sampling, LBM allows for expansion of v-FOVs to mesoscopic scales while retaining GCaMP-compatible volume rates. Our light beads are formed by a cavity-based multiplexing approach called the many-fold axial multiplexing module (MAxiMuM) that allows for scaling of the multiplicity limited by only the fluorescence lifetime of GCaMP and the interpulse interval of the laser. Crucially, MAxiMuM also allows for flexible control of the relative power and position of each beam. Using MAxiMuM, we demonstrate 30-fold axial multiplexing and a", "role": "user" }, { "content": "Capturing the intricacies of the brain's activity demands resolution, scale, and speed—the ability to visualize millions of neurons with crystal clear resolution as they actively call out from distant corners of the cortex, within a fraction of a second of one another. Now, researchers have developed a microscopy technique that will allow scientists to accomplish this feat, capturing detailed images of activity of a vast number of cells across different depths in the brain at high speed and with unprecedented clarity. Published in Nature Methods, the research demonstrates the power of this innovation, dubbed light beads microscopy, by presenting the first vivid functional movies of the near-simultaneous activity of one million neurons across the mouse brain. \"Understanding the nature of the brain's densely interconnected network requires developing novel imaging techniques that can capture the activity of neurons across vastly separated brain regions at high speed and single-cell resolution,\" says Rockefeller's Alipasha Vaziri. \"Light beads microscopy will allow us to investigate biological questions in a way that had not been possible before.\" A focus on microscopy Whether it's whiskers that seek hazards by flicking to and fro, or hand-eye-coordination that helps a human hit a baseball, animals rely upon the call and response of the sensory, motor, and visual regions of the brain. Cells from far reaches of the cortex coordinate this feat through a web of neuroactivity that weaves distant regions of the brain into interconnected symphonies. Scientists are only now beginning to untangle this web, with the help of cutting-edge microscope technology. The combination of two-photon scanning microscopy and fluorescent tags is the gold standard when it comes to imaging the activity of neurons within less transparent brain tissues, which are prone to scattering light. It involves firing a focused laser pulse at a tagged target. A few nanoseconds after the pulse hits its mark, the tag emits fluorescent light that can be interpreted to give scientists an idea of the level of neuroactivity detected. But two-photon microscopy suffers from a fundamental limitation. Neurobiologists need to record simultaneous interactions between the sensory, motor, and visual regions of the brain, but it is difficult to capture the activity in such a broad swath of the brain without sacrificing resolution or speed. The neuroactivity of one million neurons in the mouse brain, at unprecedented resolution. Credit: Alipasha Vaziri. Designing an ideal microscope for visualizing interactions between far apart brain regions can feel like plugging holes in a sinking ship. In the interests of high resolution, scientists often must sacrifice scale—or zoom out to take in the larger structure, at the cost of resolution. This can be overcome by snapping a series of high-resolution images from distant corners of the brain separately, later stitching them together. But then speed becomes an issue. \"We need to capture many neurons at distant parts of the brain at the same time at high resolution,\" Vaziri says. \"These parameters are almost mutually exclusive.\" An innovative resolution Light beads microscopy offers a creative solution and pushes the limits of imaging speed to what's maximally obtainable – only limited by physical nature of fluorescence itself. This is done by eliminating the \"deadtime\" between sequential laser pulses when no neuroactivity is recorded and at the same time the need for scanning. The technique involves breaking one strong pulse into 30 smaller sub pulses – each at a different strength – that dive into 30 different depths of scattering mouse brain but induce the same amount of fluorescence at each depth. This is accomplished with a cavity of mirrors that staggers the firing of each pulse in time and ensures that they can all reach their target depths via a single microscope focusing lens. With this approach, the only limit to the rate at which samples can be recorded is the time that it takes the fluorescent tags to flare. That means broad swaths of the brain can be recorded within the same time it would take a conventional two-photon microscope to capture a mere smattering of brain cells. Vaziri and colleagues then put light beads microscopy to the test by integrating it into a microscopy platform that allows for optical access to a large brain volume enabling the recording of the activity of more than one million neurons across the entire cortex of the mouse brain for the first time. Because Vaziri's method is an innovation that builds on two photon microscopy, many labs already have or can commercially obtain the technologies necessary to perform light beads microscopy, as described in the paper. Labs that are less familiar with these techniques could benefit from a simplified, self-contained module that Vaziri is currently developing for more widespread use. \"There's no good reason why we didn't do this five years ago,\" he says. \"It would have been possible—the microscope and laser technology existed. No one thought of it.\" Ultimately, the goal is to complement rather than replace current techniques. \"There are neurobiological questions for which the standard two-photon microscope is sufficient,\" Vaziri says. \" But light beads microscopy allows us to address questions that existing methods cannot.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Two-photon microscopy has enabled high-resolution imaging of neuroactivity at depth within scattering brain tissue. However, its various realizations have not overcome the tradeoffs between speed and spatiotemporal sampling that would be necessary to enable mesoscale volumetric recording of neuroactivity at cellular resolution and speed compatible with resolving calcium transients. Here, we introduce light beads microscopy (LBM), a scalable and spatiotemporally optimal acquisition approach limited only by fluorescence lifetime, where a set of axially separated and temporally distinct foci record the entire axial imaging range near-simultaneously, enabling volumetric recording at 1.41 × 10 8 voxels per second. Using LBM, we demonstrate mesoscopic and volumetric imaging at multiple scales in the mouse cortex, including cellular-resolution recordings within ~3 × 5 × 0.5 mm volumes containing >200,000 neurons at ~5 Hz and recordings of populations of ~1 million neurons within ~5.4 × 6 × 0.5 mm volumes at ~2 Hz, as well as higher speed (9.6 Hz) subcellular-resolution volumetric recordings. LBM provides an opportunity for discovering the neurocomputations underlying cortex-wide encoding and processing of information in the mammalian brain. Main Two-photon microscopy (2pM) 1 , 2 , 3 with genetically encodable calcium indicators (GECIs) 4 , 5 , 6 has emerged as the standard technique for imaging neuronal activity at depth within scattering brain tissue. However, anatomical and functional observations suggest that complex brain functions emerge from highly parallel computation 7 , 8 in which sensory information 9 , 10 and behavioral parameters 11 , 12 are mapped onto brain-wide neuronal populations 13 , 14 , 15 , 16 at scales beyond the fields of view (FOVs) of conventional microscopes (<0.5 mm). Maximizing volumetric FOVs (v-FOVs) toward brain-wide imaging requires both mesoscopic optical access and optimal spatiotemporal sampling, such that information is obtained as fast as possible, each voxel provides information at sufficient signal-to-noise ratio (SNR), and the microscope records only the minimum amount of information necessary to resolve features of interest (for example, cell bodies) in order to devote remaining resources to imaging the largest possible volumes at time scales compatible with calcium imaging. Many 2pM platforms have demonstrated mesoscopic optical performance 17 , 18 , 19 , 20 , 21 , 22 , 23 , however in these systems, spatiotemporal sampling remains suboptimal: the high-repetition-rate lasers typically employed lead to oversampling in the lateral plane and the need for multiple pulses per pixel to improve SNR at low pulse energies. Accordingly, performance is limited to, at most, multiplane rather than volumetric performance, slow frame rates, and low SNR, particularly when imaging at depth. As we have argued previously 24 , 25 , single-pulse-per-voxel acquisition maximizes SNR per unit power delivered to the brain, and additionally, sampling at the minimum lateral density dictated by the application frees up temporal resources toward scaling the v-FOV. Another approach for scaling the v-FOV is using parallel excitation to increase the information rate. Some systems employ laterally 26 or axially 27 , 28 , 29 extended point-spread functions (PSFs) to form projections of the volume such that only two-dimensional scanning is required, whereas others excite multiple sample locations simultaneously, using spatially resolved detection to reconstitute images 30 , 31 . However, these approaches suffer from scattering-mediated crosstalk at depth, and work best for sparsely labeled samples, reducing applicability to imaging large networks. Temporal multiplexing 19 , 23 , 25 , 32 , 33 , 34 can be used to increase information throughput by scanning n copies of a single laser pulse, which are delayed in time and directed toward separate regions of the sample. For beam-to-beam delays exceeding the fluorescence lifetime (~6–7 ns for GCaMP 33 ), fluorescence at the detector can be reassigned to reconstitute the FOV scanned by each beam, resulting in an n -fold increase in data rate. However, multiplexed systems employing typical Ti:Sapphire lasers (~80 MHz repetition rate) are limited to, at most, a roughly twofold increase in data rate 19 , 23 , 32 , 33 , 34 and suffer from the oversampling inefficiencies mentioned above. Lowering laser repetition rates to the few-MHz regime can simultaneously increase the maximum possible degree of multiplexing n and improve sampling efficiency 25 . However, many multiplexing platforms require chains of beam splitters and dedicated optical paths for delaying and steering each beam, resulting in the unfavorable scaling of system complexity with increasing n 10 , 19 , 23 , 25 , 33 , 34 and leaving the majority of the interpulse timing interval unexploited 25 . Recently, multipass temporal multiplexing schemes have been demonstrated, in which beams undergo multiple round trips through a single set of components that tag the light with a specific delay and focal position in the sample corresponding to each pass through the system 35 , 36 . While using a multipass design, it is in principle possible to achieve higher degrees of multiplicity at a reduced optical complexity, but current realizations either exhibit a fundamentally limited potential for an increase in multiplicity 36 or are inconsistent with one-pulse-per-voxel excitation 10 , 35 , 37 . Here we demonstrate LBM: a high-speed optical acquisition technique for mesoscopic and volumetric 2pM. In LBM, the microscope scans a set of axially separated and temporally distinct foci (‘beads’) as opposed to a single focus (Fig. 1a ). The beads record information throughout the entire depth range of the sample (~500 μm) within the deadtime between subsequent pulses of the laser (~200 ns), thus LBM can probe entire volumes within the time it takes to scan a single plane. Furthermore, by using efficient spatial sampling, LBM allows for expansion of v-FOVs to mesoscopic scales while retaining GCaMP-compatible volume rates. Our light beads are formed by a cavity-based multiplexing approach called the many-fold axial multiplexing module (MAxiMuM) that allows for scaling of the multiplicity limited by only the fluorescence lifetime of GCaMP and the interpulse interval of the laser. Crucially, MAxiMuM also allows for flexible control of the relative power and position of each beam. Using MAxiMuM, we demonstrate 30-fold axial multiplexing and a<|im_end|> <|im_start|>assistant Capturing the intricacies of the brain's activity demands resolution, scale, and speed—the ability to visualize millions of neurons with crystal clear resolution as they actively call out from distant corners of the cortex, within a fraction of a second of one another. Now, researchers have developed a microscopy technique that will allow scientists to accomplish this feat, capturing detailed images of activity of a vast number of cells across different depths in the brain at high speed and with unprecedented clarity. Published in Nature Methods, the research demonstrates the power of this innovation, dubbed light beads microscopy, by presenting the first vivid functional movies of the near-simultaneous activity of one million neurons across the mouse brain. "Understanding the nature of the brain's densely interconnected network requires developing novel imaging techniques that can capture the activity of neurons across vastly separated brain regions at high speed and single-cell resolution," says Rockefeller's Alipasha Vaziri. "Light beads microscopy will allow us to investigate biological questions in a way that had not been possible before." A focus on microscopy Whether it's whiskers that seek hazards by flicking to and fro, or hand-eye-coordination that helps a human hit a baseball, animals rely upon the call and response of the sensory, motor, and visual regions of the brain. Cells from far reaches of the cortex coordinate this feat through a web of neuroactivity that weaves distant regions of the brain into interconnected symphonies. Scientists are only now beginning to untangle this web, with the help of cutting-edge microscope technology. The combination of two-photon scanning microscopy and fluorescent tags is the gold standard when it comes to imaging the activity of neurons within less transparent brain tissues, which are prone to scattering light. It involves firing a focused laser pulse at a tagged target. A few nanoseconds after the pulse hits its mark, the tag emits fluorescent light that can be interpreted to give scientists an idea of the level of neuroactivity detected. But two-photon microscopy suffers from a fundamental limitation. Neurobiologists need to record simultaneous interactions between the sensory, motor, and visual regions of the brain, but it is difficult to capture the activity in such a broad swath of the brain without sacrificing resolution or speed. The neuroactivity of one million neurons in the mouse brain, at unprecedented resolution. Credit: Alipasha Vaziri. Designing an ideal microscope for visualizing interactions between far apart brain regions can feel like plugging holes in a sinking ship. In the interests of high resolution, scientists often must sacrifice scale—or zoom out to take in the larger structure, at the cost of resolution. This can be overcome by snapping a series of high-resolution images from distant corners of the brain separately, later stitching them together. But then speed becomes an issue. "We need to capture many neurons at distant parts of the brain at the same time at high resolution," Vaziri says. "These parameters are almost mutually exclusive." An innovative resolution Light beads microscopy offers a creative solution and pushes the limits of imaging speed to what's maximally obtainable – only limited by physical nature of fluorescence itself. This is done by eliminating the "deadtime" between sequential laser pulses when no neuroactivity is recorded and at the same time the need for scanning. The technique involves breaking one strong pulse into 30 smaller sub pulses – each at a different strength – that dive into 30 different depths of scattering mouse brain but induce the same amount of fluorescence at each depth. This is accomplished with a cavity of mirrors that staggers the firing of each pulse in time and ensures that they can all reach their target depths via a single microscope focusing lens. With this approach, the only limit to the rate at which samples can be recorded is the time that it takes the fluorescent tags to flare. That means broad swaths of the brain can be recorded within the same time it would take a conventional two-photon microscope to capture a mere smattering of brain cells. Vaziri and colleagues then put light beads microscopy to the test by integrating it into a microscopy platform that allows for optical access to a large brain volume enabling the recording of the activity of more than one million neurons across the entire cortex of the mouse brain for the first time. Because Vaziri's method is an innovation that builds on two photon microscopy, many labs already have or can commercially obtain the technologies necessary to perform light beads microscopy, as described in the paper. Labs that are less familiar with these techniques could benefit from a simplified, self-contained module that Vaziri is currently developing for more widespread use. "There's no good reason why we didn't do this five years ago," he says. "It would have been possible—the microscope and laser technology existed. No one thought of it." Ultimately, the goal is to complement rather than replace current techniques. "There are neurobiological questions for which the standard two-photon microscope is sufficient," Vaziri says. " But light beads microscopy allows us to address questions that existing methods cannot." <|im_end|>

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315, 279, 21120, 13, 76104, 34575, 11, 9917, 11927, 40220, 44, 1101, 6276, 369, 19303, 2585, 315, 279, 8844, 2410, 323, 2361, 315, 1855, 24310, 13, 12362, 9917, 11927, 40220, 44, 11, 584, 20461, 220, 966, 24325, 98280, 12842, 2635, 287, 323, 264, 128257, 198, 128256, 78191, 198, 41636, 1711, 279, 94603, 27121, 315, 279, 8271, 596, 5820, 18651, 11175, 11, 5569, 11, 323, 4732, 22416, 5845, 311, 51187, 11990, 315, 34313, 449, 26110, 2867, 11175, 439, 814, 22815, 1650, 704, 505, 29827, 24359, 315, 279, 49370, 11, 2949, 264, 19983, 315, 264, 2132, 315, 832, 2500, 13, 4800, 11, 12074, 617, 8040, 264, 92914, 15105, 430, 690, 2187, 14248, 311, 22829, 420, 12627, 11, 40880, 11944, 5448, 315, 5820, 315, 264, 13057, 1396, 315, 7917, 4028, 2204, 43957, 304, 279, 8271, 520, 1579, 4732, 323, 449, 31069, 32373, 13, 30114, 304, 22037, 19331, 11, 279, 3495, 32216, 279, 2410, 315, 420, 19297, 11, 42160, 3177, 55308, 92914, 11, 555, 32644, 279, 1176, 43120, 16003, 9698, 315, 279, 3221, 1355, 318, 495, 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449, 279, 1520, 315, 14713, 48448, 73757, 5557, 13, 578, 10824, 315, 1403, 63837, 26934, 36201, 92914, 323, 74864, 9681, 374, 279, 6761, 5410, 994, 433, 4131, 311, 32758, 279, 5820, 315, 34313, 2949, 2753, 18300, 8271, 39881, 11, 902, 527, 38097, 311, 72916, 3177, 13, 1102, 18065, 23677, 264, 10968, 21120, 28334, 520, 264, 38213, 2218, 13, 362, 2478, 20622, 76989, 1306, 279, 28334, 13280, 1202, 1906, 11, 279, 4877, 73880, 74864, 3177, 430, 649, 387, 33398, 311, 3041, 14248, 459, 4623, 315, 279, 2237, 315, 18247, 7323, 16914, 13, 2030, 1403, 63837, 26934, 92914, 47521, 505, 264, 16188, 20893, 13, 32359, 8385, 22012, 1205, 311, 3335, 58632, 22639, 1990, 279, 49069, 11, 9048, 11, 323, 9302, 13918, 315, 279, 8271, 11, 719, 433, 374, 5107, 311, 12602, 279, 5820, 304, 1778, 264, 7353, 93512, 315, 279, 8271, 2085, 73128, 11175, 477, 4732, 13, 578, 18247, 7323, 315, 832, 3610, 34313, 304, 279, 8814, 8271, 11, 520, 31069, 11175, 13, 16666, 25, 1708, 575, 31543, 650, 1394, 21336, 13, 7127, 287, 459, 10728, 73757, 369, 9302, 4954, 22639, 1990, 3117, 10980, 8271, 13918, 649, 2733, 1093, 628, 36368, 20349, 304, 264, 62193, 8448, 13, 763, 279, 12034, 315, 1579, 11175, 11, 14248, 3629, 2011, 28235, 5569, 51749, 15932, 704, 311, 1935, 304, 279, 8294, 6070, 11, 520, 279, 2853, 315, 11175, 13, 1115, 649, 387, 23075, 555, 80889, 264, 4101, 315, 1579, 64036, 5448, 505, 29827, 24359, 315, 279, 8271, 26214, 11, 3010, 80231, 1124, 3871, 13, 2030, 1243, 4732, 9221, 459, 4360, 13, 330, 1687, 1205, 311, 12602, 1690, 34313, 520, 29827, 5596, 315, 279, 8271, 520, 279, 1890, 892, 520, 1579, 11175, 1359, 650, 1394, 21336, 2795, 13, 330, 9673, 5137, 527, 4661, 53579, 14079, 1210, 1556, 18699, 11175, 8828, 55308, 92914, 6209, 264, 11782, 6425, 323, 41802, 279, 13693, 315, 32758, 4732, 311, 1148, 596, 31127, 750, 6994, 481, 1389, 1193, 7347, 555, 7106, 7138, 315, 97332, 5196, 13, 1115, 374, 2884, 555, 40599, 279, 330, 34854, 1712, 1, 1990, 52100, 21120, 66557, 994, 912, 18247, 7323, 374, 12715, 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3177, 55308, 92914, 6276, 603, 311, 2686, 4860, 430, 6484, 5528, 4250, 1210, 220, 128257, 198 ]

2,438

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Regulated cell death is an integral part of life, and has broad effects on organism development and homeostasis 1 . Malfunctions within the regulated cell death process, including the clearance of dying cells, can manifest in diverse pathologies throughout various tissues including the gastrointestinal tract 2 . A long appreciated, yet elusively defined relationship exists between cell death and gastrointestinal pathologies with an underlying microbial component 3 , 4 , 5 , 6 , but the direct effect of dying mammalian cells on bacterial growth is unclear. Here we advance a concept that several Enterobacteriaceae, including patient-derived clinical isolates, have an efficient growth strategy to exploit soluble factors that are released from dying gut epithelial cells. Mammalian nutrients released after caspase-3/7-dependent apoptosis boosts the growth of multiple Enterobacteriaceae and is observed using primary mouse colonic tissue, mouse and human cell lines, several apoptotic triggers, and in conventional as well as germ-free mice in vivo. The mammalian cell death nutrients induce a core transcriptional response in pathogenic Salmonella , and we identify the pyruvate formate-lyase-encoding pflB gene as a key driver of bacterial colonization in three contexts: a foodborne infection model, a TNF- and A20-dependent cell death model, and a chemotherapy-induced mucositis model. These findings introduce a new layer to the complex host–pathogen interaction, in which death-induced nutrient release acts as a source of fuel for intestinal bacteria, with implications for gut inflammation and cytotoxic chemotherapy treatment. Main Apoptosis is the primary form of regulated cell death during development and homeostasis 7 , although pyroptosis and necroptosis have important roles in various disease contexts 8 , 9 . A fascinating, yet loosely defined, relationship exists between gastrointestinal pathologies, mammalian cell death and enteric bacteria 3 , 4 , 6 . Many foodborne bacterial pathogens, including the non-typhoidal serovars of Salmonella enterica ( Salmonella ), directly or indirectly induce mammalian cell death 5 . In addition, patients with inflammatory bowel disease (IBD) have increased levels of apoptosis 10 and ‘dysbiotic’ enrichment of Enterobacteriaceae 11 . Furthermore, chemotherapeutic agents cause gastrointestinal mucositis 12 that increases the risk of developing infections 13 . Although a clear relationship exists between increases in Proteobacteria (including Enterobacteriaceae) and diseases such as IBD and intestinal cancers 14 , a direct link between dying mammalian cells and bacterial outgrowth remains unexplored. Notably, dying mammalian cells release soluble factors that act as signals between mammalian cells 15 . Given the close relationship between mammalian cell death and bacteria-centric pathologies, we tested whether mammalian intercellular signalling molecules released from apoptotic cells might provide direct fuel for bacterial growth. Apoptosis promotes bacterial growth We established primary colonocyte culture explants and induced cell death via treatment with staurosporine or doxorubicin (Fig. 1a ). Cultured explants maintained general architecture and underwent apoptotic cell death after treatment with staurosporine (Fig. 1a , Extended Data Fig. 1a–d ). Apoptotic supernatants collected from these explants significantly enhanced Salmonella growth (Fig. 1b ). Notably, increased Salmonella growth after exposure to apoptotic supernatants compared with fresh medium suggests that dying cells actively ‘secrete’ caspase-dependent growth-promoting factors into the medium (Fig. 1b ). The heterogeneous explant system contained non-epithelial cells, including CD45 + myeloid cells; however, the total CD45 + fraction as well as the dying (CD45 + TUNEL + ) populations did not increase after staurosporine treatment (Extended Data Fig. 1b ). Fig. 1: Regulated mammalian cell death enhances bacterial growth. a , Schematic of ex vivo approach and cleaved caspase 3 images from n = 3 independent experiments. KD, kinase dead; KO, knockout. Scale bar, 200 μm. b , Colony forming units (CFU) of Salmonella in fresh medium ( n = 7), live supernatants ( n = 5) or staurosporine (Stauro)-treated supernatants ( n = 5). Explants were treated with the pan-caspase inhibitor quinoline-Val-Asp-difluorophenoxymethylketone (QVD) ( n = 8), staurosporine ( n = 11), or QVD and staurosporine ( n = 8). c , Salmonella CFU in supernatants of Vil-cre +/− Casp3/7 fl/fl explants ( n = 7 live, n = 8 stauro). d , Salmonella CFU in supernatants of Vil-cre +/− Casp3/7 fl/fl ( n = 7) or Casp3/7 fl/fl control (Ctrl) ( n = 6) explants. Middle, n = 10 medium, n = 12 control, n = 7 RIPK1 KD, n = 4 Mlkl −/− . Right, gasderminD (GasD) knockout ( n = 6), Casp1/11 −/− ( n = 7), control ( n = 9). e , Left, Salmonella CFU ( n = 9 medium, apop. + QVD; n = 10 live, apop. (FADD)). Middle, bacterial CFU ( n = 4). Right, bacterial CFU ( n = 4). Box and whiskers ( b – e ) show minimum to maximum values with all independent replicates, centre denotes median, and the bounds denote the 25th to 75th percentiles. NS, not significant ( P > 0.05). * P ≤ 0.05, ** P ≤ 0.005, *** P ≤ 0.0005, one-way ANOVA with Tukey’s multiple comparisons test ( b , d (middle and right), e (left)), unpaired two-tailed Student’s t -test ( c , d (left)), multiple two-tailed Student’s t -tests ( e (middle and right). Source data . Full size image To more directly test epithelial cell apoptosis, we used colonic explants from Vil-cre +/− Casp3/7 fl/fl mice ( Vil is also known as Vil1 ), in which executioner caspase-3 and caspase-7 are both deleted specifically in epithelial cells via the Vil-cre construct 16 . In contrast to control mice, staurosporine-treated Vil-cre +/− Casp3/7 fl/fl colonocytes were unable to enhance Salmonella growth (Fig. 1c ). Doxorubicin treatment also induced apoptosis, and these supernatants enhanced Salmonella outgrowth despite the direct antimicrobial action of doxorubicin (Extended Data Fig. 1e–g ). As recent studies have highlighted the interconnectivity of different regulated cell death pathways 17 , we also tested mice that lack specific components of lytic cell death pathways. Doxorubicin-treated colonic explants from mice defective for necroptotic or pyroptotic cell death did not restrict Salmonella growth (Fig. 1d ), which demonstrates the necessity and specificity for caspase-dependent intestinal epithelial cell apoptosis", "role": "user" }, { "content": "As part of a trans-Atlantic collaboration, researchers from the team of Kodi Ravichandran (VIB-UGent Center for Inflammation Research) and the University of Virginia School of Medicine (Charlottesville, Virginia, U.S.) have discovered how intestinal bacteria can exploit nutrients that are released from dying cells as fuel to establish intestinal infections. Researchers have long been investigating two seemingly distinct fields of study: how certain bacteria colonize our intestinal tracts, and how our own cells die. But do those processes interact? Kodi Ravichandran (VIB-UGent Center for Inflammation Research), says: \"We have known for a few decades that the cell death process itself can indirectly influence bacterial infections by changing the body's immune response. At the same time, we have also been studying how dying cells can communicate with their neighbors. What CJ (CJ Anderson, postdoctoral fellow) set out to ask was: if these dying cells are secreting factors that can be recognized and sensed by healthy neighboring cells, what is to stop other organisms like intestinal bacteria from recognizing these same molecules?\" Using cell culture and healthy mouse tissue systems, the authors discovered that certain molecules are actively produced and shed by intestinal epithelial cells when they start to die. Interestingly, these molecules are directly sensed and used by intestinal bacteria such as Salmonella and E. coli. The researchers showed that this relationship between dying cells and gut bacteria, which they term death-induced nutrient release (DINNR), takes place in several disease contexts. Intestinal bacteria can use cell death-related molecules to assist in colonization during food poisoning, inflammatory conditions (resembling Inflammatory Bowel Disease (IBD) or Crohn's Disease), and chemotherapy-induced mucositis. Gastrointestinal toxicity is one of the leading side effects in cancer patients undergoing chemotherapy, and it can necessitate dose alterations that can reduce efficacy. Additionally, cancer patients receiving chemotherapy have a significantly greater risk of developing subsequent infections. \"This relationship between chemotherapy and bacterial infections was particularly interesting to us,\" says Anderson. \"Unlike foodborne infections or flareups of IBD or Crohn's Disease where a patient does not know when he or she will be 'under attack,\" physicians know exactly when they are administering chemotherapeutic drugs to cancer patients. This means we have a therapeutic window where we can try to develop some sort of combination therapy to limit some of this fuel for bacteria.\" The researchers also revealed that restricting the release of certain nutrients from dying cells, without having to stop the cell death process itself, was able to protect animals from infection. According to Anderson, this could have major implications for developing future therapeutics. \"What was exciting to us was that we do not need to cheat death itself to still see some protection. We do not need to go searching for the Holy Grail. If we can change or restrict some of these nutrients that are released during death, we can try to improve patient care. As with any piece of fundamental research, there is more work to be done, but the opportunity is there for future therapies.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Regulated cell death is an integral part of life, and has broad effects on organism development and homeostasis 1 . Malfunctions within the regulated cell death process, including the clearance of dying cells, can manifest in diverse pathologies throughout various tissues including the gastrointestinal tract 2 . A long appreciated, yet elusively defined relationship exists between cell death and gastrointestinal pathologies with an underlying microbial component 3 , 4 , 5 , 6 , but the direct effect of dying mammalian cells on bacterial growth is unclear. Here we advance a concept that several Enterobacteriaceae, including patient-derived clinical isolates, have an efficient growth strategy to exploit soluble factors that are released from dying gut epithelial cells. Mammalian nutrients released after caspase-3/7-dependent apoptosis boosts the growth of multiple Enterobacteriaceae and is observed using primary mouse colonic tissue, mouse and human cell lines, several apoptotic triggers, and in conventional as well as germ-free mice in vivo. The mammalian cell death nutrients induce a core transcriptional response in pathogenic Salmonella , and we identify the pyruvate formate-lyase-encoding pflB gene as a key driver of bacterial colonization in three contexts: a foodborne infection model, a TNF- and A20-dependent cell death model, and a chemotherapy-induced mucositis model. These findings introduce a new layer to the complex host–pathogen interaction, in which death-induced nutrient release acts as a source of fuel for intestinal bacteria, with implications for gut inflammation and cytotoxic chemotherapy treatment. Main Apoptosis is the primary form of regulated cell death during development and homeostasis 7 , although pyroptosis and necroptosis have important roles in various disease contexts 8 , 9 . A fascinating, yet loosely defined, relationship exists between gastrointestinal pathologies, mammalian cell death and enteric bacteria 3 , 4 , 6 . Many foodborne bacterial pathogens, including the non-typhoidal serovars of Salmonella enterica ( Salmonella ), directly or indirectly induce mammalian cell death 5 . In addition, patients with inflammatory bowel disease (IBD) have increased levels of apoptosis 10 and ‘dysbiotic’ enrichment of Enterobacteriaceae 11 . Furthermore, chemotherapeutic agents cause gastrointestinal mucositis 12 that increases the risk of developing infections 13 . Although a clear relationship exists between increases in Proteobacteria (including Enterobacteriaceae) and diseases such as IBD and intestinal cancers 14 , a direct link between dying mammalian cells and bacterial outgrowth remains unexplored. Notably, dying mammalian cells release soluble factors that act as signals between mammalian cells 15 . Given the close relationship between mammalian cell death and bacteria-centric pathologies, we tested whether mammalian intercellular signalling molecules released from apoptotic cells might provide direct fuel for bacterial growth. Apoptosis promotes bacterial growth We established primary colonocyte culture explants and induced cell death via treatment with staurosporine or doxorubicin (Fig. 1a ). Cultured explants maintained general architecture and underwent apoptotic cell death after treatment with staurosporine (Fig. 1a , Extended Data Fig. 1a–d ). Apoptotic supernatants collected from these explants significantly enhanced Salmonella growth (Fig. 1b ). Notably, increased Salmonella growth after exposure to apoptotic supernatants compared with fresh medium suggests that dying cells actively ‘secrete’ caspase-dependent growth-promoting factors into the medium (Fig. 1b ). The heterogeneous explant system contained non-epithelial cells, including CD45 + myeloid cells; however, the total CD45 + fraction as well as the dying (CD45 + TUNEL + ) populations did not increase after staurosporine treatment (Extended Data Fig. 1b ). Fig. 1: Regulated mammalian cell death enhances bacterial growth. a , Schematic of ex vivo approach and cleaved caspase 3 images from n = 3 independent experiments. KD, kinase dead; KO, knockout. Scale bar, 200 μm. b , Colony forming units (CFU) of Salmonella in fresh medium ( n = 7), live supernatants ( n = 5) or staurosporine (Stauro)-treated supernatants ( n = 5). Explants were treated with the pan-caspase inhibitor quinoline-Val-Asp-difluorophenoxymethylketone (QVD) ( n = 8), staurosporine ( n = 11), or QVD and staurosporine ( n = 8). c , Salmonella CFU in supernatants of Vil-cre +/− Casp3/7 fl/fl explants ( n = 7 live, n = 8 stauro). d , Salmonella CFU in supernatants of Vil-cre +/− Casp3/7 fl/fl ( n = 7) or Casp3/7 fl/fl control (Ctrl) ( n = 6) explants. Middle, n = 10 medium, n = 12 control, n = 7 RIPK1 KD, n = 4 Mlkl −/− . Right, gasderminD (GasD) knockout ( n = 6), Casp1/11 −/− ( n = 7), control ( n = 9). e , Left, Salmonella CFU ( n = 9 medium, apop. + QVD; n = 10 live, apop. (FADD)). Middle, bacterial CFU ( n = 4). Right, bacterial CFU ( n = 4). Box and whiskers ( b – e ) show minimum to maximum values with all independent replicates, centre denotes median, and the bounds denote the 25th to 75th percentiles. NS, not significant ( P > 0.05). * P ≤ 0.05, ** P ≤ 0.005, *** P ≤ 0.0005, one-way ANOVA with Tukey’s multiple comparisons test ( b , d (middle and right), e (left)), unpaired two-tailed Student’s t -test ( c , d (left)), multiple two-tailed Student’s t -tests ( e (middle and right). Source data . Full size image To more directly test epithelial cell apoptosis, we used colonic explants from Vil-cre +/− Casp3/7 fl/fl mice ( Vil is also known as Vil1 ), in which executioner caspase-3 and caspase-7 are both deleted specifically in epithelial cells via the Vil-cre construct 16 . In contrast to control mice, staurosporine-treated Vil-cre +/− Casp3/7 fl/fl colonocytes were unable to enhance Salmonella growth (Fig. 1c ). Doxorubicin treatment also induced apoptosis, and these supernatants enhanced Salmonella outgrowth despite the direct antimicrobial action of doxorubicin (Extended Data Fig. 1e–g ). As recent studies have highlighted the interconnectivity of different regulated cell death pathways 17 , we also tested mice that lack specific components of lytic cell death pathways. Doxorubicin-treated colonic explants from mice defective for necroptotic or pyroptotic cell death did not restrict Salmonella growth (Fig. 1d ), which demonstrates the necessity and specificity for caspase-dependent intestinal epithelial cell apoptosis<|im_end|> <|im_start|>assistant As part of a trans-Atlantic collaboration, researchers from the team of Kodi Ravichandran (VIB-UGent Center for Inflammation Research) and the University of Virginia School of Medicine (Charlottesville, Virginia, U.S.) have discovered how intestinal bacteria can exploit nutrients that are released from dying cells as fuel to establish intestinal infections. Researchers have long been investigating two seemingly distinct fields of study: how certain bacteria colonize our intestinal tracts, and how our own cells die. But do those processes interact? Kodi Ravichandran (VIB-UGent Center for Inflammation Research), says: "We have known for a few decades that the cell death process itself can indirectly influence bacterial infections by changing the body's immune response. At the same time, we have also been studying how dying cells can communicate with their neighbors. What CJ (CJ Anderson, postdoctoral fellow) set out to ask was: if these dying cells are secreting factors that can be recognized and sensed by healthy neighboring cells, what is to stop other organisms like intestinal bacteria from recognizing these same molecules?" Using cell culture and healthy mouse tissue systems, the authors discovered that certain molecules are actively produced and shed by intestinal epithelial cells when they start to die. Interestingly, these molecules are directly sensed and used by intestinal bacteria such as Salmonella and E. coli. The researchers showed that this relationship between dying cells and gut bacteria, which they term death-induced nutrient release (DINNR), takes place in several disease contexts. Intestinal bacteria can use cell death-related molecules to assist in colonization during food poisoning, inflammatory conditions (resembling Inflammatory Bowel Disease (IBD) or Crohn's Disease), and chemotherapy-induced mucositis. Gastrointestinal toxicity is one of the leading side effects in cancer patients undergoing chemotherapy, and it can necessitate dose alterations that can reduce efficacy. Additionally, cancer patients receiving chemotherapy have a significantly greater risk of developing subsequent infections. "This relationship between chemotherapy and bacterial infections was particularly interesting to us," says Anderson. "Unlike foodborne infections or flareups of IBD or Crohn's Disease where a patient does not know when he or she will be 'under attack," physicians know exactly when they are administering chemotherapeutic drugs to cancer patients. This means we have a therapeutic window where we can try to develop some sort of combination therapy to limit some of this fuel for bacteria." The researchers also revealed that restricting the release of certain nutrients from dying cells, without having to stop the cell death process itself, was able to protect animals from infection. According to Anderson, this could have major implications for developing future therapeutics. "What was exciting to us was that we do not need to cheat death itself to still see some protection. We do not need to go searching for the Holy Grail. If we can change or restrict some of these nutrients that are released during death, we can try to improve patient care. As with any piece of fundamental research, there is more work to be done, but the opportunity is there for future therapies." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Recent reports indicate that Smad7 promotes skeletal muscle differentiation and growth. We previously documented a non-canonical role of nuclear Smad7 during myogenesis, independent of its role in TGF-β signaling. Here further characterization of the myogenic function of Smad7 revealed β-catenin as a Smad7 interacting protein. Biochemical analysis identified a Smad7 interaction domain (SID) between aa575 and aa683 of β-catenin. Reporter gene analysis and chromatin immunoprecipitation demonstrated that Smad7 and β-catenin are cooperatively recruited to the extensively characterized ckm promoter proximal region to facilitate its muscle restricted transcriptional activation in myogenic cells. Depletion of endogenous Smad7 and β-catenin in muscle cells reduced ckm promoter activity indicating their role during myogenesis. Deletion of the β-catenin SID substantially reduced the effect of Smad7 on the ckm promoter and exogenous expression of SID abolished β-catenin function, indicating that SID functions as a trans dominant-negative regulator of β-catenin activity. β-catenin interaction with the Mediator kinase complex through its Med12 subunit led us to identify MED13 as an additional Smad7-binding partner. Collectively, these studies document a novel function of a Smad7-MED12/13-β-catenin complex at the ckm locus, indicating a key role of this complex in the program of myogenic gene expression underlying skeletal muscle development and regeneration. Introduction Developmental myogenesis, the process of terminal differentiation of skeletal muscle progenitor cells, consists of a series of well-characterized highly regulated steps that has become a paradigm for lineage acquisition and cellular differentiation 1 , 2 , 3 , 4 , 5 . During embryogenesis, pluripotent mesodermal stem cells commit to become myogenic progenitor cells 6 . Commitment to the myogenic lineage results in a binary state of either maintenance of proliferative potential and multipotency or, on appropriate cues, withdrawal from the cell cycle, activation of a battery of structural, contractile, and metabolic genes and ultimately formation of multi-nucleated, electrically excitable myofibers 1 , 7 , 8 . Also, in adult skeletal muscle, resident stem cells (satellite cells) located between the basal lamina and the plasma membrane of mature muscle fibers 9 recapitulate this “myogenic program” of differentiation in response to injury or for routine maintenance of the muscle tissue 10 . How networks of transcriptional regulators exert molecular control over developmental and adult myogenesis has been a prevalent theme in understanding the molecular control of ontogeny, physiology, and pathology of the striated muscle 10 , 11 , 12 . Extensive biochemical and genetic evidence has implicated a family of DNA-binding transcriptional regulatory proteins encoded by the myogenic regulatory factor (MRF) genes, myf5 , myod1 , myogenin ( myog ), and mrf4 , in myogenesis 10 , 13 . In conjunction with the proteins encoded by the myocyte enhancer factor 2 ( mef2a-d ) gene family, the MRF’s activate an evolutionarily conserved program of gene expression, which leads to the generation of terminally differentiated skeletal muscle cells 14 , 15 , 16 . Understanding the trans -acting factors contributing to this process has been aided in tandem by extensive analysis of the cis -regulatory elements of muscle-restricted, differentiation-induced genes such as the muscle creatine kinase ( ckm ) gene 17 , 18 , 19 . In addition to the central role played by the MRF/MEF2 axis in myogenesis 20 , other transcription factors have been implicated in the control of myogenic differentiation such as Six 1 and 4 21 , 22 , 23 , AP-1 24 , 25 , β-catenin 26 , 27 , 28 , and Smad7 29 , 30 , 31 . Since our initial observations of the pro-myogenic role of Smad7 in cultured muscle cells 29 , we have documented a novel nuclear role for Smad7 in muscle that is essentially independent of its “canonical” role as a repressor of transforming growth factor (TGF)-β signaling 31 . In addition, other groups have documented an in vivo role for Smad7 in the skeletal muscle 30 . Understanding the nature of the ancillary role played by Smad7 and other transcriptional regulators at muscle-restricted genes is therefore of some importance for our overall understanding of the molecular programming of myogenic identity. In view of the “non-canonical” nuclear role of Smad7 alluded to above, the mechanistic basis by which it contributes to the myogenic differentiation program is so far incompletely understood. We were intrigued by a report identifying a protein–protein interaction (PPI) between Smad7 and β-catenin in human prostate cancer cells 32 since both are known, independently, to be key regulators of muscle gene expression in a variety of contexts. We therefore assessed this putative PPI in cultured muscle cells. Our data support a robust interaction between Smad7 and β-catenin that contributes to the transcriptional control of a key myogenic promoter ( ckm ). We further extended these observations in characterizing the recruitment of Mediator components (Med12/13) by the β-catenin/Smad7 complex, thus connecting the muscle transcriptosome assembled on enhancers such as ckm to the basal transcription machinery. Integration of the Smad7-β-catenin complex into the network of proteins regulating the “myogenic program” expands our understanding of the unique molecular wiring encoding myogenic differentiation, growth and repair. Materials and methods Cell culture C2C12 myoblasts were obtained from the American Type Culture Collection. Cells were cultured in growth medium (GM) consisting of high-glucose Dulbecco’s modified Eagle’s medium (DMEM, Gibco), 10% fetal bovine serum (FBS), and L-Glutamine (HyClone) supplemented with 1% penicillin–streptomycin (Invitrogen, ThermoFisher). Myotube formation was induced by replacing GM with differentiation medium (DM), consisting of DMEM supplemented with 2% horse serum (Atlanta Biologicals) and 1% penicillin–streptomycin. Cells were maintained in an incubator at 95% humidity, 5% CO 2 , and 37 °C. Transfections For ectopic protein expression, cells were transfected using the calcium phosphate precipitation method for transcription reporter assays. Cells were re-fed 16 h post-transfection and harvested. For small interfering RNA (siRNA) experiments, cells were transfected with Lipofectamine 2000 (Life Technologies) using instructions provided by the manufacturer and harvested 48 h later, unless otherwise indicated. Gene silencing MISSION siRNA (Sigma-Aldrich) for rat and mouse ctnnb1 siβ-catenin#1 (SASI_Rn01_00099925), siβ-catenin#2 (SASI_Rn01_00099923), siβ-catenin#3 (SASI_Rn01_00099924), siSmad7#1 (SASI_Mm02_00290887), siSmad7#2 (SASI_Mm02_00290886), siSmad7#3 (SASI_Mm02_00290885) and universal scrambled siRNA", "role": "user" }, { "content": "York University scientists have uncovered a unique set of genes that play a role in muscle cellular gene expression and differentiation which could lead to new therapeutic targets to prevent the spread of muscle cancer. The researchers analyzed gene networks in muscle cells and found that the Smad7 and β-catenin proteins work cooperatively inside the body to regulate muscle cell differentiation, growth and repair. When these regulatory proteins work in harmony, they control the pathway for normal gene expression, resulting in normal skeletal muscle cells. The study, published in the journal Cell Death & Disease, indicates that a dysfunctional relationship between the Smad7 and β-catenin complex can lead to a situation of impaired muscle cell differentiation—a hallmark of some soft tissue cancers such as Rhabdomyosarcoma (RMS). This rare cancer, which most often affects children, forms in soft tissue, mostly skeletal muscle tissue, and sometimes in hollow organs like the bladder or uterus. \"What happens in those rhabdomyosarcoma cells is that they have a muscle cell-like character, but the difference is that normal muscle cells stop dividing,\" said John McDermott, a professor in the Department of Biology in the Faculty of Science, who supervised the study and is a contributing author. McDermott said these cells look like muscle cells, in terms of the way they function and their phenotype, but they don't stop dividing, which is why they form tumors at various sites in the body. \"Our idea is that part of the reason why those cells are defective in the differentiation program, which would mean that they would stop dividing, is that the β-catenin complex is being degraded in those cells because of an anomaly in the signaling pathway that controls that,\" said McDermott. \"If we can stabilize the β-catenin and Smad7 complex in those cells, you could potentially encourage them to differentiate and stop proliferating, which would mean that you'd stop those cells from growing in the tumor.\" The research was conducted in York's Muscle Health Research Centre - the first of its kind in Canada—which focuses on the importance of skeletal muscle to the overall health and well-being of Canadians. This new molecular genetic finding could lead to strategies for cancer treatments that target these specific molecules. The study also defines new molecular targets for therapeutic interventions in muscle wasting and cancer. \"Until you know how things work normally, it's very hard to target anything specific, so identifying the normal function of molecules is essential before assessing abnormal function in cancer cells,\" said McDermott. \"This then allows therapeutic targeting of specific molecules in order to develop pharmacology to treat the condition, or in some cases pre-existing pharmacology would be used.\" The research team—led by Ph.D. student Soma Tripathi and including Tetsuaki Miyake, a research associate and Ph.D. - focused on understanding the role of transcription factors in orchestrating tissue-specific gene expression and differentiation. They did this by identifying DNA binding proteins that are involved in transcriptional regulation during muscle development. The study also identified new regulators of muscle regeneration which could also open doors for the pharmaceutical industry to develop new treatments to address the normal but debilitating loss of muscle in the aging population. \"Muscle regeneration is a highly complex process and is regulated by a variety of transcription factors which are essentially proteins that help turn genes on or off by binding to specific genes within the genome,\" said Tripathi. \"We believe two such transcription factors, Smad7 and β-catenin, play a key role in the specific pattern of gene expression required for muscle development and repair.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Recent reports indicate that Smad7 promotes skeletal muscle differentiation and growth. We previously documented a non-canonical role of nuclear Smad7 during myogenesis, independent of its role in TGF-β signaling. Here further characterization of the myogenic function of Smad7 revealed β-catenin as a Smad7 interacting protein. Biochemical analysis identified a Smad7 interaction domain (SID) between aa575 and aa683 of β-catenin. Reporter gene analysis and chromatin immunoprecipitation demonstrated that Smad7 and β-catenin are cooperatively recruited to the extensively characterized ckm promoter proximal region to facilitate its muscle restricted transcriptional activation in myogenic cells. Depletion of endogenous Smad7 and β-catenin in muscle cells reduced ckm promoter activity indicating their role during myogenesis. Deletion of the β-catenin SID substantially reduced the effect of Smad7 on the ckm promoter and exogenous expression of SID abolished β-catenin function, indicating that SID functions as a trans dominant-negative regulator of β-catenin activity. β-catenin interaction with the Mediator kinase complex through its Med12 subunit led us to identify MED13 as an additional Smad7-binding partner. Collectively, these studies document a novel function of a Smad7-MED12/13-β-catenin complex at the ckm locus, indicating a key role of this complex in the program of myogenic gene expression underlying skeletal muscle development and regeneration. Introduction Developmental myogenesis, the process of terminal differentiation of skeletal muscle progenitor cells, consists of a series of well-characterized highly regulated steps that has become a paradigm for lineage acquisition and cellular differentiation 1 , 2 , 3 , 4 , 5 . During embryogenesis, pluripotent mesodermal stem cells commit to become myogenic progenitor cells 6 . Commitment to the myogenic lineage results in a binary state of either maintenance of proliferative potential and multipotency or, on appropriate cues, withdrawal from the cell cycle, activation of a battery of structural, contractile, and metabolic genes and ultimately formation of multi-nucleated, electrically excitable myofibers 1 , 7 , 8 . Also, in adult skeletal muscle, resident stem cells (satellite cells) located between the basal lamina and the plasma membrane of mature muscle fibers 9 recapitulate this “myogenic program” of differentiation in response to injury or for routine maintenance of the muscle tissue 10 . How networks of transcriptional regulators exert molecular control over developmental and adult myogenesis has been a prevalent theme in understanding the molecular control of ontogeny, physiology, and pathology of the striated muscle 10 , 11 , 12 . Extensive biochemical and genetic evidence has implicated a family of DNA-binding transcriptional regulatory proteins encoded by the myogenic regulatory factor (MRF) genes, myf5 , myod1 , myogenin ( myog ), and mrf4 , in myogenesis 10 , 13 . In conjunction with the proteins encoded by the myocyte enhancer factor 2 ( mef2a-d ) gene family, the MRF’s activate an evolutionarily conserved program of gene expression, which leads to the generation of terminally differentiated skeletal muscle cells 14 , 15 , 16 . Understanding the trans -acting factors contributing to this process has been aided in tandem by extensive analysis of the cis -regulatory elements of muscle-restricted, differentiation-induced genes such as the muscle creatine kinase ( ckm ) gene 17 , 18 , 19 . In addition to the central role played by the MRF/MEF2 axis in myogenesis 20 , other transcription factors have been implicated in the control of myogenic differentiation such as Six 1 and 4 21 , 22 , 23 , AP-1 24 , 25 , β-catenin 26 , 27 , 28 , and Smad7 29 , 30 , 31 . Since our initial observations of the pro-myogenic role of Smad7 in cultured muscle cells 29 , we have documented a novel nuclear role for Smad7 in muscle that is essentially independent of its “canonical” role as a repressor of transforming growth factor (TGF)-β signaling 31 . In addition, other groups have documented an in vivo role for Smad7 in the skeletal muscle 30 . Understanding the nature of the ancillary role played by Smad7 and other transcriptional regulators at muscle-restricted genes is therefore of some importance for our overall understanding of the molecular programming of myogenic identity. In view of the “non-canonical” nuclear role of Smad7 alluded to above, the mechanistic basis by which it contributes to the myogenic differentiation program is so far incompletely understood. We were intrigued by a report identifying a protein–protein interaction (PPI) between Smad7 and β-catenin in human prostate cancer cells 32 since both are known, independently, to be key regulators of muscle gene expression in a variety of contexts. We therefore assessed this putative PPI in cultured muscle cells. Our data support a robust interaction between Smad7 and β-catenin that contributes to the transcriptional control of a key myogenic promoter ( ckm ). We further extended these observations in characterizing the recruitment of Mediator components (Med12/13) by the β-catenin/Smad7 complex, thus connecting the muscle transcriptosome assembled on enhancers such as ckm to the basal transcription machinery. Integration of the Smad7-β-catenin complex into the network of proteins regulating the “myogenic program” expands our understanding of the unique molecular wiring encoding myogenic differentiation, growth and repair. Materials and methods Cell culture C2C12 myoblasts were obtained from the American Type Culture Collection. Cells were cultured in growth medium (GM) consisting of high-glucose Dulbecco’s modified Eagle’s medium (DMEM, Gibco), 10% fetal bovine serum (FBS), and L-Glutamine (HyClone) supplemented with 1% penicillin–streptomycin (Invitrogen, ThermoFisher). Myotube formation was induced by replacing GM with differentiation medium (DM), consisting of DMEM supplemented with 2% horse serum (Atlanta Biologicals) and 1% penicillin–streptomycin. Cells were maintained in an incubator at 95% humidity, 5% CO 2 , and 37 °C. Transfections For ectopic protein expression, cells were transfected using the calcium phosphate precipitation method for transcription reporter assays. Cells were re-fed 16 h post-transfection and harvested. For small interfering RNA (siRNA) experiments, cells were transfected with Lipofectamine 2000 (Life Technologies) using instructions provided by the manufacturer and harvested 48 h later, unless otherwise indicated. Gene silencing MISSION siRNA (Sigma-Aldrich) for rat and mouse ctnnb1 siβ-catenin#1 (SASI_Rn01_00099925), siβ-catenin#2 (SASI_Rn01_00099923), siβ-catenin#3 (SASI_Rn01_00099924), siSmad7#1 (SASI_Mm02_00290887), siSmad7#2 (SASI_Mm02_00290886), siSmad7#3 (SASI_Mm02_00290885) and universal scrambled siRNA<|im_end|> <|im_start|>assistant York University scientists have uncovered a unique set of genes that play a role in muscle cellular gene expression and differentiation which could lead to new therapeutic targets to prevent the spread of muscle cancer. The researchers analyzed gene networks in muscle cells and found that the Smad7 and β-catenin proteins work cooperatively inside the body to regulate muscle cell differentiation, growth and repair. When these regulatory proteins work in harmony, they control the pathway for normal gene expression, resulting in normal skeletal muscle cells. The study, published in the journal Cell Death & Disease, indicates that a dysfunctional relationship between the Smad7 and β-catenin complex can lead to a situation of impaired muscle cell differentiation—a hallmark of some soft tissue cancers such as Rhabdomyosarcoma (RMS). This rare cancer, which most often affects children, forms in soft tissue, mostly skeletal muscle tissue, and sometimes in hollow organs like the bladder or uterus. "What happens in those rhabdomyosarcoma cells is that they have a muscle cell-like character, but the difference is that normal muscle cells stop dividing," said John McDermott, a professor in the Department of Biology in the Faculty of Science, who supervised the study and is a contributing author. McDermott said these cells look like muscle cells, in terms of the way they function and their phenotype, but they don't stop dividing, which is why they form tumors at various sites in the body. "Our idea is that part of the reason why those cells are defective in the differentiation program, which would mean that they would stop dividing, is that the β-catenin complex is being degraded in those cells because of an anomaly in the signaling pathway that controls that," said McDermott. "If we can stabilize the β-catenin and Smad7 complex in those cells, you could potentially encourage them to differentiate and stop proliferating, which would mean that you'd stop those cells from growing in the tumor." The research was conducted in York's Muscle Health Research Centre - the first of its kind in Canada—which focuses on the importance of skeletal muscle to the overall health and well-being of Canadians. This new molecular genetic finding could lead to strategies for cancer treatments that target these specific molecules. The study also defines new molecular targets for therapeutic interventions in muscle wasting and cancer. "Until you know how things work normally, it's very hard to target anything specific, so identifying the normal function of molecules is essential before assessing abnormal function in cancer cells," said McDermott. "This then allows therapeutic targeting of specific molecules in order to develop pharmacology to treat the condition, or in some cases pre-existing pharmacology would be used." The research team—led by Ph.D. student Soma Tripathi and including Tetsuaki Miyake, a research associate and Ph.D. - focused on understanding the role of transcription factors in orchestrating tissue-specific gene expression and differentiation. They did this by identifying DNA binding proteins that are involved in transcriptional regulation during muscle development. The study also identified new regulators of muscle regeneration which could also open doors for the pharmaceutical industry to develop new treatments to address the normal but debilitating loss of muscle in the aging population. "Muscle regeneration is a highly complex process and is regulated by a variety of transcription factors which are essentially proteins that help turn genes on or off by binding to specific genes within the genome," said Tripathi. "We believe two such transcription factors, Smad7 and β-catenin, play a key role in the specific pattern of gene expression required for muscle development and repair." <|im_end|>

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2,315

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Shallow cumulus clouds in the trade-wind regions cool the planet by reflecting solar radiation. The response of trade cumulus clouds to climate change is a key uncertainty in climate projections 1 , 2 , 3 , 4 . Trade cumulus feedbacks in climate models are governed by changes in cloud fraction near cloud base 5 , 6 , with high-climate-sensitivity models suggesting a strong decrease in cloud-base cloudiness owing to increased lower-tropospheric mixing 5 , 6 , 7 . Here we show that new observations from the EUREC 4 A (Elucidating the role of cloud-circulation coupling in climate) field campaign 8 , 9 refute this mixing-desiccation hypothesis. We find the dynamical increase of cloudiness through mixing to overwhelm the thermodynamic control through humidity. Because mesoscale motions and the entrainment rate contribute equally to variability in mixing but have opposing effects on humidity, mixing does not desiccate clouds. The magnitude, variability and coupling of mixing and cloudiness differ markedly among climate models and with the EUREC 4 A observations. Models with large trade cumulus feedbacks tend to exaggerate the dependence of cloudiness on relative humidity as opposed to mixing and also exaggerate variability in cloudiness. Our observational analyses render models with large positive feedbacks implausible and both support and explain at the process scale a weak trade cumulus feedback. Our findings thus refute an important line of evidence for a high climate sensitivity 10 , 11 . Main Earth’s climate strongly depends on the abundance and behaviour of its smallest clouds. Shallow trade-wind cumulus clouds are rooted in the turbulent sub-cloud layer and form when thermals rise above the lifting condensation level 12 . They may grow only a few hundred metres high in dry environments or become positively buoyant and rise up to the trade-wind inversion, where they detrain condensate into stratiform cloud layers. Trade cumuli populate most of the subtropical oceans and cool the planet by reflecting the incoming solar radiation. Owing to their large geographical extent, small errors in predicting the way trade cumuli respond to warming can have a large effect on the global radiative budget. This explains why shallow cumuli in the trades are a main source of spread in the estimates of climate sensitivity of climate models 1 , 2 , 3 , 4 . Cloudiness near the base of the cumulus layer makes up two-thirds of the total cloud cover in the trades 13 and its change with warming governs the strength of the trade cumulus cloud feedback in climate models 5 , 6 . Reductions in cloud-base cloudiness in climate models are tightly coupled with increases in lower-tropospheric mixing owing to convective and large-scale circulations 5 , 6 , 7 . On the basis of this strong negative coupling between mixing and cloudiness, the hypothesis emerged that enhanced convective mixing might desiccate the lower cloud layer and reduce cloudiness in the trades 7 . This mixing-desiccation hypothesis suggests that the moisture transported by convection from the sub-cloud layer to the trade inversion is compensated by downward mixing of drier air and evaporation of clouds near cloud base. The mechanism—which is expected to become more pronounced with warming owing to the nonlinear Clausius–Clapeyron relationship—is consistent with idealized high-resolution simulations of nonprecipitating trade cumuli 14 and with the behaviour of climate models that have a strongly positive trade cumulus feedback 5 , 7 , 15 . However, the mixing-desiccation hypothesis has never been tested with observations. Using the convective mass flux at cloud base, M , as a proxy for lower-tropospheric convective mixing, the hypothesis can be tested by analysing the relationship between M and the mean relative humidity ( \${\\mathcal{R}}\$ ) and cloud fraction ( C ) at cloud base in observations, with \$C\\propto {\\mathcal{R}}\\propto {M}^{\\beta }\$ and β < 0 suggesting the mixing-desiccation mechanism to be present in nature (Fig. 1a ). Fig. 1: Illustration of two mechanisms for the coupling of mixing and cloudiness. a , The mixing-desiccation mechanism contends that E increases in response to an increase in M , which leads to a reduction in \${\\mathcal{R}}\$ and cloud-base cloudiness C , and a relationship \$C\\propto {\\mathcal{R}}\\propto {M}^{\\beta }\$ with β < 0. b , The mesoscale motion control of cloudiness instead suggests that M is equally controlled by both E and W , such that M is uncorrelated to \${\\mathcal{R}}\$ and β > 0. Full size image The mixing-desiccation mechanism is based on several assumptions that might not be operating in nature. M is commonly defined as the product of the cloud fraction and the in-cloud vertical velocity, and its variability is mostly governed by the area coverage of active clouds 16 , 17 , defined as saturated and buoyant updrafts that ventilate the sub-cloud layer. If variability in the in-cloud vertical velocity near cloud base is small, a positive relationship between C and M is expected ( β > 0; Fig. 1b ). This was demonstrated for nonprecipitating trade cumuli using Doppler radar data 17 , 18 and seems at odds with the mixing-desiccation hypothesis. Yet active clouds represent only half of the total C (refs. 19 , 20 ) and the lifetime and variability of passive clouds, such as the detritus of decaying clouds, might be more sensitive to \${\\mathcal{R}}\$ and mixing-induced drying of their environment than to M . The sub-cloud-layer mass budget provides a theoretical basis for interpreting the mixing-desiccation mechanism. It can be expressed as a budget of the sub-cloud-layer height h , $$\\frac{\\partial h}{\\partial t}+{V}_{h}\\cdot \\nabla h=E+W-M,$$ (1) in which the entrainment rate, E , representing the mass source owing to the entrainment of dry and warm cloud layer air, and the mesoscale vertical velocity, W , are balanced by the mass export owing to the convective mass flux, M (ref. 20 ). Note that we define M as the (mass) specific mass flux, which has units of velocity (see Methods ). E is the only term directly affecting the sub-cloud-layer moisture and heat budgets 21 , 22 . If an increase in", "role": "user" }, { "content": "In a major field campaign in 2020, Dr. Raphaela Vogel who is now at Universität Hamburg's Center for Earth System Research and Sustainability (CEN) and an international team from the Laboratoire de Météorologie Dynamique in Paris and the Max Planck Institute for Meteorology in Hamburg analyzed observational data they and others collected in fields of cumulus clouds near the Atlantic island of Barbados. Their analysis revealed that these clouds' contribution to climate warming has to be reassessed. \"Trade-wind clouds influence the climate system around the globe, but the data demonstrate behavior differently than previously assumed. Consequently, an extreme rise in Earth's temperatures is less likely than previously thought,\" says Vogel, an atmospheric scientist. \"Though this aspect is very important for more accurately projecting future climate scenarios, it definitely doesn't mean we can back off on climate protection.\" To date, many climate models have simulated a major reduction in trade-wind clouds, which would mean much of their cooling function would be lost and the atmosphere would consequently warm even more. The new observational data shows that this isn't likely to occur. What is certain is that, as global warming progresses, more water on the ocean's surface evaporates and the moisture near the base of trade-wind clouds increases. In contrast, the air masses in the upper part of the clouds are very dry and only become slightly moister. This produces a substantial difference in moisture above and below. In the atmosphere, this is dispelled when the air masses mix. The previous hypothesis: drier air is transported downward, causing the cloud droplets to evaporate more rapidly and making it more likely that the clouds will dissipate. The observational data from Barbados now offers the first robust quantification as to how pronounced the vertical mixing actually is, and how this affects moisture and cloud cover as a whole. As such, it is the first data to shed light on a process that is essential to understanding climate change. In brief: more intensive mixing does not make the lower layers drier or make the clouds dissipate. Rather, the data shows that the cloud cover actually increases with increasing vertical mixing. \"That's good news, because it means that trade-wind clouds are far less sensitive to global warming than has long been assumed,\" says Vogel. \"With our new observations and findings, we can now directly test how realistically climate models portray the occurrence of trade-wind clouds. In this regard, a new generation of high-resolution climate models that can simulate the dynamics of clouds around the globe down to scales of one kilometer are particularly promising. Thanks to them, future projections will be more accurate and reliable.\" The month-long field campaign EUREC4A (2020) was designed by the team members around extended flights with two research aircraft, which were equipped with different instruments and operated at different altitudes, and shipboard measurements from the R/V Meteor—A German research vessel managed by the University of Hamburg. One plane was used to drop hundreds of atmospheric probes from an altitude of nine kilometers. As they fell, the probes gathered atmospheric data on the temperature, moisture, pressure and wind. The other plane surveyed clouds at their base, at an altitude of 800 meters, while the ship performed surface-based measurements. The result: an unprecedented database that will help to understand the unclear role of clouds in the climate system—and to more accurately predict their role in future climate change. Whether clouds have a cooling or warming effect depends on how high they are. With a maximum altitude of two to three kilometers, the trade-wind clouds examined here are comparatively low, reflect sunlight, and cool the atmosphere in the process. In contrast, higher clouds amplify the greenhouse effect, warming the climate. The work is published in the journal Nature. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Shallow cumulus clouds in the trade-wind regions cool the planet by reflecting solar radiation. The response of trade cumulus clouds to climate change is a key uncertainty in climate projections 1 , 2 , 3 , 4 . Trade cumulus feedbacks in climate models are governed by changes in cloud fraction near cloud base 5 , 6 , with high-climate-sensitivity models suggesting a strong decrease in cloud-base cloudiness owing to increased lower-tropospheric mixing 5 , 6 , 7 . Here we show that new observations from the EUREC 4 A (Elucidating the role of cloud-circulation coupling in climate) field campaign 8 , 9 refute this mixing-desiccation hypothesis. We find the dynamical increase of cloudiness through mixing to overwhelm the thermodynamic control through humidity. Because mesoscale motions and the entrainment rate contribute equally to variability in mixing but have opposing effects on humidity, mixing does not desiccate clouds. The magnitude, variability and coupling of mixing and cloudiness differ markedly among climate models and with the EUREC 4 A observations. Models with large trade cumulus feedbacks tend to exaggerate the dependence of cloudiness on relative humidity as opposed to mixing and also exaggerate variability in cloudiness. Our observational analyses render models with large positive feedbacks implausible and both support and explain at the process scale a weak trade cumulus feedback. Our findings thus refute an important line of evidence for a high climate sensitivity 10 , 11 . Main Earth’s climate strongly depends on the abundance and behaviour of its smallest clouds. Shallow trade-wind cumulus clouds are rooted in the turbulent sub-cloud layer and form when thermals rise above the lifting condensation level 12 . They may grow only a few hundred metres high in dry environments or become positively buoyant and rise up to the trade-wind inversion, where they detrain condensate into stratiform cloud layers. Trade cumuli populate most of the subtropical oceans and cool the planet by reflecting the incoming solar radiation. Owing to their large geographical extent, small errors in predicting the way trade cumuli respond to warming can have a large effect on the global radiative budget. This explains why shallow cumuli in the trades are a main source of spread in the estimates of climate sensitivity of climate models 1 , 2 , 3 , 4 . Cloudiness near the base of the cumulus layer makes up two-thirds of the total cloud cover in the trades 13 and its change with warming governs the strength of the trade cumulus cloud feedback in climate models 5 , 6 . Reductions in cloud-base cloudiness in climate models are tightly coupled with increases in lower-tropospheric mixing owing to convective and large-scale circulations 5 , 6 , 7 . On the basis of this strong negative coupling between mixing and cloudiness, the hypothesis emerged that enhanced convective mixing might desiccate the lower cloud layer and reduce cloudiness in the trades 7 . This mixing-desiccation hypothesis suggests that the moisture transported by convection from the sub-cloud layer to the trade inversion is compensated by downward mixing of drier air and evaporation of clouds near cloud base. The mechanism—which is expected to become more pronounced with warming owing to the nonlinear Clausius–Clapeyron relationship—is consistent with idealized high-resolution simulations of nonprecipitating trade cumuli 14 and with the behaviour of climate models that have a strongly positive trade cumulus feedback 5 , 7 , 15 . However, the mixing-desiccation hypothesis has never been tested with observations. Using the convective mass flux at cloud base, M , as a proxy for lower-tropospheric convective mixing, the hypothesis can be tested by analysing the relationship between M and the mean relative humidity ( ${\mathcal{R}}$ ) and cloud fraction ( C ) at cloud base in observations, with $C\propto {\mathcal{R}}\propto {M}^{\beta }$ and β < 0 suggesting the mixing-desiccation mechanism to be present in nature (Fig. 1a ). Fig. 1: Illustration of two mechanisms for the coupling of mixing and cloudiness. a , The mixing-desiccation mechanism contends that E increases in response to an increase in M , which leads to a reduction in ${\mathcal{R}}$ and cloud-base cloudiness C , and a relationship $C\propto {\mathcal{R}}\propto {M}^{\beta }$ with β < 0. b , The mesoscale motion control of cloudiness instead suggests that M is equally controlled by both E and W , such that M is uncorrelated to ${\mathcal{R}}$ and β > 0. Full size image The mixing-desiccation mechanism is based on several assumptions that might not be operating in nature. M is commonly defined as the product of the cloud fraction and the in-cloud vertical velocity, and its variability is mostly governed by the area coverage of active clouds 16 , 17 , defined as saturated and buoyant updrafts that ventilate the sub-cloud layer. If variability in the in-cloud vertical velocity near cloud base is small, a positive relationship between C and M is expected ( β > 0; Fig. 1b ). This was demonstrated for nonprecipitating trade cumuli using Doppler radar data 17 , 18 and seems at odds with the mixing-desiccation hypothesis. Yet active clouds represent only half of the total C (refs. 19 , 20 ) and the lifetime and variability of passive clouds, such as the detritus of decaying clouds, might be more sensitive to ${\mathcal{R}}$ and mixing-induced drying of their environment than to M . The sub-cloud-layer mass budget provides a theoretical basis for interpreting the mixing-desiccation mechanism. It can be expressed as a budget of the sub-cloud-layer height h , $$\frac{\partial h}{\partial t}+{V}_{h}\cdot \nabla h=E+W-M,$$ (1) in which the entrainment rate, E , representing the mass source owing to the entrainment of dry and warm cloud layer air, and the mesoscale vertical velocity, W , are balanced by the mass export owing to the convective mass flux, M (ref. 20 ). Note that we define M as the (mass) specific mass flux, which has units of velocity (see Methods ). E is the only term directly affecting the sub-cloud-layer moisture and heat budgets 21 , 22 . If an increase in<|im_end|> <|im_start|>assistant In a major field campaign in 2020, Dr. Raphaela Vogel who is now at Universität Hamburg's Center for Earth System Research and Sustainability (CEN) and an international team from the Laboratoire de Météorologie Dynamique in Paris and the Max Planck Institute for Meteorology in Hamburg analyzed observational data they and others collected in fields of cumulus clouds near the Atlantic island of Barbados. Their analysis revealed that these clouds' contribution to climate warming has to be reassessed. "Trade-wind clouds influence the climate system around the globe, but the data demonstrate behavior differently than previously assumed. Consequently, an extreme rise in Earth's temperatures is less likely than previously thought," says Vogel, an atmospheric scientist. "Though this aspect is very important for more accurately projecting future climate scenarios, it definitely doesn't mean we can back off on climate protection." To date, many climate models have simulated a major reduction in trade-wind clouds, which would mean much of their cooling function would be lost and the atmosphere would consequently warm even more. The new observational data shows that this isn't likely to occur. What is certain is that, as global warming progresses, more water on the ocean's surface evaporates and the moisture near the base of trade-wind clouds increases. In contrast, the air masses in the upper part of the clouds are very dry and only become slightly moister. This produces a substantial difference in moisture above and below. In the atmosphere, this is dispelled when the air masses mix. The previous hypothesis: drier air is transported downward, causing the cloud droplets to evaporate more rapidly and making it more likely that the clouds will dissipate. The observational data from Barbados now offers the first robust quantification as to how pronounced the vertical mixing actually is, and how this affects moisture and cloud cover as a whole. As such, it is the first data to shed light on a process that is essential to understanding climate change. In brief: more intensive mixing does not make the lower layers drier or make the clouds dissipate. Rather, the data shows that the cloud cover actually increases with increasing vertical mixing. "That's good news, because it means that trade-wind clouds are far less sensitive to global warming than has long been assumed," says Vogel. "With our new observations and findings, we can now directly test how realistically climate models portray the occurrence of trade-wind clouds. In this regard, a new generation of high-resolution climate models that can simulate the dynamics of clouds around the globe down to scales of one kilometer are particularly promising. Thanks to them, future projections will be more accurate and reliable." The month-long field campaign EUREC4A (2020) was designed by the team members around extended flights with two research aircraft, which were equipped with different instruments and operated at different altitudes, and shipboard measurements from the R/V Meteor—A German research vessel managed by the University of Hamburg. One plane was used to drop hundreds of atmospheric probes from an altitude of nine kilometers. As they fell, the probes gathered atmospheric data on the temperature, moisture, pressure and wind. The other plane surveyed clouds at their base, at an altitude of 800 meters, while the ship performed surface-based measurements. The result: an unprecedented database that will help to understand the unclear role of clouds in the climate system—and to more accurately predict their role in future climate change. Whether clouds have a cooling or warming effect depends on how high they are. With a maximum altitude of two to three kilometers, the trade-wind clouds examined here are comparatively low, reflect sunlight, and cool the atmosphere in the process. In contrast, higher clouds amplify the greenhouse effect, warming the climate. The work is published in the journal Nature. <|im_end|>

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15, 23377, 279, 27890, 25520, 48738, 367, 17383, 311, 387, 3118, 304, 7138, 320, 30035, 13, 220, 16, 64, 7609, 23966, 13, 220, 16, 25, 39154, 367, 315, 1403, 24717, 369, 279, 59086, 315, 27890, 323, 9624, 1918, 13, 264, 1174, 578, 27890, 25520, 48738, 367, 17383, 82033, 430, 469, 12992, 304, 2077, 311, 459, 5376, 304, 386, 1174, 902, 11767, 311, 264, 14278, 304, 1144, 2358, 59, 10590, 5531, 90, 49, 3500, 58858, 323, 9624, 31113, 9624, 1918, 356, 1174, 323, 264, 5133, 18240, 34, 59, 782, 59091, 29252, 10590, 5531, 90, 49, 3500, 59, 782, 59091, 314, 44, 92, 61, 36802, 19674, 52400, 8, 449, 34318, 366, 220, 15, 13, 293, 1174, 578, 11083, 437, 2296, 11633, 2585, 315, 9624, 1918, 4619, 13533, 430, 386, 374, 18813, 14400, 555, 2225, 469, 323, 468, 1174, 1778, 430, 386, 374, 653, 6133, 9920, 311, 1144, 2358, 59, 10590, 5531, 90, 49, 3500, 58858, 323, 34318, 871, 220, 15, 13, 8797, 1404, 2217, 578, 27890, 25520, 48738, 367, 17383, 374, 3196, 389, 3892, 32946, 430, 2643, 539, 387, 10565, 304, 7138, 13, 386, 374, 17037, 4613, 439, 279, 2027, 315, 279, 9624, 19983, 323, 279, 304, 60297, 12414, 15798, 11, 323, 1202, 54709, 374, 10213, 27800, 555, 279, 3158, 10401, 315, 4642, 30614, 220, 845, 1174, 220, 1114, 1174, 4613, 439, 50585, 323, 75720, 519, 709, 46097, 82, 430, 71702, 349, 279, 1207, 60297, 6324, 13, 1442, 54709, 304, 279, 304, 60297, 12414, 15798, 3221, 9624, 2385, 374, 2678, 11, 264, 6928, 5133, 1990, 356, 323, 386, 374, 3685, 320, 34318, 871, 220, 15, 26, 23966, 13, 220, 16, 65, 7609, 1115, 574, 21091, 369, 2536, 10872, 575, 50644, 6696, 12454, 24520, 1701, 97674, 13206, 28608, 828, 220, 1114, 1174, 220, 972, 323, 5084, 520, 21448, 449, 279, 27890, 25520, 48738, 367, 31178, 13, 14968, 4642, 30614, 4097, 1193, 4376, 315, 279, 2860, 356, 320, 16541, 13, 220, 777, 1174, 220, 508, 883, 323, 279, 19569, 323, 54709, 315, 28979, 30614, 11, 1778, 439, 279, 3474, 1018, 355, 315, 1654, 17718, 30614, 11, 2643, 387, 810, 16614, 311, 1144, 2358, 59, 10590, 5531, 90, 49, 3500, 58858, 323, 27890, 38973, 46479, 315, 872, 4676, 1109, 311, 386, 662, 578, 1207, 60297, 48435, 3148, 8199, 5825, 264, 32887, 8197, 369, 66744, 279, 27890, 25520, 48738, 367, 17383, 13, 1102, 649, 387, 13605, 439, 264, 8199, 315, 279, 1207, 60297, 48435, 2673, 305, 1174, 27199, 59, 38118, 36802, 38520, 305, 15523, 59, 38520, 259, 92, 10, 90, 53, 52635, 71, 11281, 51953, 1144, 77, 370, 4355, 305, 86334, 98983, 5364, 4884, 3, 320, 16, 8, 304, 902, 279, 11751, 73712, 4478, 11, 469, 1174, 14393, 279, 3148, 2592, 56612, 311, 279, 11751, 73712, 315, 9235, 323, 8369, 9624, 6324, 3805, 11, 323, 279, 11083, 437, 2296, 12414, 15798, 11, 468, 1174, 527, 24770, 555, 279, 3148, 7637, 56612, 311, 279, 5804, 96978, 3148, 31405, 11, 386, 320, 1116, 13, 220, 508, 7609, 7181, 430, 584, 7124, 386, 439, 279, 320, 27428, 8, 3230, 3148, 31405, 11, 902, 706, 8316, 315, 15798, 320, 4151, 19331, 7609, 469, 374, 279, 1193, 4751, 6089, 28987, 279, 1207, 60297, 48435, 32257, 323, 8798, 42484, 220, 1691, 1174, 220, 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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The Hippo signalling pathway is an emerging growth control and tumour suppressor pathway that regulates cell proliferation and stem cell functions. Defects in Hippo signalling and hyperactivation of its downstream effectors Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) contribute to the development of cancer, which suggests that pharmacological inhibition of YAP and TAZ activity may be an effective anticancer strategy. Conversely, YAP and TAZ can also have beneficial roles in stimulating tissue repair and regeneration following injury, so their activation may be therapeutically useful in these contexts. A complex network of intracellular and extracellular signalling pathways that modulate YAP and TAZ activities have recently been identified. Here, we review the regulation of the Hippo signalling pathway, its functions in normal homeostasis and disease, and recent progress in the identification of small-molecule pathway modulators. Main The Hippo signalling pathway is an emerging growth control pathway that is conserved throughout the animal kingdom. Growing interest in the Hippo pathway is driven by studies demonstrating the fundamental role of this pathway in organ growth control, stem cell function, regeneration and tumour suppression 1 , 2 , 3 , 4 , 5 , 6 . Indeed, the Hippo pathway is deregulated with a high frequency in many diverse cancers, which suggests that altered Hippo signalling is tightly linked to tumour initiation and/or progression 7 . Hence, there is considerable excitement and speculation about targeting the Hippo pathway to treat a variety of human malignancies 8 , 9 . The main function of the Hippo pathway is to negatively regulate the activity of Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) — two homologous transcriptional co-activators that are the main downstream mediators of the Hippo pathway 10 . When activated, YAP and TAZ promote cell proliferation and inhibit cell death; YAP and TAZ are hyperactivated in many human malignancies 7 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 . Therapeutic intervention for cancer would thus involve reducing or inhibiting the oncogenic function of YAP and/or TAZ. However, to date, few small-molecule inhibitors have been discovered that target the Hippo pathway, and a prevalent view is that most Hippo pathway signalling components are not conventional drug targets. Indeed, YAP and TAZ are transcriptional co-activators with no known catalytic activity. Moreover, no known upstream regulators that specifically promote YAP and TAZ activity have demonstrated enzymatic activity 6 , 7 . Thus, inhibiting the function of YAP and TAZ may require targeting protein–protein interactions. A further complication is that YAP and TAZ are required for tissue repair and regeneration in some contexts 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , raising questions as to whether systemic and chronic manipulation of Hippo signalling might have potential deleterious side effects on normal tissue function and homeostasis. However, transient activation of YAP and TAZ may help to promote tissue repair and regeneration in the context of injury 28 , 29 . These two faces of the Hippo signalling pathway suggest that the identification and proper application of small-molecule modulators of Hippo signalling may provide exciting new approaches for cancer therapy and for regenerative medicine. Overview of the Hippo pathway The Hippo pathway relays signals from the plasma membrane into the nucleus, where it regulates the expression of a series of target genes that control diverse cellular processes such as proliferation, survival and differentiation 1 , 2 , 3 , 4 , 5 , 6 . In this regard, Hippo signalling is similar to other well-known signal transduction pathways such as the epidermal growth factor (EGF), transforming growth factor-β (TGFβ) or WNT signalling pathways. However, in contrast to these pathways, the Hippo pathway does not appear to have dedicated extracellular signalling peptides and receptors, but is instead regulated by a network of upstream components and mechanisms, many of which are also involved in regulating cell adhesion and cell polarity 3 , 6 , 31 . Nevertheless, the Hippo pathway bears considerable resemblance to other canonical signal transduction pathways as many upstream regulators feed into the core of the pathway, which is composed of two serine/threonine kinases known as the Hippo and Warts kinases in fruitflies 32 , 33 , 34 , 35 , 36 , 37 , 38 ; Hippo kinase is known as mammalian STE20-like protein kinase 1 (MST1) and MST2 in humans, whereas Warts kinase is known as large tumour suppressor homolog 1 (LATS1) kinase and LATS2 kinase in humans 38 , 39 , 40 , 41 . These kinases and their essential roles in growth control were first discovered in Drosophila melanogaster and they function together in a novel signalling pathway that has been named the 'Hippo pathway' after one of its founding members 32 . Since the discovery of the Hippo and Warts kinases, many additional components of the Hippo pathway have been identified, and a complex signalling network has emerged that integrates multiple upstream inputs from the plasma membrane into the nucleus ( Figs 1 , 2 ). In this Review, we largely refer to Hippo signalling components using the mammalian nomenclature, and the D. melanogaster components are listed in Table 1 . Figure 1: The core of the Hippo signalling pathway and its mode of action. Schematics of the core pathway components and how they interact are depicted. a | When the Hippo pathway is on, mammalian STE20-like protein kinase 1 (MST1) or MST2 phosphorylate Salvador homolog 1 (SAV1), and together they phosphorylate and activate MOB kinase activator 1A (MOB1A), MOB1B, large tumour suppressor homolog 1 (LATS1) kinase and LATS2 kinase, which then phosphorylate Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ). Phosphorylated YAP and TAZ are sequestered in the cytoplasm by the 14-3-3 protein and shunted for proteasomal degradation. As a result, the TEA domain-containing sequence-specific transcription factors (TEADs) associate with the transcription cofactor vestigial-like protein 4 (VGL4) and suppress target gene expression.", "role": "user" }, { "content": "Although fruit flies don't develop cancer, cancer and stem cell researchers have been learning a great deal from fruit flies - in particular, mutant flies with overgrown organs that resemble hippopotamuses. A fly gene called Hippo and its relatives in mammals normally block cell proliferation and limit organ size. When flies have mutations in Hippo or other genes (together dubbed the Hippo pathway), the resulting overgrowth distorts their tissues into hippopotamus-like bulges. In humans, the Hippo pathway is involved in forming embryonic stem cells, suppressing cancerous growth, and also in regenerative growth and wound healing. Working with flies, researchers at Emory have found that the abnormal growth induced by Hippo pathway disruption depends on genes involved in responding to the steroid hormone ecdysone. Their results are scheduled for publication in Developmental Cell. \"Ecdysone is, to some degree, the fly version of estrogen,\" says senior author Ken Moberg, PhD, associate professor of cell biology at Emory University School of Medicine. In fly larvae, ecdysone triggers metamorphosis, in which adult structures such as wings and eyes emerge from small compartments called imaginal discs.. Ecdysone has a chemical structure like that of estrogen, testosterone and other steroid hormones found in humans. Ecdysone is not sex-specific, but it acts with the same mechanism as other steroid hormones, diffusing into cells and binding proteins that bind DNA and regulate gene activity. Postdoctoral fellow Can Zhang, PhD and MD, PhD student Brian Robinson are co-first authors of the Developmental Cell paper. Collaborators at University of Massachusetts, Boston led by Alexey Veraksa, PhD contributed to the paper. The research team discovered that when the Hippo pathway's control is broken, the resulting excess growth in fly imaginal discs,depends on proteins involved in the ecdysone response. The genes that are activated by this combination of Hippo and ecdysone signals in imaginal disc 'tumors' include genes that are usually turned on only in germline stem cells, found in flies' reproductive organs. Activation of these germline stem cell factors by the Hippo pathway requires ecdysone response genes, the researchers found. The researchers concentrated on a protein in flies called Yorkie, which is usually restrained by \"upstream\" parts of the Hippo pathway. When unleashed, Yorkie travels into the cell nucleus and turns on growth-related genes. \"We found that Yorkie does not just engage a developmental growth program in disc tumors,\" Moberg says. \"It is capable of turning on an ectopic program only seen in germline stem cells.\" The researchers were able to detect a physical interaction between Yorkie and Taiman, a protein important in ecdysone response. Taiman's closest human relative is named Amplified in Breast Cancer-1 or AIB1. These findings point to possible connections in human biology between AIB1 and the Yorkie homologs Yap1 and Taz, Moberg says. \"Since both groups of these proteins are often overexpressed in human cancers, we think our findings may have implications for the study of proliferative mechanisms in cancers and possibly cancer stem cells,\" he says. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The Hippo signalling pathway is an emerging growth control and tumour suppressor pathway that regulates cell proliferation and stem cell functions. Defects in Hippo signalling and hyperactivation of its downstream effectors Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) contribute to the development of cancer, which suggests that pharmacological inhibition of YAP and TAZ activity may be an effective anticancer strategy. Conversely, YAP and TAZ can also have beneficial roles in stimulating tissue repair and regeneration following injury, so their activation may be therapeutically useful in these contexts. A complex network of intracellular and extracellular signalling pathways that modulate YAP and TAZ activities have recently been identified. Here, we review the regulation of the Hippo signalling pathway, its functions in normal homeostasis and disease, and recent progress in the identification of small-molecule pathway modulators. Main The Hippo signalling pathway is an emerging growth control pathway that is conserved throughout the animal kingdom. Growing interest in the Hippo pathway is driven by studies demonstrating the fundamental role of this pathway in organ growth control, stem cell function, regeneration and tumour suppression 1 , 2 , 3 , 4 , 5 , 6 . Indeed, the Hippo pathway is deregulated with a high frequency in many diverse cancers, which suggests that altered Hippo signalling is tightly linked to tumour initiation and/or progression 7 . Hence, there is considerable excitement and speculation about targeting the Hippo pathway to treat a variety of human malignancies 8 , 9 . The main function of the Hippo pathway is to negatively regulate the activity of Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) — two homologous transcriptional co-activators that are the main downstream mediators of the Hippo pathway 10 . When activated, YAP and TAZ promote cell proliferation and inhibit cell death; YAP and TAZ are hyperactivated in many human malignancies 7 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 . Therapeutic intervention for cancer would thus involve reducing or inhibiting the oncogenic function of YAP and/or TAZ. However, to date, few small-molecule inhibitors have been discovered that target the Hippo pathway, and a prevalent view is that most Hippo pathway signalling components are not conventional drug targets. Indeed, YAP and TAZ are transcriptional co-activators with no known catalytic activity. Moreover, no known upstream regulators that specifically promote YAP and TAZ activity have demonstrated enzymatic activity 6 , 7 . Thus, inhibiting the function of YAP and TAZ may require targeting protein–protein interactions. A further complication is that YAP and TAZ are required for tissue repair and regeneration in some contexts 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , raising questions as to whether systemic and chronic manipulation of Hippo signalling might have potential deleterious side effects on normal tissue function and homeostasis. However, transient activation of YAP and TAZ may help to promote tissue repair and regeneration in the context of injury 28 , 29 . These two faces of the Hippo signalling pathway suggest that the identification and proper application of small-molecule modulators of Hippo signalling may provide exciting new approaches for cancer therapy and for regenerative medicine. Overview of the Hippo pathway The Hippo pathway relays signals from the plasma membrane into the nucleus, where it regulates the expression of a series of target genes that control diverse cellular processes such as proliferation, survival and differentiation 1 , 2 , 3 , 4 , 5 , 6 . In this regard, Hippo signalling is similar to other well-known signal transduction pathways such as the epidermal growth factor (EGF), transforming growth factor-β (TGFβ) or WNT signalling pathways. However, in contrast to these pathways, the Hippo pathway does not appear to have dedicated extracellular signalling peptides and receptors, but is instead regulated by a network of upstream components and mechanisms, many of which are also involved in regulating cell adhesion and cell polarity 3 , 6 , 31 . Nevertheless, the Hippo pathway bears considerable resemblance to other canonical signal transduction pathways as many upstream regulators feed into the core of the pathway, which is composed of two serine/threonine kinases known as the Hippo and Warts kinases in fruitflies 32 , 33 , 34 , 35 , 36 , 37 , 38 ; Hippo kinase is known as mammalian STE20-like protein kinase 1 (MST1) and MST2 in humans, whereas Warts kinase is known as large tumour suppressor homolog 1 (LATS1) kinase and LATS2 kinase in humans 38 , 39 , 40 , 41 . These kinases and their essential roles in growth control were first discovered in Drosophila melanogaster and they function together in a novel signalling pathway that has been named the 'Hippo pathway' after one of its founding members 32 . Since the discovery of the Hippo and Warts kinases, many additional components of the Hippo pathway have been identified, and a complex signalling network has emerged that integrates multiple upstream inputs from the plasma membrane into the nucleus ( Figs 1 , 2 ). In this Review, we largely refer to Hippo signalling components using the mammalian nomenclature, and the D. melanogaster components are listed in Table 1 . Figure 1: The core of the Hippo signalling pathway and its mode of action. Schematics of the core pathway components and how they interact are depicted. a | When the Hippo pathway is on, mammalian STE20-like protein kinase 1 (MST1) or MST2 phosphorylate Salvador homolog 1 (SAV1), and together they phosphorylate and activate MOB kinase activator 1A (MOB1A), MOB1B, large tumour suppressor homolog 1 (LATS1) kinase and LATS2 kinase, which then phosphorylate Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ). Phosphorylated YAP and TAZ are sequestered in the cytoplasm by the 14-3-3 protein and shunted for proteasomal degradation. As a result, the TEA domain-containing sequence-specific transcription factors (TEADs) associate with the transcription cofactor vestigial-like protein 4 (VGL4) and suppress target gene expression.<|im_end|> <|im_start|>assistant Although fruit flies don't develop cancer, cancer and stem cell researchers have been learning a great deal from fruit flies - in particular, mutant flies with overgrown organs that resemble hippopotamuses. A fly gene called Hippo and its relatives in mammals normally block cell proliferation and limit organ size. When flies have mutations in Hippo or other genes (together dubbed the Hippo pathway), the resulting overgrowth distorts their tissues into hippopotamus-like bulges. In humans, the Hippo pathway is involved in forming embryonic stem cells, suppressing cancerous growth, and also in regenerative growth and wound healing. Working with flies, researchers at Emory have found that the abnormal growth induced by Hippo pathway disruption depends on genes involved in responding to the steroid hormone ecdysone. Their results are scheduled for publication in Developmental Cell. "Ecdysone is, to some degree, the fly version of estrogen," says senior author Ken Moberg, PhD, associate professor of cell biology at Emory University School of Medicine. In fly larvae, ecdysone triggers metamorphosis, in which adult structures such as wings and eyes emerge from small compartments called imaginal discs.. Ecdysone has a chemical structure like that of estrogen, testosterone and other steroid hormones found in humans. Ecdysone is not sex-specific, but it acts with the same mechanism as other steroid hormones, diffusing into cells and binding proteins that bind DNA and regulate gene activity. Postdoctoral fellow Can Zhang, PhD and MD, PhD student Brian Robinson are co-first authors of the Developmental Cell paper. Collaborators at University of Massachusetts, Boston led by Alexey Veraksa, PhD contributed to the paper. The research team discovered that when the Hippo pathway's control is broken, the resulting excess growth in fly imaginal discs,depends on proteins involved in the ecdysone response. The genes that are activated by this combination of Hippo and ecdysone signals in imaginal disc 'tumors' include genes that are usually turned on only in germline stem cells, found in flies' reproductive organs. Activation of these germline stem cell factors by the Hippo pathway requires ecdysone response genes, the researchers found. The researchers concentrated on a protein in flies called Yorkie, which is usually restrained by "upstream" parts of the Hippo pathway. When unleashed, Yorkie travels into the cell nucleus and turns on growth-related genes. "We found that Yorkie does not just engage a developmental growth program in disc tumors," Moberg says. "It is capable of turning on an ectopic program only seen in germline stem cells." The researchers were able to detect a physical interaction between Yorkie and Taiman, a protein important in ecdysone response. Taiman's closest human relative is named Amplified in Breast Cancer-1 or AIB1. These findings point to possible connections in human biology between AIB1 and the Yorkie homologs Yap1 and Taz, Moberg says. "Since both groups of these proteins are often overexpressed in human cancers, we think our findings may have implications for the study of proliferative mechanisms in cancers and possibly cancer stem cells," he says. <|im_end|>

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2,106

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The proportion of Europeans descending from Neolithic farmers ∼ 10 thousand years ago (KYA) or Palaeolithic hunter-gatherers has been much debated. The male-specific region of the Y chromosome (MSY) has been widely applied to this question, but unbiased estimates of diversity and time depth have been lacking. Here we show that European patrilineages underwent a recent continent-wide expansion. Resequencing of 3.7 Mb of MSY DNA in 334 males, comprising 17 European and Middle Eastern populations, defines a phylogeny containing 5,996 single-nucleotide polymorphisms. Dating indicates that three major lineages (I1, R1a and R1b), accounting for 64% of our sample, have very recent coalescent times, ranging between 3.5 and 7.3 KYA. A continuous swathe of 13/17 populations share similar histories featuring a demographic expansion starting ∼ 2.1–4.2 KYA. Our results are compatible with ancient MSY DNA data, and contrast with data on mitochondrial DNA, indicating a widespread male-specific phenomenon that focuses interest on the social structure of Bronze Age Europe. Introduction Controversy has surrounded the origins and antiquity of the people of Europe, focused on the proportions descending from Neolithic farmers originating ∼ 10 thousand years ago (KYA), or from earlier Palaeolithic hunter-gatherers. Early studies observed a European SE–NW cline in classical gene frequency data which was ascribed to demic diffusion of farmers 1 , or, in an alternative view, to the first Palaeolithic colonization 2 . More recent autosomal genome-wide SNP data sets reflect current population structure 3 , 4 and admixture during the last 3,000 years 5 , but have provided little insight into older population processes. Most debate on European prehistory has been stimulated by analyses of uniparentally-inherited markers. Spatial patterns in maternally-inherited mitochondrial DNA (mtDNA) are non-clinal, with age estimates of haplogroups (hg) taken to suggest a major Palaeolithic contribution 6 . Analyses of diversity in the male-specific region of the Y chromosome (MSY) show significant frequency clines in major lineages 7 , and geographical distributions and dates based on short-tandem repeats (STRs) have led to interpretations of both Palaeolithic 8 and Neolithic 9 major components. The most frequent western European lineage, hg R1b-M269, was originally believed to have originated in the Palaeolithic 10 , but in more recent analysis was assigned a Neolithic origin 11 , a claim challenged in turn 12 on the basis of STR choice and sample ascertainment. In general, dates based on STRs are problematic because of uncertainty about appropriate mutation rates, and possible long-term mutation saturation due to their stepwise mutation processes 13 . Palaeolithic dates for the major lineages are challenged by scanty ancient MSY DNA data, which suggest a marked discontinuity between 5–7 KYA and the present 14 . A major cause of the controversy about MSY evidence is that unbiased estimates of diversity and time depth have until recently been impossible to obtain in large samples. Next-generation sequencing (NGS) generally offers unbiased ascertainment of MSY SNPs, providing phylogenies in which topologies inform about past demography, and branch lengths are in principle proportional to time, avoiding dating problems associated with STRs. Some insights have emerged from recent work 15 , 16 , but no systematic population-based NGS study across Europe has yet been undertaken. Here, we use targeted NGS of European and Middle Eastern populations to show that Europe was affected by a major continent-wide expansion in patrilineages that post-dates the Neolithic transition. Resequencing at high coverage of 3.7 Mb of MSY DNA, in each of 334 males comprising 17 population samples, defines an unbiased phylogeny containing 5,996 high-confidence single-nucleotide polymorphisms (SNPs). Dating indicates that three major lineages (I1, R1a and R1b), accounting for 64% of the sampled chromosomes, have very recent coalescent times, ranging between 3.5 and 7.3 KYA. In demographic reconstructions 17 a continuous swathe of 13/17 populations from the Balkans to the British and Irish Isles share similar histories featuring a minimum effective population size ∼ 2.1–4.2 KYA, followed by expansion to the present. Together with other data on maternally inherited mtDNA 16 , 18 and autosomal DNA 19 , our results indicate a recent widespread male-specific phenomenon that may point to social selection, and refocuses interest on the social and population structure of Bronze Age Europe. Results Samples and approach To address the lack of a systematic population-based NGS study of European MSY diversity, we assembled a collection of 20 randomly chosen male DNA samples from each of 17 populations from Europe and the Middle East ( Supplementary Table 1 ). We used a sequence-capture approach to successfully generate 3.7 Mb of unique MSY sequence from 334 of the total set of 340 males. Mean read-depth of 51 × allowed us to call a set of 5,996 high-confidence SNPs ( Supplementary Data 1 ), with a minimum 6 × read-depth. SNP calls were validated using publicly available Y-chromosome sequence information from genome-wide data ( Supplementary Table 2 ). SNPs have been deposited in NCBI dbSNP database and ss numbers can be found in Supplementary Data 1 . Phylogeography of European MSY lineages We constructed a maximum-parsimony tree displaying the phylogenetic relationships between SNP haplotypes ( Fig. 1a ; Supplementary Fig. 1 ), rooted by reference to two MSY sequences 13 from the basal haplogroups A and B. Our sequenced regions cover many previously known SNPs, which allowed us to apply established haplogroup names 20 to clades. Figure 1b shows the geographical distribution of these haplogroups in our samples, which is consistent with previous studies of specific SNPs using larger per-population sample sizes 10 . As expected, the commonest haplogroup is R1b-M269 (43.1%), with highest frequency in the north-west, followed by I1-M253 (13.8%), I2-P215 (9.0%), R1a-M198 (7.5%) and J2-M172 (7.5%). Some clades show geographically-restricted distributions, with hg N1c-M178 being most frequent in the Saami, and sub-lineages of haplogroups E, G and J prevalent in the Mediterranean area. Figure 1: Phylogeny and geographical distribution of European MSY lineages. ( a ) Maximum-parsimony tree of European MSY lineages defined here by resequencing. Branch lengths are proportional to molecular divergence among haplotypes. Key mutation names are given next to", "role": "user" }, { "content": "Geneticists from the University of Leicester have discovered that most European men descend from just a handful of Bronze Age forefathers, due to a 'population explosion' several thousand years ago. The project, which was funded by the Wellcome Trust, was led by Professor Mark Jobling from the University of Leicester's Department of Genetics and the study is published in the prestigious journal Nature Communications. The research team determined the DNA sequences of a large part of the Y chromosome, passed exclusively from fathers to sons, in 334 men from 17 European and Middle Eastern populations. This research used new methods for analysing DNA variation that provides a less biased picture of diversity, and also a better estimate of the timing of population events. This allowed the construction of a genealogical tree of European Y chromosomes that could be used to calculate the ages of branches. Three very young branches, whose shapes indicate recent expansions, account for the Y chromosomes of 64% of the men studied. Professor Jobling said: \"The population expansion falls within the Bronze Age, which involved changes in burial practices, the spread of horse-riding and developments in weaponry. Dominant males linked with these cultures could be responsible for the Y chromosome patterns we see today.\" In addition, past population sizes were estimated, and showed that a continuous swathe of populations from the Balkans to the British Isles underwent an explosion in male population size between 2000 and 4000 years ago. This contrasts with previous results for the Y chromosome, and also with the picture presented by maternally-inherited mitochondrial DNA, which suggests much more ancient population growth. Previous research has focused on the proportion of modern Europeans descending from Paleolithic—Old Stone Age—hunter-gatherer populations or more recent Neolithic farmers, reflecting a transition that began about 10,000 years ago. Chiara Batini from the University of Leicester's Department of Genetics, lead author of the study, added: \"Given the cultural complexity of the Bronze Age, it's difficult to link a particular event to the population growth that we infer. But Y-chromosome DNA sequences from skeletal remains are becoming available, and this will help us to understand what happened, and when.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The proportion of Europeans descending from Neolithic farmers ∼ 10 thousand years ago (KYA) or Palaeolithic hunter-gatherers has been much debated. The male-specific region of the Y chromosome (MSY) has been widely applied to this question, but unbiased estimates of diversity and time depth have been lacking. Here we show that European patrilineages underwent a recent continent-wide expansion. Resequencing of 3.7 Mb of MSY DNA in 334 males, comprising 17 European and Middle Eastern populations, defines a phylogeny containing 5,996 single-nucleotide polymorphisms. Dating indicates that three major lineages (I1, R1a and R1b), accounting for 64% of our sample, have very recent coalescent times, ranging between 3.5 and 7.3 KYA. A continuous swathe of 13/17 populations share similar histories featuring a demographic expansion starting ∼ 2.1–4.2 KYA. Our results are compatible with ancient MSY DNA data, and contrast with data on mitochondrial DNA, indicating a widespread male-specific phenomenon that focuses interest on the social structure of Bronze Age Europe. Introduction Controversy has surrounded the origins and antiquity of the people of Europe, focused on the proportions descending from Neolithic farmers originating ∼ 10 thousand years ago (KYA), or from earlier Palaeolithic hunter-gatherers. Early studies observed a European SE–NW cline in classical gene frequency data which was ascribed to demic diffusion of farmers 1 , or, in an alternative view, to the first Palaeolithic colonization 2 . More recent autosomal genome-wide SNP data sets reflect current population structure 3 , 4 and admixture during the last 3,000 years 5 , but have provided little insight into older population processes. Most debate on European prehistory has been stimulated by analyses of uniparentally-inherited markers. Spatial patterns in maternally-inherited mitochondrial DNA (mtDNA) are non-clinal, with age estimates of haplogroups (hg) taken to suggest a major Palaeolithic contribution 6 . Analyses of diversity in the male-specific region of the Y chromosome (MSY) show significant frequency clines in major lineages 7 , and geographical distributions and dates based on short-tandem repeats (STRs) have led to interpretations of both Palaeolithic 8 and Neolithic 9 major components. The most frequent western European lineage, hg R1b-M269, was originally believed to have originated in the Palaeolithic 10 , but in more recent analysis was assigned a Neolithic origin 11 , a claim challenged in turn 12 on the basis of STR choice and sample ascertainment. In general, dates based on STRs are problematic because of uncertainty about appropriate mutation rates, and possible long-term mutation saturation due to their stepwise mutation processes 13 . Palaeolithic dates for the major lineages are challenged by scanty ancient MSY DNA data, which suggest a marked discontinuity between 5–7 KYA and the present 14 . A major cause of the controversy about MSY evidence is that unbiased estimates of diversity and time depth have until recently been impossible to obtain in large samples. Next-generation sequencing (NGS) generally offers unbiased ascertainment of MSY SNPs, providing phylogenies in which topologies inform about past demography, and branch lengths are in principle proportional to time, avoiding dating problems associated with STRs. Some insights have emerged from recent work 15 , 16 , but no systematic population-based NGS study across Europe has yet been undertaken. Here, we use targeted NGS of European and Middle Eastern populations to show that Europe was affected by a major continent-wide expansion in patrilineages that post-dates the Neolithic transition. Resequencing at high coverage of 3.7 Mb of MSY DNA, in each of 334 males comprising 17 population samples, defines an unbiased phylogeny containing 5,996 high-confidence single-nucleotide polymorphisms (SNPs). Dating indicates that three major lineages (I1, R1a and R1b), accounting for 64% of the sampled chromosomes, have very recent coalescent times, ranging between 3.5 and 7.3 KYA. In demographic reconstructions 17 a continuous swathe of 13/17 populations from the Balkans to the British and Irish Isles share similar histories featuring a minimum effective population size ∼ 2.1–4.2 KYA, followed by expansion to the present. Together with other data on maternally inherited mtDNA 16 , 18 and autosomal DNA 19 , our results indicate a recent widespread male-specific phenomenon that may point to social selection, and refocuses interest on the social and population structure of Bronze Age Europe. Results Samples and approach To address the lack of a systematic population-based NGS study of European MSY diversity, we assembled a collection of 20 randomly chosen male DNA samples from each of 17 populations from Europe and the Middle East ( Supplementary Table 1 ). We used a sequence-capture approach to successfully generate 3.7 Mb of unique MSY sequence from 334 of the total set of 340 males. Mean read-depth of 51 × allowed us to call a set of 5,996 high-confidence SNPs ( Supplementary Data 1 ), with a minimum 6 × read-depth. SNP calls were validated using publicly available Y-chromosome sequence information from genome-wide data ( Supplementary Table 2 ). SNPs have been deposited in NCBI dbSNP database and ss numbers can be found in Supplementary Data 1 . Phylogeography of European MSY lineages We constructed a maximum-parsimony tree displaying the phylogenetic relationships between SNP haplotypes ( Fig. 1a ; Supplementary Fig. 1 ), rooted by reference to two MSY sequences 13 from the basal haplogroups A and B. Our sequenced regions cover many previously known SNPs, which allowed us to apply established haplogroup names 20 to clades. Figure 1b shows the geographical distribution of these haplogroups in our samples, which is consistent with previous studies of specific SNPs using larger per-population sample sizes 10 . As expected, the commonest haplogroup is R1b-M269 (43.1%), with highest frequency in the north-west, followed by I1-M253 (13.8%), I2-P215 (9.0%), R1a-M198 (7.5%) and J2-M172 (7.5%). Some clades show geographically-restricted distributions, with hg N1c-M178 being most frequent in the Saami, and sub-lineages of haplogroups E, G and J prevalent in the Mediterranean area. Figure 1: Phylogeny and geographical distribution of European MSY lineages. ( a ) Maximum-parsimony tree of European MSY lineages defined here by resequencing. Branch lengths are proportional to molecular divergence among haplotypes. Key mutation names are given next to<|im_end|> <|im_start|>assistant Geneticists from the University of Leicester have discovered that most European men descend from just a handful of Bronze Age forefathers, due to a 'population explosion' several thousand years ago. The project, which was funded by the Wellcome Trust, was led by Professor Mark Jobling from the University of Leicester's Department of Genetics and the study is published in the prestigious journal Nature Communications. The research team determined the DNA sequences of a large part of the Y chromosome, passed exclusively from fathers to sons, in 334 men from 17 European and Middle Eastern populations. This research used new methods for analysing DNA variation that provides a less biased picture of diversity, and also a better estimate of the timing of population events. This allowed the construction of a genealogical tree of European Y chromosomes that could be used to calculate the ages of branches. Three very young branches, whose shapes indicate recent expansions, account for the Y chromosomes of 64% of the men studied. Professor Jobling said: "The population expansion falls within the Bronze Age, which involved changes in burial practices, the spread of horse-riding and developments in weaponry. Dominant males linked with these cultures could be responsible for the Y chromosome patterns we see today." In addition, past population sizes were estimated, and showed that a continuous swathe of populations from the Balkans to the British Isles underwent an explosion in male population size between 2000 and 4000 years ago. This contrasts with previous results for the Y chromosome, and also with the picture presented by maternally-inherited mitochondrial DNA, which suggests much more ancient population growth. Previous research has focused on the proportion of modern Europeans descending from Paleolithic—Old Stone Age—hunter-gatherer populations or more recent Neolithic farmers, reflecting a transition that began about 10,000 years ago. Chiara Batini from the University of Leicester's Department of Genetics, lead author of the study, added: "Given the cultural complexity of the Bronze Age, it's difficult to link a particular event to the population growth that we infer. But Y-chromosome DNA sequences from skeletal remains are becoming available, and this will help us to understand what happened, and when." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The relationships between crop productivity and climate variability drivers are often assumed to be stationary over time. However, this may not be true in a warming climate. Here we use a crop model and a machine learning algorithm to demonstrate the changing impacts of climate drivers on wheat productivity in Australia. We find that, from the end of the nineteenth century to the 1980s, wheat productivity was mainly subject to the impacts of the El Niño Southern Oscillation. Since the 1990s, the impacts from the El Niño Southern Oscillation have been decreasing, but those from the Indian Ocean Dipole have been increasing. The warming climate has brought more occurrences of positive Indian Ocean Dipole events, resulting in severe yield reductions in recent decades. Our findings highlight the need to adapt seasonal forecasting to the changing impacts of climate variability to inform the management of climate-induced yield losses. Main Rapid increases in global population and affluence call for increased quantity in food supply. Although the impacts of climate warming on agriculture may vary in different regions 1 , overall, global agriculture will need to double its production of major cereal crops to feed 10 billion people by the 2050s, translating to a ~2.4% growth in crop production per year (ref. 2 ). As food systems are increasingly globalized and interdependent, it is expected that a large portion of this growth will come from an increase in crop yields in the countries that are currently the primary crop-producing and crop-exporting countries. However, maintaining stable crop yields in these countries (especially with a Mediterranean climate) is challenging as year-to-year climate variability often subjects crops to unfavourable climate conditions, including floods, droughts and heat stress. The climate variability can be managed by optimizing farm inputs (for example, seed and fertilizer) in potentially ‘good’ or ‘bad’ seasons if weather anomalies can be reliably informed in advance. However, skilful weather forecasts are reliable only within a 2-week horizon, which is usually not enough for cultivation plans to be made in terms of seasonal crops. Instead, producers are increasingly being informed by seasonal forecasts that rely on the behaviour of large-scale climate drivers. Weather conditions (for example, rainfall and temperature) in many regions can be regularly influenced by large-scale climate drivers from surrounding oceans 3 , 4 , such as the El Niño Southern Oscillation (ENSO), the most prominent inter-annual phenomenon in the tropical Pacific. Consequently, there is a relation chain that climate drivers modulate local weather that affect crop productivity. Furthermore, scientific advances have improved the skill in forecasting the dynamics of climate drivers, with lead times ranging from several months up to a year 5 . Farmers can benefit from the routine availability of climate driver forecasts by changing their strategies to adapt to the upcoming season. The relationships between crop productivity and climate drivers are generally region specific. However, ENSO has been shown to be a dominant driver, with over 28% of global cropland subjected to considerable impacts of ENSO anomalies during 1961–2010 (ref. 6 ). ENSO-based seasonal climate or crop yield forecasting approaches for different regions were developed decades ago 7 , 8 . These are mostly derived from traditional linear regression or correlation analyses that do not allow for potential non-linear changes in the impacts of ENSO or changes in the relative importance of different climate drivers that could develop under a background of climate warming. Previous studies have revealed that climate drivers are non-stationary phenomena, and their characteristics (for example, spatial patterns, variance, duration and frequency) and impacts on regional climate conditions can change over time. For example, ENSO characteristics can change over time 9 , and its impacts can be modified by modes of climate variability operating on inter-decadal and longer timescales 10 . Australia is one of the world’s largest producers and exporters of wheat, accounting for 10–15% of annual global wheat exports. Consequently, Australia plays a key role in global food supply at present, and is expected to continue to do so in the future. It is well established that inter-annual variability of Australia’s climate is heavily influenced by climate drivers from the three surrounding oceans: ENSO in the Pacific Ocean, the Indian Ocean Dipole (IOD, an east–west gradient of sea surface temperature (SST) across the tropical Indian Ocean), and the Southern Annular Mode (SAM, a north–south movement of the mid-latitude circumpolar westerly winds) over the Southern Ocean 3 , 11 , 12 . IOD variability is being altered by climate change 13 and has played a more important role in several severe drought events in Indian-Ocean-rim countries during recent decades 14 , 15 . Similarly, climate change is resulting in changes in SAM that are outside the range of pre-industrial natural variability of the last millennium 16 . Therefore, it is likely that the impacts of large-scale climate drivers on crop yields are not stable. In this Article, we use the Australian wheatbelt as a case region to explore the potential changing impacts of climate drivers on crop yields. Improving our understanding of any changes in the impacts of these climate drivers on Australian wheat productivity has important implications for increasing the resilience of global food production. Results Descriptive statistics of wheat productivity and climate drivers Climate drivers can change from decade to decade. To sample this variation, long-term datasets of climate drivers and crop yields are needed to evaluate potential changes in climate variability and its impacts on crop yields. Long-term climate driver data are relatively easy to obtain, but observed crop yield datasets at century scale are rare. An additional challenge is that it is difficult to isolate the impacts of climate fluctuations on crop productivity in such datasets, as change in observed crop yields is also driven by many other non-climatic factors, including changes in agronomic management practices and technology development. We address these challenges by simulating wheat yield data with rainfall, solar radiation, and maximum and minimum temperature from a climate dataset starting in 1889, with all other non-climatic factors kept constant", "role": "user" }, { "content": "A team of researchers affiliated with multiple institutions in China and Australia attributes reduced rainfall on Australian wheat fields to disruptions to the Indian Ocean Dipole due to climate change. The study is published in Nature Food. Prior research has shown that the Indian Ocean Dipole (IOD) has a major impact on the amount of rainfall in Australia. In years with a positive IOD, warm sea surface water is pushed by winds toward Africa, leaving cooler water near Indonesia and parts of Australia. This results in less rainfall in both areas. During years of negative IOD, the reverse occurs, and more rain falls on Australia. In neutral years, the IOD has no impact on rain in Australia. Prior research has also shown that wet La Niña and dry El Niño events also have an impact on the amount of rainfall in Australia. In this new effort, the researchers studied these events as the region grows warmer due to climate change using machine learning. The work involved studying rainfall patterns over Australia going back to the 1800s. They trained a machine-learning application to recognize impacts of changes to the IOD and/or La Niña and El Niño events using the data they compiled. They used data from the machine learning app to create a model depicting weather conditions for the region over the past several years and predicting what might occur in the future. They also added data regarding wheat yields, crop management changes, sowing and reaping times and the kinds of wheat that have been planted. The model showed that as the climate has grown warmer, there have been more frequent positive IOD events, leading to less rainfall, which has led to slowly decreasing crop yields—a finding that matches reports from wheat farmers. They also found that during times when positive IOD events coincided with El Niño events, Australia experienced extremely dry conditions. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The relationships between crop productivity and climate variability drivers are often assumed to be stationary over time. However, this may not be true in a warming climate. Here we use a crop model and a machine learning algorithm to demonstrate the changing impacts of climate drivers on wheat productivity in Australia. We find that, from the end of the nineteenth century to the 1980s, wheat productivity was mainly subject to the impacts of the El Niño Southern Oscillation. Since the 1990s, the impacts from the El Niño Southern Oscillation have been decreasing, but those from the Indian Ocean Dipole have been increasing. The warming climate has brought more occurrences of positive Indian Ocean Dipole events, resulting in severe yield reductions in recent decades. Our findings highlight the need to adapt seasonal forecasting to the changing impacts of climate variability to inform the management of climate-induced yield losses. Main Rapid increases in global population and affluence call for increased quantity in food supply. Although the impacts of climate warming on agriculture may vary in different regions 1 , overall, global agriculture will need to double its production of major cereal crops to feed 10 billion people by the 2050s, translating to a ~2.4% growth in crop production per year (ref. 2 ). As food systems are increasingly globalized and interdependent, it is expected that a large portion of this growth will come from an increase in crop yields in the countries that are currently the primary crop-producing and crop-exporting countries. However, maintaining stable crop yields in these countries (especially with a Mediterranean climate) is challenging as year-to-year climate variability often subjects crops to unfavourable climate conditions, including floods, droughts and heat stress. The climate variability can be managed by optimizing farm inputs (for example, seed and fertilizer) in potentially ‘good’ or ‘bad’ seasons if weather anomalies can be reliably informed in advance. However, skilful weather forecasts are reliable only within a 2-week horizon, which is usually not enough for cultivation plans to be made in terms of seasonal crops. Instead, producers are increasingly being informed by seasonal forecasts that rely on the behaviour of large-scale climate drivers. Weather conditions (for example, rainfall and temperature) in many regions can be regularly influenced by large-scale climate drivers from surrounding oceans 3 , 4 , such as the El Niño Southern Oscillation (ENSO), the most prominent inter-annual phenomenon in the tropical Pacific. Consequently, there is a relation chain that climate drivers modulate local weather that affect crop productivity. Furthermore, scientific advances have improved the skill in forecasting the dynamics of climate drivers, with lead times ranging from several months up to a year 5 . Farmers can benefit from the routine availability of climate driver forecasts by changing their strategies to adapt to the upcoming season. The relationships between crop productivity and climate drivers are generally region specific. However, ENSO has been shown to be a dominant driver, with over 28% of global cropland subjected to considerable impacts of ENSO anomalies during 1961–2010 (ref. 6 ). ENSO-based seasonal climate or crop yield forecasting approaches for different regions were developed decades ago 7 , 8 . These are mostly derived from traditional linear regression or correlation analyses that do not allow for potential non-linear changes in the impacts of ENSO or changes in the relative importance of different climate drivers that could develop under a background of climate warming. Previous studies have revealed that climate drivers are non-stationary phenomena, and their characteristics (for example, spatial patterns, variance, duration and frequency) and impacts on regional climate conditions can change over time. For example, ENSO characteristics can change over time 9 , and its impacts can be modified by modes of climate variability operating on inter-decadal and longer timescales 10 . Australia is one of the world’s largest producers and exporters of wheat, accounting for 10–15% of annual global wheat exports. Consequently, Australia plays a key role in global food supply at present, and is expected to continue to do so in the future. It is well established that inter-annual variability of Australia’s climate is heavily influenced by climate drivers from the three surrounding oceans: ENSO in the Pacific Ocean, the Indian Ocean Dipole (IOD, an east–west gradient of sea surface temperature (SST) across the tropical Indian Ocean), and the Southern Annular Mode (SAM, a north–south movement of the mid-latitude circumpolar westerly winds) over the Southern Ocean 3 , 11 , 12 . IOD variability is being altered by climate change 13 and has played a more important role in several severe drought events in Indian-Ocean-rim countries during recent decades 14 , 15 . Similarly, climate change is resulting in changes in SAM that are outside the range of pre-industrial natural variability of the last millennium 16 . Therefore, it is likely that the impacts of large-scale climate drivers on crop yields are not stable. In this Article, we use the Australian wheatbelt as a case region to explore the potential changing impacts of climate drivers on crop yields. Improving our understanding of any changes in the impacts of these climate drivers on Australian wheat productivity has important implications for increasing the resilience of global food production. Results Descriptive statistics of wheat productivity and climate drivers Climate drivers can change from decade to decade. To sample this variation, long-term datasets of climate drivers and crop yields are needed to evaluate potential changes in climate variability and its impacts on crop yields. Long-term climate driver data are relatively easy to obtain, but observed crop yield datasets at century scale are rare. An additional challenge is that it is difficult to isolate the impacts of climate fluctuations on crop productivity in such datasets, as change in observed crop yields is also driven by many other non-climatic factors, including changes in agronomic management practices and technology development. We address these challenges by simulating wheat yield data with rainfall, solar radiation, and maximum and minimum temperature from a climate dataset starting in 1889, with all other non-climatic factors kept constant<|im_end|> <|im_start|>assistant A team of researchers affiliated with multiple institutions in China and Australia attributes reduced rainfall on Australian wheat fields to disruptions to the Indian Ocean Dipole due to climate change. The study is published in Nature Food. Prior research has shown that the Indian Ocean Dipole (IOD) has a major impact on the amount of rainfall in Australia. In years with a positive IOD, warm sea surface water is pushed by winds toward Africa, leaving cooler water near Indonesia and parts of Australia. This results in less rainfall in both areas. During years of negative IOD, the reverse occurs, and more rain falls on Australia. In neutral years, the IOD has no impact on rain in Australia. Prior research has also shown that wet La Niña and dry El Niño events also have an impact on the amount of rainfall in Australia. In this new effort, the researchers studied these events as the region grows warmer due to climate change using machine learning. The work involved studying rainfall patterns over Australia going back to the 1800s. They trained a machine-learning application to recognize impacts of changes to the IOD and/or La Niña and El Niño events using the data they compiled. They used data from the machine learning app to create a model depicting weather conditions for the region over the past several years and predicting what might occur in the future. They also added data regarding wheat yields, crop management changes, sowing and reaping times and the kinds of wheat that have been planted. The model showed that as the climate has grown warmer, there have been more frequent positive IOD events, leading to less rainfall, which has led to slowly decreasing crop yields—a finding that matches reports from wheat farmers. They also found that during times when positive IOD events coincided with El Niño events, Australia experienced extremely dry conditions. <|im_end|>

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1,636

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Global ageing poses a substantial economic burden on health and social care costs. Enabling a greater proportion of older people to stay healthy for longer is key to the future sustainability of health, social and economic policy. Frailty and associated decrease in resilience plays a central role in poor health in later life. In this study, we present a population level assessment of the metabolic phenotype associated with frailty. Analysis of serum from 1191 older individuals (aged between 56 and 84 years old) and subsequent longitudinal validation (on 786 subjects) was carried out using liquid and gas chromatography-mass spectrometry metabolomics and stratified across a frailty index designed to quantitatively summarize vulnerability. Through multivariate regression and network modelling and mROC modeling we identified 12 significant metabolites (including three tocotrienols and six carnitines) that differentiate frail and non-frail phenotypes. Our study provides evidence that the dysregulation of carnitine shuttle and vitamin E pathways play a role in the risk of frailty. Introduction A consequence of ageing is the decline in biological function that will eventually lead to a progressive deterioration of physiological performance, a decline in the ability to respond to stress and an associated increase in vulnerability. Since 1950 life expectancy has been rising at a rate of more than three years per decade, and since the onset of the millennium this has risen to five years per decade 1 . As a consequence, it is estimated that between 2015 and 2050 the global proportion of over 60-year olds will increase from 12 to 22% 2 , while the number of over-65s is forecast to triple by 2050 3 , even though recent evidence suggests that maximum lifespan could be fixed 4 , 5 . While increasing life expectancies are a positive development, all individuals are still currently subject to natural constraints and face decline in health status with age (albeit at rates that vary across populations and sub-populations 6 ) increasing the risk of exposure to chronic age-related disorders 7 . So, in 2015 the global healthy life expectancy at birth (HALE) was calculated to be 63.1 years 8 , which indicates a substantial burden of later life morbidity, even though rises in HALE are a testament to continuing global healthcare advancements including medical diagnosis and treatment of cardiovascular disease 9 , immunization 10 , smoking cessation 11 , healthy diet 12 and an increased understanding of social determinants of health 13 . Such demographic shifts and resulting population ageing are leading public health practitioners and policy makers to actively push for global innovations that can positively shape the health of future elderly populations 14 , 15 , 16 . Indeed, healthy ageing in later life has enormous potential to affect society as a whole. Consequently, to mitigate the potential economic and social strains that flow from population ageing brings call for direct government initiatives to develop appropriate public health interventions to reduce the impact of functional decline associated with frailty. Clinically, the effects of frailty are defined as a multimodal syndrome emphasized by a loss of internal reserves (energy, physical ability, balance, cognition, and health) that gives rise to biological vulnerability within an individual. This inherent complexity means that there is no single diagnostic tool available to identify the presence and extent of frailty. However, a myriad of scoring instruments are reported within the literature. These typically assess a number of negative outcomes, or distal phenotypes, and are validated by stratifying the scoring aspects of large patient cohorts such as surgical prognosis 15 , primary care interventions 16 , 17 , 18 , 19 , 20 and associated key detrimental events and are subsequently used in the development of instruments that can be used to evaluate the presence of frailty, such as the frailty phenotype 21 and frailty index (FI) 22 . Although these methods have acceptable performance in identification of frailty status, they have some limitations, including subjectivity of individual answers, resource utilisation costs and lack of linkage to underlying biological mechanisms 23 . Orthogonal to such procedures, biochemical assessments of frailty in the context of biomarker detection are sought after as they hold the potential to identify biological pathways that contribute to a frailty phenotype, offering opportunities in developing strategies for the identification and management of frailty. A focus for the bio-gerontology community within this area has been the chemistry of life contained within the central dogma of molecular biology. Several large cohort studies have demonstrated correlation between mitochondrial DNA and energy co-factors alongside mortality 24 , 25 , dysregulation of transcriptional networks and age-dependent decline 26 , alongside metabolic signatures of biological ageing in young 27 and older people 28 . By contrast, no such large scale, population level comparison of frailty identified using a validated measure versus metabolism has been undertaken. Yet the ability to uncover downstream biochemical relationships by applying metabolomics based approaches hold great potential for the development of public health strategies to reduce the risk of frailty and its adverse consequences. As the complex links between age-related frailty and the underlying life-course, social, psychological, genetic and metabolic processes remain unclear, the fRaill project ( ) takes an interdisciplinary approach to examine the causal processes relating to frailty and wellbeing at older ages. Within this work, we performed high-throughput untargeted mass spectrometry-based metabolic profiling coupled with pathway and network analysis on longitudinal serum samples, taken four years apart, from a cohort of well-phenotyped ageing (≥58 years old) subjects from the English Longitudinal Study of Ageing ( ). The aim of this approach is to stratify metabolic phenotypes (metabotypes 29 ) over a FI derived from over 60 measured indicators and assess whether associated biochemical networks relate to biological degeneration associated with frailty. From this work we have identified a panel of 12 metabolites associated with the FI and from these, two chemical classes (tocotrienols and carnitines) exhibit significantly modulated under-expression when overlaid across the FI. Subsequent network enrichment analysis and statistical modelling has identified carnitine shuttle and vitamin E metabolism as two", "role": "user" }, { "content": "Signs of frailty, and the risks it brings, could be identified in young and old people alike through a new assessment developed in a study led by researchers at the University of Strathclyde. Increasing risk of frailty is a defining characteristic of the ageing process but it has no precise clinical definition and there are currently no analytical techniques that can accurately quantify its status. Furthermore, little is known about the underlying biological mechanisms of frailty but the new research has revealed a set of blood biomarkers that can predict its extent. Further down the line, it could potentially achieve this with people as young as in their 20s or 30s. The assessment could also determine whether a patient would be able to withstand intensive courses of treatment, such as chemotherapy, as well as helping to understand, prevent, cure or minimise age-related impairments. The research also involved partners from the Universities of Manchester, Liverpool and Edinburgh and Yale University. It has been published in the journal Nature Communications. Dr. Nicholas Rattray, a Chancellor's Fellow with Strathclyde Institute of Pharmacy and Biomedical Sciences, led the study. He said: \"Being able to measure the frailty status of a person is currently a very subjective clinical assessment and is ultimately causing a delay in the personalisation of therapeutic options for frail patients. \"By using cutting-edge analytical techniques such as mass spectrometry based metabolomics, this research has opened the door to developing ways to rapidly and accurately quantify frailty and apply this knowledge directly within the clinical environment. \"We believe this assessment is the first of its kind. It could lead to a far deeper understanding of the ageing process and how to potentially develop intervention strategies for ageing poorly.\" Professor Roy Goodacre from the University of Liverpool said: \"I am excited by this work as this shows that large-scale metabolomics has for the first time shown clear biochemical changes in people with frailty which may with future work lead to therapy to help revert these individuals back to a resilient phenotype which will improve quality of life.\" Professor James Nazroo, from the University of Manchester said \"These crucially important findings pave the way for providing accurate diagnostic procedures for identifying risk of frailty, but also for understanding the mechanisms that lie behind that risk and the possibility of intervening to reduce risk and the negative consequences that follow from frailty.\" Professor Neil Pendleton from the University of Manchester said \"identification of frailty is complex, requiring expertise not widely available. Using these findings could offer potential to expand opportunities for diagnosis when interventions are possible.\" Although there is currently no widely accepted clinical or biomedical definition of frailty, there exists a series of clinical scoring metrics, or frailty indices, which can help in the assessment of a patient's resilience. They include measures of physical fitness, falls and fractures, vision, hearing, chronic diseases and depression. The researchers analysed blood serum samples from 1191 people aged between 56 and 84 and followed up on 786 of the participants four years later. They weighed and identified molecules in the samples from the blood of 1200 elderly people, using machine learning to categorise bio-signatures of frailty. A set of 12 metabolites—substances produced in metabolism—were identified and were found to differentiate between frail and non-frail people. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Global ageing poses a substantial economic burden on health and social care costs. Enabling a greater proportion of older people to stay healthy for longer is key to the future sustainability of health, social and economic policy. Frailty and associated decrease in resilience plays a central role in poor health in later life. In this study, we present a population level assessment of the metabolic phenotype associated with frailty. Analysis of serum from 1191 older individuals (aged between 56 and 84 years old) and subsequent longitudinal validation (on 786 subjects) was carried out using liquid and gas chromatography-mass spectrometry metabolomics and stratified across a frailty index designed to quantitatively summarize vulnerability. Through multivariate regression and network modelling and mROC modeling we identified 12 significant metabolites (including three tocotrienols and six carnitines) that differentiate frail and non-frail phenotypes. Our study provides evidence that the dysregulation of carnitine shuttle and vitamin E pathways play a role in the risk of frailty. Introduction A consequence of ageing is the decline in biological function that will eventually lead to a progressive deterioration of physiological performance, a decline in the ability to respond to stress and an associated increase in vulnerability. Since 1950 life expectancy has been rising at a rate of more than three years per decade, and since the onset of the millennium this has risen to five years per decade 1 . As a consequence, it is estimated that between 2015 and 2050 the global proportion of over 60-year olds will increase from 12 to 22% 2 , while the number of over-65s is forecast to triple by 2050 3 , even though recent evidence suggests that maximum lifespan could be fixed 4 , 5 . While increasing life expectancies are a positive development, all individuals are still currently subject to natural constraints and face decline in health status with age (albeit at rates that vary across populations and sub-populations 6 ) increasing the risk of exposure to chronic age-related disorders 7 . So, in 2015 the global healthy life expectancy at birth (HALE) was calculated to be 63.1 years 8 , which indicates a substantial burden of later life morbidity, even though rises in HALE are a testament to continuing global healthcare advancements including medical diagnosis and treatment of cardiovascular disease 9 , immunization 10 , smoking cessation 11 , healthy diet 12 and an increased understanding of social determinants of health 13 . Such demographic shifts and resulting population ageing are leading public health practitioners and policy makers to actively push for global innovations that can positively shape the health of future elderly populations 14 , 15 , 16 . Indeed, healthy ageing in later life has enormous potential to affect society as a whole. Consequently, to mitigate the potential economic and social strains that flow from population ageing brings call for direct government initiatives to develop appropriate public health interventions to reduce the impact of functional decline associated with frailty. Clinically, the effects of frailty are defined as a multimodal syndrome emphasized by a loss of internal reserves (energy, physical ability, balance, cognition, and health) that gives rise to biological vulnerability within an individual. This inherent complexity means that there is no single diagnostic tool available to identify the presence and extent of frailty. However, a myriad of scoring instruments are reported within the literature. These typically assess a number of negative outcomes, or distal phenotypes, and are validated by stratifying the scoring aspects of large patient cohorts such as surgical prognosis 15 , primary care interventions 16 , 17 , 18 , 19 , 20 and associated key detrimental events and are subsequently used in the development of instruments that can be used to evaluate the presence of frailty, such as the frailty phenotype 21 and frailty index (FI) 22 . Although these methods have acceptable performance in identification of frailty status, they have some limitations, including subjectivity of individual answers, resource utilisation costs and lack of linkage to underlying biological mechanisms 23 . Orthogonal to such procedures, biochemical assessments of frailty in the context of biomarker detection are sought after as they hold the potential to identify biological pathways that contribute to a frailty phenotype, offering opportunities in developing strategies for the identification and management of frailty. A focus for the bio-gerontology community within this area has been the chemistry of life contained within the central dogma of molecular biology. Several large cohort studies have demonstrated correlation between mitochondrial DNA and energy co-factors alongside mortality 24 , 25 , dysregulation of transcriptional networks and age-dependent decline 26 , alongside metabolic signatures of biological ageing in young 27 and older people 28 . By contrast, no such large scale, population level comparison of frailty identified using a validated measure versus metabolism has been undertaken. Yet the ability to uncover downstream biochemical relationships by applying metabolomics based approaches hold great potential for the development of public health strategies to reduce the risk of frailty and its adverse consequences. As the complex links between age-related frailty and the underlying life-course, social, psychological, genetic and metabolic processes remain unclear, the fRaill project ( ) takes an interdisciplinary approach to examine the causal processes relating to frailty and wellbeing at older ages. Within this work, we performed high-throughput untargeted mass spectrometry-based metabolic profiling coupled with pathway and network analysis on longitudinal serum samples, taken four years apart, from a cohort of well-phenotyped ageing (≥58 years old) subjects from the English Longitudinal Study of Ageing ( ). The aim of this approach is to stratify metabolic phenotypes (metabotypes 29 ) over a FI derived from over 60 measured indicators and assess whether associated biochemical networks relate to biological degeneration associated with frailty. From this work we have identified a panel of 12 metabolites associated with the FI and from these, two chemical classes (tocotrienols and carnitines) exhibit significantly modulated under-expression when overlaid across the FI. Subsequent network enrichment analysis and statistical modelling has identified carnitine shuttle and vitamin E metabolism as two<|im_end|> <|im_start|>assistant Signs of frailty, and the risks it brings, could be identified in young and old people alike through a new assessment developed in a study led by researchers at the University of Strathclyde. Increasing risk of frailty is a defining characteristic of the ageing process but it has no precise clinical definition and there are currently no analytical techniques that can accurately quantify its status. Furthermore, little is known about the underlying biological mechanisms of frailty but the new research has revealed a set of blood biomarkers that can predict its extent. Further down the line, it could potentially achieve this with people as young as in their 20s or 30s. The assessment could also determine whether a patient would be able to withstand intensive courses of treatment, such as chemotherapy, as well as helping to understand, prevent, cure or minimise age-related impairments. The research also involved partners from the Universities of Manchester, Liverpool and Edinburgh and Yale University. It has been published in the journal Nature Communications. Dr. Nicholas Rattray, a Chancellor's Fellow with Strathclyde Institute of Pharmacy and Biomedical Sciences, led the study. He said: "Being able to measure the frailty status of a person is currently a very subjective clinical assessment and is ultimately causing a delay in the personalisation of therapeutic options for frail patients. "By using cutting-edge analytical techniques such as mass spectrometry based metabolomics, this research has opened the door to developing ways to rapidly and accurately quantify frailty and apply this knowledge directly within the clinical environment. "We believe this assessment is the first of its kind. It could lead to a far deeper understanding of the ageing process and how to potentially develop intervention strategies for ageing poorly." Professor Roy Goodacre from the University of Liverpool said: "I am excited by this work as this shows that large-scale metabolomics has for the first time shown clear biochemical changes in people with frailty which may with future work lead to therapy to help revert these individuals back to a resilient phenotype which will improve quality of life." Professor James Nazroo, from the University of Manchester said "These crucially important findings pave the way for providing accurate diagnostic procedures for identifying risk of frailty, but also for understanding the mechanisms that lie behind that risk and the possibility of intervening to reduce risk and the negative consequences that follow from frailty." Professor Neil Pendleton from the University of Manchester said "identification of frailty is complex, requiring expertise not widely available. Using these findings could offer potential to expand opportunities for diagnosis when interventions are possible." Although there is currently no widely accepted clinical or biomedical definition of frailty, there exists a series of clinical scoring metrics, or frailty indices, which can help in the assessment of a patient's resilience. They include measures of physical fitness, falls and fractures, vision, hearing, chronic diseases and depression. The researchers analysed blood serum samples from 1191 people aged between 56 and 84 and followed up on 786 of the participants four years later. They weighed and identified molecules in the samples from the blood of 1200 elderly people, using machine learning to categorise bio-signatures of frailty. A set of 12 metabolites—substances produced in metabolism—were identified and were found to differentiate between frail and non-frail people. <|im_end|>

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1,946

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Human machine interfaces that can track head motion will result in advances in physical rehabilitation, improved augmented reality/virtual reality systems, and aid in the study of human behavior. This paper presents a head position monitoring and classification system using thin flexible strain sensing threads placed on the neck of an individual. A wireless circuit module consisting of impedance readout circuitry and a Bluetooth module records and transmits strain information to a computer. A data processing algorithm for motion recognition provides near real-time quantification of head position. Incoming data is filtered, normalized and divided into data segments. A set of features is extracted from each data segment and employed as input to nine classifiers including Support Vector Machine, Naive Bayes and KNN for position prediction. A testing accuracy of around 92% was achieved for a set of nine head orientations. Results indicate that this human machine interface platform is accurate, flexible, easy to use, and cost effective. Introduction The monitoring of head motions can be very useful in many applications including the study of human behavior. For example, it can improve our understanding of one’s attention, focus and emotional state. In a classroom setting, head movements can be translated into students’ gaze direction and serve to detect students’ attentiveness during class 1 . Similarly, this technology can be applied to a driving situation, where a distracted or tired driver can be alerted through detecting abnormalities in their head motion. Head motions such as tilting and nodding when speaking or singing encode a person’s emotional intent and serve as an indication for the speakers’ interpersonal relationship in dialogs 2 , 3 . Many of the current head and neck motion monitoring systems have been developed for measuring the Cervical Range of Motion (CROM) in the diagnosis of neck pain. Most of these designs employ an Inertial Measurement Unit (IMU) to obtain highly precise measurements required by the underlying application. For example, a wearable wireless inertial sensor has been proposed by Raya et al. 4 . Their design employed a MEMS-based IMU sensor consisting of the 3-axis gyroscopes, accelerometers, and magnetometers to achieve nine degrees of freedom. The measurements require the use of two of such sensors, one placed on the forehead and one on the vertebrae. Alternative methods have also been presented, Al-Nasri et al. utilized a commercially available C-stretch band to measure neck movement by placing the band around the top of the head 5 . Sarig-Bahat et al. made use of the current virtual reality technology to measure the range of motion of the neck 6 . However, in certain non-medical situations and for our purposes, general motion monitoring instead of precise measurement of motion angles is needed. Radar technologies including Millimeter-Wave Doppler Radar and frequency-modulated continuous-wave (FMCW) radar have been utilized for this purpose in papers written by Raja et al. 7 and Chae et al. 8 . Others like Inokuchi et al. and Chui et al. have proposed methods using cameras to provide video streaming and analyze motion using image processing 9 , 10 . While these methods all allow for accurate monitoring of head motion, they also present a high level of complexity in usability and design as well as low portability. Furthermore current methods present limits on usability such that the person to be monitored has to stay at a fixed location. For situations such as a classroom setting or group activity setting, where the monitoring of one’s head motion can contribute to our understanding of one’s attention, focus and emotional state, the costliness of the current designs post obstacles for such situations where a low cost head motion sensing systems are needed in bulk. Smart thread-based sensors would provide an alternative possibility to the current head motion monitoring methods with high flexibility and efficiency. Current thread-based sensors utilize manufacturing procedures that include use of materials that directly measure strain as well as others for which strain is inferred based on changes in the electrical conductivity of an extrinsically applied coating 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 . With their increasing popularity, thread-based sensors have been used as means for non-obtrusive data collection methods for sweat and respiration monitoring as well as for joint and finger motion detection 23 , 24 , 25 . Extrinsically coated sensor thread has been used for gas detection purposes 26 and electromagnetic devices like antennas 26 , 27 , 28 . Our group has developed a carbon-coated strain sensor and demonstrated its use in gait monitoring 20 , 21 , 22 . In this paper, we incorporate the use of thread-based sensors into the monitoring and collection of head motion. This enables a cost-effective, flexible, and portable method with high usability for everyday and large scale monitoring. We propose a method for head motion monitoring and classification using thread-based sensors. The design consists of two carbon-coated thread-based strain sensors arranged in a cross-over “X” configuration, the electronic interface for data collection, and data processing methods that allow for close to real-time determination of head orientation. The sensors are placed on the back of the neck. The sensor position is concealed thus better suited for daily use and improves from the existing c-stretch band method 5 that places the sensor on the top of the head. Data is collected through impedance readout boards and transferred to nearby Bluetooth enabled devices. The data are divided into segments of fixed length from which a time series of features are extracted for classification of head orientation into one of nine positions. Specifically, with rotating left and right being the horizontal axis and flexing down and up being the vertical axis, the motion captured can be classified according to the location along either the horizontal or vertical axis as shown in Fig. 1 . With the straightforward concepts behind the thread-based sensor, this design can be easily reproduced for other motion detection and monitoring. Moreover, the platform", "role": "user" }, { "content": "Engineers at Tufts University have created and demonstrated flexible thread-based sensors that can measure movement of the neck, providing data on the direction, angle of rotation and degree of displacement of the head. The discovery raises the potential for thin, inconspicuous tatoo-like patches that could, according to the Tufts team, measure athletic performance, monitor worker or driver fatigue, assist with physical therapy, enhance virtual reality games and systems, and improve computer generated imagery in cinematography. The technology, described today in Scientific Reports, adds to a growing number of thread-based sensors developed by Tufts engineers that can be woven into textiles, measuring gases and chemicals in the environment or metabolites in sweat. In their experiments, the researchers placed two threads in an \"X\" pattern on the back of a subject's neck. Coated with an electrically conducting carbon-based ink, the sensors detect motion when the threads bend, creating strain that changes the way they conduct electricity. When the subject performed a series of head movements, the wires sent signals to a small Bluetooth module, which then transmitted data wirelessly to a computer or smartphone for analysis. The data analysis involved sophisticated machine learning approaches to interpret the signals and translate them to quantitate head movements in real time, with 93% accuracy. In this way, the sensors and processor track motion without interference from wires, bulky devices, or limiting conditions such as the use of cameras, or confinement to a room or lab space. While algorithms will need to be specialized for each location on the body, the proof of principle demonstrates that thread sensors could be used to measure movement in other limbs, according to the researchers. The skin patches or even form-fitting clothing containing the threads could be used to track movement in settings where the measurements are most relelvant, such as in the field, the workplace, or a classroom. The fact that a camera is not needed provides for additional privacy. \"This is a promising demonstration of how we could make sensors that monitor our health, performance, and environment in a non-intrusive way,\" said Yiwen Jiang, an undergraduate student at Tufts University School of Engineering and first author of the study. \"More work needs to be done to improve the sensors' scope and precision, which in this case could mean gathering data from a larger array of threads regularly spaced or arranged in a pattern, and developing algorithms that improve the quantification of articulated movement.\" Other types of wearable motion sensor designs have included 3-axis gyroscopes, accelerometers and magnetometers to detect movement of the subject in relation to their surroundings. Those sensors are based on inertial measurements—quantifying how the body accelerates, rotates or moves up and down -and tend to be bulkier and more inconvenient. For example, with other systems, in order to measure head movement, it is necessary to place one sensor on the forehead and another on the neck above the vertebrae. The obtrusive placement of equipment can interfere with the subjects' free movement or simply the convenience of not being conscious of being measured. For situations such as on the athletic field, the novel thread-based sensor paradigm could be a game changer. By placing thin tatoo-like patches on different joints, an athlete could carry motion sensors to detect their physical movement and form, while thread-based sweat sensors, described in earlier work by the Tufts team, could also potentially track their electrolytes, lactate and other biological markers of performance in sweat. On the road, a thread sensor patch could alert to truck driver fatigue or other situations where tracking operator alertness is critical, monitoring the head movements of someone about to nod off. \"If we can take this technology further, there could be a wide range of applications in healthcare as well,\" said Jiang. \"For example, those researching Parkinson's disease and other neuromuscular diseases could also track movements of subjects in their normal settings and daily lives to gather data on their condition and the effectiveness of treatments.\" \"The objective in creating thread-based sensors is to make them 'disappear' as far as the person wearing them is concerned,\" said Sameer Sonkusale, professor of electrical and computer engineering at Tufts' School of Engineering, director of the Tufts Nanolab, and corresponding author of the study. \"Creating a coated thread capable of measuring movement is a remarkable achievement, made even more notable by the fact that Yiwen developed this invention as an undergraduate. We look forward to refining the technology and exploring its many possibilities.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Human machine interfaces that can track head motion will result in advances in physical rehabilitation, improved augmented reality/virtual reality systems, and aid in the study of human behavior. This paper presents a head position monitoring and classification system using thin flexible strain sensing threads placed on the neck of an individual. A wireless circuit module consisting of impedance readout circuitry and a Bluetooth module records and transmits strain information to a computer. A data processing algorithm for motion recognition provides near real-time quantification of head position. Incoming data is filtered, normalized and divided into data segments. A set of features is extracted from each data segment and employed as input to nine classifiers including Support Vector Machine, Naive Bayes and KNN for position prediction. A testing accuracy of around 92% was achieved for a set of nine head orientations. Results indicate that this human machine interface platform is accurate, flexible, easy to use, and cost effective. Introduction The monitoring of head motions can be very useful in many applications including the study of human behavior. For example, it can improve our understanding of one’s attention, focus and emotional state. In a classroom setting, head movements can be translated into students’ gaze direction and serve to detect students’ attentiveness during class 1 . Similarly, this technology can be applied to a driving situation, where a distracted or tired driver can be alerted through detecting abnormalities in their head motion. Head motions such as tilting and nodding when speaking or singing encode a person’s emotional intent and serve as an indication for the speakers’ interpersonal relationship in dialogs 2 , 3 . Many of the current head and neck motion monitoring systems have been developed for measuring the Cervical Range of Motion (CROM) in the diagnosis of neck pain. Most of these designs employ an Inertial Measurement Unit (IMU) to obtain highly precise measurements required by the underlying application. For example, a wearable wireless inertial sensor has been proposed by Raya et al. 4 . Their design employed a MEMS-based IMU sensor consisting of the 3-axis gyroscopes, accelerometers, and magnetometers to achieve nine degrees of freedom. The measurements require the use of two of such sensors, one placed on the forehead and one on the vertebrae. Alternative methods have also been presented, Al-Nasri et al. utilized a commercially available C-stretch band to measure neck movement by placing the band around the top of the head 5 . Sarig-Bahat et al. made use of the current virtual reality technology to measure the range of motion of the neck 6 . However, in certain non-medical situations and for our purposes, general motion monitoring instead of precise measurement of motion angles is needed. Radar technologies including Millimeter-Wave Doppler Radar and frequency-modulated continuous-wave (FMCW) radar have been utilized for this purpose in papers written by Raja et al. 7 and Chae et al. 8 . Others like Inokuchi et al. and Chui et al. have proposed methods using cameras to provide video streaming and analyze motion using image processing 9 , 10 . While these methods all allow for accurate monitoring of head motion, they also present a high level of complexity in usability and design as well as low portability. Furthermore current methods present limits on usability such that the person to be monitored has to stay at a fixed location. For situations such as a classroom setting or group activity setting, where the monitoring of one’s head motion can contribute to our understanding of one’s attention, focus and emotional state, the costliness of the current designs post obstacles for such situations where a low cost head motion sensing systems are needed in bulk. Smart thread-based sensors would provide an alternative possibility to the current head motion monitoring methods with high flexibility and efficiency. Current thread-based sensors utilize manufacturing procedures that include use of materials that directly measure strain as well as others for which strain is inferred based on changes in the electrical conductivity of an extrinsically applied coating 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 . With their increasing popularity, thread-based sensors have been used as means for non-obtrusive data collection methods for sweat and respiration monitoring as well as for joint and finger motion detection 23 , 24 , 25 . Extrinsically coated sensor thread has been used for gas detection purposes 26 and electromagnetic devices like antennas 26 , 27 , 28 . Our group has developed a carbon-coated strain sensor and demonstrated its use in gait monitoring 20 , 21 , 22 . In this paper, we incorporate the use of thread-based sensors into the monitoring and collection of head motion. This enables a cost-effective, flexible, and portable method with high usability for everyday and large scale monitoring. We propose a method for head motion monitoring and classification using thread-based sensors. The design consists of two carbon-coated thread-based strain sensors arranged in a cross-over “X” configuration, the electronic interface for data collection, and data processing methods that allow for close to real-time determination of head orientation. The sensors are placed on the back of the neck. The sensor position is concealed thus better suited for daily use and improves from the existing c-stretch band method 5 that places the sensor on the top of the head. Data is collected through impedance readout boards and transferred to nearby Bluetooth enabled devices. The data are divided into segments of fixed length from which a time series of features are extracted for classification of head orientation into one of nine positions. Specifically, with rotating left and right being the horizontal axis and flexing down and up being the vertical axis, the motion captured can be classified according to the location along either the horizontal or vertical axis as shown in Fig. 1 . With the straightforward concepts behind the thread-based sensor, this design can be easily reproduced for other motion detection and monitoring. Moreover, the platform<|im_end|> <|im_start|>assistant Engineers at Tufts University have created and demonstrated flexible thread-based sensors that can measure movement of the neck, providing data on the direction, angle of rotation and degree of displacement of the head. The discovery raises the potential for thin, inconspicuous tatoo-like patches that could, according to the Tufts team, measure athletic performance, monitor worker or driver fatigue, assist with physical therapy, enhance virtual reality games and systems, and improve computer generated imagery in cinematography. The technology, described today in Scientific Reports, adds to a growing number of thread-based sensors developed by Tufts engineers that can be woven into textiles, measuring gases and chemicals in the environment or metabolites in sweat. In their experiments, the researchers placed two threads in an "X" pattern on the back of a subject's neck. Coated with an electrically conducting carbon-based ink, the sensors detect motion when the threads bend, creating strain that changes the way they conduct electricity. When the subject performed a series of head movements, the wires sent signals to a small Bluetooth module, which then transmitted data wirelessly to a computer or smartphone for analysis. The data analysis involved sophisticated machine learning approaches to interpret the signals and translate them to quantitate head movements in real time, with 93% accuracy. In this way, the sensors and processor track motion without interference from wires, bulky devices, or limiting conditions such as the use of cameras, or confinement to a room or lab space. While algorithms will need to be specialized for each location on the body, the proof of principle demonstrates that thread sensors could be used to measure movement in other limbs, according to the researchers. The skin patches or even form-fitting clothing containing the threads could be used to track movement in settings where the measurements are most relelvant, such as in the field, the workplace, or a classroom. The fact that a camera is not needed provides for additional privacy. "This is a promising demonstration of how we could make sensors that monitor our health, performance, and environment in a non-intrusive way," said Yiwen Jiang, an undergraduate student at Tufts University School of Engineering and first author of the study. "More work needs to be done to improve the sensors' scope and precision, which in this case could mean gathering data from a larger array of threads regularly spaced or arranged in a pattern, and developing algorithms that improve the quantification of articulated movement." Other types of wearable motion sensor designs have included 3-axis gyroscopes, accelerometers and magnetometers to detect movement of the subject in relation to their surroundings. Those sensors are based on inertial measurements—quantifying how the body accelerates, rotates or moves up and down -and tend to be bulkier and more inconvenient. For example, with other systems, in order to measure head movement, it is necessary to place one sensor on the forehead and another on the neck above the vertebrae. The obtrusive placement of equipment can interfere with the subjects' free movement or simply the convenience of not being conscious of being measured. For situations such as on the athletic field, the novel thread-based sensor paradigm could be a game changer. By placing thin tatoo-like patches on different joints, an athlete could carry motion sensors to detect their physical movement and form, while thread-based sweat sensors, described in earlier work by the Tufts team, could also potentially track their electrolytes, lactate and other biological markers of performance in sweat. On the road, a thread sensor patch could alert to truck driver fatigue or other situations where tracking operator alertness is critical, monitoring the head movements of someone about to nod off. "If we can take this technology further, there could be a wide range of applications in healthcare as well," said Jiang. "For example, those researching Parkinson's disease and other neuromuscular diseases could also track movements of subjects in their normal settings and daily lives to gather data on their condition and the effectiveness of treatments." "The objective in creating thread-based sensors is to make them 'disappear' as far as the person wearing them is concerned," said Sameer Sonkusale, professor of electrical and computer engineering at Tufts' School of Engineering, director of the Tufts Nanolab, and corresponding author of the study. "Creating a coated thread capable of measuring movement is a remarkable achievement, made even more notable by the fact that Yiwen developed this invention as an undergraduate. We look forward to refining the technology and exploring its many possibilities." <|im_end|>

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1778, 430, 279, 1732, 311, 387, 41223, 706, 311, 4822, 520, 264, 8521, 3813, 13, 1789, 15082, 1778, 439, 264, 24978, 6376, 477, 1912, 5820, 6376, 11, 1405, 279, 16967, 315, 832, 753, 2010, 11633, 649, 17210, 311, 1057, 8830, 315, 832, 753, 6666, 11, 5357, 323, 14604, 1614, 11, 279, 2853, 49958, 315, 279, 1510, 14769, 1772, 32116, 369, 1778, 15082, 1405, 264, 3428, 2853, 2010, 11633, 60199, 6067, 527, 4460, 304, 20155, 13, 16147, 4617, 6108, 26148, 1053, 3493, 459, 10778, 13336, 311, 279, 1510, 2010, 11633, 16967, 5528, 449, 1579, 25152, 323, 15374, 13, 9303, 4617, 6108, 26148, 29166, 15266, 16346, 430, 2997, 1005, 315, 7384, 430, 6089, 6767, 26800, 439, 1664, 439, 3885, 369, 902, 26800, 374, 68695, 3196, 389, 4442, 304, 279, 20314, 98971, 315, 459, 11741, 1354, 2740, 9435, 41394, 220, 806, 1174, 220, 717, 1174, 220, 1032, 1174, 220, 975, 1174, 220, 868, 1174, 220, 845, 1174, 220, 1114, 1174, 220, 972, 1174, 220, 777, 1174, 220, 508, 1174, 220, 1691, 1174, 220, 1313, 662, 3161, 872, 7859, 23354, 11, 4617, 6108, 26148, 617, 1027, 1511, 439, 3445, 369, 2536, 93549, 376, 22784, 828, 4526, 5528, 369, 28566, 323, 594, 29579, 16967, 439, 1664, 439, 369, 10496, 323, 14654, 11633, 18468, 220, 1419, 1174, 220, 1187, 1174, 220, 914, 662, 72334, 1354, 2740, 49482, 12271, 4617, 706, 1027, 1511, 369, 6962, 18468, 10096, 220, 1627, 323, 66669, 7766, 1093, 87851, 220, 1627, 1174, 220, 1544, 1174, 220, 1591, 662, 5751, 1912, 706, 8040, 264, 12782, 23283, 660, 26800, 12271, 323, 21091, 1202, 1005, 304, 342, 1339, 16967, 220, 508, 1174, 220, 1691, 1174, 220, 1313, 662, 763, 420, 5684, 11, 584, 33435, 279, 1005, 315, 4617, 6108, 26148, 1139, 279, 16967, 323, 4526, 315, 2010, 11633, 13, 1115, 20682, 264, 2853, 53421, 11, 19303, 11, 323, 23665, 1749, 449, 1579, 76160, 369, 18254, 323, 3544, 5569, 16967, 13, 1226, 30714, 264, 1749, 369, 2010, 11633, 16967, 323, 24790, 1701, 4617, 6108, 26148, 13, 578, 2955, 17610, 315, 1403, 12782, 23283, 660, 4617, 6108, 26800, 26148, 28902, 304, 264, 5425, 29352, 1054, 55, 863, 6683, 11, 279, 14683, 3834, 369, 828, 4526, 11, 323, 828, 8863, 5528, 430, 2187, 369, 3345, 311, 1972, 7394, 26314, 315, 2010, 17140, 13, 578, 26148, 527, 9277, 389, 279, 1203, 315, 279, 13272, 13, 578, 12271, 2361, 374, 44133, 8617, 2731, 32599, 369, 7446, 1005, 323, 36050, 505, 279, 6484, 272, 5594, 10420, 7200, 1749, 220, 20, 430, 7634, 279, 12271, 389, 279, 1948, 315, 279, 2010, 13, 2956, 374, 14890, 1555, 91048, 1373, 412, 21126, 323, 23217, 311, 14373, 24783, 9147, 7766, 13, 578, 828, 527, 18255, 1139, 21282, 315, 8521, 3160, 505, 902, 264, 892, 4101, 315, 4519, 527, 28532, 369, 24790, 315, 2010, 17140, 1139, 832, 315, 11888, 10093, 13, 45863, 11, 449, 42496, 2163, 323, 1314, 1694, 279, 16600, 8183, 323, 5882, 287, 1523, 323, 709, 1694, 279, 12414, 8183, 11, 279, 11633, 17439, 649, 387, 21771, 4184, 311, 279, 3813, 3235, 3060, 279, 16600, 477, 12414, 8183, 439, 6982, 304, 23966, 13, 220, 16, 662, 3161, 279, 31439, 19476, 4920, 279, 4617, 6108, 12271, 11, 420, 2955, 649, 387, 6847, 55717, 369, 1023, 11633, 18468, 323, 16967, 13, 23674, 11, 279, 5452, 128257, 198, 128256, 78191, 198, 4674, 388, 520, 29749, 45544, 3907, 617, 3549, 323, 21091, 19303, 4617, 6108, 26148, 430, 649, 6767, 7351, 315, 279, 13272, 11, 8405, 828, 389, 279, 5216, 11, 9392, 315, 12984, 323, 8547, 315, 44153, 315, 279, 2010, 13, 578, 18841, 25930, 279, 4754, 369, 15792, 11, 28093, 2203, 292, 9373, 72813, 2689, 12970, 29760, 430, 1436, 11, 4184, 311, 279, 29749, 45544, 2128, 11, 6767, 29703, 5178, 11, 8891, 12128, 477, 5696, 36709, 11, 7945, 449, 7106, 15419, 11, 18885, 4200, 8903, 3953, 323, 6067, 11, 323, 7417, 6500, 8066, 41545, 304, 88122, 5814, 13, 578, 5557, 11, 7633, 3432, 304, 38130, 29140, 11, 11621, 311, 264, 7982, 1396, 315, 4617, 6108, 26148, 8040, 555, 29749, 45544, 25175, 430, 649, 387, 56874, 1139, 94082, 11, 30090, 45612, 323, 26333, 304, 279, 4676, 477, 28168, 3695, 304, 28566, 13, 763, 872, 21896, 11, 279, 12074, 9277, 1403, 14906, 304, 459, 330, 55, 1, 5497, 389, 279, 1203, 315, 264, 3917, 596, 13272, 13, 3623, 660, 449, 459, 9249, 750, 31474, 12782, 6108, 27513, 11, 279, 26148, 11388, 11633, 994, 279, 14906, 37920, 11, 6968, 26800, 430, 4442, 279, 1648, 814, 6929, 18200, 13, 3277, 279, 3917, 10887, 264, 4101, 315, 2010, 19567, 11, 279, 36108, 3288, 17738, 311, 264, 2678, 24783, 4793, 11, 902, 1243, 34699, 828, 9244, 16117, 311, 264, 6500, 477, 22234, 369, 6492, 13, 578, 828, 6492, 6532, 27877, 5780, 6975, 20414, 311, 14532, 279, 17738, 323, 15025, 1124, 311, 10484, 20227, 2010, 19567, 304, 1972, 892, 11, 449, 220, 6365, 4, 13708, 13, 763, 420, 1648, 11, 279, 26148, 323, 18121, 3839, 11633, 2085, 32317, 505, 36108, 11, 78921, 7766, 11, 477, 33994, 4787, 1778, 439, 279, 1005, 315, 18632, 11, 477, 66678, 311, 264, 3130, 477, 10278, 3634, 13, 6104, 26249, 690, 1205, 311, 387, 28175, 369, 1855, 3813, 389, 279, 2547, 11, 279, 11311, 315, 17966, 32216, 430, 4617, 26148, 1436, 387, 1511, 311, 6767, 7351, 304, 1023, 49695, 11, 4184, 311, 279, 12074, 13, 578, 6930, 29760, 477, 1524, 1376, 2269, 15154, 17895, 8649, 279, 14906, 1436, 387, 1511, 311, 3839, 7351, 304, 5110, 1405, 279, 22323, 527, 1455, 14049, 22580, 519, 11, 1778, 439, 304, 279, 2115, 11, 279, 27465, 11, 477, 264, 24978, 13, 578, 2144, 430, 264, 6382, 374, 539, 4460, 5825, 369, 5217, 12625, 13, 330, 2028, 374, 264, 26455, 30816, 315, 1268, 584, 1436, 1304, 26148, 430, 8891, 1057, 2890, 11, 5178, 11, 323, 4676, 304, 264, 2536, 3502, 376, 22784, 1648, 1359, 1071, 48934, 17378, 61922, 11, 459, 41534, 5575, 520, 29749, 45544, 3907, 6150, 315, 17005, 323, 1176, 3229, 315, 279, 4007, 13, 330, 7816, 990, 3966, 311, 387, 2884, 311, 7417, 279, 26148, 6, 7036, 323, 16437, 11, 902, 304, 420, 1162, 1436, 3152, 23738, 828, 505, 264, 8294, 1358, 315, 14906, 15870, 64928, 477, 28902, 304, 264, 5497, 11, 323, 11469, 26249, 430, 7417, 279, 10484, 2461, 315, 83280, 7351, 1210, 7089, 4595, 315, 78348, 11633, 12271, 14769, 617, 5343, 220, 18, 36421, 67968, 82025, 11, 14511, 33504, 323, 33297, 33504, 311, 11388, 7351, 315, 279, 3917, 304, 12976, 311, 872, 40190, 13, 13266, 26148, 527, 3196, 389, 81073, 532, 22323, 2345, 31548, 7922, 1268, 279, 2547, 14511, 988, 11, 90159, 477, 11031, 709, 323, 1523, 482, 438, 8541, 311, 387, 20155, 1291, 323, 810, 84783, 13, 1789, 3187, 11, 449, 1023, 6067, 11, 304, 2015, 311, 6767, 2010, 7351, 11, 433, 374, 5995, 311, 2035, 832, 12271, 389, 279, 52354, 323, 2500, 389, 279, 13272, 3485, 279, 5309, 51313, 68, 13, 578, 1536, 376, 22784, 22165, 315, 7241, 649, 40978, 449, 279, 15223, 6, 1949, 7351, 477, 5042, 279, 19679, 315, 539, 1694, 17371, 315, 1694, 17303, 13, 1789, 15082, 1778, 439, 389, 279, 29703, 2115, 11, 279, 11775, 4617, 6108, 12271, 49340, 1436, 387, 264, 1847, 62439, 13, 3296, 25012, 15792, 72813, 2689, 12970, 29760, 389, 2204, 35358, 11, 459, 34880, 1436, 6920, 11633, 26148, 311, 11388, 872, 7106, 7351, 323, 1376, 11, 1418, 4617, 6108, 28566, 26148, 11, 7633, 304, 6931, 990, 555, 279, 29749, 45544, 2128, 11, 1436, 1101, 13893, 3839, 872, 73396, 2392, 11, 51644, 349, 323, 1023, 24156, 24915, 315, 5178, 304, 28566, 13, 1952, 279, 5754, 11, 264, 4617, 12271, 11140, 1436, 5225, 311, 11092, 5696, 36709, 477, 1023, 15082, 1405, 15194, 5793, 5225, 2136, 374, 9200, 11, 16967, 279, 2010, 19567, 315, 4423, 922, 311, 16387, 1022, 13, 330, 2746, 584, 649, 1935, 420, 5557, 4726, 11, 1070, 1436, 387, 264, 7029, 2134, 315, 8522, 304, 18985, 439, 1664, 1359, 1071, 61922, 13, 330, 2520, 3187, 11, 1884, 45243, 62145, 596, 8624, 323, 1023, 21143, 442, 355, 22077, 19338, 1436, 1101, 3839, 19567, 315, 15223, 304, 872, 4725, 5110, 323, 7446, 6439, 311, 9762, 828, 389, 872, 3044, 323, 279, 27375, 315, 22972, 1210, 330, 791, 16945, 304, 6968, 4617, 6108, 26148, 374, 311, 1304, 1124, 364, 4338, 41866, 6, 439, 3117, 439, 279, 1732, 12512, 1124, 374, 11920, 1359, 1071, 26823, 261, 12103, 79566, 1604, 11, 14561, 315, 20314, 323, 6500, 15009, 520, 29749, 45544, 6, 6150, 315, 17005, 11, 7690, 315, 279, 29749, 45544, 33242, 337, 370, 11, 323, 12435, 3229, 315, 279, 4007, 13, 330, 26021, 264, 49482, 4617, 13171, 315, 30090, 7351, 374, 264, 23649, 26501, 11, 1903, 1524, 810, 28289, 555, 279, 2144, 430, 48934, 17378, 8040, 420, 28229, 439, 459, 41534, 13, 1226, 1427, 4741, 311, 74285, 279, 5557, 323, 24919, 1202, 1690, 24525, 1210, 220, 128257, 198 ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Background Commercial cuts yield is an important trait for beef production, which affects the final value of the products, but its direct determination is a challenging procedure to be implemented in practice. The measurement of ribeye area (REA) and backfat thickness (BFT) can be used as indirect measures of meat yield. REA and BFT are important traits studied in beef cattle due to their strong implication in technological (carcass yield) and nutritional characteristics of meat products, like the degree of muscularity and total body fat. Thus, the aim of this work was to study the Longissimus dorsi muscle transcriptome of Nellore cattle, associated with REA and BFT, to find differentially expressed (DE) genes, metabolic pathways, and biological processes that may regulate these traits. Results By comparing the gene expression level between groups with extreme genomic estimated breeding values (GEBV), 101 DE genes for REA and 18 for BFT (false discovery rate, FDR 10%) were identified. Functional enrichment analysis for REA identified two KEGG pathways, MAPK (Mitogen-Activated Protein Kinase) signaling pathway and endocytosis pathway, and three biological processes, response to endoplasmic reticulum stress, cellular protein modification process, and macromolecule modification. The MAPK pathway is responsible for fundamental cellular processes, such as growth, differentiation, and hypertrophy. For BFT, 18 biological processes were found to be altered and grouped into 8 clusters of semantically similar terms. The DE genes identified in the biological processes for BFT were ACHE, SRD5A1, RSAD2 and RSPO3 . RSAD2 has been previously shown to be associated with lipid droplet content and lipid biosynthesis. Conclusion In this study, we identified genes, metabolic pathways, and biological processes, involved in differentiation, proliferation, protein turnover, hypertrophy, as well as adipogenesis and lipid biosynthesis related to REA and BFT. These results enlighten some of the molecular processes involved in muscle and fat deposition, which are economically important carcass traits for beef production. Background Meat is the most important source of animal protein for the human diet; it consists mainly of skeletal muscle, and of varying amounts of connective tissue, implicated on its qualitative and quantitative characteristics, as well as small amounts of epithelial and nervous tissues. Meat represents the edible portion of the carcass, in other words, the part that will be destined for the final consumers and can be represented by the yield of commercial cuts [ 1 , 2 ]. Commercial cuts yield is economically important since it affects the final value of the products due to the proportion of fat, muscle, and bone in the carcasses. The direct determination of meat yield is difficult in practice, therefore the measures of ribeye area (REA) and backfat thickness (BFT), sections of the Longissimus dorsi muscle, are often used as indirect measures of this trait [ 3 , 4 , 5 ]. REA and BFT are well studied traits in beef cattle due to their implication in technological and nutritional characteristics of meat products. The ribeye area is used as an indicator of degree of muscularity, edible mass of carcass and yield of cuts with high commercial value. This measure can also be associated with the length and weight of the carcass (hot carcass weight) [ 3 , 6 , 7 ]. The amount of BFT deposited on the carcass is related to the total body fat and plays a major role in beef’s flavor and juiciness, which is directly associated with production costs. In the meat industry, an adequate layer of fat acts as a thermal insulator during carcass cooling process, avoiding problems such as cold shortening [ 8 , 9 ]. Also, the layer of fat is an important source of essential fatty acids and acts in the transport of fat-soluble vitamins, constituting a source of energy and insulation for the body of the animal [ 10 ]. Selection based on body composition, particularly on the relative proportion of muscle and fat in the carcass, is critical in meat-producing animals [ 5 , 11 ]. Most carcass traits have moderate to high heritability, indicating that the selection may result in significant genetic progress [ 5 ]. According to Costa et al. [ 12 ] and Clímaco et al. [ 10 ], feedlot finished zebu breeds may present the same proportion of edible portion as other genotypes (crosses with taurine breeds), and even greater muscularity and higher carcass yield. Several tools have been developed to improve the accuracy of animal selection and thus improve economically important traits in beef cattle, such as large-scale genotyping platforms, high-density panels of single nucleotide polymorphisms (SNP), and genome-wide association studies (GWAS). Besides these, many studies have used RNA Sequencing (RNA-Seq) to unravel complex traits in production animals. This high-throughput technology has been successfully employed in beef cattle for traits such as muscle development, intramuscular fat, and fatty acid profile, with interesting results of the phenotypic differences within and between populations [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. Meat quality and carcass traits are influenced by a complex network of gene interactions in the muscle [ 21 ]. Therefore, elucidating the relationships between genes and how these genes, in turn, influence the carcass traits is critical for understanding the development of the animals, as well as the biological processes (BP) and metabolic pathways that may influence the final amount of fat and muscle in the carcasses. Tizioto et al. [ 22 ] working with this same population of Nellore steers, identified six QTL (quantitative trait loci) that individually explained 0.8% of the additive genetic variance of REA, and a QTL that explained 0.36% of the variation in BFT. Gomes et al. [ 23 ] reported that SNPs in genes related to protein turnover, like genes regulating the ubiquitin-proteasome system, may be associated with growth and carcass traits in bovine. Junior et al. [ 24 ] found SNP-windows located on chromosomes 5, 6, 7, 8, 10, 12, 13, 16, 17, 20, 24 and 29 that together explained 8.72% and 11.38% of the genetic variance for REA and", "role": "user" }, { "content": "Brazil has the world's largest commercial beef herd, numbering over 225 million, yet only 20 percent of Brazil's production is intended for export. Because of this, beef ranks 10th on the list of products exported by Brazil, after soybeans, iron ore, oil, sugarcane, automobiles, chicken, cellulose, soybean meal and coffee. Experts suggest that exports could be much higher if Brazilian beef were of a quality similar to that produced in Australia, Argentina or Uruguay. In addition to obtaining more tender meat, another goal of research is to improve productivity. To achieve this, genetic improvement techniques are used to breed animals that gain weight more quickly or that better resist disease. \"Brazil is the world's second largest producer of beef, in an industry whose 2016 revenue exceeded US$ 5 billion. The cost of producing Brazilian beef is one of the lowest in the world, but in order to expand market importance, beef production needs to adapt to the standards established by importers. Among quality concerns, tenderness, the amount and the type of marbling can influence the sensory characteristics and nutritional value of the beef,\" said Luciana Correia de Almeida Regitano, a researcher at the Brazilian Agricultural Research Corporation - EMBRAPA and faculty member of the Federal University of São Carlos (in São Paulo, Brazil). Regitano explained that in Brazil, over 80 percent of beef cattle is Nelore. The breed, of the subspecies Bos taurus indicus, originated in India, but it does not produce meat that is as tender as Angus (Bos taurus taurus), which originated in Europe and presents more marbling. \"Nelore cattle weigh less and have lower productivity and less tender meat. As a result, their price is lower,\" she said. Regitano leads a follow-up to a previous study that enabled the identification of genomic areas associated with the beef's production and quality characteristics. \"We initially bred approximately 800 animals for three years on five farms, from birth to slaughter, measuring the phenotypic characteristics such as growth, production, meat quality and feed efficiency. We also collected samples of DNA and subjected them to high-density genotyping to determine specific mutations that cover the whole genome. We analyzed more than 700,000 specific mutations dispersed throughout the genome, which provided us with data on the segregation of chromosomal segments,\" she said. \"In 2012, we had another project approved by FAPESP that allowed us to expand the initial study and analyze tissue samples to determine the complete sequence of messenger RNAs and all microRNAs found in the tissue. MicroRNAs are small RNA molecules that modulate how messenger RNAs will be translated into proteins,\" Regitano explained. The proteins from the tissue samples collected were also analyzed. \"We were able to obtain a data set on 45 different phenotypes and sequenced the messenger RNA and microRNA of 200 muscle samples and 30 liver samples, in addition to analyzing proteins from 65 muscle samples. With support from the CNPq, we were also able to sequence the complete genome, each nucleotide of the genome, of 20 animals. This provided a very important set of data from which we have obtained multiple layers of genomic information on a single animal,\" she said. Genomic tools \"Among the objectives of our current study are complementing the analyses of genomic association to include new phenotypes, integrating the analyses of the functional genome (RNA, microRNA and proteins), assessing the significance of the copy number variation (CNV) and training human resources in the fields of bioinformatics and genomics,\" Regitano explained. Copy number variation is defined as a type of genomic structural variation that includes amplifications and losses of a specific region, which could involve and possibly be one or more complete genes. \"We are studying how these alterations could influence the expression of all the genes in muscle as well as the phenotypes assessed,\" the researcher asserted. The study led to the publication of a series of articles that are expanding knowledge of the possibilities for using genomic tools that can lead to gains in quality and productivity in beef production. In an article published in the journal BMC Genomics, Regitano and her group identified genes, metabolic pathways and biological processes involved in the differentiation, proliferation, protein conversion, hypertrophy and synthesis of lipids related to the area of the loin eye, a measurement that correlates with the muscularity of the animal and the thickness of its subcutaneous fat, both characteristics that have a direct impact on carcass quality and productivity. The results of the research point to molecular processes related to the deposit of muscles and fat, which are economically important characteristics for beef production. In another article, published in the journalPLOS ONE in 2016, Regitano and her colleagues described a broad genomic analysis of CNVs obtained from 723 bulls. The researchers identified 2,600 regions that represent nearly 6.5 percent of the complete genome of the animals. The results represent the first comprehensive study of the copy number variations of Nelore cattle, with the identification of regions in which genetic alterations could have important implications in breeding animals whose meat is more tender, thus improving its potential for export and higher prices. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Background Commercial cuts yield is an important trait for beef production, which affects the final value of the products, but its direct determination is a challenging procedure to be implemented in practice. The measurement of ribeye area (REA) and backfat thickness (BFT) can be used as indirect measures of meat yield. REA and BFT are important traits studied in beef cattle due to their strong implication in technological (carcass yield) and nutritional characteristics of meat products, like the degree of muscularity and total body fat. Thus, the aim of this work was to study the Longissimus dorsi muscle transcriptome of Nellore cattle, associated with REA and BFT, to find differentially expressed (DE) genes, metabolic pathways, and biological processes that may regulate these traits. Results By comparing the gene expression level between groups with extreme genomic estimated breeding values (GEBV), 101 DE genes for REA and 18 for BFT (false discovery rate, FDR 10%) were identified. Functional enrichment analysis for REA identified two KEGG pathways, MAPK (Mitogen-Activated Protein Kinase) signaling pathway and endocytosis pathway, and three biological processes, response to endoplasmic reticulum stress, cellular protein modification process, and macromolecule modification. The MAPK pathway is responsible for fundamental cellular processes, such as growth, differentiation, and hypertrophy. For BFT, 18 biological processes were found to be altered and grouped into 8 clusters of semantically similar terms. The DE genes identified in the biological processes for BFT were ACHE, SRD5A1, RSAD2 and RSPO3 . RSAD2 has been previously shown to be associated with lipid droplet content and lipid biosynthesis. Conclusion In this study, we identified genes, metabolic pathways, and biological processes, involved in differentiation, proliferation, protein turnover, hypertrophy, as well as adipogenesis and lipid biosynthesis related to REA and BFT. These results enlighten some of the molecular processes involved in muscle and fat deposition, which are economically important carcass traits for beef production. Background Meat is the most important source of animal protein for the human diet; it consists mainly of skeletal muscle, and of varying amounts of connective tissue, implicated on its qualitative and quantitative characteristics, as well as small amounts of epithelial and nervous tissues. Meat represents the edible portion of the carcass, in other words, the part that will be destined for the final consumers and can be represented by the yield of commercial cuts [ 1 , 2 ]. Commercial cuts yield is economically important since it affects the final value of the products due to the proportion of fat, muscle, and bone in the carcasses. The direct determination of meat yield is difficult in practice, therefore the measures of ribeye area (REA) and backfat thickness (BFT), sections of the Longissimus dorsi muscle, are often used as indirect measures of this trait [ 3 , 4 , 5 ]. REA and BFT are well studied traits in beef cattle due to their implication in technological and nutritional characteristics of meat products. The ribeye area is used as an indicator of degree of muscularity, edible mass of carcass and yield of cuts with high commercial value. This measure can also be associated with the length and weight of the carcass (hot carcass weight) [ 3 , 6 , 7 ]. The amount of BFT deposited on the carcass is related to the total body fat and plays a major role in beef’s flavor and juiciness, which is directly associated with production costs. In the meat industry, an adequate layer of fat acts as a thermal insulator during carcass cooling process, avoiding problems such as cold shortening [ 8 , 9 ]. Also, the layer of fat is an important source of essential fatty acids and acts in the transport of fat-soluble vitamins, constituting a source of energy and insulation for the body of the animal [ 10 ]. Selection based on body composition, particularly on the relative proportion of muscle and fat in the carcass, is critical in meat-producing animals [ 5 , 11 ]. Most carcass traits have moderate to high heritability, indicating that the selection may result in significant genetic progress [ 5 ]. According to Costa et al. [ 12 ] and Clímaco et al. [ 10 ], feedlot finished zebu breeds may present the same proportion of edible portion as other genotypes (crosses with taurine breeds), and even greater muscularity and higher carcass yield. Several tools have been developed to improve the accuracy of animal selection and thus improve economically important traits in beef cattle, such as large-scale genotyping platforms, high-density panels of single nucleotide polymorphisms (SNP), and genome-wide association studies (GWAS). Besides these, many studies have used RNA Sequencing (RNA-Seq) to unravel complex traits in production animals. This high-throughput technology has been successfully employed in beef cattle for traits such as muscle development, intramuscular fat, and fatty acid profile, with interesting results of the phenotypic differences within and between populations [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. Meat quality and carcass traits are influenced by a complex network of gene interactions in the muscle [ 21 ]. Therefore, elucidating the relationships between genes and how these genes, in turn, influence the carcass traits is critical for understanding the development of the animals, as well as the biological processes (BP) and metabolic pathways that may influence the final amount of fat and muscle in the carcasses. Tizioto et al. [ 22 ] working with this same population of Nellore steers, identified six QTL (quantitative trait loci) that individually explained 0.8% of the additive genetic variance of REA, and a QTL that explained 0.36% of the variation in BFT. Gomes et al. [ 23 ] reported that SNPs in genes related to protein turnover, like genes regulating the ubiquitin-proteasome system, may be associated with growth and carcass traits in bovine. Junior et al. [ 24 ] found SNP-windows located on chromosomes 5, 6, 7, 8, 10, 12, 13, 16, 17, 20, 24 and 29 that together explained 8.72% and 11.38% of the genetic variance for REA and<|im_end|> <|im_start|>assistant Brazil has the world's largest commercial beef herd, numbering over 225 million, yet only 20 percent of Brazil's production is intended for export. Because of this, beef ranks 10th on the list of products exported by Brazil, after soybeans, iron ore, oil, sugarcane, automobiles, chicken, cellulose, soybean meal and coffee. Experts suggest that exports could be much higher if Brazilian beef were of a quality similar to that produced in Australia, Argentina or Uruguay. In addition to obtaining more tender meat, another goal of research is to improve productivity. To achieve this, genetic improvement techniques are used to breed animals that gain weight more quickly or that better resist disease. "Brazil is the world's second largest producer of beef, in an industry whose 2016 revenue exceeded US$ 5 billion. The cost of producing Brazilian beef is one of the lowest in the world, but in order to expand market importance, beef production needs to adapt to the standards established by importers. Among quality concerns, tenderness, the amount and the type of marbling can influence the sensory characteristics and nutritional value of the beef," said Luciana Correia de Almeida Regitano, a researcher at the Brazilian Agricultural Research Corporation - EMBRAPA and faculty member of the Federal University of São Carlos (in São Paulo, Brazil). Regitano explained that in Brazil, over 80 percent of beef cattle is Nelore. The breed, of the subspecies Bos taurus indicus, originated in India, but it does not produce meat that is as tender as Angus (Bos taurus taurus), which originated in Europe and presents more marbling. "Nelore cattle weigh less and have lower productivity and less tender meat. As a result, their price is lower," she said. Regitano leads a follow-up to a previous study that enabled the identification of genomic areas associated with the beef's production and quality characteristics. "We initially bred approximately 800 animals for three years on five farms, from birth to slaughter, measuring the phenotypic characteristics such as growth, production, meat quality and feed efficiency. We also collected samples of DNA and subjected them to high-density genotyping to determine specific mutations that cover the whole genome. We analyzed more than 700,000 specific mutations dispersed throughout the genome, which provided us with data on the segregation of chromosomal segments," she said. "In 2012, we had another project approved by FAPESP that allowed us to expand the initial study and analyze tissue samples to determine the complete sequence of messenger RNAs and all microRNAs found in the tissue. MicroRNAs are small RNA molecules that modulate how messenger RNAs will be translated into proteins," Regitano explained. The proteins from the tissue samples collected were also analyzed. "We were able to obtain a data set on 45 different phenotypes and sequenced the messenger RNA and microRNA of 200 muscle samples and 30 liver samples, in addition to analyzing proteins from 65 muscle samples. With support from the CNPq, we were also able to sequence the complete genome, each nucleotide of the genome, of 20 animals. This provided a very important set of data from which we have obtained multiple layers of genomic information on a single animal," she said. Genomic tools "Among the objectives of our current study are complementing the analyses of genomic association to include new phenotypes, integrating the analyses of the functional genome (RNA, microRNA and proteins), assessing the significance of the copy number variation (CNV) and training human resources in the fields of bioinformatics and genomics," Regitano explained. Copy number variation is defined as a type of genomic structural variation that includes amplifications and losses of a specific region, which could involve and possibly be one or more complete genes. "We are studying how these alterations could influence the expression of all the genes in muscle as well as the phenotypes assessed," the researcher asserted. The study led to the publication of a series of articles that are expanding knowledge of the possibilities for using genomic tools that can lead to gains in quality and productivity in beef production. In an article published in the journal BMC Genomics, Regitano and her group identified genes, metabolic pathways and biological processes involved in the differentiation, proliferation, protein conversion, hypertrophy and synthesis of lipids related to the area of the loin eye, a measurement that correlates with the muscularity of the animal and the thickness of its subcutaneous fat, both characteristics that have a direct impact on carcass quality and productivity. The results of the research point to molecular processes related to the deposit of muscles and fat, which are economically important characteristics for beef production. In another article, published in the journalPLOS ONE in 2016, Regitano and her colleagues described a broad genomic analysis of CNVs obtained from 723 bulls. The researchers identified 2,600 regions that represent nearly 6.5 percent of the complete genome of the animals. The results represent the first comprehensive study of the copy number variations of Nelore cattle, with the identification of regions in which genetic alterations could have important implications in breeding animals whose meat is more tender, thus improving its potential for export and higher prices. <|im_end|>

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2,452

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Immersion optics enable creation of systems with improved optical concentration and coupling by taking advantage of the fact that the luminance of light is proportional to the square of the refractive index in a lossless optical system. Immersion graded index optical concentrators, that do not need to track the source, are described in terms of theory, simulations, and experiments. We introduce a generalized design guide equation which follows the Pareto function and can be used to create various immersion graded index optics depending on the application requirements of concentration, refractive index, height, and efficiency. We present glass and polymer fabrication techniques for creating broadband transparent graded index materials with large refractive index ranges, (refractive index ratio) 2 of ~2, going many fold beyond what is seen in nature or the optics industry. The prototypes demonstrate 3x optical concentration with over 90% efficiency. We report via functional prototypes that graded-index-lens concentrators perform close to the theoretical maximum limit and we introduce simple, inexpensive, design-flexible, and scalable fabrication techniques for their implementation. Introduction Harnessing the plentiful solar energy reaching the earth via photovoltaics will play a major role in satisfying our future energy needs in a sustainable way. One promising approach is concentrated photovoltaics 1 , and several ways to achieve concentration are being used in the field 2 , 3 - Fresnel lenses 4 , 5 , mirrors 6 , 7 , parabolic concentrators 8 , 9 , secondary high-index optics 10 , waveguides 11 , 12 , 13 , immersion lenses 14 , surface nanotexturing 15 . The majority of these require active tracking of the Sun as they have to face the light source within a few degrees. Some of the above are passive concentrators, i.e., do not need to track the Sun, however they still offer modest acceptance angles that do not span the available 2π steradians. We present a passive concentrator device, AGILE (Axially Graded Index LEns) 16 . Henceforth, this immersion graded index optical concentrator is written as AGILE in the manuscript. AGILE does not need solar tracking and follows the cosine projection maximum limit, concentrating light incident on it from all angles. The AGILE allows for non-pointing (i.e., removing the need to track the Sun) concentration systems which reduce the amount of photovoltaic (PV) material required but also efficiently absorb diffuse light. Light scattering is present due to cloud cover and atmosphere; and diffuse light can be as high as 20% even on a sunny day 17 . Figure 1a depicts how light is concentrated in the AGILE concentrator. Light rays incident from the entire 2π steradians enter the larger aperture with refractive index (RI) of 1, curve towards the normal via refraction along the height of the cone in the axial gradient RI, reflect from the sidewalls, and reach the smaller output aperture with high RI, e.g., silicon with RI ~ 3.5, without need to track the light source. Figure 1c portrays the AGILE concentrator array system, made up of the repeated unit shown in Fig. 1 b, that absorbs all the incident light and hence appears dark. Video clip of the AGILE array system is attached in the supplementary material. In this video, the AGILE does not have metallic reflective sidewalls so that the graded index material can be visualised. AGILE allows near perfect antireflection and coupling, encapsulation, space for circuitry and cooling, and conformal design. These immersion graded index optics can also realize applications in areas like light management in solid state lighting, laser couplers, display technology etc. Fig. 1: AGILE (Axially Graded Index LEns) concept and concentrator array system vision. a Depiction of the optical concentration action, b repeating unit of AGILE, c concentrator arrays with built-in anti-reflection and encapsulation, no need for tracking the source, and spatially separated PV cells which have advantages of reduced PV material use, hence lower cost with space for cooling and circuitry. Full size image Comparison of different concentrator designs Ray tracing simulations were performed with the software FRED. We performed simulations to compare optical concentration efficiencies of cone geometries with different RI profile fills. All the concentrators simulated in Fig. 2 have the same geometry- the input diameter is 3.5, the output diameter is 1, the height is 5, and the interior sidewalls of the cone are optically reflective. These are dimension-independent simulations in the ray domain, i.e., in the regime where the device dimensions are several times larger than the wavelength of the incident light. Details of scale invariance are presented in appendix A in the supplementary file. The angle of the incident ray array, theta, was swept from 0 to 90° in one plane as the structure has rotational symmetry. Figure 2 shows the cone geometries’ optical concentration efficiency, i.e., light transmission to the smaller output aperture versus incidence angle compared to the cosine theta theoretical maximum, i.e., projection limit when not tracking the light source. The results show that the concentrator that is air filled, homogeneously filled with RI = 3.5, or homogeneous filled with RI = 3.5 along with a lens-top reject a substantial amount of the incident light. In contrast, an AGILE with a linear gradient index from ambient to the detector material (i.e., RI from 1 to 3.5) concentrates light close to the theoretical limit. In these simulations, Fresnel reflections at the top surface are not included in most curves unless denoted in the chart legend, as an antireflection thin film can be added at the top surface. However, as seen in the curves where Fresnel reflections are included, the AGILE is unchanged, while the lens-top and high-index filled cones have reduced transmissions. Fig. 2: Ray tracing simulations for different concentrator designs with different refractive index profiles for comparison. AGILE with theoretical refractive index gradient from 1 to 3.5 tracks the upper bound limit for passive concentrators well (cosine projection maximum) and concentrates light across the incidence angles Full size image The AGILE theoretical concept While designing optical concentrators, the constant brightness theorem 18 , 19 ,", "role": "user" }, { "content": "Researchers have imagined, designed, and tested an elegant lens device that can efficiently gather light from all angles and concentrate it at a fixed output position. These graded index optics also have applications in areas such as light management in solid-state lighting, laser couplers, and display technology to improve coupling and resolution. Even with the impressive and continuous advances in solar technologies, the question remains: How can we efficiently collect energy from sunlight coming from varying angles from sunrise to sunset? Solar panels work best when sunlight hits them directly. To capture as much energy as possible, many solar arrays actively rotate towards the sun as it moves across the sky. This makes them more efficient, but also more expensive and complicated to build and maintain than a stationary system. These active systems may not be necessary in the future. At Stanford University, engineering researcher Nina Vaidya designed an elegant device that can efficiently gather and concentrate light that falls on it, regardless of the angle and frequency of that light. A paper describing the system's performance, and the theory behind it, is the cover story in the July issue of Microsystems & Nanoengineering, authored by Vaidya and her doctoral advisor Olav Solgaard, professor of electrical engineering at Stanford. \"It's a completely passive system—it doesn't need energy to track the source or have any moving parts,\" said Vaidya, who is now an assistant professor at the University of Southampton, UK. \"Without optical focus that moves positions or need for tracking systems, concentrating light becomes much simpler.\" The device, which the researchers are calling AGILE—an acronym for Axially Graded Index Lens—is deceptively straightforward. It looks like an upside-down pyramid with the point lopped off. Light enters the square, tile-able top from any number of angles and is funneled down to create a brighter spot at the output. In their prototypes, the researchers were able to capture over 90% of the light that hit the surface and create spots at the output that were three times brighter than the incoming light. Installed in a layer on top of solar cells, they could make solar arrays more efficient and capture not only direct sunlight, but also diffuse light that has been scattered by the Earth's atmosphere, weather, and seasons. A top layer of AGILE could replace the existing encapsulation that protects solar arrays, remove the need to track the sun, create space for cooling and circuitry to run between the narrowing pyramids of the individual devices, and most importantly, reduce the amount of solar cell area needed to produce energy—and hence reduce the costs. And the uses aren't limited to terrestrial solar installations: if applied to solar arrays being sent into space, an AGILE layer could both concentrate light without solar tracking and provide necessary protection from radiation. AGILE (Axially Graded Index LEns) concept and concentrator array system vision. a Depiction of the optical concentration action, b repeating unit of AGILE, c concentrator arrays with built-in anti-reflection and encapsulation, no need for tracking the source, and spatially separated PV cells which have advantages of reduced PV material use, hence lower cost with space for cooling and circuitry. Credit: Microsystems & Nanoengineering (2022). DOI: 10.1038/s41378-022-00377-z Envisioning the perfect AGILE The basic premise behind AGILE is similar to using a magnifying glass to burn spots on leaves on a sunny day. The lens of the magnifying glass focuses the sun's rays into a smaller, brighter point. But with a magnifying glass, the focal point moves as the sun does. Vaidya and Solgaard found a way to create a lens that takes rays from all angles but always concentrates light at the same output position. \"We wanted to create something that takes in light and concentrates it at the same position, even as the source changes direction,\" said Vaidya. \"We don't want to have to keep moving our detector or solar cell or moving the system to face the source.\" Vaidya and Solgaard determined that theoretically, it would be possible to collect and concentrate scattered light using an engineered material that smoothly increased in refractive index—a property that describes how quickly light travels through a material—causing the light to bend and curve towards a focal point. At the surface of the material, the light would hardly bend at all. By the time it reached the other side, it would be almost vertical and focused. \"The best solutions are often the simplest of ideas. An ideal AGILE has, at the very front of it, the same refractive index as the air and it gradually gets higher—the light bends in a perfectly smooth curve,\" said Solgaard. \"But in a practical situation, you're not going to have that ideal AGILE.\" From theory to reality For the prototypes, the researchers layered together different glasses and polymers that bend light to different degrees, creating what's known as a graded index material. The layers change the light's direction in steps instead of a smooth curve, which the researchers found to be a good approximation of the ideal AGILE. The sides of the prototypes are mirrored, so any light going in the wrong direction is bounced back towards the output. One of the biggest challenges was finding and creating the right materials, Vaidya says. The material layers in the AGILE prototype let a broad spectrum of light, from near-ultraviolet to infrared, pass through it and bend that light increasingly towards the output with a wide range of refractive indices, which is not seen in nature or the present optics industry. These materials used also had to be compatible with each other—if one glass expanded in response to heat at a different rate than another, the whole device could crack—and robust enough to be machined into shape and remain durable. \"It's one of these 'moonshot' engineering adventures, going right from theory to real prototypes,\" said Vaidya. \"There are a lot of theory papers and great ideas out there, but it's hard to turn them into reality with real designs and real materials pushing the boundaries of what was deemed impossible before.\" After exploring many materials, creating new fabrication techniques, and testing multiple prototypes, the researchers landed on AGILE designs that performed well using commercially available polymers and glasses. AGILE has also been fabricated using 3D printing in the authors' prior work that created lightweight and design-flexible polymeric lenses with nanometer-scale surface roughness. Vaidya hopes the AGILE designs will be able to be put to use in the solar industry and other areas as well. AGILE has several potential applications in areas like laser coupling, display technologies, and illumination—such as solid-state lighting, which is more energy efficient than older methods of lighting. \"Using our efforts and knowledge to make meaningful engineering systems has been my driving force, even when some trials were not working out,\" said Vaidya. \"To be able to use these new materials, these new fabrication techniques, and this new AGILE concept to create better solar concentrators has been very rewarding. Abundant and affordable clean energy is a vital part of addressing the urgent climate and sustainability challenges, and we need to catalyze engineering solutions to make that a reality.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Immersion optics enable creation of systems with improved optical concentration and coupling by taking advantage of the fact that the luminance of light is proportional to the square of the refractive index in a lossless optical system. Immersion graded index optical concentrators, that do not need to track the source, are described in terms of theory, simulations, and experiments. We introduce a generalized design guide equation which follows the Pareto function and can be used to create various immersion graded index optics depending on the application requirements of concentration, refractive index, height, and efficiency. We present glass and polymer fabrication techniques for creating broadband transparent graded index materials with large refractive index ranges, (refractive index ratio) 2 of ~2, going many fold beyond what is seen in nature or the optics industry. The prototypes demonstrate 3x optical concentration with over 90% efficiency. We report via functional prototypes that graded-index-lens concentrators perform close to the theoretical maximum limit and we introduce simple, inexpensive, design-flexible, and scalable fabrication techniques for their implementation. Introduction Harnessing the plentiful solar energy reaching the earth via photovoltaics will play a major role in satisfying our future energy needs in a sustainable way. One promising approach is concentrated photovoltaics 1 , and several ways to achieve concentration are being used in the field 2 , 3 - Fresnel lenses 4 , 5 , mirrors 6 , 7 , parabolic concentrators 8 , 9 , secondary high-index optics 10 , waveguides 11 , 12 , 13 , immersion lenses 14 , surface nanotexturing 15 . The majority of these require active tracking of the Sun as they have to face the light source within a few degrees. Some of the above are passive concentrators, i.e., do not need to track the Sun, however they still offer modest acceptance angles that do not span the available 2π steradians. We present a passive concentrator device, AGILE (Axially Graded Index LEns) 16 . Henceforth, this immersion graded index optical concentrator is written as AGILE in the manuscript. AGILE does not need solar tracking and follows the cosine projection maximum limit, concentrating light incident on it from all angles. The AGILE allows for non-pointing (i.e., removing the need to track the Sun) concentration systems which reduce the amount of photovoltaic (PV) material required but also efficiently absorb diffuse light. Light scattering is present due to cloud cover and atmosphere; and diffuse light can be as high as 20% even on a sunny day 17 . Figure 1a depicts how light is concentrated in the AGILE concentrator. Light rays incident from the entire 2π steradians enter the larger aperture with refractive index (RI) of 1, curve towards the normal via refraction along the height of the cone in the axial gradient RI, reflect from the sidewalls, and reach the smaller output aperture with high RI, e.g., silicon with RI ~ 3.5, without need to track the light source. Figure 1c portrays the AGILE concentrator array system, made up of the repeated unit shown in Fig. 1 b, that absorbs all the incident light and hence appears dark. Video clip of the AGILE array system is attached in the supplementary material. In this video, the AGILE does not have metallic reflective sidewalls so that the graded index material can be visualised. AGILE allows near perfect antireflection and coupling, encapsulation, space for circuitry and cooling, and conformal design. These immersion graded index optics can also realize applications in areas like light management in solid state lighting, laser couplers, display technology etc. Fig. 1: AGILE (Axially Graded Index LEns) concept and concentrator array system vision. a Depiction of the optical concentration action, b repeating unit of AGILE, c concentrator arrays with built-in anti-reflection and encapsulation, no need for tracking the source, and spatially separated PV cells which have advantages of reduced PV material use, hence lower cost with space for cooling and circuitry. Full size image Comparison of different concentrator designs Ray tracing simulations were performed with the software FRED. We performed simulations to compare optical concentration efficiencies of cone geometries with different RI profile fills. All the concentrators simulated in Fig. 2 have the same geometry- the input diameter is 3.5, the output diameter is 1, the height is 5, and the interior sidewalls of the cone are optically reflective. These are dimension-independent simulations in the ray domain, i.e., in the regime where the device dimensions are several times larger than the wavelength of the incident light. Details of scale invariance are presented in appendix A in the supplementary file. The angle of the incident ray array, theta, was swept from 0 to 90° in one plane as the structure has rotational symmetry. Figure 2 shows the cone geometries’ optical concentration efficiency, i.e., light transmission to the smaller output aperture versus incidence angle compared to the cosine theta theoretical maximum, i.e., projection limit when not tracking the light source. The results show that the concentrator that is air filled, homogeneously filled with RI = 3.5, or homogeneous filled with RI = 3.5 along with a lens-top reject a substantial amount of the incident light. In contrast, an AGILE with a linear gradient index from ambient to the detector material (i.e., RI from 1 to 3.5) concentrates light close to the theoretical limit. In these simulations, Fresnel reflections at the top surface are not included in most curves unless denoted in the chart legend, as an antireflection thin film can be added at the top surface. However, as seen in the curves where Fresnel reflections are included, the AGILE is unchanged, while the lens-top and high-index filled cones have reduced transmissions. Fig. 2: Ray tracing simulations for different concentrator designs with different refractive index profiles for comparison. AGILE with theoretical refractive index gradient from 1 to 3.5 tracks the upper bound limit for passive concentrators well (cosine projection maximum) and concentrates light across the incidence angles Full size image The AGILE theoretical concept While designing optical concentrators, the constant brightness theorem 18 , 19 ,<|im_end|> <|im_start|>assistant Researchers have imagined, designed, and tested an elegant lens device that can efficiently gather light from all angles and concentrate it at a fixed output position. These graded index optics also have applications in areas such as light management in solid-state lighting, laser couplers, and display technology to improve coupling and resolution. Even with the impressive and continuous advances in solar technologies, the question remains: How can we efficiently collect energy from sunlight coming from varying angles from sunrise to sunset? Solar panels work best when sunlight hits them directly. To capture as much energy as possible, many solar arrays actively rotate towards the sun as it moves across the sky. This makes them more efficient, but also more expensive and complicated to build and maintain than a stationary system. These active systems may not be necessary in the future. At Stanford University, engineering researcher Nina Vaidya designed an elegant device that can efficiently gather and concentrate light that falls on it, regardless of the angle and frequency of that light. A paper describing the system's performance, and the theory behind it, is the cover story in the July issue of Microsystems & Nanoengineering, authored by Vaidya and her doctoral advisor Olav Solgaard, professor of electrical engineering at Stanford. "It's a completely passive system—it doesn't need energy to track the source or have any moving parts," said Vaidya, who is now an assistant professor at the University of Southampton, UK. "Without optical focus that moves positions or need for tracking systems, concentrating light becomes much simpler." The device, which the researchers are calling AGILE—an acronym for Axially Graded Index Lens—is deceptively straightforward. It looks like an upside-down pyramid with the point lopped off. Light enters the square, tile-able top from any number of angles and is funneled down to create a brighter spot at the output. In their prototypes, the researchers were able to capture over 90% of the light that hit the surface and create spots at the output that were three times brighter than the incoming light. Installed in a layer on top of solar cells, they could make solar arrays more efficient and capture not only direct sunlight, but also diffuse light that has been scattered by the Earth's atmosphere, weather, and seasons. A top layer of AGILE could replace the existing encapsulation that protects solar arrays, remove the need to track the sun, create space for cooling and circuitry to run between the narrowing pyramids of the individual devices, and most importantly, reduce the amount of solar cell area needed to produce energy—and hence reduce the costs. And the uses aren't limited to terrestrial solar installations: if applied to solar arrays being sent into space, an AGILE layer could both concentrate light without solar tracking and provide necessary protection from radiation. AGILE (Axially Graded Index LEns) concept and concentrator array system vision. a Depiction of the optical concentration action, b repeating unit of AGILE, c concentrator arrays with built-in anti-reflection and encapsulation, no need for tracking the source, and spatially separated PV cells which have advantages of reduced PV material use, hence lower cost with space for cooling and circuitry. Credit: Microsystems & Nanoengineering (2022). DOI: 10.1038/s41378-022-00377-z Envisioning the perfect AGILE The basic premise behind AGILE is similar to using a magnifying glass to burn spots on leaves on a sunny day. The lens of the magnifying glass focuses the sun's rays into a smaller, brighter point. But with a magnifying glass, the focal point moves as the sun does. Vaidya and Solgaard found a way to create a lens that takes rays from all angles but always concentrates light at the same output position. "We wanted to create something that takes in light and concentrates it at the same position, even as the source changes direction," said Vaidya. "We don't want to have to keep moving our detector or solar cell or moving the system to face the source." Vaidya and Solgaard determined that theoretically, it would be possible to collect and concentrate scattered light using an engineered material that smoothly increased in refractive index—a property that describes how quickly light travels through a material—causing the light to bend and curve towards a focal point. At the surface of the material, the light would hardly bend at all. By the time it reached the other side, it would be almost vertical and focused. "The best solutions are often the simplest of ideas. An ideal AGILE has, at the very front of it, the same refractive index as the air and it gradually gets higher—the light bends in a perfectly smooth curve," said Solgaard. "But in a practical situation, you're not going to have that ideal AGILE." From theory to reality For the prototypes, the researchers layered together different glasses and polymers that bend light to different degrees, creating what's known as a graded index material. The layers change the light's direction in steps instead of a smooth curve, which the researchers found to be a good approximation of the ideal AGILE. The sides of the prototypes are mirrored, so any light going in the wrong direction is bounced back towards the output. One of the biggest challenges was finding and creating the right materials, Vaidya says. The material layers in the AGILE prototype let a broad spectrum of light, from near-ultraviolet to infrared, pass through it and bend that light increasingly towards the output with a wide range of refractive indices, which is not seen in nature or the present optics industry. These materials used also had to be compatible with each other—if one glass expanded in response to heat at a different rate than another, the whole device could crack—and robust enough to be machined into shape and remain durable. "It's one of these 'moonshot' engineering adventures, going right from theory to real prototypes," said Vaidya. "There are a lot of theory papers and great ideas out there, but it's hard to turn them into reality with real designs and real materials pushing the boundaries of what was deemed impossible before." After exploring many materials, creating new fabrication techniques, and testing multiple prototypes, the researchers landed on AGILE designs that performed well using commercially available polymers and glasses. AGILE has also been fabricated using 3D printing in the authors' prior work that created lightweight and design-flexible polymeric lenses with nanometer-scale surface roughness. Vaidya hopes the AGILE designs will be able to be put to use in the solar industry and other areas as well. AGILE has several potential applications in areas like laser coupling, display technologies, and illumination—such as solid-state lighting, which is more energy efficient than older methods of lighting. "Using our efforts and knowledge to make meaningful engineering systems has been my driving force, even when some trials were not working out," said Vaidya. "To be able to use these new materials, these new fabrication techniques, and this new AGILE concept to create better solar concentrators has been very rewarding. Abundant and affordable clean energy is a vital part of addressing the urgent climate and sustainability challenges, and we need to catalyze engineering solutions to make that a reality." <|im_end|>

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2,807

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Inhomogeneous temporal processes, like those appearing in human communications, neuron spike trains and seismic signals, consist of high-activity bursty intervals alternating with long low-activity periods. In recent studies such bursty behavior has been characterized by a fat-tailed inter-event time distribution, while temporal correlations were measured by the autocorrelation function. However, these characteristic functions are not capable to fully characterize temporally correlated heterogenous behavior. Here we show that the distribution of the number of events in a bursty period serves as a good indicator of the dependencies, leading to the universal observation of power-law distribution for a broad class of phenomena. We find that the correlations in these quite different systems can be commonly interpreted by memory effects and described by a simple phenomenological model, which displays temporal behavior qualitatively similar to that in real systems. Introduction In nature there are various phenomena, from earthquakes 1 to sunspots 2 and neuronal activity 3 , that show temporally inhomogeneous sequence of events, in which the overall dynamics is determined by aggregate effects of competing processes. This happens also in human dynamics as a result of individual decision making and of various kinds of correlations with one's social environment. These systems can be characterized by intermittent switching between periods of low activity and high activity bursts 4 , 5 , 6 , which can appear as a collective phenomenon similar to processes seen in self-organized criticality 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 . In contrast with such self-organized patterns intermittent switching can be detected at the individual level as well (see Fig. 1 ), seen for single neuron firings or for earthquakes at a single location 17 , 18 , 19 , 20 , 21 where the famous Omori's law 22 , 23 describes the temporal decay of aftershock rates at a given spot. Figure 1 Activity of single entities with color-coded inter-event times. (a): Sequence of earthquakes with magnitude larger than two at a single location (South of Chishima Island, 8th–9th October 1994) (b): Firing sequence of a single neuron (from rat's hippocampal) (c): Outgoing mobile phone call sequence of an individual. Shorter the time between the consecutive events darker the color. Full size image Further examples of bursty behavior at the individual level have been observed in the digital records of human communication activities through different channels 4 , 24 , 25 , 26 , 27 , 28 . Over the last few years different explanations have been proposed about the origin of inhomogeneous human dynamics 4 , 24 , 29 , including the single event level 30 and about the impact of circadian and weekly fluctuations 31 . Moreover, by using novel technology of Radio Frequency ID's, heterogeneous temporal behavior was observed in the dynamics of face-to-face interactions 32 , 33 . This was explained by a reinforcement dynamics 34 , 35 driving the decision making process at the single entity level. For systems with discrete event dynamics it is usual to characterize the observed temporal inhomogeneities by the inter-event time distributions, P ( t ie ), where t ie = t i + 1 − t i denotes the time between consecutive events. A broad P ( t ie ) 3 , 25 , 36 reflects large variability in the inter-event times and denotes heterogeneous temporal behavior. Note that P ( t ie ) alone tells nothing about the presence of correlations, usually characterized by the autocorrelation function, A (τ), or by the power spectrum density. However, for temporally heterogeneous signals of independent events with fat-tailed P ( t ie ) the Hurst exponent can assign false positive correlations 37 together with the autocorrelation function (see Supplementary Information ). To understand the mechanisms behind these phenomena, it is important to know whether there are true correlations in these systems. Hence for systems showing fat-tailed inter-event time distributions, there is a need to develop new measures that are sensitive to correlations but insensitive to fat tails. In this paper we define a new measure that is capable of detecting whether temporal correlations are present, even in the case of heterogeneous signals. By analyzing the empirical datasets of human communication, earthquake activity and neuron spike trains, we observe universal features induced by temporal correlations. In the analysis we establish a close relationship between the observed correlations and memory effects and propose a phenomenological model that implements memory driven correlated behavior. Results Correlated events A sequence of discrete temporal events can be interpreted as a time-dependent point process, X ( t ), where X ( t i ) = 1 at each time step t i when an event takes place, otherwise X ( t i ) = 0. To detect bursty clusters in this binary event sequence we have to identify those events we consider correlated. The smallest temporal scale at which correlations can emerge in the dynamics is between consecutive events. If only X ( t ) is known, we can assume two consecutive actions at t i and t i + 1 to be related if they follow each other within a short time interval, t i + 1 − t i ≤ Δ t 30 , 38 . For events with the duration d i this condition is slightly modified: t i + 1 −( t i + d i ) ≤ Δ t . This definition allows us to detect bursty periods, defined as a sequence of events where each event follows the previous one within a time interval Δ t . By counting the number of events, E , that belong to the same bursty period, we can calculate their distribution P ( E ) in a signal. For a sequence of independent events, P ( E ) is uniquely determined by the inter-event time distribution P ( t ie ) as follows: for n > 0. Here the integral defines the probability to draw an inter-event time P ( t ie", "role": "user" }, { "content": "Several complex systems live in periods of short bursts of high activity followed by long uneventful intermissions. This phenomenon called burstiness can be modelled and predicted with mathematical algorithms. Research of Dr Márton Karsai of Aalto University Department of Biomedical Engineering and Computational Science, now shows that burstiness has universal features in very different systems. Karsai and his collaborators – Dean Kimmo Kaski of Aalto University School of Science, FidiPro Professor in Aalto University János Kertész, and the world-renowned physicist and network theorist Professor Albert-László Barabási – studied burstiness in human mobile and email communication, in neuron spike trains, and in seismic activity in earthquakes. The results have recently been published in Nature Scientific Reports. \"The method we developed helped us to highlight a novel universal feature of bursty behaviour. This is one step beyond the state of the art assumptions regarding the phenomena of burstiness,\" assesses Karsai the significance of the group's work. The research focuses on the dynamic phenomena of burstiness, that is, the mechanisms of temporal fluctuation of levels of activity. We make, for instance, several phone calls and send many emails in a short spurts of time, and otherwise not so much. Neurons fire in spike trains, and earth quakes in similar temporal patterns. There are not only connections between consecutive events but also in events within bursty periods. The common feature shared by the studied systems is that beyond being bursty, the bursty events evolve rather in long trains of events than in pairs – contrary to what existing modelling methods have lead to assume. \"We observed that bursts are not independent but rather clustered and they evolve in long bursty trains, which contain several correlated events. The universality of the analysed systems come from the fact that the size distribution of these trains scale very similarly in human communication, neuron firing and earthquakes,\" describes Karsai the group's results. All the systems share both a threshold mechanism of a sort and memory effects within their processes. Earth begins to shake when accumulated stress relaxes, and one quake can trigger several aftershocks. Neurons fire in consecutive spike trains when they receive enough excitatory stimuli. Humans make choices between countless virtual options; one phone call or email often turns into many. \"These correlations can be interpreted as a very simple memory process where the actual state of the system depends not only on the previous bursty event but also from all the other events that have evolved in the actual burst train,\" points out Karsai. \"We hope that our approach will help to disclose other unknown features of correlated heterogeneous temporal behaviour. The methodology can be applied in many different fields of science, engineering and business. For instance, by predicting human communication behaviour, one can better design the usage of resources in telecommunication or help service providers make better business plans.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Inhomogeneous temporal processes, like those appearing in human communications, neuron spike trains and seismic signals, consist of high-activity bursty intervals alternating with long low-activity periods. In recent studies such bursty behavior has been characterized by a fat-tailed inter-event time distribution, while temporal correlations were measured by the autocorrelation function. However, these characteristic functions are not capable to fully characterize temporally correlated heterogenous behavior. Here we show that the distribution of the number of events in a bursty period serves as a good indicator of the dependencies, leading to the universal observation of power-law distribution for a broad class of phenomena. We find that the correlations in these quite different systems can be commonly interpreted by memory effects and described by a simple phenomenological model, which displays temporal behavior qualitatively similar to that in real systems. Introduction In nature there are various phenomena, from earthquakes 1 to sunspots 2 and neuronal activity 3 , that show temporally inhomogeneous sequence of events, in which the overall dynamics is determined by aggregate effects of competing processes. This happens also in human dynamics as a result of individual decision making and of various kinds of correlations with one's social environment. These systems can be characterized by intermittent switching between periods of low activity and high activity bursts 4 , 5 , 6 , which can appear as a collective phenomenon similar to processes seen in self-organized criticality 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 . In contrast with such self-organized patterns intermittent switching can be detected at the individual level as well (see Fig. 1 ), seen for single neuron firings or for earthquakes at a single location 17 , 18 , 19 , 20 , 21 where the famous Omori's law 22 , 23 describes the temporal decay of aftershock rates at a given spot. Figure 1 Activity of single entities with color-coded inter-event times. (a): Sequence of earthquakes with magnitude larger than two at a single location (South of Chishima Island, 8th–9th October 1994) (b): Firing sequence of a single neuron (from rat's hippocampal) (c): Outgoing mobile phone call sequence of an individual. Shorter the time between the consecutive events darker the color. Full size image Further examples of bursty behavior at the individual level have been observed in the digital records of human communication activities through different channels 4 , 24 , 25 , 26 , 27 , 28 . Over the last few years different explanations have been proposed about the origin of inhomogeneous human dynamics 4 , 24 , 29 , including the single event level 30 and about the impact of circadian and weekly fluctuations 31 . Moreover, by using novel technology of Radio Frequency ID's, heterogeneous temporal behavior was observed in the dynamics of face-to-face interactions 32 , 33 . This was explained by a reinforcement dynamics 34 , 35 driving the decision making process at the single entity level. For systems with discrete event dynamics it is usual to characterize the observed temporal inhomogeneities by the inter-event time distributions, P ( t ie ), where t ie = t i + 1 − t i denotes the time between consecutive events. A broad P ( t ie ) 3 , 25 , 36 reflects large variability in the inter-event times and denotes heterogeneous temporal behavior. Note that P ( t ie ) alone tells nothing about the presence of correlations, usually characterized by the autocorrelation function, A (τ), or by the power spectrum density. However, for temporally heterogeneous signals of independent events with fat-tailed P ( t ie ) the Hurst exponent can assign false positive correlations 37 together with the autocorrelation function (see Supplementary Information ). To understand the mechanisms behind these phenomena, it is important to know whether there are true correlations in these systems. Hence for systems showing fat-tailed inter-event time distributions, there is a need to develop new measures that are sensitive to correlations but insensitive to fat tails. In this paper we define a new measure that is capable of detecting whether temporal correlations are present, even in the case of heterogeneous signals. By analyzing the empirical datasets of human communication, earthquake activity and neuron spike trains, we observe universal features induced by temporal correlations. In the analysis we establish a close relationship between the observed correlations and memory effects and propose a phenomenological model that implements memory driven correlated behavior. Results Correlated events A sequence of discrete temporal events can be interpreted as a time-dependent point process, X ( t ), where X ( t i ) = 1 at each time step t i when an event takes place, otherwise X ( t i ) = 0. To detect bursty clusters in this binary event sequence we have to identify those events we consider correlated. The smallest temporal scale at which correlations can emerge in the dynamics is between consecutive events. If only X ( t ) is known, we can assume two consecutive actions at t i and t i + 1 to be related if they follow each other within a short time interval, t i + 1 − t i ≤ Δ t 30 , 38 . For events with the duration d i this condition is slightly modified: t i + 1 −( t i + d i ) ≤ Δ t . This definition allows us to detect bursty periods, defined as a sequence of events where each event follows the previous one within a time interval Δ t . By counting the number of events, E , that belong to the same bursty period, we can calculate their distribution P ( E ) in a signal. For a sequence of independent events, P ( E ) is uniquely determined by the inter-event time distribution P ( t ie ) as follows: for n > 0. Here the integral defines the probability to draw an inter-event time P ( t ie<|im_end|> <|im_start|>assistant Several complex systems live in periods of short bursts of high activity followed by long uneventful intermissions. This phenomenon called burstiness can be modelled and predicted with mathematical algorithms. Research of Dr Márton Karsai of Aalto University Department of Biomedical Engineering and Computational Science, now shows that burstiness has universal features in very different systems. Karsai and his collaborators – Dean Kimmo Kaski of Aalto University School of Science, FidiPro Professor in Aalto University János Kertész, and the world-renowned physicist and network theorist Professor Albert-László Barabási – studied burstiness in human mobile and email communication, in neuron spike trains, and in seismic activity in earthquakes. The results have recently been published in Nature Scientific Reports. "The method we developed helped us to highlight a novel universal feature of bursty behaviour. This is one step beyond the state of the art assumptions regarding the phenomena of burstiness," assesses Karsai the significance of the group's work. The research focuses on the dynamic phenomena of burstiness, that is, the mechanisms of temporal fluctuation of levels of activity. We make, for instance, several phone calls and send many emails in a short spurts of time, and otherwise not so much. Neurons fire in spike trains, and earth quakes in similar temporal patterns. There are not only connections between consecutive events but also in events within bursty periods. The common feature shared by the studied systems is that beyond being bursty, the bursty events evolve rather in long trains of events than in pairs – contrary to what existing modelling methods have lead to assume. "We observed that bursts are not independent but rather clustered and they evolve in long bursty trains, which contain several correlated events. The universality of the analysed systems come from the fact that the size distribution of these trains scale very similarly in human communication, neuron firing and earthquakes," describes Karsai the group's results. All the systems share both a threshold mechanism of a sort and memory effects within their processes. Earth begins to shake when accumulated stress relaxes, and one quake can trigger several aftershocks. Neurons fire in consecutive spike trains when they receive enough excitatory stimuli. Humans make choices between countless virtual options; one phone call or email often turns into many. "These correlations can be interpreted as a very simple memory process where the actual state of the system depends not only on the previous bursty event but also from all the other events that have evolved in the actual burst train," points out Karsai. "We hope that our approach will help to disclose other unknown features of correlated heterogeneous temporal behaviour. The methodology can be applied in many different fields of science, engineering and business. For instance, by predicting human communication behaviour, one can better design the usage of resources in telecommunication or help service providers make better business plans." <|im_end|>

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1,835

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Electron heating is a fundamental and multidisciplinary phenomenon in partially ionized gases, from the planet’s ionosphere to laboratory-scale plasmas. Plasmas produced at ambient or reduced pressures have recently shown potential for scientific and industrial applications. However, electron heating, which is strongly coupled to the physicochemical properties of these plasmas, has been poorly understood. We experimentally found the rapid structural transition from non-local to local electron heating in collisional radio-frequency discharges at atmospheric-to-subatmospheric pressures. As the gas pressure decreased from 760 to 200 Torr, the time-averaged electron density increased from 1.3 × 10 12 to 1.3 × 10 13 cm −3 , and the electron temperature decreased from 2.5 to 1.1 eV at the maximum allowable discharge current in the abnormal α-mode in the plasma bulk. The spatiotemporal evolution of the electron temperature clearly shows that the electron temperature increases uniformly throughout the bulk plasma region during sheath expansion and collapse at 760 Torr, but the electron heating weakens with sheath collapse as the gas pressure decreases. Introduction Most natural phenomena, to our knowledge, are associated with gas pressure and arise from pressure changes. For ionized gases, including those in the earth’s atmosphere and laboratory-scale plasmas, it is also one of the most crucial parameters that influence the ionization process because it is related to electron-neutral collisional coupling and electron mobility. In the earth’s ionosphere, where the gas pressure is under 10 −6 bar, free electrons and ions readily respond to the electromagnetic field and affect geophysical phenomena, which do not appear in the lower atmosphere 1 , 2 , 3 . Advances in knowledge through scientific studies on electron kinetics and heating at given pressure have unveiled anomalous phenomena and their mechanisms. Alongside with ionized gases in the atmosphere, many studies have investigated the pressure dependence of the electron characteristics of laboratory plasmas, and previous works have shown the great influence of gas pressure on plasma properties 4 , 5 . However, in contrast to low-pressure plasmas (e.g., under 1 mTorr), plasma properties in the high-pressure regime, including atmospheric pressure, are not well understood; yet, the electron diagnostic for such plasmas still remains a significant challenge. Due to the different plasma characteristics at different pressures in the subatmospheric-to-atmospheric pressure range, characterizing the plasma over such a pressure range is a prerequisite for understanding the underlying principles of plasmas and for industrial plasma applications 6 . One example is the dielectric barrier discharge (DBD). Because of the potential implementation of DBD actuators as aerodynamic devices in gas turbines and airplanes, the effects of gas pressure on the characteristics of DBD actuators have been actively investigated over the expected range of pressures 7 , 8 . Over the past several decades, plasmas generated at ambient pressure have received great attention as a multidisciplinary topic due to their complexity, and there has been a dramatic increase in plasma applications. Recent publications clearly demonstrate possible utilizations of atmospheric-pressure plasmas and their outstanding results 9 , 10 , 11 , 12 . In most applications, various plasma sources are used as generators of reactive chemical species because the contribution of plasmas to processing targets is dominated by chemical reactions. Moreover, short-lived reactive species, which are key players in most plasma applications, are remotely produced and controlled via the photolysis or post-discharge reactions of long-lived species 13 , 14 , 15 , 16 . Thus, direct contact of the target with the plasma or releasing the plasma into ambient air is not a key requirement in certain applications, and attempts to utilize plasmas in the subatmospheric pressure range have recently increased. However, as previously mentioned, despite the remarkable demand and interest in plasmas at atmospheric-to-subatmospheric pressures, not many studies have been performed to determine the effect of gas pressure on the electron kinetics, which are directly coupled to the chemical reactions in plasmas near atmospheric pressure. This is mainly because suitable and available electron diagnostics for these plasmas are lacking. Here, we report the electron properties, i.e., electron density ( n e ) and temperature ( T e ), and electron kinetics of radio-frequency (rf) argon capacitive discharges in a pressure range from 200 to 760 Torr. To understand the electron properties under different pressure condition, we have experimentally investigated the electron heating structures during an rf cycle based on the measured spatiotemporal distribution of the neutral bremsstrahlung and electron temperature. The results clearly demonstrate the rapid structural transition from non-local to local electron heating; the electron heating during the sheath collapse weakens as the pressure decreases. Results The root mean square (rms) current versus the rms voltage ( I rms - V rms ) and the rms current versus the power dissipated in the plasma ( I rms - P dis ) curves are shown in Fig. 1(a,b) , respectively. As all the discharges were operated in the abnormal α-mode, V rms and P dis are almost linearly proportional to I rms . As presented in the figure, the accessible ranges of V rms and P dis decrease with the decreasing pressure. The slopes of the I rms - V rms curves slightly increase with the decreasing pressure. According to the one-dimensional (1-D), simple resistor-capacitor series circuit model, which is an acceptable model for atmospheric-pressure capacitive discharges 6 , the slope of the I rms - V rms curve is roughly \$1/2{\\rm{\\pi }}(13.56[{\\rm{MHz}}])/(1.52{\\varepsilon }_{0}S/d)\$ , where ε 0 is the permittivity in a vacuum, S is the cross sectional area of the plasma, and d is the sheath thickness. Therefore, an increase in the slope as the pressure decreases indicates an increase in the sheath thickness. Consequently, because the voltage drop across the sheath increases as the sheath thickness increases at the same discharge current, the rf power that dissipates in the plasma decreases as the gas pressure decreases, as seen in Fig. 1(b) . An analytical solution for a collisional sheath 17 presents the relation between the gas pressure, p , the sheath thickness, s m . The thickness of an ion-dominated collisional", "role": "user" }, { "content": "A KAIST research team successfully identified the underlying principles behind electron heating, which is one of the most important phenomena in plasmas. As the electric heating determines wide range of physical and chemical properties of plasmas, this outcome will allow relevant industries to extend and effectively customize a range of plasma characteristics for their specific needs. Plasma, frequently called the fourth state of matter, can be mostly formed by artificially energizing gases in standard temperature (25°C) and pressure (1 atm) range. Among the many types of plasma, atmospheric-pressure plasmas have been gaining a great deal of attention due to their unique features and applicability in various scientific and industrial fields. Because plasma characteristics strongly depends on gas pressure in the sub-atmospheric to atmospheric pressure range, characterizing the plasma at different pressures is a prerequisite for understanding the fundamental principles of plasmas and for their industrial applications. In that sense, information on the spatio-temporal evolution in the electron density and temperature is very important because various physical and chemical reactions within a plasma arise from electrons. Hence, electron heating has been an interesting topic in the field of plasma. Because collisions between free electrons and neutral gases are frequent under atmospheric-pressure conditions, there are physical limits to measuring the electron density and temperature in plasmas using conventional diagnostic tools, thus the principles behind free electron heating could not be experimentally revealed. Moreover, lacking information on a key parameter of electron heating and its controlling methods is troublesome and limit improving the reactivity and applicability of such plasmas. Figure 2. Nanosecond-resolved visualization of electron heating. Spatiotemporal evolution of neutral bremsstrahlung at 514.5 nm. Credit: The Korea Advanced Institute of Science and Technology (KAIST) To address these issues, Professor Wonho Choe and his team from the Department of Nuclear and Quantum Engineering employed neutral bremsstrahlung-based electron diagnostics in order to accurately examine the electron density and temperature in target plasmas. In addition, a novel imaging diagnostics for two dimensional distribution of electron information was developed. Using the diagnostic technique they developed, the team measured the nanosecond-resolved electron temperature in weakly ionized collisional plasmas, and they succeeded in revealing the spatiotemporal distribution and the fundamental principle involved in the electron heating process. The team successfully revealed the fundamental principle of the electron heating process under atmospheric to sub-atmospheric pressure (0.25-1atm) conditions through conducting the experiment on the spatiotemporal evolution of electron temperature. Their findings of the underlying research data on free electrons in weakly ionized collisional plasmas will contribute to enhancing the field of plasma science and their commercial applications. Professor Choe said, \"The results of this study provide a clear picture of electron heating in weakly ionized plasmas under conditions where collisions between free electrons and neutral particles are frequent. We hope this study will be informative and helpful in utilizing and commercializing atmospheric-pressure plasma sources in the near future.\" Articles related to this research, led by Research Professor Sanghoo Park, were published in Scientific Reports on May 14 and July 5. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Electron heating is a fundamental and multidisciplinary phenomenon in partially ionized gases, from the planet’s ionosphere to laboratory-scale plasmas. Plasmas produced at ambient or reduced pressures have recently shown potential for scientific and industrial applications. However, electron heating, which is strongly coupled to the physicochemical properties of these plasmas, has been poorly understood. We experimentally found the rapid structural transition from non-local to local electron heating in collisional radio-frequency discharges at atmospheric-to-subatmospheric pressures. As the gas pressure decreased from 760 to 200 Torr, the time-averaged electron density increased from 1.3 × 10 12 to 1.3 × 10 13 cm −3 , and the electron temperature decreased from 2.5 to 1.1 eV at the maximum allowable discharge current in the abnormal α-mode in the plasma bulk. The spatiotemporal evolution of the electron temperature clearly shows that the electron temperature increases uniformly throughout the bulk plasma region during sheath expansion and collapse at 760 Torr, but the electron heating weakens with sheath collapse as the gas pressure decreases. Introduction Most natural phenomena, to our knowledge, are associated with gas pressure and arise from pressure changes. For ionized gases, including those in the earth’s atmosphere and laboratory-scale plasmas, it is also one of the most crucial parameters that influence the ionization process because it is related to electron-neutral collisional coupling and electron mobility. In the earth’s ionosphere, where the gas pressure is under 10 −6 bar, free electrons and ions readily respond to the electromagnetic field and affect geophysical phenomena, which do not appear in the lower atmosphere 1 , 2 , 3 . Advances in knowledge through scientific studies on electron kinetics and heating at given pressure have unveiled anomalous phenomena and their mechanisms. Alongside with ionized gases in the atmosphere, many studies have investigated the pressure dependence of the electron characteristics of laboratory plasmas, and previous works have shown the great influence of gas pressure on plasma properties 4 , 5 . However, in contrast to low-pressure plasmas (e.g., under 1 mTorr), plasma properties in the high-pressure regime, including atmospheric pressure, are not well understood; yet, the electron diagnostic for such plasmas still remains a significant challenge. Due to the different plasma characteristics at different pressures in the subatmospheric-to-atmospheric pressure range, characterizing the plasma over such a pressure range is a prerequisite for understanding the underlying principles of plasmas and for industrial plasma applications 6 . One example is the dielectric barrier discharge (DBD). Because of the potential implementation of DBD actuators as aerodynamic devices in gas turbines and airplanes, the effects of gas pressure on the characteristics of DBD actuators have been actively investigated over the expected range of pressures 7 , 8 . Over the past several decades, plasmas generated at ambient pressure have received great attention as a multidisciplinary topic due to their complexity, and there has been a dramatic increase in plasma applications. Recent publications clearly demonstrate possible utilizations of atmospheric-pressure plasmas and their outstanding results 9 , 10 , 11 , 12 . In most applications, various plasma sources are used as generators of reactive chemical species because the contribution of plasmas to processing targets is dominated by chemical reactions. Moreover, short-lived reactive species, which are key players in most plasma applications, are remotely produced and controlled via the photolysis or post-discharge reactions of long-lived species 13 , 14 , 15 , 16 . Thus, direct contact of the target with the plasma or releasing the plasma into ambient air is not a key requirement in certain applications, and attempts to utilize plasmas in the subatmospheric pressure range have recently increased. However, as previously mentioned, despite the remarkable demand and interest in plasmas at atmospheric-to-subatmospheric pressures, not many studies have been performed to determine the effect of gas pressure on the electron kinetics, which are directly coupled to the chemical reactions in plasmas near atmospheric pressure. This is mainly because suitable and available electron diagnostics for these plasmas are lacking. Here, we report the electron properties, i.e., electron density ( n e ) and temperature ( T e ), and electron kinetics of radio-frequency (rf) argon capacitive discharges in a pressure range from 200 to 760 Torr. To understand the electron properties under different pressure condition, we have experimentally investigated the electron heating structures during an rf cycle based on the measured spatiotemporal distribution of the neutral bremsstrahlung and electron temperature. The results clearly demonstrate the rapid structural transition from non-local to local electron heating; the electron heating during the sheath collapse weakens as the pressure decreases. Results The root mean square (rms) current versus the rms voltage ( I rms - V rms ) and the rms current versus the power dissipated in the plasma ( I rms - P dis ) curves are shown in Fig. 1(a,b) , respectively. As all the discharges were operated in the abnormal α-mode, V rms and P dis are almost linearly proportional to I rms . As presented in the figure, the accessible ranges of V rms and P dis decrease with the decreasing pressure. The slopes of the I rms - V rms curves slightly increase with the decreasing pressure. According to the one-dimensional (1-D), simple resistor-capacitor series circuit model, which is an acceptable model for atmospheric-pressure capacitive discharges 6 , the slope of the I rms - V rms curve is roughly $1/2{\rm{\pi }}(13.56[{\rm{MHz}}])/(1.52{\varepsilon }_{0}S/d)$ , where ε 0 is the permittivity in a vacuum, S is the cross sectional area of the plasma, and d is the sheath thickness. Therefore, an increase in the slope as the pressure decreases indicates an increase in the sheath thickness. Consequently, because the voltage drop across the sheath increases as the sheath thickness increases at the same discharge current, the rf power that dissipates in the plasma decreases as the gas pressure decreases, as seen in Fig. 1(b) . An analytical solution for a collisional sheath 17 presents the relation between the gas pressure, p , the sheath thickness, s m . The thickness of an ion-dominated collisional<|im_end|> <|im_start|>assistant A KAIST research team successfully identified the underlying principles behind electron heating, which is one of the most important phenomena in plasmas. As the electric heating determines wide range of physical and chemical properties of plasmas, this outcome will allow relevant industries to extend and effectively customize a range of plasma characteristics for their specific needs. Plasma, frequently called the fourth state of matter, can be mostly formed by artificially energizing gases in standard temperature (25°C) and pressure (1 atm) range. Among the many types of plasma, atmospheric-pressure plasmas have been gaining a great deal of attention due to their unique features and applicability in various scientific and industrial fields. Because plasma characteristics strongly depends on gas pressure in the sub-atmospheric to atmospheric pressure range, characterizing the plasma at different pressures is a prerequisite for understanding the fundamental principles of plasmas and for their industrial applications. In that sense, information on the spatio-temporal evolution in the electron density and temperature is very important because various physical and chemical reactions within a plasma arise from electrons. Hence, electron heating has been an interesting topic in the field of plasma. Because collisions between free electrons and neutral gases are frequent under atmospheric-pressure conditions, there are physical limits to measuring the electron density and temperature in plasmas using conventional diagnostic tools, thus the principles behind free electron heating could not be experimentally revealed. Moreover, lacking information on a key parameter of electron heating and its controlling methods is troublesome and limit improving the reactivity and applicability of such plasmas. Figure 2. Nanosecond-resolved visualization of electron heating. Spatiotemporal evolution of neutral bremsstrahlung at 514.5 nm. Credit: The Korea Advanced Institute of Science and Technology (KAIST) To address these issues, Professor Wonho Choe and his team from the Department of Nuclear and Quantum Engineering employed neutral bremsstrahlung-based electron diagnostics in order to accurately examine the electron density and temperature in target plasmas. In addition, a novel imaging diagnostics for two dimensional distribution of electron information was developed. Using the diagnostic technique they developed, the team measured the nanosecond-resolved electron temperature in weakly ionized collisional plasmas, and they succeeded in revealing the spatiotemporal distribution and the fundamental principle involved in the electron heating process. The team successfully revealed the fundamental principle of the electron heating process under atmospheric to sub-atmospheric pressure (0.25-1atm) conditions through conducting the experiment on the spatiotemporal evolution of electron temperature. Their findings of the underlying research data on free electrons in weakly ionized collisional plasmas will contribute to enhancing the field of plasma science and their commercial applications. Professor Choe said, "The results of this study provide a clear picture of electron heating in weakly ionized plasmas under conditions where collisions between free electrons and neutral particles are frequent. We hope this study will be informative and helpful in utilizing and commercializing atmospheric-pressure plasma sources in the near future." Articles related to this research, led by Research Professor Sanghoo Park, were published in Scientific Reports on May 14 and July 5. <|im_end|>

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11, 420, 15632, 690, 2187, 9959, 19647, 311, 13334, 323, 13750, 32187, 264, 2134, 315, 32426, 17910, 369, 872, 3230, 3966, 13, 65632, 11, 14134, 2663, 279, 11999, 1614, 315, 5030, 11, 649, 387, 10213, 14454, 555, 78220, 4602, 4954, 45612, 304, 5410, 9499, 320, 914, 32037, 8, 323, 7410, 320, 16, 70887, 8, 2134, 13, 22395, 279, 1690, 4595, 315, 32426, 11, 45475, 89561, 628, 300, 7044, 617, 1027, 30240, 264, 2294, 3568, 315, 6666, 4245, 311, 872, 5016, 4519, 323, 4666, 2968, 304, 5370, 12624, 323, 13076, 5151, 13, 9393, 32426, 17910, 16917, 14117, 389, 6962, 7410, 304, 279, 1207, 29883, 8801, 33349, 311, 45475, 7410, 2134, 11, 3752, 4954, 279, 32426, 520, 2204, 40850, 374, 264, 80884, 369, 8830, 279, 16188, 16565, 315, 628, 300, 7044, 323, 369, 872, 13076, 8522, 13, 763, 430, 5647, 11, 2038, 389, 279, 993, 6400, 69290, 10020, 15740, 304, 279, 17130, 17915, 323, 9499, 374, 1633, 3062, 1606, 5370, 7106, 323, 11742, 25481, 2949, 264, 32426, 31889, 505, 57678, 13, 32140, 11, 17130, 24494, 706, 1027, 459, 7185, 8712, 304, 279, 2115, 315, 32426, 13, 9393, 48453, 1990, 1949, 57678, 323, 21277, 45612, 527, 21420, 1234, 45475, 89561, 4787, 11, 1070, 527, 7106, 13693, 311, 30090, 279, 17130, 17915, 323, 9499, 304, 628, 300, 7044, 1701, 21349, 15439, 7526, 11, 8617, 279, 16565, 4920, 1949, 17130, 24494, 1436, 539, 387, 9526, 750, 10675, 13, 23674, 11, 32161, 2038, 389, 264, 1401, 5852, 315, 17130, 24494, 323, 1202, 26991, 5528, 374, 78518, 323, 4017, 18899, 279, 312, 7323, 323, 4666, 2968, 315, 1778, 628, 300, 7044, 13, 19575, 220, 17, 13, 33242, 974, 1321, 11849, 8905, 42148, 315, 17130, 24494, 13, 3165, 9491, 354, 3342, 10020, 15740, 315, 21277, 5395, 1026, 496, 17137, 2234, 520, 220, 20998, 13, 20, 26807, 13, 16666, 25, 578, 12126, 21844, 10181, 315, 10170, 323, 12053, 320, 27542, 3931, 8, 2057, 2686, 1521, 4819, 11, 17054, 43549, 6292, 921, 4748, 323, 813, 2128, 505, 279, 6011, 315, 38544, 323, 56413, 17005, 20011, 21277, 5395, 1026, 496, 17137, 2234, 6108, 17130, 50518, 304, 2015, 311, 30357, 21635, 279, 17130, 17915, 323, 9499, 304, 2218, 628, 300, 7044, 13, 763, 5369, 11, 264, 11775, 32758, 50518, 369, 1403, 56987, 8141, 315, 17130, 2038, 574, 8040, 13, 12362, 279, 15439, 15105, 814, 8040, 11, 279, 2128, 17303, 279, 20622, 974, 1321, 11849, 8905, 17130, 9499, 304, 7621, 398, 28772, 1534, 19277, 278, 628, 300, 7044, 11, 323, 814, 26399, 304, 31720, 279, 993, 9491, 354, 3342, 10020, 8141, 323, 279, 16188, 17966, 6532, 304, 279, 17130, 24494, 1920, 13, 578, 2128, 7946, 10675, 279, 16188, 17966, 315, 279, 17130, 24494, 1920, 1234, 45475, 311, 1207, 29883, 8801, 33349, 7410, 320, 15, 13, 914, 12, 16, 266, 76, 8, 4787, 1555, 31474, 279, 9526, 389, 279, 993, 9491, 354, 3342, 10020, 15740, 315, 17130, 9499, 13, 11205, 14955, 315, 279, 16940, 3495, 828, 389, 1949, 57678, 304, 7621, 398, 28772, 1534, 19277, 278, 628, 300, 7044, 690, 17210, 311, 47594, 279, 2115, 315, 32426, 8198, 323, 872, 8518, 8522, 13, 17054, 921, 4748, 1071, 11, 330, 791, 3135, 315, 420, 4007, 3493, 264, 2867, 6945, 315, 17130, 24494, 304, 7621, 398, 28772, 1534, 628, 300, 7044, 1234, 4787, 1405, 48453, 1990, 1949, 57678, 323, 21277, 19252, 527, 21420, 13, 1226, 3987, 420, 4007, 690, 387, 39319, 323, 11190, 304, 35988, 323, 8518, 4954, 45475, 89561, 32426, 8336, 304, 279, 3221, 3938, 1210, 29461, 5552, 311, 420, 3495, 11, 6197, 555, 8483, 17054, 52022, 119820, 5657, 11, 1051, 4756, 304, 38130, 29140, 389, 3297, 220, 975, 323, 5887, 220, 20, 13, 220, 128257, 198 ]

2,007

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Efforts to date the oldest modern human fossils in eastern Africa, from Omo-Kibish 1 , 2 , 3 and Herto 4 , 5 in Ethiopia, have drawn on a variety of chronometric evidence, including 40 Ar/ 39 Ar ages of stratigraphically associated tuffs. The ages that are generally reported for these fossils are around 197 thousand years (kyr) for the Kibish Omo I 3 , 6 , 7 , and around 160–155 kyr for the Herto hominins 5 , 8 . However, the stratigraphic relationships and tephra correlations that underpin these estimates have been challenged 6 , 8 . Here we report geochemical analyses that link the Kamoya’s Hominid Site (KHS) Tuff 9 , which conclusively overlies the member of the Omo-Kibish Formation that contains Omo I, with a major explosive eruption of Shala volcano in the Main Ethiopian Rift. By dating the proximal deposits of this eruption, we obtain a new minimum age for the Omo fossils of 233 ± 22 kyr. Contrary to previous arguments 6 , 8 , we also show that the KHS Tuff does not correlate with another widespread tephra layer, the Waidedo Vitric Tuff, and therefore cannot anchor a minimum age for the Herto fossils. Shifting the age of the oldest known Homo sapiens fossils in eastern Africa to before around 200 thousand years ago is consistent with independent evidence for greater antiquity of the modern human lineage 10 . Main Only eight sites in Africa have yielded possible early anatomically modern Homo sapiens fossils from the late Middle Pleistocene (approximately 350–130 thousand years ago (ka)) 11 . Most of these have considerable age uncertainty or debatable H. sapiens apomorphy 11 . A principal method for constraining the fossil ages is the use of single-crystal 40 Ar/ 39 Ar isotope dating applied to stratigraphically associated volcanic ash (tephra) beds 12 , 13 , 14 . However, many distal tephra deposits consist largely of glass and lack suitable crystals for dating. In this case, geochemical fingerprinting can be used to match a tephra layer to more readily dated proximal deposits with larger, more abundant phenocrysts. The most widely accepted fossils that are interpreted as possessing unequivocal modern cranial apomorphies (that is, a tall cranial vault and a chin) and classified as H. sapiens are two Ethiopian finds 11 , 15 , 16 , namely the Omo I 1 and Herto specimens 4 . Accordingly, the evidence that constrains their ages assumes particular importance but is a topic of considerable geochronological controversy 3 , 6 , 8 . The Omo I remains were discovered in the late 1960s in the lower Omo valley of southern Ethiopia 1 , 14 , at the surface of a siltstone near the top of Member I of the Omo-Kibish Formation (Fig. 1a, b ). The maximum age of Omo I was derived from the 40 Ar/ 39 Ar age of 196 ± 4 kyr (2 σ ) 3 , 6 , 17 obtained for alkali feldspar phenocrysts from the three youngest pumice clasts that were sampled from a heterogeneous tuffaceous deposit correlated with the Nakaa’kire Tuff 3 , which is reported to lie “near, but probably slightly below” the fossils 3 (Fig. 1b ). Recalculated using a more widely adopted age of 28.201 million years (Myr) for the irradiation monitor (sanidine from the Fish Canyon Tuff of Colorado) 18 , the Nakaa’kire Tuff age shifts marginally to 197 ± 4 kyr. Owing to the uncertain stratigraphic relationship between this tuff and the hominin fossils 19 , much attention has been focused on dating the KHS Tuff—a widespread, more-than-2-m-thick deposit of fine ash fallout at the base of Member II of the Omo-Kibish Formation (Fig. 1b ). The KHS Tuff overlies Member I, where Omo I was retrieved around 1.4 m lower down section, and is demonstrably younger than the fossils 3 , 9 . Although the Nakaa’kire Tuff was identified in several sections below the KHS Tuff, the latter was not found in the same section from which the dated pumice clasts correlated with the Nakaa’kire Tuff (on the basis of major element composition) were sampled 3 . The fine grain size of the KHS Tuff has precluded direct 40 Ar/ 39 Ar dating, and no correlation to a source volcano or proximal pyroclastic unit has to our knowledge been made previously. However, drawing on published major element glass compositions, it has been correlated with both tephra TA-55 20 , 21 from the Konso Formation and the directly 40 Ar/ 39 Ar-dated 184 ± 10 kyr unit D 22 (recalculated age) of the Gademotta Formation 6 (Fig. 1b ). Relating the sediment flux in the Omo-Kibish basin with high lake levels that correspond to Mediterranean sapropel deposition 9 , 23 , a slightly younger age for the KHS Tuff of around 172 kyr has also been proposed 6 . Either of these ages (184 or 172 kyr) would be consistent with the proposed age of 197 ± 4 kyr for Omo I. Fig. 1: Late Middle Pleistocene tephrostratigraphy of the Main Ethiopian Rift. a , Map of the MER showing silicic volcanoes and the late Middle Pleistocene sedimentary formations and relevant tephra units. White boxes with blue edges depict former correlatives of the KHS Tuff 6 , 8 b , Synthetic stratigraphic logs of the late Middle Pleistocene formations showing former correlations for the Alyio Tuff 6 (green), Konso SVT (pink, also identified in the Chew Bahir sediment core 33 ), new correlations for Konso unit TA-56 (yellow), and source eruptions (stars). LHM, lower Herto Member; UHM, upper Herto Member. c , Tephra ETH18-8 above the KHS Tuff at the KS locality in the Omo-Kibish Formation 9 . Full size image The Herto H. sapiens fossils were recovered in the late 1990s in the Middle Awash 4 , 5 (Afar rift; Fig. 1a ). They were preserved in a sandstone within the upper Herto Member of the Bouri Formation (Fig. 1b ). This sandstone is capped by the Waidedo", "role": "user" }, { "content": "The age of the oldest fossils in eastern Africa widely recognized as representing our species, Homo sapiens, has long been uncertain. Now, dating of a massive volcanic eruption in Ethiopia reveals they are much older than previously thought. The remains—known as Omo I—were found in Ethiopia in the late 1960s, and scientists have been attempting to date them precisely ever since, by using the chemical fingerprints of volcanic ash layers found above and below the sediments in which the fossils were found. An international team of scientists, led by the University of Cambridge, has reassessed the age of the Omo I remains—and Homo sapiens as a species. Earlier attempts to date the fossils suggested they were less than 200,000 years old, but the new research shows they must be older than a colossal volcanic eruption that took place 230,000 years ago. The results are reported in the journal Nature. The Omo I remains were found in the Omo Kibish Formation in southwestern Ethiopia, within the East African Rift valley. The region is an area of high volcanic activity, and a rich source of early human remains and artifacts such as stone tools. By dating the layers of volcanic ash above and below where archaeological and fossil materials are found, scientists identified Omo I as the earliest evidence of our species, Homo sapiens. \"Using these methods, the generally accepted age of the Omo fossils is under 200,000 years, but there's been a lot of uncertainty around this date,\" said Dr. Céline Vidal from Cambridge's Department of Geography, the paper's lead author. \"The fossils were found in a sequence, below a thick layer of volcanic ash that nobody had managed to date with radiometric techniques because the ash is too fine-grained.\" As part of a four-year project led by Professor Clive Oppenheimer, Vidal and her colleagues have been attempting to date all the major volcanic eruptions in the Ethiopian Rift around the time of the emergence of Homo sapiens, a period known as the late Middle Pleistocene. The researchers collected pumice rock samples from the volcanic deposits and ground them down to sub-millimeter size. \"Each eruption has its own fingerprint—its own evolutionary story below the surface, which is determined by the pathway the magma followed,\" said Vidal. \"Once you've crushed the rock, you free the minerals within, and then you can date them, and identify the chemical signature of the volcanic glass that holds the minerals together.\" The researchers carried out new geochemical analysis to link the fingerprint of the thick volcanic ash layer from the Kamoya Hominin Site (KHS ash) with an eruption of Shala volcano, more than 400 kilometers away. The team then dated pumice samples from the volcano to 230,000 years ago. Since the Omo I fossils were found deeper than this particular ash layer, they must be more than 230,000 years old. \"First I found there was a geochemical match, but we didn't have the age of the Shala eruption,\" said Vidal. \"I immediately sent the samples of Shala volcano to our colleagues in Glasgow so they could measure the age of the rocks. When I received the results and found out that the oldest Homo sapiens from the region was older than previously assumed, I was really excited.\" \"The Omo Kibish Formation is an extensive sedimentary deposit which has been barely accessed and investigated in the past,\" said co-author and co-leader of the field investigation Professor Asfawossen Asrat from Addis Ababa University in Ethiopia, who is currently at BIUST in Botswana. \"Our closer look into the stratigraphy of the Omo Kibish Formation, particularly the ash layers, allowed us to push the age of the oldest Homo sapiens in the region to at least 230,000 years.\" \"Unlike other Middle Pleistocene fossils which are thought to belong to the early stages of the Homo sapiens lineage, Omo I possesses unequivocal modern human characteristics, such as a tall and globular cranial vault and a chin,\" said co-author Dr. Aurélien Mounier from the Musée de l'Homme in Paris. \"The new date estimate, de facto, makes it the oldest unchallenged Homo sapiens in Africa.\" The researchers say that while this study shows a new minimum age for Homo sapiens in eastern Africa, it's possible that new finds and new studies may extend the age of our species even further back in time. \"We can only date humanity based on the fossils that we have, so it's impossible to say that this is the definitive age of our species,\" said Vidal. \"The study of human evolution is always in motion: boundaries and timelines change as our understanding improves. But these fossils show just how resilient humans are: that we survived, thrived and migrated in an area that was so prone to natural disasters.\" \"It's probably no coincidence that our earliest ancestors lived in such a geologically active rift valley—it collected rainfall in lakes, providing fresh water and attracting animals, and served as a natural migration corridor stretching thousands of kilometers,\" said Oppenheimer. \"The volcanoes provided fantastic materials to make stone tools and from time to time we had to develop our cognitive skills when large eruptions transformed the landscape.\" \"Our forensic approach provides a new minimum age for Homo sapiens in eastern Africa, but the challenge still remains to provide a cap, a maximum age, for their emergence, which is widely believed to have taken place in this region,\" said co-author Professor Christine Lane, head of the Cambridge Tephra Laboratory where much of the work was carried out. \"It's possible that new finds and new studies may extend the age of our species even further back in time.\" \"There are many other ash layers we are trying to correlate with eruptions of the Ethiopian Rift and ash deposits from other sedimentary formations,\" said Vidal. \"In time, we hope to better constrain the age of other fossils in the region.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Efforts to date the oldest modern human fossils in eastern Africa, from Omo-Kibish 1 , 2 , 3 and Herto 4 , 5 in Ethiopia, have drawn on a variety of chronometric evidence, including 40 Ar/ 39 Ar ages of stratigraphically associated tuffs. The ages that are generally reported for these fossils are around 197 thousand years (kyr) for the Kibish Omo I 3 , 6 , 7 , and around 160–155 kyr for the Herto hominins 5 , 8 . However, the stratigraphic relationships and tephra correlations that underpin these estimates have been challenged 6 , 8 . Here we report geochemical analyses that link the Kamoya’s Hominid Site (KHS) Tuff 9 , which conclusively overlies the member of the Omo-Kibish Formation that contains Omo I, with a major explosive eruption of Shala volcano in the Main Ethiopian Rift. By dating the proximal deposits of this eruption, we obtain a new minimum age for the Omo fossils of 233 ± 22 kyr. Contrary to previous arguments 6 , 8 , we also show that the KHS Tuff does not correlate with another widespread tephra layer, the Waidedo Vitric Tuff, and therefore cannot anchor a minimum age for the Herto fossils. Shifting the age of the oldest known Homo sapiens fossils in eastern Africa to before around 200 thousand years ago is consistent with independent evidence for greater antiquity of the modern human lineage 10 . Main Only eight sites in Africa have yielded possible early anatomically modern Homo sapiens fossils from the late Middle Pleistocene (approximately 350–130 thousand years ago (ka)) 11 . Most of these have considerable age uncertainty or debatable H. sapiens apomorphy 11 . A principal method for constraining the fossil ages is the use of single-crystal 40 Ar/ 39 Ar isotope dating applied to stratigraphically associated volcanic ash (tephra) beds 12 , 13 , 14 . However, many distal tephra deposits consist largely of glass and lack suitable crystals for dating. In this case, geochemical fingerprinting can be used to match a tephra layer to more readily dated proximal deposits with larger, more abundant phenocrysts. The most widely accepted fossils that are interpreted as possessing unequivocal modern cranial apomorphies (that is, a tall cranial vault and a chin) and classified as H. sapiens are two Ethiopian finds 11 , 15 , 16 , namely the Omo I 1 and Herto specimens 4 . Accordingly, the evidence that constrains their ages assumes particular importance but is a topic of considerable geochronological controversy 3 , 6 , 8 . The Omo I remains were discovered in the late 1960s in the lower Omo valley of southern Ethiopia 1 , 14 , at the surface of a siltstone near the top of Member I of the Omo-Kibish Formation (Fig. 1a, b ). The maximum age of Omo I was derived from the 40 Ar/ 39 Ar age of 196 ± 4 kyr (2 σ ) 3 , 6 , 17 obtained for alkali feldspar phenocrysts from the three youngest pumice clasts that were sampled from a heterogeneous tuffaceous deposit correlated with the Nakaa’kire Tuff 3 , which is reported to lie “near, but probably slightly below” the fossils 3 (Fig. 1b ). Recalculated using a more widely adopted age of 28.201 million years (Myr) for the irradiation monitor (sanidine from the Fish Canyon Tuff of Colorado) 18 , the Nakaa’kire Tuff age shifts marginally to 197 ± 4 kyr. Owing to the uncertain stratigraphic relationship between this tuff and the hominin fossils 19 , much attention has been focused on dating the KHS Tuff—a widespread, more-than-2-m-thick deposit of fine ash fallout at the base of Member II of the Omo-Kibish Formation (Fig. 1b ). The KHS Tuff overlies Member I, where Omo I was retrieved around 1.4 m lower down section, and is demonstrably younger than the fossils 3 , 9 . Although the Nakaa’kire Tuff was identified in several sections below the KHS Tuff, the latter was not found in the same section from which the dated pumice clasts correlated with the Nakaa’kire Tuff (on the basis of major element composition) were sampled 3 . The fine grain size of the KHS Tuff has precluded direct 40 Ar/ 39 Ar dating, and no correlation to a source volcano or proximal pyroclastic unit has to our knowledge been made previously. However, drawing on published major element glass compositions, it has been correlated with both tephra TA-55 20 , 21 from the Konso Formation and the directly 40 Ar/ 39 Ar-dated 184 ± 10 kyr unit D 22 (recalculated age) of the Gademotta Formation 6 (Fig. 1b ). Relating the sediment flux in the Omo-Kibish basin with high lake levels that correspond to Mediterranean sapropel deposition 9 , 23 , a slightly younger age for the KHS Tuff of around 172 kyr has also been proposed 6 . Either of these ages (184 or 172 kyr) would be consistent with the proposed age of 197 ± 4 kyr for Omo I. Fig. 1: Late Middle Pleistocene tephrostratigraphy of the Main Ethiopian Rift. a , Map of the MER showing silicic volcanoes and the late Middle Pleistocene sedimentary formations and relevant tephra units. White boxes with blue edges depict former correlatives of the KHS Tuff 6 , 8 b , Synthetic stratigraphic logs of the late Middle Pleistocene formations showing former correlations for the Alyio Tuff 6 (green), Konso SVT (pink, also identified in the Chew Bahir sediment core 33 ), new correlations for Konso unit TA-56 (yellow), and source eruptions (stars). LHM, lower Herto Member; UHM, upper Herto Member. c , Tephra ETH18-8 above the KHS Tuff at the KS locality in the Omo-Kibish Formation 9 . Full size image The Herto H. sapiens fossils were recovered in the late 1990s in the Middle Awash 4 , 5 (Afar rift; Fig. 1a ). They were preserved in a sandstone within the upper Herto Member of the Bouri Formation (Fig. 1b ). This sandstone is capped by the Waidedo<|im_end|> <|im_start|>assistant The age of the oldest fossils in eastern Africa widely recognized as representing our species, Homo sapiens, has long been uncertain. Now, dating of a massive volcanic eruption in Ethiopia reveals they are much older than previously thought. The remains—known as Omo I—were found in Ethiopia in the late 1960s, and scientists have been attempting to date them precisely ever since, by using the chemical fingerprints of volcanic ash layers found above and below the sediments in which the fossils were found. An international team of scientists, led by the University of Cambridge, has reassessed the age of the Omo I remains—and Homo sapiens as a species. Earlier attempts to date the fossils suggested they were less than 200,000 years old, but the new research shows they must be older than a colossal volcanic eruption that took place 230,000 years ago. The results are reported in the journal Nature. The Omo I remains were found in the Omo Kibish Formation in southwestern Ethiopia, within the East African Rift valley. The region is an area of high volcanic activity, and a rich source of early human remains and artifacts such as stone tools. By dating the layers of volcanic ash above and below where archaeological and fossil materials are found, scientists identified Omo I as the earliest evidence of our species, Homo sapiens. "Using these methods, the generally accepted age of the Omo fossils is under 200,000 years, but there's been a lot of uncertainty around this date," said Dr. Céline Vidal from Cambridge's Department of Geography, the paper's lead author. "The fossils were found in a sequence, below a thick layer of volcanic ash that nobody had managed to date with radiometric techniques because the ash is too fine-grained." As part of a four-year project led by Professor Clive Oppenheimer, Vidal and her colleagues have been attempting to date all the major volcanic eruptions in the Ethiopian Rift around the time of the emergence of Homo sapiens, a period known as the late Middle Pleistocene. The researchers collected pumice rock samples from the volcanic deposits and ground them down to sub-millimeter size. "Each eruption has its own fingerprint—its own evolutionary story below the surface, which is determined by the pathway the magma followed," said Vidal. "Once you've crushed the rock, you free the minerals within, and then you can date them, and identify the chemical signature of the volcanic glass that holds the minerals together." The researchers carried out new geochemical analysis to link the fingerprint of the thick volcanic ash layer from the Kamoya Hominin Site (KHS ash) with an eruption of Shala volcano, more than 400 kilometers away. The team then dated pumice samples from the volcano to 230,000 years ago. Since the Omo I fossils were found deeper than this particular ash layer, they must be more than 230,000 years old. "First I found there was a geochemical match, but we didn't have the age of the Shala eruption," said Vidal. "I immediately sent the samples of Shala volcano to our colleagues in Glasgow so they could measure the age of the rocks. When I received the results and found out that the oldest Homo sapiens from the region was older than previously assumed, I was really excited." "The Omo Kibish Formation is an extensive sedimentary deposit which has been barely accessed and investigated in the past," said co-author and co-leader of the field investigation Professor Asfawossen Asrat from Addis Ababa University in Ethiopia, who is currently at BIUST in Botswana. "Our closer look into the stratigraphy of the Omo Kibish Formation, particularly the ash layers, allowed us to push the age of the oldest Homo sapiens in the region to at least 230,000 years." "Unlike other Middle Pleistocene fossils which are thought to belong to the early stages of the Homo sapiens lineage, Omo I possesses unequivocal modern human characteristics, such as a tall and globular cranial vault and a chin," said co-author Dr. Aurélien Mounier from the Musée de l'Homme in Paris. "The new date estimate, de facto, makes it the oldest unchallenged Homo sapiens in Africa." The researchers say that while this study shows a new minimum age for Homo sapiens in eastern Africa, it's possible that new finds and new studies may extend the age of our species even further back in time. "We can only date humanity based on the fossils that we have, so it's impossible to say that this is the definitive age of our species," said Vidal. "The study of human evolution is always in motion: boundaries and timelines change as our understanding improves. But these fossils show just how resilient humans are: that we survived, thrived and migrated in an area that was so prone to natural disasters." "It's probably no coincidence that our earliest ancestors lived in such a geologically active rift valley—it collected rainfall in lakes, providing fresh water and attracting animals, and served as a natural migration corridor stretching thousands of kilometers," said Oppenheimer. "The volcanoes provided fantastic materials to make stone tools and from time to time we had to develop our cognitive skills when large eruptions transformed the landscape." "Our forensic approach provides a new minimum age for Homo sapiens in eastern Africa, but the challenge still remains to provide a cap, a maximum age, for their emergence, which is widely believed to have taken place in this region," said co-author Professor Christine Lane, head of the Cambridge Tephra Laboratory where much of the work was carried out. "It's possible that new finds and new studies may extend the age of our species even further back in time." "There are many other ash layers we are trying to correlate with eruptions of the Ethiopian Rift and ash deposits from other sedimentary formations," said Vidal. "In time, we hope to better constrain the age of other fossils in the region." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Monotremata is a clade of egg-lying mammals, represented by the living platypus and echidnas, which is endemic to Australia, and adjacent islands. Occurrence of basal monotremes in the Early Cretaceous of Australia has led to the consensus that this clade originated on that continent, arriving later to South America. Here we report on the discovery of a Late Cretaceous monotreme from southern Argentina, demonstrating that monotremes were present in circumpolar regions by the end of the Mesozoic, and that their distinctive anatomical features were probably present in these ancient forms as well. Introduction The fossil record and extant distribution of monotremes is almost restricted to Australasia, with the single exception of a fossil ornithorhynchid from the earliest Cenozoic in Patagonia 1 . In this context, occurrence of a monotreme in Patagonia was interpreted as the result of a single dispersal from Australia to South America, before or during the Late Cretaceous or early Paleocene 2 , 3 , 4 , 5 , 6 . The aim of present contribution is to report on the discovery of a new monotreme, Patagorhynchus pascuali n.gen. et sp., which represents the first Cretaceous toothed monotreme from Gondwana. The material here reported consists of a fragmentary right jaw preserving the lower molar 2 showing the dilambdodon pattern characteristic of monotremes. The molar was collected from levels of the Chorrillo Formation (Upper Cretaceous, Early Maastrichtian 7 ), cropping out in SW Santa Cruz province, Patagonia, Argentina. It was found in association with both terrestrial and aquatic mollusks, calyptocephalellid anurans, chelid turtles, snakes, ornithopod, sauropod, and non-avian and avian theropod remains 7 , 8 . As far as mammals is concerned, the same fossil spot yielded a molar of the gondwanatherian Magallanodon baikashkenke 9 and isolated caudal vertebrae regarded as Mammalia incertae sedis 8 . From almost equivalents levels belonging to the Dorotea Formation (Valle del Río de las Chinas, southern Chile), remains of Magallanodon and the meridiolestidan Orretherium have been reported 10 , 11 . Results Mammalia, Linnaeus 1758 Monotremata, Bonaparte, 1837 Patagorhynchus gen. nov. (monotypic genus) Etymology Patago , from Patagonia, and rhynchus , nose. Diagnosis Patagorhynchus differs from basal monotremaformes (including Steropodon ) in having a dilambdodont crown morphology and a labial cingulid; 12 dilambdodont disposition of cusps and crests on molar crown is shared with Teinolophos and ornithorhynchids; Patagorhynchus and ornithorhynchids differ from the basal monotremaformes Teinolophos in having notably low and mesiodistally expanded teeth with the anterior lobe (equivalent to trigonid) positioned lower than the posterior one (equivalent to talonid), in having talonid composed of two (rather than one) transverse lophids, and lacking a labial cingulid. The anterior cingulid of Patagorhynchus is wider than that in Teinolophos but narrower than that in Obdurodon . Patagorhynchus shares with the toothed monotremes Obdurodon and Monotrematum both lingual and buccal extremes of the V-shaped lobe (equivalent to trigonid) with one buccal and two lingual cusps, with the first being more elevated than the latter two, and a complete mid-valley. Patagorhynchus bears two roots on m2 (as also probably in Monotrematum ) and differs from Obdurodon and Ornithorhynchus , in which more than 5 roots are present. The lobes of Patagorhynchus and Obdurodon show hypsodonty, in contrast with the much more brachyodont molariforms of Monotrematum . Patagorhynchus exhibits the following features that are lacking in other monotremes, and may be considered autapomorphic among monotremes: mid-valley labially diverges (i.e., the length of the labial edge of this valley represents two times its lingual length) and anterior cingulid labially narrow and does not reach the labial margin of the protoconid. Type and the only species Patagorhynchus pascuali sp. nov. (Figs. 1 , 2a and Supplementary Fig. 3 ). Fig. 1: Images of Patagorhynchus pascuali , MPM-PV-23087. Lower molar 2 and part of the right jaw, in a , occlusal view; b , medial/lingual view; c , lateral/labial view; d , posterior view; e , anterior view. Scale bar: length 2 mm. Abbreviations, ac, anterior cingulid; alv, alveolus; ant, anterior; ar, anterior root; hy, hypoconid; hl, hypoconulid; lapcc, labial posterior cingular cusp; liacc, lingual anterior cingular cusp; me, metaconid; mv, mid-valley; NC1, neomorphic cusp 1; pa, paraconid; pc, posterior cingulid; pr, protoconid; prt, posterior root. Full size image Fig. 2: Comparisons of the second lower molar of selected monotremaformes in occlusal view. a , Patagorhynchus pascuali (based in MPM-PV-23087); b , Obdurodon insignis 2 , 19 ; c , Monotrematum sudamericanum 17 ; d , Teinolophus trusleri 20 . Not to scale. Abbreviations: NC1, neoformation cusp 1. Full size image Patagorhynchus pascuali sp. nov. Etymology Species name honors the Argentine paleomammalogist Rosendo Pascual (1923–2012), who described the first Cenozoic monotreme remains from Patagonia, thus demonstrating the presence of this clade outside Australia. Holotype MPM-PV-23087, Museo Padre Molina (Rio Gallegos, Santa Cruz, Argentina), a right lower m2 attached to a fragment of dentary. Collected by N. R. Chimento during a joint Argentine-Japanese field trip in March 2022. Diagnosis The same as for genus by monotypy. Type locality and age La Anita farm, Santa Cruz Province, Patagonia, Argentina. The tooth was collected from the “Puma Cave” fossil site (S 50 30.639 W 72 33.617), Chorrillo Formation, early Maastrichtian 7 , 8 . This new discovery expands the list of Late Cretaceous mammaliaforms recorded in the Chorrillo Formation and equivalent Dorotea Formation in southern Chile, previously known to include gondwanatherians ( Magallanodon ) and dryolestoids ( Orretherium ) 9 , 10 , 11 , 13 . Description Despite the occlusal surface being somewhat damaged, the morphology of the main cusps and anatomical details can be clearly discerned. The tooth is identified as a second lower molar based on the similarities with the m2 of Obdurodon , including a subrectangular-shaped outline in occlusal view, the presence of two lobes each bearing three cusps, a mid-valley lacking cusps, and prominent anterior and posterior cingulids (Fig. 1 ). Immediately anterior to m2, the fragmentary mandible shows a partially preserved and relatively small alveolus on the labial margin, which presumably corresponds to one of the", "role": "user" }, { "content": "It was just a tooth and a fragment of jaw bone—discovered in an excavation layer of the Chorrillo Formation, a unique geological formation in Patagonia, Argentina. Field researchers found it amongst fossils of both terrestrial and aquatic mollusks, frogs, turtles, and snakes, as well as theropod and sauropod dinosaur fossils. Based on the sediment layer, the tooth dates from the Maastrichtian Stage, a timeframe at the end of the Late Cretaceous ranging from 72.1 million to 66 million years ago. Surprisingly, the unusual morphology of the tooth clearly showed that it belongs to a member of the monotreme clade, the small group of egg-laying mammals that today includes the platypus and echidna. Further analysis found that the tooth is most similar to Australian platypuses older than 20 million years in the fossil record. Together, it shows a long history of conserved monotreme tooth morphology and an ancient connection between Australia and South America. The research team from Argentina, Australia, and Japan have published their findings in a paper titled \"First monotreme from the Late Cretaceous of South America\" in Communications Biology. This find isn't the first ancient platypus-like tooth found in Patagonia. Thirty years ago, paleo mammalogist Rosendo Pascual described a 62 million-year-old monotreme tooth, challenging what had been thought to be the clades exclusively Australasian existence. In honor of that discovery, the new find has been named Patagorhynchus pascuali. Patagorhynchus pascuali is older than the previous find. How did it get there? Most likely, it swam. Look at any map today, and you will see a lot of ocean between Australia and Argentina, many thousands of miles of deep water. But long ago, the lands were much closer. Even if Patagorhynchus pascuali only just arrived in Patagonia 70 million years ago it would have had an easy time making the trip. Australia and Argentina were both much further south than they are today, connected to Antarctica or only separated by small islands and channels. The circumpolar environment would have been warmer than it is today, supporting a more vibrant animal and plant life. If the tooth does belong to a creature that closely resembles a modern-day platypus, a good river and lake swimmer like that would have no problem traversing coastal waters or short stretches that once separated South America from Australia. It may be interesting to note that a different clade of mammal, marsupials, often regarded as a quintessentially Australian animal, didn't originate there. The Australian marsupials of today originated in South America and likely took a similar path (in reverse) as the Patagonian platypus over 50 million years ago. More about monotremes Monotremes are a group of mammals that lay eggs instead of giving birth to live young. They have other special features, such as a cloaca—a single opening for excretion and reproduction—a trait they have in common with all amphibians, reptiles, and birds. While the rest of us mammals stopped laying eggs over 160 million years ago, monotremes stuck with it. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Monotremata is a clade of egg-lying mammals, represented by the living platypus and echidnas, which is endemic to Australia, and adjacent islands. Occurrence of basal monotremes in the Early Cretaceous of Australia has led to the consensus that this clade originated on that continent, arriving later to South America. Here we report on the discovery of a Late Cretaceous monotreme from southern Argentina, demonstrating that monotremes were present in circumpolar regions by the end of the Mesozoic, and that their distinctive anatomical features were probably present in these ancient forms as well. Introduction The fossil record and extant distribution of monotremes is almost restricted to Australasia, with the single exception of a fossil ornithorhynchid from the earliest Cenozoic in Patagonia 1 . In this context, occurrence of a monotreme in Patagonia was interpreted as the result of a single dispersal from Australia to South America, before or during the Late Cretaceous or early Paleocene 2 , 3 , 4 , 5 , 6 . The aim of present contribution is to report on the discovery of a new monotreme, Patagorhynchus pascuali n.gen. et sp., which represents the first Cretaceous toothed monotreme from Gondwana. The material here reported consists of a fragmentary right jaw preserving the lower molar 2 showing the dilambdodon pattern characteristic of monotremes. The molar was collected from levels of the Chorrillo Formation (Upper Cretaceous, Early Maastrichtian 7 ), cropping out in SW Santa Cruz province, Patagonia, Argentina. It was found in association with both terrestrial and aquatic mollusks, calyptocephalellid anurans, chelid turtles, snakes, ornithopod, sauropod, and non-avian and avian theropod remains 7 , 8 . As far as mammals is concerned, the same fossil spot yielded a molar of the gondwanatherian Magallanodon baikashkenke 9 and isolated caudal vertebrae regarded as Mammalia incertae sedis 8 . From almost equivalents levels belonging to the Dorotea Formation (Valle del Río de las Chinas, southern Chile), remains of Magallanodon and the meridiolestidan Orretherium have been reported 10 , 11 . Results Mammalia, Linnaeus 1758 Monotremata, Bonaparte, 1837 Patagorhynchus gen. nov. (monotypic genus) Etymology Patago , from Patagonia, and rhynchus , nose. Diagnosis Patagorhynchus differs from basal monotremaformes (including Steropodon ) in having a dilambdodont crown morphology and a labial cingulid; 12 dilambdodont disposition of cusps and crests on molar crown is shared with Teinolophos and ornithorhynchids; Patagorhynchus and ornithorhynchids differ from the basal monotremaformes Teinolophos in having notably low and mesiodistally expanded teeth with the anterior lobe (equivalent to trigonid) positioned lower than the posterior one (equivalent to talonid), in having talonid composed of two (rather than one) transverse lophids, and lacking a labial cingulid. The anterior cingulid of Patagorhynchus is wider than that in Teinolophos but narrower than that in Obdurodon . Patagorhynchus shares with the toothed monotremes Obdurodon and Monotrematum both lingual and buccal extremes of the V-shaped lobe (equivalent to trigonid) with one buccal and two lingual cusps, with the first being more elevated than the latter two, and a complete mid-valley. Patagorhynchus bears two roots on m2 (as also probably in Monotrematum ) and differs from Obdurodon and Ornithorhynchus , in which more than 5 roots are present. The lobes of Patagorhynchus and Obdurodon show hypsodonty, in contrast with the much more brachyodont molariforms of Monotrematum . Patagorhynchus exhibits the following features that are lacking in other monotremes, and may be considered autapomorphic among monotremes: mid-valley labially diverges (i.e., the length of the labial edge of this valley represents two times its lingual length) and anterior cingulid labially narrow and does not reach the labial margin of the protoconid. Type and the only species Patagorhynchus pascuali sp. nov. (Figs. 1 , 2a and Supplementary Fig. 3 ). Fig. 1: Images of Patagorhynchus pascuali , MPM-PV-23087. Lower molar 2 and part of the right jaw, in a , occlusal view; b , medial/lingual view; c , lateral/labial view; d , posterior view; e , anterior view. Scale bar: length 2 mm. Abbreviations, ac, anterior cingulid; alv, alveolus; ant, anterior; ar, anterior root; hy, hypoconid; hl, hypoconulid; lapcc, labial posterior cingular cusp; liacc, lingual anterior cingular cusp; me, metaconid; mv, mid-valley; NC1, neomorphic cusp 1; pa, paraconid; pc, posterior cingulid; pr, protoconid; prt, posterior root. Full size image Fig. 2: Comparisons of the second lower molar of selected monotremaformes in occlusal view. a , Patagorhynchus pascuali (based in MPM-PV-23087); b , Obdurodon insignis 2 , 19 ; c , Monotrematum sudamericanum 17 ; d , Teinolophus trusleri 20 . Not to scale. Abbreviations: NC1, neoformation cusp 1. Full size image Patagorhynchus pascuali sp. nov. Etymology Species name honors the Argentine paleomammalogist Rosendo Pascual (1923–2012), who described the first Cenozoic monotreme remains from Patagonia, thus demonstrating the presence of this clade outside Australia. Holotype MPM-PV-23087, Museo Padre Molina (Rio Gallegos, Santa Cruz, Argentina), a right lower m2 attached to a fragment of dentary. Collected by N. R. Chimento during a joint Argentine-Japanese field trip in March 2022. Diagnosis The same as for genus by monotypy. Type locality and age La Anita farm, Santa Cruz Province, Patagonia, Argentina. The tooth was collected from the “Puma Cave” fossil site (S 50 30.639 W 72 33.617), Chorrillo Formation, early Maastrichtian 7 , 8 . This new discovery expands the list of Late Cretaceous mammaliaforms recorded in the Chorrillo Formation and equivalent Dorotea Formation in southern Chile, previously known to include gondwanatherians ( Magallanodon ) and dryolestoids ( Orretherium ) 9 , 10 , 11 , 13 . Description Despite the occlusal surface being somewhat damaged, the morphology of the main cusps and anatomical details can be clearly discerned. The tooth is identified as a second lower molar based on the similarities with the m2 of Obdurodon , including a subrectangular-shaped outline in occlusal view, the presence of two lobes each bearing three cusps, a mid-valley lacking cusps, and prominent anterior and posterior cingulids (Fig. 1 ). Immediately anterior to m2, the fragmentary mandible shows a partially preserved and relatively small alveolus on the labial margin, which presumably corresponds to one of the<|im_end|> <|im_start|>assistant It was just a tooth and a fragment of jaw bone—discovered in an excavation layer of the Chorrillo Formation, a unique geological formation in Patagonia, Argentina. Field researchers found it amongst fossils of both terrestrial and aquatic mollusks, frogs, turtles, and snakes, as well as theropod and sauropod dinosaur fossils. Based on the sediment layer, the tooth dates from the Maastrichtian Stage, a timeframe at the end of the Late Cretaceous ranging from 72.1 million to 66 million years ago. Surprisingly, the unusual morphology of the tooth clearly showed that it belongs to a member of the monotreme clade, the small group of egg-laying mammals that today includes the platypus and echidna. Further analysis found that the tooth is most similar to Australian platypuses older than 20 million years in the fossil record. Together, it shows a long history of conserved monotreme tooth morphology and an ancient connection between Australia and South America. The research team from Argentina, Australia, and Japan have published their findings in a paper titled "First monotreme from the Late Cretaceous of South America" in Communications Biology. This find isn't the first ancient platypus-like tooth found in Patagonia. Thirty years ago, paleo mammalogist Rosendo Pascual described a 62 million-year-old monotreme tooth, challenging what had been thought to be the clades exclusively Australasian existence. In honor of that discovery, the new find has been named Patagorhynchus pascuali. Patagorhynchus pascuali is older than the previous find. How did it get there? Most likely, it swam. Look at any map today, and you will see a lot of ocean between Australia and Argentina, many thousands of miles of deep water. But long ago, the lands were much closer. Even if Patagorhynchus pascuali only just arrived in Patagonia 70 million years ago it would have had an easy time making the trip. Australia and Argentina were both much further south than they are today, connected to Antarctica or only separated by small islands and channels. The circumpolar environment would have been warmer than it is today, supporting a more vibrant animal and plant life. If the tooth does belong to a creature that closely resembles a modern-day platypus, a good river and lake swimmer like that would have no problem traversing coastal waters or short stretches that once separated South America from Australia. It may be interesting to note that a different clade of mammal, marsupials, often regarded as a quintessentially Australian animal, didn't originate there. The Australian marsupials of today originated in South America and likely took a similar path (in reverse) as the Patagonian platypus over 50 million years ago. More about monotremes Monotremes are a group of mammals that lay eggs instead of giving birth to live young. They have other special features, such as a cloaca—a single opening for excretion and reproduction—a trait they have in common with all amphibians, reptiles, and birds. While the rest of us mammals stopped laying eggs over 160 million years ago, monotremes stuck with it. <|im_end|>

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46000, 272, 287, 360, 307, 26, 550, 11, 18940, 444, 307, 26, 96784, 11, 46000, 3789, 13, 8797, 1404, 2217, 23966, 13, 220, 17, 25, 23611, 19941, 315, 279, 2132, 4827, 296, 7569, 315, 4183, 1647, 52262, 1764, 630, 288, 304, 18274, 4256, 278, 1684, 13, 264, 1174, 7281, 351, 269, 71, 69581, 355, 281, 5171, 52266, 320, 31039, 304, 386, 8971, 9483, 53, 12, 9870, 4044, 1237, 293, 1174, 4761, 1072, 299, 15357, 54127, 285, 220, 17, 1174, 220, 777, 2652, 272, 1174, 3206, 354, 1864, 27349, 31837, 78818, 372, 220, 1114, 2652, 294, 1174, 2722, 258, 337, 5237, 355, 490, 355, 47879, 220, 508, 662, 2876, 311, 5569, 13, 27063, 7430, 17583, 25, 20660, 16, 11, 36182, 1659, 272, 30863, 220, 16, 13, 8797, 1404, 2217, 7281, 351, 269, 71, 69581, 355, 281, 5171, 52266, 993, 13, 6747, 13, 19421, 99174, 51567, 836, 49593, 279, 82822, 28639, 316, 8836, 32051, 380, 16870, 8862, 393, 5171, 940, 320, 5926, 18, 4235, 679, 17, 705, 889, 7633, 279, 1176, 356, 268, 96614, 292, 78316, 9831, 8625, 505, 7281, 6241, 689, 11, 8617, 45296, 279, 9546, 315, 420, 1206, 1037, 4994, 8494, 13, 16071, 4249, 386, 8971, 9483, 53, 12, 9870, 4044, 11, 51108, 78, 26367, 265, 33518, 2259, 320, 89146, 10845, 1978, 437, 11, 16376, 21510, 11, 32164, 705, 264, 1314, 4827, 296, 17, 12673, 311, 264, 12569, 315, 18653, 661, 13, 4349, 2258, 555, 452, 13, 432, 13, 921, 15377, 2391, 264, 10496, 82822, 12278, 29789, 2115, 8577, 304, 5587, 220, 2366, 17, 13, 95452, 578, 1890, 439, 369, 64677, 555, 1647, 37941, 88, 13, 4078, 69187, 323, 4325, 5034, 76726, 8961, 11, 16376, 21510, 38894, 11, 7281, 6241, 689, 11, 32164, 13, 578, 26588, 574, 14890, 505, 279, 1054, 47, 13722, 50492, 863, 31376, 2816, 320, 50, 220, 1135, 220, 966, 13, 23079, 468, 220, 5332, 220, 1644, 13, 21717, 705, 921, 17847, 22532, 72466, 11, 4216, 386, 5418, 496, 4970, 1122, 220, 22, 1174, 220, 23, 662, 1115, 502, 18841, 52956, 279, 1160, 315, 36931, 356, 2171, 77140, 36041, 19379, 10008, 12715, 304, 279, 921, 17847, 22532, 72466, 323, 13890, 25225, 1295, 64, 72466, 304, 18561, 34100, 11, 8767, 3967, 311, 2997, 342, 2159, 16965, 1894, 5493, 320, 7023, 543, 276, 77152, 883, 323, 9235, 62095, 17390, 320, 2582, 265, 700, 2411, 883, 220, 24, 1174, 220, 605, 1174, 220, 806, 1174, 220, 1032, 662, 7817, 18185, 279, 18274, 4256, 278, 7479, 1694, 14738, 20727, 11, 279, 79612, 315, 279, 1925, 81070, 1725, 323, 75893, 950, 3649, 649, 387, 9539, 42645, 291, 13, 578, 26588, 374, 11054, 439, 264, 2132, 4827, 296, 7569, 3196, 389, 279, 43874, 449, 279, 296, 17, 315, 4761, 1072, 299, 15357, 1174, 2737, 264, 1207, 2921, 4328, 35831, 21782, 304, 18274, 4256, 278, 1684, 11, 279, 9546, 315, 1403, 41253, 288, 1855, 18534, 2380, 81070, 1725, 11, 264, 5209, 46254, 3258, 32161, 81070, 1725, 11, 323, 21102, 37229, 323, 46000, 272, 287, 360, 3447, 320, 30035, 13, 220, 16, 7609, 69352, 37229, 311, 296, 17, 11, 279, 12569, 661, 11837, 1260, 5039, 264, 26310, 34683, 323, 12309, 2678, 453, 588, 337, 355, 389, 279, 10278, 532, 4850, 11, 902, 36548, 34310, 311, 832, 315, 279, 128257, 198, 128256, 78191, 198, 2181, 574, 1120, 264, 26588, 323, 264, 12569, 315, 16942, 17685, 2345, 4338, 21468, 304, 459, 97539, 6324, 315, 279, 921, 17847, 22532, 72466, 11, 264, 5016, 86278, 18488, 304, 7281, 6241, 689, 11, 32164, 13, 8771, 12074, 1766, 433, 24059, 81473, 315, 2225, 80492, 323, 72491, 55509, 355, 2857, 11, 90546, 11, 72503, 11, 323, 57196, 11, 439, 1664, 439, 9139, 454, 347, 323, 33254, 897, 347, 63989, 81473, 13, 20817, 389, 279, 59132, 6324, 11, 279, 26588, 13003, 505, 279, 386, 5418, 496, 4970, 1122, 22891, 11, 264, 71053, 520, 279, 842, 315, 279, 36931, 356, 2171, 77140, 24950, 505, 220, 5332, 13, 16, 3610, 311, 220, 2287, 3610, 1667, 4227, 13, 8242, 49264, 11, 279, 19018, 79612, 315, 279, 26588, 9539, 8710, 430, 433, 17623, 311, 264, 4562, 315, 279, 78316, 9831, 1206, 1037, 11, 279, 2678, 1912, 315, 19151, 2922, 17718, 56669, 430, 3432, 5764, 279, 46089, 1100, 355, 323, 31972, 307, 3458, 13, 15903, 6492, 1766, 430, 279, 26588, 374, 1455, 4528, 311, 13673, 46089, 1100, 4881, 9191, 1109, 220, 508, 3610, 1667, 304, 279, 31376, 3335, 13, 32255, 11, 433, 5039, 264, 1317, 3925, 315, 1615, 2841, 78316, 9831, 26588, 79612, 323, 459, 14154, 3717, 1990, 8494, 323, 4987, 5270, 13, 578, 3495, 2128, 505, 32164, 11, 8494, 11, 323, 6457, 617, 4756, 872, 14955, 304, 264, 5684, 25891, 330, 5451, 78316, 9831, 505, 279, 36931, 356, 2171, 77140, 315, 4987, 5270, 1, 304, 26545, 40023, 13, 1115, 1505, 4536, 956, 279, 1176, 14154, 46089, 1100, 355, 12970, 26588, 1766, 304, 7281, 6241, 689, 13, 67720, 1667, 4227, 11, 28639, 78, 36041, 32051, 380, 16870, 8862, 393, 5171, 940, 7633, 264, 220, 5538, 3610, 4771, 6418, 78316, 9831, 26588, 11, 17436, 1148, 1047, 1027, 3463, 311, 387, 279, 1206, 3536, 24121, 6126, 300, 1122, 14209, 13, 763, 16044, 315, 430, 18841, 11, 279, 502, 1505, 706, 1027, 7086, 7281, 351, 269, 71, 69581, 355, 281, 5171, 52266, 13, 7281, 351, 269, 71, 69581, 355, 281, 5171, 52266, 374, 9191, 1109, 279, 3766, 1505, 13, 2650, 1550, 433, 636, 1070, 30, 7648, 4461, 11, 433, 2064, 309, 13, 9372, 520, 904, 2472, 3432, 11, 323, 499, 690, 1518, 264, 2763, 315, 18435, 1990, 8494, 323, 32164, 11, 1690, 9214, 315, 8931, 315, 5655, 3090, 13, 2030, 1317, 4227, 11, 279, 12098, 1051, 1790, 12401, 13, 7570, 422, 7281, 351, 269, 71, 69581, 355, 281, 5171, 52266, 1193, 1120, 11721, 304, 7281, 6241, 689, 220, 2031, 3610, 1667, 4227, 433, 1053, 617, 1047, 459, 4228, 892, 3339, 279, 8577, 13, 8494, 323, 32164, 1051, 2225, 1790, 4726, 10007, 1109, 814, 527, 3432, 11, 8599, 311, 72787, 477, 1193, 19180, 555, 2678, 30100, 323, 12006, 13, 578, 4319, 1538, 7569, 4676, 1053, 617, 1027, 46039, 1109, 433, 374, 3432, 11, 12899, 264, 810, 34076, 10065, 323, 6136, 2324, 13, 1442, 279, 26588, 1587, 9352, 311, 264, 17661, 430, 15499, 53291, 264, 6617, 11477, 46089, 1100, 355, 11, 264, 1695, 15140, 323, 22553, 16587, 1195, 1093, 430, 1053, 617, 912, 3575, 30517, 287, 35335, 21160, 477, 2875, 50699, 430, 3131, 19180, 4987, 5270, 505, 8494, 13, 1102, 1253, 387, 7185, 311, 5296, 430, 264, 2204, 1206, 1037, 315, 36041, 278, 11, 48449, 455, 10522, 11, 3629, 27458, 439, 264, 40757, 434, 31668, 13673, 10065, 11, 3287, 956, 82316, 1070, 13, 578, 13673, 48449, 455, 10522, 315, 3432, 44853, 304, 4987, 5270, 323, 4461, 3952, 264, 4528, 1853, 320, 258, 10134, 8, 439, 279, 7281, 6241, 1122, 46089, 1100, 355, 927, 220, 1135, 3610, 1667, 4227, 13, 4497, 922, 78316, 1864, 288, 3206, 354, 1864, 288, 527, 264, 1912, 315, 56669, 430, 11203, 19335, 4619, 315, 7231, 7342, 311, 3974, 3995, 13, 2435, 617, 1023, 3361, 4519, 11, 1778, 439, 264, 5405, 17544, 29096, 3254, 8736, 369, 506, 89790, 323, 39656, 29096, 18027, 814, 617, 304, 4279, 449, 682, 89022, 5493, 11, 64873, 3742, 11, 323, 20229, 13, 6104, 279, 2800, 315, 603, 56669, 10717, 35744, 19335, 927, 220, 6330, 3610, 1667, 4227, 11, 78316, 1864, 288, 16075, 449, 433, 13, 220, 128257, 198 ]

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Aims/hypothesis Exposure to an intrauterine hyperglycaemic environment has been suggested to increase the offspring’s later risk for being overweight or having metabolic abnormalities, but conclusive evidence for pregnancies affected by maternal type 1 diabetes is still lacking. This study aims to analyse the relationship between maternal type 1 diabetes and the offspring’s metabolic health and investigate whether birthweight and/or changes in the offspring’s metabolome are in the potential pathway. Methods We analysed data from 610 and 2169 offspring having a first-degree relative with type 1 diabetes from the TEENDIAB and BABYDIAB/BABYDIET cohorts, respectively. Anthropometric and metabolic outcomes, assessed longitudinally at 0.3–18 years of age, were compared between offspring of mothers with type 1 diabetes and offspring of non-diabetic mothers but with fathers or siblings with type 1 diabetes using mixed regression models. Non-targeted metabolomic measurements were carried out in 500 individuals from TEENDIAB and analysed with maternal type 1 diabetes and offspring overweight status. Results The offspring of mothers with type 1 diabetes had a higher BMI SD score (SDS) and an increased risk for being overweight than the offspring of non-diabetic mothers (e.g. OR for overweight status in TEENDIAB 2.40 [95% CI 1.41, 4.06]). Further, waist circumference SDS, fasting levels of glucose, insulin and C-peptide, and insulin resistance and abdominal obesity were significantly increased in the offspring of mothers with type 1 diabetes, even when adjusted for potential confounders and birthweight. Metabolite patterns related to androgenic steroids and branched-chain amino acids were found to be associated with offspring’s overweight status, but no significant associations were observed between maternal type 1 diabetes and metabolite concentrations in the offspring. Conclusions/interpretation Maternal type 1 diabetes is associated with offspring’s overweight status and metabolic health in later life, but this is unlikely to be caused by alterations in the offspring’s metabolome. Working on a manuscript? Avoid the common mistakes Introduction Obesity and excess weight in children and adolescents remains a major public health problem because it induces other metabolic disorders, such as diabetes and cardiovascular disease [ 1 ]. A growing body of evidence supports the concept of fuel-mediated teratogenesis, in which intrauterine exposure to hyperglycaemia leads to excess fetal glucose and insulin, and thus overgrowth of the fetus [ 2 ]. These exposures during fetal life have been reported to extend beyond the neonatal period and influence metabolic complications in later life. Various studies have shown evidence associating gestational diabetes and type 2 diabetes with later adiposity, increased BMI, insulin resistance, impaired glucose tolerance, higher cholesterol, hypertension and type 2 diabetes in the offspring [ 3 , 4 , 5 , 6 ], but less evidence exists to support a similar effect of maternal type 1 diabetes on offspring health. However, it appears relevant to differentiate between type 1 diabetes, gestational diabetes and type 2 diabetes, because the last two are associated with maternal obesity, while type 1 diabetes is not. Studies which reported a positive association of maternal type 1 diabetes with BMI or metabolic outcomes in the offspring [ 7 , 8 , 9 , 10 ] were cross-sectional in design and limited with respect to their sample size ( n < 600 in each). Furthermore, two of these studies were based on children born as early as 1978–1985 [ 7 ] and 1982–1991 [ 10 ], respectively, when diabetes care in pregnant women was probably less good than nowadays [ 11 ]. Previous analyses of our own data indicated that children with non-diabetic and type 1 diabetic mothers follow different growth patterns [ 12 , 13 ], and also that a potential association between maternal type 1 diabetes and risk of being overweight in the offspring is not independent of birthweight and breastfeeding duration [ 14 ]. Here, we analysed data from two prospective cohort studies containing over 2770 children of whom more than 1500 were exposed to maternal type 1 diabetes during pregnancy. A subset of 500 children were also characterised for non-targeted metabolomics; these are of particular interest as recent studies have shown significant associations between metabolic concentrations and childhood obesity [ 15 , 16 , 17 ], while the associations between maternal type 1 diabetes and metabolic profile in the offspring have not yet been investigated. The aims of this study were to investigate: (1) whether there are differences in anthropometric and metabolic outcomes between offspring of mothers with type 1 diabetes and non-diabetic mothers; and (2) whether birthweight and/or changes in the offspring’s metabolome may be in the potential pathway from maternal type 1 diabetes to later overweight status and poor metabolic health in the offspring. Methods Our analysis was based on the prospective German cohorts TEENDIAB and BABYDIAB/BABYDIET. These cohorts include children with a familial background of type 1 diabetes and have already been combined for other research questions [ 18 , 19 ]. All parents gave written informed consent for participation. The studies were approved by the ethical committees of the Technische Universität München (number 2149/08) and Hannover Medical School (number 5644); the Bavarian General Medical Council (number 95357) and Ludwig-Maximilians University (number 329/00), respectively. TEENDIAB study The TEENDIAB study is a prospective cohort study conducted in the cities of Munich and Hannover, Germany. During 2009–2015, this study recruited 610 children aged 6–16 years who were resident in Germany and had at least one parent or sibling with type 1 diabetes [ 20 ]. Children were followed, on average, every 6 months from 6 to 18 years of age until 2016. Maternal characteristics and offspring measurements At the first visit, information on type 1 diabetes, smoking status and education level of the parents as well as monthly family income was obtained via self-administered questionnaire. Birthweight information was taken from health records collected during the well-baby preventive health programme, which is routinely offered to all children in Germany. During each visit, weight was measured digitally or using a beam scale with a precision of ±100 g in light clothing. Height was measured using a stadiometer with a precision of ±1 mm. Waist circumference", "role": "user" }, { "content": "Children of mothers with type 1 diabetes are at significantly higher risk of being overweight and of exhibiting insulin resistance. This was published by scientists from Helmholtz Zentrum München and the Technical University of Munich in the journal Diabetologia. Type 1 diabetes is the most common metabolic disorder in childhood. But what effects does this condition have when sufferers themselves have children? It was already known that children of parents with type 1 diabetes are at much higher risk of developing the disease than the rest of the population. \"Moreover, there were also sporadic indications from previous studies that children of mothers with type 1 diabetes are also at increased risk of having metabolic syndrome, as the intermittent high blood glucose levels in the uterus appear to have long-term effects on the child's metabolism and body weight,\" explains Dr. Andreas Beyerlein. \"We now had the possibility to investigate this hypothesis with a large and appropriate dataset,\" adds the statistician and epidemiologist, who led the study together with Prof. Dr. Anette-Gabriele Ziegler from the Institute of Diabetes Research at Helmholtz Zentrum München. Nearly 2,800 children followed over an 18 year period The starting point for their work were three large studies aimed at understanding the mechanisms underlying type 1 diabetes (TEENDIAB, BABYDIAB and BABYDIET). \"In total, we studied data from nearly 2,800 children with a first-degree relative with type 1 diabetes,\" explains lead author Anitha Pitchika. \"Their metabolic status and body weight were tracked up to the age of 18.\" \"This analysis was possible only now with our dataset which contains such a large number of mothers with type 1 diabetes,\" adds Anette-Gabriele Ziegler. \"A few decades ago, mothers with this condition were often advised not to get pregnant due to the high risk of complications at birth.\" The researchers found that children of mothers with type 1 diabetes had a significantly higher body mass index than children from mothers without diabetes. \"Children in the TEENDIAB study were for instance almost twice as likely to become overweight,\" explains Andreas Beyerlein. Other parameters, such as waist circumference, fasting blood glucose level and risk for insulin resistance, were also significantly higher if the mother had type 1 diabetes. The scientists corrected for a number of possible confounding factors, such as the mother's socioeconomic status and high birth weight. To find out to what extent the differences were due to fundamental changes in the child's metabolism, the researchers collected metabolomics data from 500 children in the TEENDIAB study. As it turned out, however, they did not find any significant changes in metabolic products and pathways caused by maternal type 1 diabetes. \"Our study shows that children of mothers with type 1 diabetes are not only at significantly higher risk of having the condition itself, but are also at greater risk of being overweight and developing insulin resistance,\" says Anette-Gabriele Ziegler, summarizing the findings. \"We would therefore advise that paediatricians should bear this correlation in mind, so that they can react on early warning signs in such children.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Aims/hypothesis Exposure to an intrauterine hyperglycaemic environment has been suggested to increase the offspring’s later risk for being overweight or having metabolic abnormalities, but conclusive evidence for pregnancies affected by maternal type 1 diabetes is still lacking. This study aims to analyse the relationship between maternal type 1 diabetes and the offspring’s metabolic health and investigate whether birthweight and/or changes in the offspring’s metabolome are in the potential pathway. Methods We analysed data from 610 and 2169 offspring having a first-degree relative with type 1 diabetes from the TEENDIAB and BABYDIAB/BABYDIET cohorts, respectively. Anthropometric and metabolic outcomes, assessed longitudinally at 0.3–18 years of age, were compared between offspring of mothers with type 1 diabetes and offspring of non-diabetic mothers but with fathers or siblings with type 1 diabetes using mixed regression models. Non-targeted metabolomic measurements were carried out in 500 individuals from TEENDIAB and analysed with maternal type 1 diabetes and offspring overweight status. Results The offspring of mothers with type 1 diabetes had a higher BMI SD score (SDS) and an increased risk for being overweight than the offspring of non-diabetic mothers (e.g. OR for overweight status in TEENDIAB 2.40 [95% CI 1.41, 4.06]). Further, waist circumference SDS, fasting levels of glucose, insulin and C-peptide, and insulin resistance and abdominal obesity were significantly increased in the offspring of mothers with type 1 diabetes, even when adjusted for potential confounders and birthweight. Metabolite patterns related to androgenic steroids and branched-chain amino acids were found to be associated with offspring’s overweight status, but no significant associations were observed between maternal type 1 diabetes and metabolite concentrations in the offspring. Conclusions/interpretation Maternal type 1 diabetes is associated with offspring’s overweight status and metabolic health in later life, but this is unlikely to be caused by alterations in the offspring’s metabolome. Working on a manuscript? Avoid the common mistakes Introduction Obesity and excess weight in children and adolescents remains a major public health problem because it induces other metabolic disorders, such as diabetes and cardiovascular disease [ 1 ]. A growing body of evidence supports the concept of fuel-mediated teratogenesis, in which intrauterine exposure to hyperglycaemia leads to excess fetal glucose and insulin, and thus overgrowth of the fetus [ 2 ]. These exposures during fetal life have been reported to extend beyond the neonatal period and influence metabolic complications in later life. Various studies have shown evidence associating gestational diabetes and type 2 diabetes with later adiposity, increased BMI, insulin resistance, impaired glucose tolerance, higher cholesterol, hypertension and type 2 diabetes in the offspring [ 3 , 4 , 5 , 6 ], but less evidence exists to support a similar effect of maternal type 1 diabetes on offspring health. However, it appears relevant to differentiate between type 1 diabetes, gestational diabetes and type 2 diabetes, because the last two are associated with maternal obesity, while type 1 diabetes is not. Studies which reported a positive association of maternal type 1 diabetes with BMI or metabolic outcomes in the offspring [ 7 , 8 , 9 , 10 ] were cross-sectional in design and limited with respect to their sample size ( n < 600 in each). Furthermore, two of these studies were based on children born as early as 1978–1985 [ 7 ] and 1982–1991 [ 10 ], respectively, when diabetes care in pregnant women was probably less good than nowadays [ 11 ]. Previous analyses of our own data indicated that children with non-diabetic and type 1 diabetic mothers follow different growth patterns [ 12 , 13 ], and also that a potential association between maternal type 1 diabetes and risk of being overweight in the offspring is not independent of birthweight and breastfeeding duration [ 14 ]. Here, we analysed data from two prospective cohort studies containing over 2770 children of whom more than 1500 were exposed to maternal type 1 diabetes during pregnancy. A subset of 500 children were also characterised for non-targeted metabolomics; these are of particular interest as recent studies have shown significant associations between metabolic concentrations and childhood obesity [ 15 , 16 , 17 ], while the associations between maternal type 1 diabetes and metabolic profile in the offspring have not yet been investigated. The aims of this study were to investigate: (1) whether there are differences in anthropometric and metabolic outcomes between offspring of mothers with type 1 diabetes and non-diabetic mothers; and (2) whether birthweight and/or changes in the offspring’s metabolome may be in the potential pathway from maternal type 1 diabetes to later overweight status and poor metabolic health in the offspring. Methods Our analysis was based on the prospective German cohorts TEENDIAB and BABYDIAB/BABYDIET. These cohorts include children with a familial background of type 1 diabetes and have already been combined for other research questions [ 18 , 19 ]. All parents gave written informed consent for participation. The studies were approved by the ethical committees of the Technische Universität München (number 2149/08) and Hannover Medical School (number 5644); the Bavarian General Medical Council (number 95357) and Ludwig-Maximilians University (number 329/00), respectively. TEENDIAB study The TEENDIAB study is a prospective cohort study conducted in the cities of Munich and Hannover, Germany. During 2009–2015, this study recruited 610 children aged 6–16 years who were resident in Germany and had at least one parent or sibling with type 1 diabetes [ 20 ]. Children were followed, on average, every 6 months from 6 to 18 years of age until 2016. Maternal characteristics and offspring measurements At the first visit, information on type 1 diabetes, smoking status and education level of the parents as well as monthly family income was obtained via self-administered questionnaire. Birthweight information was taken from health records collected during the well-baby preventive health programme, which is routinely offered to all children in Germany. During each visit, weight was measured digitally or using a beam scale with a precision of ±100 g in light clothing. Height was measured using a stadiometer with a precision of ±1 mm. Waist circumference<|im_end|> <|im_start|>assistant Children of mothers with type 1 diabetes are at significantly higher risk of being overweight and of exhibiting insulin resistance. This was published by scientists from Helmholtz Zentrum München and the Technical University of Munich in the journal Diabetologia. Type 1 diabetes is the most common metabolic disorder in childhood. But what effects does this condition have when sufferers themselves have children? It was already known that children of parents with type 1 diabetes are at much higher risk of developing the disease than the rest of the population. "Moreover, there were also sporadic indications from previous studies that children of mothers with type 1 diabetes are also at increased risk of having metabolic syndrome, as the intermittent high blood glucose levels in the uterus appear to have long-term effects on the child's metabolism and body weight," explains Dr. Andreas Beyerlein. "We now had the possibility to investigate this hypothesis with a large and appropriate dataset," adds the statistician and epidemiologist, who led the study together with Prof. Dr. Anette-Gabriele Ziegler from the Institute of Diabetes Research at Helmholtz Zentrum München. Nearly 2,800 children followed over an 18 year period The starting point for their work were three large studies aimed at understanding the mechanisms underlying type 1 diabetes (TEENDIAB, BABYDIAB and BABYDIET). "In total, we studied data from nearly 2,800 children with a first-degree relative with type 1 diabetes," explains lead author Anitha Pitchika. "Their metabolic status and body weight were tracked up to the age of 18." "This analysis was possible only now with our dataset which contains such a large number of mothers with type 1 diabetes," adds Anette-Gabriele Ziegler. "A few decades ago, mothers with this condition were often advised not to get pregnant due to the high risk of complications at birth." The researchers found that children of mothers with type 1 diabetes had a significantly higher body mass index than children from mothers without diabetes. "Children in the TEENDIAB study were for instance almost twice as likely to become overweight," explains Andreas Beyerlein. Other parameters, such as waist circumference, fasting blood glucose level and risk for insulin resistance, were also significantly higher if the mother had type 1 diabetes. The scientists corrected for a number of possible confounding factors, such as the mother's socioeconomic status and high birth weight. To find out to what extent the differences were due to fundamental changes in the child's metabolism, the researchers collected metabolomics data from 500 children in the TEENDIAB study. As it turned out, however, they did not find any significant changes in metabolic products and pathways caused by maternal type 1 diabetes. "Our study shows that children of mothers with type 1 diabetes are not only at significantly higher risk of having the condition itself, but are also at greater risk of being overweight and developing insulin resistance," says Anette-Gabriele Ziegler, summarizing the findings. "We would therefore advise that paediatricians should bear this correlation in mind, so that they can react on early warning signs in such children." <|im_end|>

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2,007

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Atherosclerosis is the process that underlies heart attack and stroke. A characteristic feature of the atherosclerotic plaque is the accumulation of apoptotic cells in the necrotic core. Prophagocytic antibody-based therapies are currently being explored to stimulate the phagocytic clearance of apoptotic cells; however, these therapies can cause off-target clearance of healthy tissues, which leads to toxicities such as anaemia. Here we developed a macrophage-specific nanotherapy based on single-walled carbon nanotubes loaded with a chemical inhibitor of the antiphagocytic CD47-SIRPα signalling axis. We demonstrate that these single-walled carbon nanotubes accumulate within the atherosclerotic plaque, reactivate lesional phagocytosis and reduce the plaque burden in atheroprone apolipoprotein-E-deficient mice without compromising safety, and thereby overcome a key translational barrier for this class of drugs. Single-cell RNA sequencing analysis reveals that prophagocytic single-walled carbon nanotubes decrease the expression of inflammatory genes linked to cytokine and chemokine pathways in lesional macrophages, which demonstrates the potential of ‘Trojan horse’ nanoparticles to prevent atherosclerotic cardiovascular disease. Main The phagocytic clearance of apoptotic cells (ACs) is a routine homeostatic process that protects tissues from exposure to the inflammatory contents of dying cells 1 , 2 , 3 . To remove these cells, the body engages in a process known as efferocytosis (‘to take to the grave’). Efferocytosis is a highly conserved process triggered by ‘eat me’ ligands, which signal to phagocytes to induce engulfment 1 . Conversely, cells may overexpress ‘don’t eat me’ ligands to avoid removal 4 . By delivering an antiphagocytic signal that enables immune evasion, the upregulation of the ‘don’t eat me’ molecule, CD47, is a major mechanism by which cancers establish and propagate disease 4 , 5 . We recently discovered that CD47 signalling also has a critical role in atherosclerosis 6 . Atherosclerosis is the process that underlies heart attack and stroke and has remained the leading cause of death in the United States for nearly the past century 7 , 8 . While pursuing the mechanism by which apoptotic vascular cells escape clearance from the diseased artery, we found that CD47 is markedly upregulated in the atherosclerotic plaque 6 . CD47 functions as a ligand for the signal regulatory protein-α (SIRPα) on macrophages 9 . After this interaction, SIRPα activates the Src homology 2 domain-containing phosphatase-1 (SHP-1) to mediate the intracellular signalling that suppresses phagocytic function 10 . This signalling cascade renders diseased vascular cells resistant to removal and promotes plaque expansion. In hyperlipidaemic mice, CD47-blocking antibodies normalize the defect in efferocytosis, prevent the progression of established lesions, and protect against plaque rupture 6 . However, the antibody-mediated blockade of CD47 also accelerates the off-target removal of certain healthy tissue, which includes the Fc-mediated elimination of red blood cells (RBCs) in the spleen 6 , 11 , 12 . The resulting anaemia and reduced oxygen-carrying capacity may exacerbate ischaemia in individuals with atherosclerotic disease, and thus limit the translational potential of the systemic pro-efferocytic therapies currently in development. To develop a method that more specifically and safely restores impaired efferocytic activity, we precision-engineered nanoparticles (NPs) that interrupt CD47-SIRPα signalling in monocytes and macrophages. The system, termed SWNT-SHP1i, involves a backbone of polyethylene glycol (PEG)-functionalized single-walled carbon nanotubes (SWNTs) loaded with (1) a fluorescent probe Cy5.5 and (2) a small-molecule inhibitor of CD47’s downstream effector molecule, SHP-1 (Fig. 1a ). PEG-functionalized SWNTs were chosen because of their ultrahigh loading capacity 13 , favourable toxicology 14 , 15 and ability to accumulate within a specific leukocyte subset, Ly-6C hi monocytes (inflammatory monocytes) 16 . The selectivity for this cell type is important, as Ly-6C hi monocytes are the primary circulating cells recruited to the diseased artery, where they differentiate into lesional macrophages 17 , 18 , 19 . In addition to regulating the inflammatory response, macrophages have a homeostatic role as phagocytes that scavenge lipids and apoptotic debris 20 . As their phagocytic capacity becomes impaired in advanced atherosclerosis, strategies that restore the ‘appetite’ of macrophages have the potential to both combat plaque expansion and prevent the inflammation that results from postapoptotic necrosis. We hypothesized that leveraging SWNTs as a ‘Trojan horse’ would enable us to achieve a plaque-specific modulation of the CD47-SIRPα-SHP-1 axis, and thereby promote the clearance of diseased cells in the lesion and minimize toxicities elsewhere in the body. Fig. 1: SWNT-SHP1i promotes the phagocytosis of ACs by macrophages. a , Schematic of SWNT-SHP1i, which comprises a backbone of SWNTs functionalized with phospholipid PEG (DSPE-PEG, 1,2-distearoyl- sn -glycero-3-phosphoethanolamine- N -[amino(polyethylene glycol)]) to form biocompatible nanotubes, Cy5.5 fluorophore for tracking in vivo delivery and SHP1i via π – π stacking and hydrophobic interactions with the nanotube surface. b , Negative staining TEM images show the cylindrical morphology of SWNTs with their surrounding PEG phospholipid layer. Bare SWNTs apparently have a diameter of ~2–3 nm (inner white line). The adsorbed phospholipid PEG chains result in an increased SWNT diameter to ~5–6 nm (outer white line). Inset: magnified TEM image. c , Ultraviolet–visible spectra of SWNTs, SWNT-Cy5.5 and SWNT-SHP1i. d , Release curve of SHP1i from SWNT-Cy5.5 in serum, which demonstrates the controlled release over 7 days ( n = 3 biologically independent experiments). e , Flow cytometry histograms of uptake studies with murine macrophages (RAW264.7) (left), endothelial cells (centre), and VSMCs (right). f , Cellular uptake assays demonstrate the propensity of SWNTs to specifically accumulate in murine macrophages (RAW264.7) ( n = a minimum of three biologically independent experiments). *** P = 0.0001 and **** P < 0.0001 by one-way analysis of variance (ANOVA) with a Tukey post hoc test. g , In vitro phagocytosis assays confirm that SWNT-SHP1i augments the clearance of apoptotic vascular cells by macrophages at least as potently as the gold standard anti-CD47 antibodies, compared with SHP1i and SWNT-Cy5.5 controls ( n = 5 biologically independent experiments). On the left are representative flow cytometry plots. * P < 0.05 by an unpaired two-tailed t -test and ** P < 0.01 by one-way ANOVA with a Tukey post hoc test. For all the graphs, the data are expressed as the", "role": "user" }, { "content": "Michigan State University and Stanford University scientists have invented a nanoparticle that eats away—from the inside out—portions of plaques that cause heart attacks. Bryan Smith, associate professor of biomedical engineering at MSU, and a team of scientists created a \"Trojan Horse\" nanoparticle that can be directed to eat debris, reducing and stabilizing plaque. The discovery could be a potential treatment for atherosclerosis, a leading cause of death in the United States. The results, published in the current issue of Nature Nanotechnology, showcases the nanoparticle that homes in on atherosclerotic plaque due to its high selectivity to a particular immune cell type—monocytes and macrophages. Once inside the macrophages in those plaques, it delivers a drug agent that stimulates the cell to engulf and eat cellular debris. Basically, it removes the diseased/dead cells in the plaque core. By reinvigorating the macrophages, plaque size is reduced and stabilized. Smith said that future clinical trials on the nanoparticle are expected to reduce the risk of most types of heart attacks, with minimal side effects due to the unprecedented selectivity of the nanodrug. Smith's studies focus on intercepting the signaling of the receptors in the macrophages and sending a message via small molecules using nano-immunotherapeutic platforms. Previous studies have acted on the surface of the cells, but this new approach works intracellularly and has been effective in stimulating macrophages. \"We found we could stimulate the macrophages to selectively eat dead and dying cells—these inflammatory cells are precursor cells to atherosclerosis—that are part of the cause of heart attacks,\" Smith said. \"We could deliver a small molecule inside the macrophages to tell them to begin eating again.\" This approach also has applications beyond atherosclerosis, he added. \"We were able to marry a groundbreaking finding in atherosclerosis by our collaborators with the state-of-the-art selectivity and delivery capabilities of our advanced nanomaterial platform. We demonstrated the nanomaterials were able to selectively seek out and deliver a message to the very cells needed,\" Smith said. \"It gives a particular energy to our future work, which will include clinical translation of these nanomaterials using large animal models and human tissue tests. We believe it is better than previous methods.\" Smith has filed a provisional patent and will begin marketing it later this year. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Atherosclerosis is the process that underlies heart attack and stroke. A characteristic feature of the atherosclerotic plaque is the accumulation of apoptotic cells in the necrotic core. Prophagocytic antibody-based therapies are currently being explored to stimulate the phagocytic clearance of apoptotic cells; however, these therapies can cause off-target clearance of healthy tissues, which leads to toxicities such as anaemia. Here we developed a macrophage-specific nanotherapy based on single-walled carbon nanotubes loaded with a chemical inhibitor of the antiphagocytic CD47-SIRPα signalling axis. We demonstrate that these single-walled carbon nanotubes accumulate within the atherosclerotic plaque, reactivate lesional phagocytosis and reduce the plaque burden in atheroprone apolipoprotein-E-deficient mice without compromising safety, and thereby overcome a key translational barrier for this class of drugs. Single-cell RNA sequencing analysis reveals that prophagocytic single-walled carbon nanotubes decrease the expression of inflammatory genes linked to cytokine and chemokine pathways in lesional macrophages, which demonstrates the potential of ‘Trojan horse’ nanoparticles to prevent atherosclerotic cardiovascular disease. Main The phagocytic clearance of apoptotic cells (ACs) is a routine homeostatic process that protects tissues from exposure to the inflammatory contents of dying cells 1 , 2 , 3 . To remove these cells, the body engages in a process known as efferocytosis (‘to take to the grave’). Efferocytosis is a highly conserved process triggered by ‘eat me’ ligands, which signal to phagocytes to induce engulfment 1 . Conversely, cells may overexpress ‘don’t eat me’ ligands to avoid removal 4 . By delivering an antiphagocytic signal that enables immune evasion, the upregulation of the ‘don’t eat me’ molecule, CD47, is a major mechanism by which cancers establish and propagate disease 4 , 5 . We recently discovered that CD47 signalling also has a critical role in atherosclerosis 6 . Atherosclerosis is the process that underlies heart attack and stroke and has remained the leading cause of death in the United States for nearly the past century 7 , 8 . While pursuing the mechanism by which apoptotic vascular cells escape clearance from the diseased artery, we found that CD47 is markedly upregulated in the atherosclerotic plaque 6 . CD47 functions as a ligand for the signal regulatory protein-α (SIRPα) on macrophages 9 . After this interaction, SIRPα activates the Src homology 2 domain-containing phosphatase-1 (SHP-1) to mediate the intracellular signalling that suppresses phagocytic function 10 . This signalling cascade renders diseased vascular cells resistant to removal and promotes plaque expansion. In hyperlipidaemic mice, CD47-blocking antibodies normalize the defect in efferocytosis, prevent the progression of established lesions, and protect against plaque rupture 6 . However, the antibody-mediated blockade of CD47 also accelerates the off-target removal of certain healthy tissue, which includes the Fc-mediated elimination of red blood cells (RBCs) in the spleen 6 , 11 , 12 . The resulting anaemia and reduced oxygen-carrying capacity may exacerbate ischaemia in individuals with atherosclerotic disease, and thus limit the translational potential of the systemic pro-efferocytic therapies currently in development. To develop a method that more specifically and safely restores impaired efferocytic activity, we precision-engineered nanoparticles (NPs) that interrupt CD47-SIRPα signalling in monocytes and macrophages. The system, termed SWNT-SHP1i, involves a backbone of polyethylene glycol (PEG)-functionalized single-walled carbon nanotubes (SWNTs) loaded with (1) a fluorescent probe Cy5.5 and (2) a small-molecule inhibitor of CD47’s downstream effector molecule, SHP-1 (Fig. 1a ). PEG-functionalized SWNTs were chosen because of their ultrahigh loading capacity 13 , favourable toxicology 14 , 15 and ability to accumulate within a specific leukocyte subset, Ly-6C hi monocytes (inflammatory monocytes) 16 . The selectivity for this cell type is important, as Ly-6C hi monocytes are the primary circulating cells recruited to the diseased artery, where they differentiate into lesional macrophages 17 , 18 , 19 . In addition to regulating the inflammatory response, macrophages have a homeostatic role as phagocytes that scavenge lipids and apoptotic debris 20 . As their phagocytic capacity becomes impaired in advanced atherosclerosis, strategies that restore the ‘appetite’ of macrophages have the potential to both combat plaque expansion and prevent the inflammation that results from postapoptotic necrosis. We hypothesized that leveraging SWNTs as a ‘Trojan horse’ would enable us to achieve a plaque-specific modulation of the CD47-SIRPα-SHP-1 axis, and thereby promote the clearance of diseased cells in the lesion and minimize toxicities elsewhere in the body. Fig. 1: SWNT-SHP1i promotes the phagocytosis of ACs by macrophages. a , Schematic of SWNT-SHP1i, which comprises a backbone of SWNTs functionalized with phospholipid PEG (DSPE-PEG, 1,2-distearoyl- sn -glycero-3-phosphoethanolamine- N -[amino(polyethylene glycol)]) to form biocompatible nanotubes, Cy5.5 fluorophore for tracking in vivo delivery and SHP1i via π – π stacking and hydrophobic interactions with the nanotube surface. b , Negative staining TEM images show the cylindrical morphology of SWNTs with their surrounding PEG phospholipid layer. Bare SWNTs apparently have a diameter of ~2–3 nm (inner white line). The adsorbed phospholipid PEG chains result in an increased SWNT diameter to ~5–6 nm (outer white line). Inset: magnified TEM image. c , Ultraviolet–visible spectra of SWNTs, SWNT-Cy5.5 and SWNT-SHP1i. d , Release curve of SHP1i from SWNT-Cy5.5 in serum, which demonstrates the controlled release over 7 days ( n = 3 biologically independent experiments). e , Flow cytometry histograms of uptake studies with murine macrophages (RAW264.7) (left), endothelial cells (centre), and VSMCs (right). f , Cellular uptake assays demonstrate the propensity of SWNTs to specifically accumulate in murine macrophages (RAW264.7) ( n = a minimum of three biologically independent experiments). *** P = 0.0001 and **** P < 0.0001 by one-way analysis of variance (ANOVA) with a Tukey post hoc test. g , In vitro phagocytosis assays confirm that SWNT-SHP1i augments the clearance of apoptotic vascular cells by macrophages at least as potently as the gold standard anti-CD47 antibodies, compared with SHP1i and SWNT-Cy5.5 controls ( n = 5 biologically independent experiments). On the left are representative flow cytometry plots. * P < 0.05 by an unpaired two-tailed t -test and ** P < 0.01 by one-way ANOVA with a Tukey post hoc test. For all the graphs, the data are expressed as the<|im_end|> <|im_start|>assistant Michigan State University and Stanford University scientists have invented a nanoparticle that eats away—from the inside out—portions of plaques that cause heart attacks. Bryan Smith, associate professor of biomedical engineering at MSU, and a team of scientists created a "Trojan Horse" nanoparticle that can be directed to eat debris, reducing and stabilizing plaque. The discovery could be a potential treatment for atherosclerosis, a leading cause of death in the United States. The results, published in the current issue of Nature Nanotechnology, showcases the nanoparticle that homes in on atherosclerotic plaque due to its high selectivity to a particular immune cell type—monocytes and macrophages. Once inside the macrophages in those plaques, it delivers a drug agent that stimulates the cell to engulf and eat cellular debris. Basically, it removes the diseased/dead cells in the plaque core. By reinvigorating the macrophages, plaque size is reduced and stabilized. Smith said that future clinical trials on the nanoparticle are expected to reduce the risk of most types of heart attacks, with minimal side effects due to the unprecedented selectivity of the nanodrug. Smith's studies focus on intercepting the signaling of the receptors in the macrophages and sending a message via small molecules using nano-immunotherapeutic platforms. Previous studies have acted on the surface of the cells, but this new approach works intracellularly and has been effective in stimulating macrophages. "We found we could stimulate the macrophages to selectively eat dead and dying cells—these inflammatory cells are precursor cells to atherosclerosis—that are part of the cause of heart attacks," Smith said. "We could deliver a small molecule inside the macrophages to tell them to begin eating again." This approach also has applications beyond atherosclerosis, he added. "We were able to marry a groundbreaking finding in atherosclerosis by our collaborators with the state-of-the-art selectivity and delivery capabilities of our advanced nanomaterial platform. We demonstrated the nanomaterials were able to selectively seek out and deliver a message to the very cells needed," Smith said. "It gives a particular energy to our future work, which will include clinical translation of these nanomaterials using large animal models and human tissue tests. We believe it is better than previous methods." Smith has filed a provisional patent and will begin marketing it later this year. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Immune checkpoint inhibitor (ICI) treatments benefit some patients with metastatic cancers, but predictive biomarkers are needed. Findings in selected cancer types suggest that tumor mutational burden (TMB) may predict clinical response to ICI. To examine this association more broadly, we analyzed the clinical and genomic data of 1,662 advanced cancer patients treated with ICI, and 5,371 non-ICI-treated patients, whose tumors underwent targeted next-generation sequencing (MSK-IMPACT). Among all patients, higher somatic TMB (highest 20% in each histology) was associated with better overall survival. For most cancer histologies, an association between higher TMB and improved survival was observed. The TMB cutpoints associated with improved survival varied markedly between cancer types. These data indicate that TMB is associated with improved survival in patients receiving ICI across a wide variety of cancer types, but that there may not be one universal definition of high TMB. Main In recent years, ICI therapy has revolutionized the treatment of patients with advanced-stage cancers. These agents include antibodies that target CTLA-4 or PD-1/PD-L1 1 . Durable benefit, however, is limited to a minority of patients. Recently, several large phase 3 trials have reported negative results in both unselected patients and selected groups, highlighting the clinical need to identify better predictive biomarkers 2 , 3 , 4 , 5 . Early reports have suggested that PD-L1 immunohistochemistry, T-cell infiltration levels, T-cell receptor clonality, gene expression signatures and peripheral blood markers may correlate with clinical response 6 . Additionally, an association between high mutational load and clinical benefit was observed in small cohorts of patients with melanoma treated with CTLA-4 blockade 7 , 8 , and non-small cell lung cancer (NSCLC), patients with melanoma and bladder cancer treated with PD-1/PD-L1 inhibitors 9 , 10 , 11 . However, it is unclear whether TMB is robustly predictive of clinical benefit across diverse human cancers, or outside of these specific clinical trial populations. In previous studies, mutation load was determined by using whole-exome sequencing, which is not widely utilized in routine clinical care. Currently, the majority of precision oncology platforms use next-generation sequencing of targeted gene panels. At Memorial Sloan Kettering Cancer Center (MSK), as part of clinical care, patients undergo genomic profiling with the Food & Drug Administration (FDA)-authorized Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay 12 . This test is performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory environment and identifies somatic exonic mutations in a predefined subset of 468 cancer-related genes (earlier versions included 341 or 410 genes), by using both tumor-derived and matched germline normal DNA. We examined the association between nonsynonymous somatic TMB, as measured by MSK-IMPACT, and overall survival after treatment with ICI. The cohort included 1,662 patients whose tumors were profiled by next-generation sequencing and who had received at least one dose of ICI therapy, representing a variety of cancer types with a sufficient number of patients for analysis (Supplementary Fig. 1 ). Patients who had received atezolizumab, avelumab, durvalumab, ipilimumab, nivolumab, pembrolizumab or tremelimumab as monotherapy or in combination were included in the study. Most patients (1,446, representing 94% of tumors excluding glioma) had stage IV or metastatic disease. A small number of patients had locoregionally recurrent disease ( n = 10) or were melanoma patients with regionally advanced unresectable disease (stage III, n = 989 (Supplementary Table 1 ). In total, 146 received anti-CTLA-4, 1,256 received anti-PD-1 or PD-L1, and 260 received a combination of anti-CTLA-4 and anti-PD-1/PD-L1 therapies. A large number of patients had cancers for which ICI is FDA-approved, including 350 NSCLCs, 321 melanomas, 151 renal cell carcinomas, 214 bladder cancers and 138 head and neck squamous cell cancers (Supplementary Table 2 ). To calculate TMB, the total number of somatic nonsynonymous mutations was normalized to the total number of megabases sequenced. Overall survival was measured from the date of first ICI treatment to time of death or most recent follow-up. The median follow-up was 19 months (range 0–80, with 830 (50%) patients alive and censored at most recent follow-up). We defined TMB subgroups by percentile within each histology. We took this approach because the median and range of mutational load have been shown to vary across tumor types 13 ; therefore, a universal cutoff for ‘high TMB’ would be enriched for tumor types with higher mutation load. Across the entire cohort, stratifying tumors by TMB decile within histology showed that a higher number of mutations was associated with improved overall survival. This significant association, stratified by histology, was seen across a variety of cutpoints chosen to define the high-TMB group (ranging from the top 10–50%; Fig. 1a and Supplementary Figs. 3 and 4 ). A clear trend toward decreasing hazard ratio (HR) of death with increasing TMB cutoff was observed across cancer types, demonstrating increasing benefit from ICI with higher TMB (Fig. 1b and Supplementary Fig. 3 ) 14 . Fig. 1: Effect of mutational load on overall survival after ICI treatment. a , Kaplan–Meier curves for patients with tumors falling into the depicted deciles of TMB within each histology. Overall survival is from the first dose of ICI. Two-sided log-rank P values are indicated for all patients, with univariate Cox regression HR of 0.76 (95% confidence interval (CI) 0.62–0.94) and 0.52 (95% CI 0.42–0.64) for the 10–20% and top 10% groups, respectively, compared with the bottom 80% group. b , Cox regression hazard ratios for overall survival of 1,662 patients, at the depicted percentile cutoffs of TMB across all cancer subtypes. Solid black circles represent HRs with P < 0.05 (two-sided log-rank P value). Full size image To confirm that these results were present across multiple cancer types, we performed two additional analyses. First, a multivariable analysis across the entire cohort using Cox proportional-hazards regression demonstrated that the tumor mutation burden was significantly associated with overall survival both as a continuous variable (HR = 0.985, P = 3.4 × 10 −7 ) and with a binary cutoff (top 20% of each histology, HR = 0.61, P = 1.3 × 10 −7 ), with adjustment for", "role": "user" }, { "content": "A large team of researchers affiliated with Sloan Kettering Cancer Center, Weill Cornell Medical Center and Columbia University Medical Center has found that the mutational load of a tumor may be a useful way to predict a response to checkpoint-inhibitor immunotherapy across different types of cancer. In their paper published in the journal Nature Genetics, the group describes their study of over 1,500 patients with advanced cancer who had undergone checkpoint-inhibitor immunotherapy, and what they found. Checkpoint-inhibitor immunotherapy is a type of treatment for cancer patients whereby an attempt is made to prevent cancer cells from suppressing the body's natural immune response, allowing it to fight tumor development. Unfortunately, for some patients, it does not work as well as for others. In their search to understand why this is the case, medical scientists have also been trying to figure out which patients would benefit from such treatment and which will not. Doing so would save precious time for those patients who will not benefit from it, allowing doctors to prescribe a more effective treatment. In this new effort, the researchers found what they believe is a reliable way to test patients prior to administration of treatment—testing their mutational load. A mutational load, also known as tumor mutation burden, is a number that describes the rate of DNA faults in a tumor, which is a way of quantifying mutation rates in tumors. The study consisted of sequencing cells from a very large number of cancer patients, both those who had undergone checkpoint-inhibitor immunotherapy and those who had not, and looking for a pattern that would indicate differences. They found that those patients with higher mutational loads responded better to checkpoint-inhibitor immunotherapy than did those who had smaller load readings. They also found that different types of cancers had different load thresholds. The team notes that they do not know why a high mutation rate makes patients better candidates for checkpoint-inhibitor immunotherapy, but they do have a theory. They think it might be because higher mutation rates tend to result in cell proteins that are more mangled and easier for the immune system to recognize. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Immune checkpoint inhibitor (ICI) treatments benefit some patients with metastatic cancers, but predictive biomarkers are needed. Findings in selected cancer types suggest that tumor mutational burden (TMB) may predict clinical response to ICI. To examine this association more broadly, we analyzed the clinical and genomic data of 1,662 advanced cancer patients treated with ICI, and 5,371 non-ICI-treated patients, whose tumors underwent targeted next-generation sequencing (MSK-IMPACT). Among all patients, higher somatic TMB (highest 20% in each histology) was associated with better overall survival. For most cancer histologies, an association between higher TMB and improved survival was observed. The TMB cutpoints associated with improved survival varied markedly between cancer types. These data indicate that TMB is associated with improved survival in patients receiving ICI across a wide variety of cancer types, but that there may not be one universal definition of high TMB. Main In recent years, ICI therapy has revolutionized the treatment of patients with advanced-stage cancers. These agents include antibodies that target CTLA-4 or PD-1/PD-L1 1 . Durable benefit, however, is limited to a minority of patients. Recently, several large phase 3 trials have reported negative results in both unselected patients and selected groups, highlighting the clinical need to identify better predictive biomarkers 2 , 3 , 4 , 5 . Early reports have suggested that PD-L1 immunohistochemistry, T-cell infiltration levels, T-cell receptor clonality, gene expression signatures and peripheral blood markers may correlate with clinical response 6 . Additionally, an association between high mutational load and clinical benefit was observed in small cohorts of patients with melanoma treated with CTLA-4 blockade 7 , 8 , and non-small cell lung cancer (NSCLC), patients with melanoma and bladder cancer treated with PD-1/PD-L1 inhibitors 9 , 10 , 11 . However, it is unclear whether TMB is robustly predictive of clinical benefit across diverse human cancers, or outside of these specific clinical trial populations. In previous studies, mutation load was determined by using whole-exome sequencing, which is not widely utilized in routine clinical care. Currently, the majority of precision oncology platforms use next-generation sequencing of targeted gene panels. At Memorial Sloan Kettering Cancer Center (MSK), as part of clinical care, patients undergo genomic profiling with the Food & Drug Administration (FDA)-authorized Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay 12 . This test is performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory environment and identifies somatic exonic mutations in a predefined subset of 468 cancer-related genes (earlier versions included 341 or 410 genes), by using both tumor-derived and matched germline normal DNA. We examined the association between nonsynonymous somatic TMB, as measured by MSK-IMPACT, and overall survival after treatment with ICI. The cohort included 1,662 patients whose tumors were profiled by next-generation sequencing and who had received at least one dose of ICI therapy, representing a variety of cancer types with a sufficient number of patients for analysis (Supplementary Fig. 1 ). Patients who had received atezolizumab, avelumab, durvalumab, ipilimumab, nivolumab, pembrolizumab or tremelimumab as monotherapy or in combination were included in the study. Most patients (1,446, representing 94% of tumors excluding glioma) had stage IV or metastatic disease. A small number of patients had locoregionally recurrent disease ( n = 10) or were melanoma patients with regionally advanced unresectable disease (stage III, n = 989 (Supplementary Table 1 ). In total, 146 received anti-CTLA-4, 1,256 received anti-PD-1 or PD-L1, and 260 received a combination of anti-CTLA-4 and anti-PD-1/PD-L1 therapies. A large number of patients had cancers for which ICI is FDA-approved, including 350 NSCLCs, 321 melanomas, 151 renal cell carcinomas, 214 bladder cancers and 138 head and neck squamous cell cancers (Supplementary Table 2 ). To calculate TMB, the total number of somatic nonsynonymous mutations was normalized to the total number of megabases sequenced. Overall survival was measured from the date of first ICI treatment to time of death or most recent follow-up. The median follow-up was 19 months (range 0–80, with 830 (50%) patients alive and censored at most recent follow-up). We defined TMB subgroups by percentile within each histology. We took this approach because the median and range of mutational load have been shown to vary across tumor types 13 ; therefore, a universal cutoff for ‘high TMB’ would be enriched for tumor types with higher mutation load. Across the entire cohort, stratifying tumors by TMB decile within histology showed that a higher number of mutations was associated with improved overall survival. This significant association, stratified by histology, was seen across a variety of cutpoints chosen to define the high-TMB group (ranging from the top 10–50%; Fig. 1a and Supplementary Figs. 3 and 4 ). A clear trend toward decreasing hazard ratio (HR) of death with increasing TMB cutoff was observed across cancer types, demonstrating increasing benefit from ICI with higher TMB (Fig. 1b and Supplementary Fig. 3 ) 14 . Fig. 1: Effect of mutational load on overall survival after ICI treatment. a , Kaplan–Meier curves for patients with tumors falling into the depicted deciles of TMB within each histology. Overall survival is from the first dose of ICI. Two-sided log-rank P values are indicated for all patients, with univariate Cox regression HR of 0.76 (95% confidence interval (CI) 0.62–0.94) and 0.52 (95% CI 0.42–0.64) for the 10–20% and top 10% groups, respectively, compared with the bottom 80% group. b , Cox regression hazard ratios for overall survival of 1,662 patients, at the depicted percentile cutoffs of TMB across all cancer subtypes. Solid black circles represent HRs with P < 0.05 (two-sided log-rank P value). Full size image To confirm that these results were present across multiple cancer types, we performed two additional analyses. First, a multivariable analysis across the entire cohort using Cox proportional-hazards regression demonstrated that the tumor mutation burden was significantly associated with overall survival both as a continuous variable (HR = 0.985, P = 3.4 × 10 −7 ) and with a binary cutoff (top 20% of each histology, HR = 0.61, P = 1.3 × 10 −7 ), with adjustment for<|im_end|> <|im_start|>assistant A large team of researchers affiliated with Sloan Kettering Cancer Center, Weill Cornell Medical Center and Columbia University Medical Center has found that the mutational load of a tumor may be a useful way to predict a response to checkpoint-inhibitor immunotherapy across different types of cancer. In their paper published in the journal Nature Genetics, the group describes their study of over 1,500 patients with advanced cancer who had undergone checkpoint-inhibitor immunotherapy, and what they found. Checkpoint-inhibitor immunotherapy is a type of treatment for cancer patients whereby an attempt is made to prevent cancer cells from suppressing the body's natural immune response, allowing it to fight tumor development. Unfortunately, for some patients, it does not work as well as for others. In their search to understand why this is the case, medical scientists have also been trying to figure out which patients would benefit from such treatment and which will not. Doing so would save precious time for those patients who will not benefit from it, allowing doctors to prescribe a more effective treatment. In this new effort, the researchers found what they believe is a reliable way to test patients prior to administration of treatment—testing their mutational load. A mutational load, also known as tumor mutation burden, is a number that describes the rate of DNA faults in a tumor, which is a way of quantifying mutation rates in tumors. The study consisted of sequencing cells from a very large number of cancer patients, both those who had undergone checkpoint-inhibitor immunotherapy and those who had not, and looking for a pattern that would indicate differences. They found that those patients with higher mutational loads responded better to checkpoint-inhibitor immunotherapy than did those who had smaller load readings. They also found that different types of cancers had different load thresholds. The team notes that they do not know why a high mutation rate makes patients better candidates for checkpoint-inhibitor immunotherapy, but they do have a theory. They think it might be because higher mutation rates tend to result in cell proteins that are more mangled and easier for the immune system to recognize. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Pyrethrum extracts from flower heads of Chrysanthemum spp. have been used worldwide in insecticides and repellents. While the molecular mechanisms of its insecticidal action are known, the molecular basis of pyrethrum repellency remains a mystery. In this study, we find that the principal components of pyrethrum, pyrethrins, and a minor component, (E)-β-farnesene (EBF), each activate a specific type of olfactory receptor neurons in Aedes aegypti mosquitoes. We identify Ae. aegypti odorant receptor 31 (AaOr31) as a cognate Or for EBF and find that Or31-mediated repellency is significantly synergized by pyrethrin-induced activation of voltage-gated sodium channels. Thus, pyrethrum exerts spatial repellency through a novel, dual-target mechanism. Elucidation of this two-target mechanism may have potential implications in the design and development of a new generation of synthetic repellents against major mosquito vectors of infectious diseases. Introduction Mosquito-transmitted human diseases, such as malaria and dengue fever, represent significant burdens to global human health and cause considerable human suffering. One of the most effective measures to reduce disease transmission involves the use of insect repellents to prevent human contacts with mosquitoes. Pyrethrum extract from the dried and crushed flower heads of Chrysanthemum (Tanacetum cinerariifolium ) began to be used as an insect repellent against biting arthropods thousands of years ago 1 , 2 . Today, T, cinerariifolium plants are grown commercially in many parts of the world, particularly in East Africa and Australia, for extraction of pyrethrum 3 , 4 and pyrethrum and its synthetic analogs, pyrethroids, are key active ingredients in a variety of commercial insect-repelling products, such as mosquito coils, emanators, vaporizer mats, textile finishes, hessian strips/ribbons 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 . Pyrethrins, the major insecticidal components, are used to control a wide range of pests in both agricultural and non-agricultural settings and may pose harmful effects on bees when used outdoor. In addition, pyrethrum-producing Chrysanthemum spp. are recommended as “companion” plants to repel pest insects 14 . Pyrethrins and pyrethroids exert potent insecticidal activities by hyper-activating insect voltage-gated sodium channels, thereby causing rapid paralysis, known as knockdown, and eventual lethality 15 , 16 , 17 . While the molecular mechanism of insecticidal lethal action of these compounds is well-established, the molecular mechanism(s) underlying the repellency elicited by pyrethrum and pyrethroids, at sublethal levels, remains a mystery. Various possibilities have been proposed, including contact-based repellency, spatial repellency, neuronal irritation, olfactory responses 11 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 . However, it is not clear how these possibilities relate to each other, and, most importantly, if olfactory responses are involved, what is the identity of the odorant receptor(s) responsible for pyrethrum repellency. In this study, we took a combination of molecular genetics, electrophysiological and behavioral approaches to gain insights into pyrethrum repellency in Aedes aegypti , the primary vector of viruses that cause dengue fever, Zika, yellow fever and chikungunya. We aimed to address the following key questions: (i) Is pyrethrum repellency odorant receptor (Or)-mediated? (ii) If yes, which Or(s) is activated by pyrethrum? (iii) What component(s) of pyrethrum extract activates the Or(s)? and (iv) Is there a synergistic interaction among pyrethrum components in repellency? Our study resolved all these questions and revealed a novel, dual-target mechanism for insect repellency, involving dual activation of olfactory repellency pathways and voltage-gated sodium channels. The discovery has significant basic and practical implications in understanding the mechanisms and development of insect repellents against mosquitoes and other human disease vectors. Results Pyrethrum elicits spatial repellency First, we determined whether pyrethrum elicits spatial repellency using a hand-in-cage assay 27 . In this behavioral assay, mosquitoes are attracted to a human hand in a modified glove (Fig. 1a ) that has a screened window on the back of the glove. Mosquitoes would land on a piece of mesh secured on the top of the window. Between the top mesh and the hand is a second mesh, which was above the hand and treated with a test compound or solvent, but mosquitoes cannot make direct contact with the second mesh (Fig. 1a ). The landing frequency of female Rockefeller mosquitoes (wild-type Ae. aegypti ) onto the top mesh was significantly reduced when the second mesh was treated with pyrethrum (Sigma-Aldrich), and pyrethrum repellency increased in a dose-dependent manner (Fig. 1b ). Similar spatial pyrethrum repellency was also observed in female Kisumu mosquitoes (wild-type Anopheles gambiae ) (Supplementary Fig. 1a ). These results clearly show contact-independent, spatial repellency of pyrethrum against mosquitoes. Fig. 1: Pyrethrum elicits spatial repellency in Ae. aegypti mosquitoes. a A schematic depiction of the setup for the hand-in-cage assay as previously described 27 . b Dose-dependent pyrethrum repellency in Rockefeller (wild-type) mosquitoes ( n = 7 cages for control; n = 9 cages for 10 −3 (v v −1 ); n = 8 cages for 10 −2 (v v −1 ) from 3 batches of mosquitoes; t = 2.68, df = 14, P = 0.0181 for control vs . pyrethrum at 10 −3 and t = 9.58, df = 13, P < 0.0001 for control vs . pyrethrum at 10 −2 ). c Representative EAG response traces of Orlando (wild-type) mosquitoes to pyrethrum (10 −2 v v −1 ). d Repellency of pyrethrum (10 −2 v v −1 ) against Orlando or orco −/− mutant mosquitoes ( n = 6 cages for each of the controls; n = 8 cages for pyrethrum in Orlando, n = 7 cages for pyrethrum in orco −/− , from 3 batches of mosquitoes; t = 11.74, df = 12, P < 0.0001 for control vs. pyrethrum in Orlando, U = 3, P = 0.008 for control vs. pyrethrum in orco −/− , and t = 6.53, df = 13, P < 0.0001, for Orlando vs. orco −/− for pyrethrum). e Representative EAG response traces of orco −/− mosquitoes to pyrethrum (10 −2 v v −1 ). f Comparison of EAG responses in Orlando and orco −/−", "role": "user" }, { "content": "With mosquito season upon us, people are stocking up on repellents to prevent itchy bites. Bug repellents are important because they don't just protect against the buzzing, blood-sucking little pests—they also safeguard against the diseases they carry, which kill some 700,000 people worldwide each year. Surprisingly, despite widespread use, no one understood exactly how most mosquito repellents keep the insects away. Now researchers are starting to uncover the first pieces of the puzzle. A new study has identified a scent receptor in mosquitoes that helps them sniff out and avoid trace amounts of pyrethrum, a plant extract used for centuries to repel biting insects. One of the oldest insecticides known, pyrethrum comes from the dried, crushed flowers of certain chrysanthemum species. Pyrethrum breaks down quickly in sunlight and isn't readily absorbed through the skin, so the insecticide has long been considered one of the safer options for use around children and pets. What makes pyrethrum toxic to mosquitoes has been known for some time. It works by binding to tiny pores in the insects' nerve cells and paralyzing them on contact. But it has another property whose mode of action is more of a mystery. At lower concentrations it protects not by killing mosquitoes but by preventing them from getting close enough to land and bite in the first place. Led by biology professor Ke Dong, who recently joined the faculty at Duke University, the team did a variety of tests to understand how mosquitoes detect and avoid pyrethrum, and which of the extract's chemical components help them do it. First, they had people don a special rubber glove and put their hand in a cage holding 50 hungry mosquitoes. The glove had a window screen on the back made of two layers of loose-fitting mesh. The top layer acts as a barrier that mosquitoes are unable to bite through. Normally, mosquitoes find the heat and aroma of human skin wafting through the mesh irresistible, and are quick to land and check it out. But when the bottom layer of mesh closest to the skin was treated with pyrethrum, they lost interest. These early experiments confirmed that mosquitoes don't have to get close enough to taste or touch pyrethrum-treated skin or clothing to stay away. To find out if smell was involved, the researchers attached tiny wire electrodes to the small hairs covering the mosquitoes' antennae and measured their electrical responses to puffs of air containing chemicals released by pyrethrum and other repellents. A mosquito's ability to smell comes from special receptors embedded in nerve cells on the insect's antennae and mouth parts. Once odor molecules wafting through the air stimulate these receptors, the nerve cells send a message to the brain, which identifies the smell. Dong and her colleagues were able to pinpoint a specific ingredient in pyrethrum flower extracts, called EBF, which activates a smell receptor in the mosquito's antenna called Or31. They found that EBF works together with other components called pyrethrins to make an especially off-putting bouquet. Even tiny doses that mosquitoes barely seem to notice when the compounds occur alone—fewer than five odor molecules per million molecules of air—can send the insects flying or crawling away when they occur in combination. While the researchers focused on the mosquito species Aedes aegypti—which spreads viruses such as Zika, yellow fever and dengue—they also found Or31 odor receptors with strikingly similar protein sequences in six other mosquito species. More than 200 types of mosquitoes live in the United States alone; about a dozen of which spread germs that can make people sick. With mosquitoes becoming increasingly resistant to our best chemical defenses, researchers are constantly on the lookout for new ways to fight them. These findings, published May 5 in the journal Nature Communications, could help researchers develop new broad-spectrum repellents to keep a variety of mosquitoes at bay, and by extension stop them from biting people and spreading disease. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Pyrethrum extracts from flower heads of Chrysanthemum spp. have been used worldwide in insecticides and repellents. While the molecular mechanisms of its insecticidal action are known, the molecular basis of pyrethrum repellency remains a mystery. In this study, we find that the principal components of pyrethrum, pyrethrins, and a minor component, (E)-β-farnesene (EBF), each activate a specific type of olfactory receptor neurons in Aedes aegypti mosquitoes. We identify Ae. aegypti odorant receptor 31 (AaOr31) as a cognate Or for EBF and find that Or31-mediated repellency is significantly synergized by pyrethrin-induced activation of voltage-gated sodium channels. Thus, pyrethrum exerts spatial repellency through a novel, dual-target mechanism. Elucidation of this two-target mechanism may have potential implications in the design and development of a new generation of synthetic repellents against major mosquito vectors of infectious diseases. Introduction Mosquito-transmitted human diseases, such as malaria and dengue fever, represent significant burdens to global human health and cause considerable human suffering. One of the most effective measures to reduce disease transmission involves the use of insect repellents to prevent human contacts with mosquitoes. Pyrethrum extract from the dried and crushed flower heads of Chrysanthemum (Tanacetum cinerariifolium ) began to be used as an insect repellent against biting arthropods thousands of years ago 1 , 2 . Today, T, cinerariifolium plants are grown commercially in many parts of the world, particularly in East Africa and Australia, for extraction of pyrethrum 3 , 4 and pyrethrum and its synthetic analogs, pyrethroids, are key active ingredients in a variety of commercial insect-repelling products, such as mosquito coils, emanators, vaporizer mats, textile finishes, hessian strips/ribbons 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 . Pyrethrins, the major insecticidal components, are used to control a wide range of pests in both agricultural and non-agricultural settings and may pose harmful effects on bees when used outdoor. In addition, pyrethrum-producing Chrysanthemum spp. are recommended as “companion” plants to repel pest insects 14 . Pyrethrins and pyrethroids exert potent insecticidal activities by hyper-activating insect voltage-gated sodium channels, thereby causing rapid paralysis, known as knockdown, and eventual lethality 15 , 16 , 17 . While the molecular mechanism of insecticidal lethal action of these compounds is well-established, the molecular mechanism(s) underlying the repellency elicited by pyrethrum and pyrethroids, at sublethal levels, remains a mystery. Various possibilities have been proposed, including contact-based repellency, spatial repellency, neuronal irritation, olfactory responses 11 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 . However, it is not clear how these possibilities relate to each other, and, most importantly, if olfactory responses are involved, what is the identity of the odorant receptor(s) responsible for pyrethrum repellency. In this study, we took a combination of molecular genetics, electrophysiological and behavioral approaches to gain insights into pyrethrum repellency in Aedes aegypti , the primary vector of viruses that cause dengue fever, Zika, yellow fever and chikungunya. We aimed to address the following key questions: (i) Is pyrethrum repellency odorant receptor (Or)-mediated? (ii) If yes, which Or(s) is activated by pyrethrum? (iii) What component(s) of pyrethrum extract activates the Or(s)? and (iv) Is there a synergistic interaction among pyrethrum components in repellency? Our study resolved all these questions and revealed a novel, dual-target mechanism for insect repellency, involving dual activation of olfactory repellency pathways and voltage-gated sodium channels. The discovery has significant basic and practical implications in understanding the mechanisms and development of insect repellents against mosquitoes and other human disease vectors. Results Pyrethrum elicits spatial repellency First, we determined whether pyrethrum elicits spatial repellency using a hand-in-cage assay 27 . In this behavioral assay, mosquitoes are attracted to a human hand in a modified glove (Fig. 1a ) that has a screened window on the back of the glove. Mosquitoes would land on a piece of mesh secured on the top of the window. Between the top mesh and the hand is a second mesh, which was above the hand and treated with a test compound or solvent, but mosquitoes cannot make direct contact with the second mesh (Fig. 1a ). The landing frequency of female Rockefeller mosquitoes (wild-type Ae. aegypti ) onto the top mesh was significantly reduced when the second mesh was treated with pyrethrum (Sigma-Aldrich), and pyrethrum repellency increased in a dose-dependent manner (Fig. 1b ). Similar spatial pyrethrum repellency was also observed in female Kisumu mosquitoes (wild-type Anopheles gambiae ) (Supplementary Fig. 1a ). These results clearly show contact-independent, spatial repellency of pyrethrum against mosquitoes. Fig. 1: Pyrethrum elicits spatial repellency in Ae. aegypti mosquitoes. a A schematic depiction of the setup for the hand-in-cage assay as previously described 27 . b Dose-dependent pyrethrum repellency in Rockefeller (wild-type) mosquitoes ( n = 7 cages for control; n = 9 cages for 10 −3 (v v −1 ); n = 8 cages for 10 −2 (v v −1 ) from 3 batches of mosquitoes; t = 2.68, df = 14, P = 0.0181 for control vs . pyrethrum at 10 −3 and t = 9.58, df = 13, P < 0.0001 for control vs . pyrethrum at 10 −2 ). c Representative EAG response traces of Orlando (wild-type) mosquitoes to pyrethrum (10 −2 v v −1 ). d Repellency of pyrethrum (10 −2 v v −1 ) against Orlando or orco −/− mutant mosquitoes ( n = 6 cages for each of the controls; n = 8 cages for pyrethrum in Orlando, n = 7 cages for pyrethrum in orco −/− , from 3 batches of mosquitoes; t = 11.74, df = 12, P < 0.0001 for control vs. pyrethrum in Orlando, U = 3, P = 0.008 for control vs. pyrethrum in orco −/− , and t = 6.53, df = 13, P < 0.0001, for Orlando vs. orco −/− for pyrethrum). e Representative EAG response traces of orco −/− mosquitoes to pyrethrum (10 −2 v v −1 ). f Comparison of EAG responses in Orlando and orco −/−<|im_end|> <|im_start|>assistant With mosquito season upon us, people are stocking up on repellents to prevent itchy bites. Bug repellents are important because they don't just protect against the buzzing, blood-sucking little pests—they also safeguard against the diseases they carry, which kill some 700,000 people worldwide each year. Surprisingly, despite widespread use, no one understood exactly how most mosquito repellents keep the insects away. Now researchers are starting to uncover the first pieces of the puzzle. A new study has identified a scent receptor in mosquitoes that helps them sniff out and avoid trace amounts of pyrethrum, a plant extract used for centuries to repel biting insects. One of the oldest insecticides known, pyrethrum comes from the dried, crushed flowers of certain chrysanthemum species. Pyrethrum breaks down quickly in sunlight and isn't readily absorbed through the skin, so the insecticide has long been considered one of the safer options for use around children and pets. What makes pyrethrum toxic to mosquitoes has been known for some time. It works by binding to tiny pores in the insects' nerve cells and paralyzing them on contact. But it has another property whose mode of action is more of a mystery. At lower concentrations it protects not by killing mosquitoes but by preventing them from getting close enough to land and bite in the first place. Led by biology professor Ke Dong, who recently joined the faculty at Duke University, the team did a variety of tests to understand how mosquitoes detect and avoid pyrethrum, and which of the extract's chemical components help them do it. First, they had people don a special rubber glove and put their hand in a cage holding 50 hungry mosquitoes. The glove had a window screen on the back made of two layers of loose-fitting mesh. The top layer acts as a barrier that mosquitoes are unable to bite through. Normally, mosquitoes find the heat and aroma of human skin wafting through the mesh irresistible, and are quick to land and check it out. But when the bottom layer of mesh closest to the skin was treated with pyrethrum, they lost interest. These early experiments confirmed that mosquitoes don't have to get close enough to taste or touch pyrethrum-treated skin or clothing to stay away. To find out if smell was involved, the researchers attached tiny wire electrodes to the small hairs covering the mosquitoes' antennae and measured their electrical responses to puffs of air containing chemicals released by pyrethrum and other repellents. A mosquito's ability to smell comes from special receptors embedded in nerve cells on the insect's antennae and mouth parts. Once odor molecules wafting through the air stimulate these receptors, the nerve cells send a message to the brain, which identifies the smell. Dong and her colleagues were able to pinpoint a specific ingredient in pyrethrum flower extracts, called EBF, which activates a smell receptor in the mosquito's antenna called Or31. They found that EBF works together with other components called pyrethrins to make an especially off-putting bouquet. Even tiny doses that mosquitoes barely seem to notice when the compounds occur alone—fewer than five odor molecules per million molecules of air—can send the insects flying or crawling away when they occur in combination. While the researchers focused on the mosquito species Aedes aegypti—which spreads viruses such as Zika, yellow fever and dengue—they also found Or31 odor receptors with strikingly similar protein sequences in six other mosquito species. More than 200 types of mosquitoes live in the United States alone; about a dozen of which spread germs that can make people sick. With mosquitoes becoming increasingly resistant to our best chemical defenses, researchers are constantly on the lookout for new ways to fight them. These findings, published May 5 in the journal Nature Communications, could help researchers develop new broad-spectrum repellents to keep a variety of mosquitoes at bay, and by extension stop them from biting people and spreading disease. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Cancer develops through a process of somatic evolution 1 , 2 . Sequencing data from a single biopsy represent a snapshot of this process that can reveal the timing of specific genomic aberrations and the changing influence of mutational processes 3 . Here, by whole-genome sequencing analysis of 2,658 cancers as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) 4 , we reconstruct the life history and evolution of mutational processes and driver mutation sequences of 38 types of cancer. Early oncogenesis is characterized by mutations in a constrained set of driver genes, and specific copy number gains, such as trisomy 7 in glioblastoma and isochromosome 17q in medulloblastoma. The mutational spectrum changes significantly throughout tumour evolution in 40% of samples. A nearly fourfold diversification of driver genes and increased genomic instability are features of later stages. Copy number alterations often occur in mitotic crises, and lead to simultaneous gains of chromosomal segments. Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer, and highlight opportunities for early cancer detection. Main Similar to the evolution in species, the approximately 10 14 cells in the human body are subject to the forces of mutation and selection 1 . This process of somatic evolution begins in the zygote and only comes to rest at death, as cells are constantly exposed to mutagenic stresses, introducing 1–10 mutations per cell division 2 . These mutagenic forces lead to a gradual accumulation of point mutations throughout life, observed in a range of healthy tissues 5 , 6 , 7 , 8 , 9 , 10 , 11 and cancers 12 . Although these mutations are predominantly selectively neutral passenger mutations, some are proliferatively advantageous driver mutations 13 . The types of mutation in cancer genomes are well studied, but little is known about the times when these lesions arise during somatic evolution and where the boundary between normal evolution and cancer progression should be drawn. Sequencing of bulk tumour samples enables partial reconstruction of the evolutionary history of individual tumours, based on the catalogue of somatic mutations they have accumulated 3 , 14 , 15 . These inferences include timing of chromosomal gains during early somatic evolution 16 , phylogenetic analysis of late cancer evolution using matched primary and metastatic tumour samples from individual patients 17 , 18 , 19 , 20 , and temporal ordering of driver mutations across many samples 21 , 22 . The PCAWG Consortium has aggregated whole-genome sequencing data from 2,658 cancers 4 , generated by the ICGC and TCGA, and produced high-accuracy somatic variant calls, driver mutations, and mutational signatures 4 , 23 , 24 (Methods and Supplementary Information ). Here, we leverage the PCAWG dataset to characterize the evolutionary history of 2,778 cancer samples from 2,658 unique donors across 38 cancer types. We infer timing and patterns of chromosomal evolution and learn typical sequences of mutations across samples of each cancer type. We then define broad periods of tumour evolution and examine how drivers and mutational signatures vary between these epochs. Using clock-like mutational processes, we map mutation timing estimates into approximate real time. Combined, these analyses allow us to sketch out the typical evolutionary trajectories of cancer, and map them in real time relative to the point of diagnosis. Reconstructing the life history of tumours The genome of a cancer cell is shaped by the cumulative somatic aberrations that have arisen during its evolutionary past, and part of this history can be reconstructed from whole-genome sequencing data 3 (Fig. 1a ). Initially, each point mutation occurs on a single chromosome in a single cell, which gives rise to a lineage of cells bearing the same mutation. If that chromosomal locus is subsequently duplicated, any point mutation on this allele preceding the gain will subsequently be present on the two resulting allelic copies, unlike mutations succeeding the gain, or mutations on the other allele. As sequencing data enable the measurement of the number of allelic copies, one can define categories of early and late clonal variants, preceding or succeeding copy number gains, as well as unspecified clonal variants, which are common to all cancer cells, but cannot be timed further. Lastly, we identify subclonal mutations, which are present in only a subset of cells and have occurred after the most recent common ancestor (MRCA) of all cancer cells in the tumour sample ( Supplementary Information ). Fig. 1: Timing clonal copy number gains using allele frequencies of point mutations. a , Principles of timing mutations and copy number gains based on whole-genome sequencing. The number of sequencing reads reporting point mutations can be used to discriminate variants as early or late clonal (green or purple, respectively) in cases of specific copy number gains, as well as clonal (blue) or subclonal (red) in cases without. b , Annotated point mutations in one sample based on VAF (top), copy number (CN) state and structural variants (middle), and resulting timing estimates (bottom). LOH, loss of heterozygosity. c , Overview of the molecular timing distribution of copy number gains across cancer types. Pie charts depict the distribution of the inferred mutation time for a given copy number gain in a cancer type. Green denotes early clonal gains, with a gradient to purple for late gains. The size of each chart is proportional to the recurrence of this event. Abbreviations for each cancer type are defined in Supplementary Table 1 . d , Heat maps representing molecular timing estimates of gains on different chromosome arms ( x axis) for individual samples ( y axis) for selected tumour types. e , Temporal patterns of two near-diploid cases illustrating synchronous gains (top) and asynchronous gains (bottom). f , Left, distribution of synchronous and asynchronous gain patterns across samples, split by WGD status. Uninformative samples have too few or too small gains for accurate timing. Right,", "role": "user" }, { "content": "Early signs of cancer can appear years before diagnosis and developing tests for these genetic signs could provide new ways to spot cancer early, according to new research led by the Crick and EMBL-EBI, and supported by an international cancer genomics consortium, the Pan-Cancer Analysis of Whole Genomes Project. The collaboration included Wellcome Sanger Institute, Broad Institute of MIT and Harvard, Big Data Institute at the University of Oxford and Oregon Health & Science University. The study, published in Nature, looked at 47 million genetic changes in more than 2,500 human tumours, across 38 cancer types. By looking at how many times a single change had been replicated and copied across chromosomes, the researchers were able to determine the order in which they happened and the relative timing between them. Using this method, they found that just over 20% of mutations can be considered early events in a tumour's development, with some of these changes taking place years, even decades, before the cancer is found. Of these early mutations, half fall within the same nine genes, meaning there is a small number of genes that are common drivers of early cancer development. \"We've developed the first timelines of genetic mutations across the spectrum of cancer types. For more than 30 cancers, we now know what specific genetic changes are likely to happen, and when these are likely to take place. Unlocking these patterns means it should now be possible to develop new diagnostic tests, that pick up signs of cancer much earlier,\" says Peter Van Loo, co-lead author and group leader in the Cancer Genomics Laboratory at the Crick. As cells in the body grow and divide, errors can be introduced in their DNA. While most of these changes do not significantly alter our cells, some are harmful and are associated with the formation and growth of tumours. These DNA errors continue to accumulate in cancerous cells, so a tumour can ultimately be made up of cells with many different genetic mutations. \"We have learned that cancer is the endpoint of a lifelong evolutionary process that drives our cells. This process is fuelled by mutations in the cells' genomes,\" says Moritz Gerstung, co-lead author and Group Leader at EMBL's European Bioinformatics Institute (EMBL-EBI). \"These mutations occur as we age. Usually, there are no consequences to these mutations, but sometimes, the consequences can be dramatic. This process usually culminates within the decades prior to cancer diagnosis, but in some cases, we have been able to identify alterations as old as the patient.\" The research identified cancer types in which mutations tend to happen particularly early, for example, ovarian cancer and two types of brain tumours, glioblastoma and medulloblastoma. It also revealed the specific changes that are likely to happen early in each of the more than 30 cancer types. One of the most common early changes in many cancers, including ovarian cancer, affects a gene called TP53. In glioblastoma, an extra copy of chromosome 7 is very frequently gained early, while for pancreatic neuroendocrine cancer a number of chromosomes are lost in the initial stages of tumour development. \"What's extraordinary is how some of the genetic changes appear to have occurred many years before diagnosis, long before any other signs that a cancer may develop, and perhaps even in apparently normal tissue,\" says Clemency Jolly, co-lead author and Ph.D. student in the Cancer Genomics Laboratory at the Crick. In a separate paper from the international consortium, also published in Nature today, Crick researchers identified the cancers that are likely to have many different mutations enter their DNA at the same time, as well as the timing of these events and the genes likely to be affected. For example, 22% of the 2,500 tumours studied were found to have experienced an event called chromothripsis, where a DNA strand breaks in many places at once and the pieces are rearranged incorrectly. This process was found to be an important and critically early event in the evolution of most cancers, particularly in melanomas. These two papers are part of a collection published in Nature from the Pan-Cancer Analysis of Whole Genomes Consortium. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Cancer develops through a process of somatic evolution 1 , 2 . Sequencing data from a single biopsy represent a snapshot of this process that can reveal the timing of specific genomic aberrations and the changing influence of mutational processes 3 . Here, by whole-genome sequencing analysis of 2,658 cancers as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) 4 , we reconstruct the life history and evolution of mutational processes and driver mutation sequences of 38 types of cancer. Early oncogenesis is characterized by mutations in a constrained set of driver genes, and specific copy number gains, such as trisomy 7 in glioblastoma and isochromosome 17q in medulloblastoma. The mutational spectrum changes significantly throughout tumour evolution in 40% of samples. A nearly fourfold diversification of driver genes and increased genomic instability are features of later stages. Copy number alterations often occur in mitotic crises, and lead to simultaneous gains of chromosomal segments. Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer, and highlight opportunities for early cancer detection. Main Similar to the evolution in species, the approximately 10 14 cells in the human body are subject to the forces of mutation and selection 1 . This process of somatic evolution begins in the zygote and only comes to rest at death, as cells are constantly exposed to mutagenic stresses, introducing 1–10 mutations per cell division 2 . These mutagenic forces lead to a gradual accumulation of point mutations throughout life, observed in a range of healthy tissues 5 , 6 , 7 , 8 , 9 , 10 , 11 and cancers 12 . Although these mutations are predominantly selectively neutral passenger mutations, some are proliferatively advantageous driver mutations 13 . The types of mutation in cancer genomes are well studied, but little is known about the times when these lesions arise during somatic evolution and where the boundary between normal evolution and cancer progression should be drawn. Sequencing of bulk tumour samples enables partial reconstruction of the evolutionary history of individual tumours, based on the catalogue of somatic mutations they have accumulated 3 , 14 , 15 . These inferences include timing of chromosomal gains during early somatic evolution 16 , phylogenetic analysis of late cancer evolution using matched primary and metastatic tumour samples from individual patients 17 , 18 , 19 , 20 , and temporal ordering of driver mutations across many samples 21 , 22 . The PCAWG Consortium has aggregated whole-genome sequencing data from 2,658 cancers 4 , generated by the ICGC and TCGA, and produced high-accuracy somatic variant calls, driver mutations, and mutational signatures 4 , 23 , 24 (Methods and Supplementary Information ). Here, we leverage the PCAWG dataset to characterize the evolutionary history of 2,778 cancer samples from 2,658 unique donors across 38 cancer types. We infer timing and patterns of chromosomal evolution and learn typical sequences of mutations across samples of each cancer type. We then define broad periods of tumour evolution and examine how drivers and mutational signatures vary between these epochs. Using clock-like mutational processes, we map mutation timing estimates into approximate real time. Combined, these analyses allow us to sketch out the typical evolutionary trajectories of cancer, and map them in real time relative to the point of diagnosis. Reconstructing the life history of tumours The genome of a cancer cell is shaped by the cumulative somatic aberrations that have arisen during its evolutionary past, and part of this history can be reconstructed from whole-genome sequencing data 3 (Fig. 1a ). Initially, each point mutation occurs on a single chromosome in a single cell, which gives rise to a lineage of cells bearing the same mutation. If that chromosomal locus is subsequently duplicated, any point mutation on this allele preceding the gain will subsequently be present on the two resulting allelic copies, unlike mutations succeeding the gain, or mutations on the other allele. As sequencing data enable the measurement of the number of allelic copies, one can define categories of early and late clonal variants, preceding or succeeding copy number gains, as well as unspecified clonal variants, which are common to all cancer cells, but cannot be timed further. Lastly, we identify subclonal mutations, which are present in only a subset of cells and have occurred after the most recent common ancestor (MRCA) of all cancer cells in the tumour sample ( Supplementary Information ). Fig. 1: Timing clonal copy number gains using allele frequencies of point mutations. a , Principles of timing mutations and copy number gains based on whole-genome sequencing. The number of sequencing reads reporting point mutations can be used to discriminate variants as early or late clonal (green or purple, respectively) in cases of specific copy number gains, as well as clonal (blue) or subclonal (red) in cases without. b , Annotated point mutations in one sample based on VAF (top), copy number (CN) state and structural variants (middle), and resulting timing estimates (bottom). LOH, loss of heterozygosity. c , Overview of the molecular timing distribution of copy number gains across cancer types. Pie charts depict the distribution of the inferred mutation time for a given copy number gain in a cancer type. Green denotes early clonal gains, with a gradient to purple for late gains. The size of each chart is proportional to the recurrence of this event. Abbreviations for each cancer type are defined in Supplementary Table 1 . d , Heat maps representing molecular timing estimates of gains on different chromosome arms ( x axis) for individual samples ( y axis) for selected tumour types. e , Temporal patterns of two near-diploid cases illustrating synchronous gains (top) and asynchronous gains (bottom). f , Left, distribution of synchronous and asynchronous gain patterns across samples, split by WGD status. Uninformative samples have too few or too small gains for accurate timing. Right,<|im_end|> <|im_start|>assistant Early signs of cancer can appear years before diagnosis and developing tests for these genetic signs could provide new ways to spot cancer early, according to new research led by the Crick and EMBL-EBI, and supported by an international cancer genomics consortium, the Pan-Cancer Analysis of Whole Genomes Project. The collaboration included Wellcome Sanger Institute, Broad Institute of MIT and Harvard, Big Data Institute at the University of Oxford and Oregon Health & Science University. The study, published in Nature, looked at 47 million genetic changes in more than 2,500 human tumours, across 38 cancer types. By looking at how many times a single change had been replicated and copied across chromosomes, the researchers were able to determine the order in which they happened and the relative timing between them. Using this method, they found that just over 20% of mutations can be considered early events in a tumour's development, with some of these changes taking place years, even decades, before the cancer is found. Of these early mutations, half fall within the same nine genes, meaning there is a small number of genes that are common drivers of early cancer development. "We've developed the first timelines of genetic mutations across the spectrum of cancer types. For more than 30 cancers, we now know what specific genetic changes are likely to happen, and when these are likely to take place. Unlocking these patterns means it should now be possible to develop new diagnostic tests, that pick up signs of cancer much earlier," says Peter Van Loo, co-lead author and group leader in the Cancer Genomics Laboratory at the Crick. As cells in the body grow and divide, errors can be introduced in their DNA. While most of these changes do not significantly alter our cells, some are harmful and are associated with the formation and growth of tumours. These DNA errors continue to accumulate in cancerous cells, so a tumour can ultimately be made up of cells with many different genetic mutations. "We have learned that cancer is the endpoint of a lifelong evolutionary process that drives our cells. This process is fuelled by mutations in the cells' genomes," says Moritz Gerstung, co-lead author and Group Leader at EMBL's European Bioinformatics Institute (EMBL-EBI). "These mutations occur as we age. Usually, there are no consequences to these mutations, but sometimes, the consequences can be dramatic. This process usually culminates within the decades prior to cancer diagnosis, but in some cases, we have been able to identify alterations as old as the patient." The research identified cancer types in which mutations tend to happen particularly early, for example, ovarian cancer and two types of brain tumours, glioblastoma and medulloblastoma. It also revealed the specific changes that are likely to happen early in each of the more than 30 cancer types. One of the most common early changes in many cancers, including ovarian cancer, affects a gene called TP53. In glioblastoma, an extra copy of chromosome 7 is very frequently gained early, while for pancreatic neuroendocrine cancer a number of chromosomes are lost in the initial stages of tumour development. "What's extraordinary is how some of the genetic changes appear to have occurred many years before diagnosis, long before any other signs that a cancer may develop, and perhaps even in apparently normal tissue," says Clemency Jolly, co-lead author and Ph.D. student in the Cancer Genomics Laboratory at the Crick. In a separate paper from the international consortium, also published in Nature today, Crick researchers identified the cancers that are likely to have many different mutations enter their DNA at the same time, as well as the timing of these events and the genes likely to be affected. For example, 22% of the 2,500 tumours studied were found to have experienced an event called chromothripsis, where a DNA strand breaks in many places at once and the pieces are rearranged incorrectly. This process was found to be an important and critically early event in the evolution of most cancers, particularly in melanomas. These two papers are part of a collection published in Nature from the Pan-Cancer Analysis of Whole Genomes Consortium. <|im_end|>

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2,167

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Recurring outbursts associated with matter flowing onto compact stellar remnants (such as black holes, neutron stars and white dwarfs) in close binary systems provide a way of constraining the poorly understood accretion process. The light curves of these outbursts are shaped by the efficiency of angular-momentum (and thus mass) transport in the accretion disks, which has traditionally been encoded in a viscosity parameter, α . Numerical simulations 1 , 2 , 3 of the magneto-rotational instability that is believed to be the physical mechanism behind this transport yield values of α of roughly 0.1–0.2, consistent with values determined from observations of accreting white dwarfs 4 . Equivalent viscosity parameters have hitherto not been estimated for disks around neutron stars or black holes. Here we report the results of an analysis of archival X-ray light curves of 21 outbursts in black-hole X-ray binaries. By applying a Bayesian approach to a model of accretion, we determine corresponding values of α of around 0.2–1.0. These high values may be interpreted as an indication either of a very high intrinsic rate of angular-momentum transport in the disk, which could be sustained by the magneto-rotational instability only if a large-scale magnetic field threads the disk 5 , 6 , 7 , or that mass is being lost from the disk through substantial outflows, which strongly shape the outburst in the black-hole X-ray binary. The lack of correlation between our estimates of α and the accretion state of the binaries implies that such outflows can remove a substantial fraction of the disk mass in all accretion states and therefore suggests that the outflows correspond to magnetically driven disk winds rather than thermally driven ones, which require specific radiative conditions 8 . Main The disk-instability model 9 , 10 , 11 , 12 , 13 , 14 was developed to explain outbursts in compact binaries in which a white dwarf accretes from a low-mass companion 15 . A cool (neutral) quiescent disk is built up through steady mass transfer from the companion star, causing the temperature of the disk to increase. At some radius (called the ignition radius), the temperature of the disk will eventually reach the temperature at which hydrogen ionizes. This triggers a thermal–viscous instability within the disk, due to the steep temperature dependence of opacity in this temperature range. As a result, the disk cycles between a hot, ionized, outburst state and a cold, neutral, quiescent state. The growth of the thermal–viscous instability at the ignition radius results in two heating fronts propagating inwards and outwards through the disk. This propagation brings the disk into a hot state, causing rapid in-fall of matter onto the compact object and a bright optical and ultraviolet outburst. As the disk is depleted over time (because mass falls onto the compact stellar remnant at a higher rate than it is being transferred from the companion star), the temperature and mass-accretion rate in the outer radii will eventually be reduced to the point at which hydrogen can recombine. This triggers the formation and propagation of a cooling front that returns the disk to its quiescent (neutral) state. This predicted behaviour, which is characterized by alternating periods of outbursts and quiescence, matches observations of accreting white dwarfs well. However, changes to the theory are needed for the close binaries known as low-mass X-ray binaries, which contain more compact stellar remnants (such as neutron stars and stellar-mass black holes). There are 18 confirmed black-hole low-mass X-ray binaries in our Galaxy, identified through bright X-ray outbursts which indicate rapid accretion episodes 16 . These outbursts 16 last considerably longer, and recur much less frequently, than those from many types of accreting white dwarf, owing to heating of the outer disk by X-rays emitted in the inner regions of the accretion flow 17 . X-ray irradiation keeps the accretion disk in its hot (ionized) state over the viscous timescale. This timescale, which is encoded in observed outburst light curves, is related to the efficiency of angular-momentum transport directly and thus provides a means of measuring this efficiency. See Methods and Extended Data Fig. 1 for a detailed discussion of the characteristic three-stage outburst decay profile present in the light curve of a black-hole low-mass X-ray binary. The magneto-rotational instability is thought to provide the physical mechanism behind angular-momentum (and mass) transport in accretion disks 18 . The effective viscosity in these disks, which is commonly parameterized using the α viscosity prescription 19 , encapsulates the efficiency of this transport process. Physically, the viscosity parameter α sets the viscous time of the accretion flow through the disk and thus, according to the disk-instability model, is encoded within the decay profile of the light curve of an outburst. A disk with higher viscosity (higher α ) in outburst will accrete mass more quickly, resulting in shorter decay times and shorter outburst durations 20 . The α viscosity has been inferred only in (non-irradiated) disks around accreting white dwarfs, by comparing the outburst timescales from observed light curves to synthetic model light curves created by numerical disk codes for different α inputs 4 . Values of α have not previously been measured in irradiated accretion disks, such as those around stellar-mass black holes in low-mass X-ray binaries. The assertion 21 that α ≈ 0.2–0.4 in such systems was deduced from calculations 20 of “detailed models of complete light curves”, not from detailed comparison of models with observations. Note that we learned of a recent study 22 of the black-hole low-mass X-ray binary 4U 1543–475 after acceptance of this manuscript. Accordingly, we have built a Bayesian approach that characterizes the angular-momentum (and mass) transport that occurs in disks in low-mass X-ray binary systems. The α viscosity parameter in a hot, outbursting disk ( α h ) sets the timescale on which matter moves through the hot (ionized) portion of the disk and thus controls the duration of the first stage of the decay profile observed in an X-ray light curve (see Methods for details). This (viscous)", "role": "user" }, { "content": "New research shows the first evidence of strong winds around black holes throughout bright outburst events when a black hole rapidly consumes mass. The study, published in Nature, sheds new light on how mass transfers to black holes and how black holes can affect the environment around them. The research was conducted by an international team of researchers, led by scientists in the University of Alberta's Department of Physics. Using data from three international space agencies spanning 20 years, the scientists used new statistical techniques to study outbursts from stellar-mass black hole X-ray binary systems. Their results show evidence of consistent and strong winds surrounding black holes throughout outbursts. Until now, strong winds had only been seen in limited parts of these events. \"Winds must blow away a large fraction of the matter a black hole could eat,'' described Bailey Tetarenko, PhD student and lead author on the study. \"In one of our models, the winds removed 80 per cent of the black hole's potential meal.\" Depending on their size, stellar-mass black holes have the capacity to consume everything within a 3 to 150 kilometre radius. \"Not even light can escape from this close to a black hole,\" explained Gregory Sivakoff, associate professor of physics and co-author. Other, much larger black holes, called supermassive black holes, appear to have affected the formation of entire galaxies. \"But even supermassive black holes are smaller than our solar system. While they are small, black holes can have surprisingly large effects,\" explained Sivakoff. So, what exactly causes these winds in space? For now, it remains a mystery. \"We think magnetic fields play a key role. But we'll need to do a great deal of future investigation to understand these winds,\" explained Craig Heinke, associate professor of physics and co-author. \"Strong disk winds traced throughout outbursts in black-hole X-ray binaries\" will be published online January 22 in Nature. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Recurring outbursts associated with matter flowing onto compact stellar remnants (such as black holes, neutron stars and white dwarfs) in close binary systems provide a way of constraining the poorly understood accretion process. The light curves of these outbursts are shaped by the efficiency of angular-momentum (and thus mass) transport in the accretion disks, which has traditionally been encoded in a viscosity parameter, α . Numerical simulations 1 , 2 , 3 of the magneto-rotational instability that is believed to be the physical mechanism behind this transport yield values of α of roughly 0.1–0.2, consistent with values determined from observations of accreting white dwarfs 4 . Equivalent viscosity parameters have hitherto not been estimated for disks around neutron stars or black holes. Here we report the results of an analysis of archival X-ray light curves of 21 outbursts in black-hole X-ray binaries. By applying a Bayesian approach to a model of accretion, we determine corresponding values of α of around 0.2–1.0. These high values may be interpreted as an indication either of a very high intrinsic rate of angular-momentum transport in the disk, which could be sustained by the magneto-rotational instability only if a large-scale magnetic field threads the disk 5 , 6 , 7 , or that mass is being lost from the disk through substantial outflows, which strongly shape the outburst in the black-hole X-ray binary. The lack of correlation between our estimates of α and the accretion state of the binaries implies that such outflows can remove a substantial fraction of the disk mass in all accretion states and therefore suggests that the outflows correspond to magnetically driven disk winds rather than thermally driven ones, which require specific radiative conditions 8 . Main The disk-instability model 9 , 10 , 11 , 12 , 13 , 14 was developed to explain outbursts in compact binaries in which a white dwarf accretes from a low-mass companion 15 . A cool (neutral) quiescent disk is built up through steady mass transfer from the companion star, causing the temperature of the disk to increase. At some radius (called the ignition radius), the temperature of the disk will eventually reach the temperature at which hydrogen ionizes. This triggers a thermal–viscous instability within the disk, due to the steep temperature dependence of opacity in this temperature range. As a result, the disk cycles between a hot, ionized, outburst state and a cold, neutral, quiescent state. The growth of the thermal–viscous instability at the ignition radius results in two heating fronts propagating inwards and outwards through the disk. This propagation brings the disk into a hot state, causing rapid in-fall of matter onto the compact object and a bright optical and ultraviolet outburst. As the disk is depleted over time (because mass falls onto the compact stellar remnant at a higher rate than it is being transferred from the companion star), the temperature and mass-accretion rate in the outer radii will eventually be reduced to the point at which hydrogen can recombine. This triggers the formation and propagation of a cooling front that returns the disk to its quiescent (neutral) state. This predicted behaviour, which is characterized by alternating periods of outbursts and quiescence, matches observations of accreting white dwarfs well. However, changes to the theory are needed for the close binaries known as low-mass X-ray binaries, which contain more compact stellar remnants (such as neutron stars and stellar-mass black holes). There are 18 confirmed black-hole low-mass X-ray binaries in our Galaxy, identified through bright X-ray outbursts which indicate rapid accretion episodes 16 . These outbursts 16 last considerably longer, and recur much less frequently, than those from many types of accreting white dwarf, owing to heating of the outer disk by X-rays emitted in the inner regions of the accretion flow 17 . X-ray irradiation keeps the accretion disk in its hot (ionized) state over the viscous timescale. This timescale, which is encoded in observed outburst light curves, is related to the efficiency of angular-momentum transport directly and thus provides a means of measuring this efficiency. See Methods and Extended Data Fig. 1 for a detailed discussion of the characteristic three-stage outburst decay profile present in the light curve of a black-hole low-mass X-ray binary. The magneto-rotational instability is thought to provide the physical mechanism behind angular-momentum (and mass) transport in accretion disks 18 . The effective viscosity in these disks, which is commonly parameterized using the α viscosity prescription 19 , encapsulates the efficiency of this transport process. Physically, the viscosity parameter α sets the viscous time of the accretion flow through the disk and thus, according to the disk-instability model, is encoded within the decay profile of the light curve of an outburst. A disk with higher viscosity (higher α ) in outburst will accrete mass more quickly, resulting in shorter decay times and shorter outburst durations 20 . The α viscosity has been inferred only in (non-irradiated) disks around accreting white dwarfs, by comparing the outburst timescales from observed light curves to synthetic model light curves created by numerical disk codes for different α inputs 4 . Values of α have not previously been measured in irradiated accretion disks, such as those around stellar-mass black holes in low-mass X-ray binaries. The assertion 21 that α ≈ 0.2–0.4 in such systems was deduced from calculations 20 of “detailed models of complete light curves”, not from detailed comparison of models with observations. Note that we learned of a recent study 22 of the black-hole low-mass X-ray binary 4U 1543–475 after acceptance of this manuscript. Accordingly, we have built a Bayesian approach that characterizes the angular-momentum (and mass) transport that occurs in disks in low-mass X-ray binary systems. The α viscosity parameter in a hot, outbursting disk ( α h ) sets the timescale on which matter moves through the hot (ionized) portion of the disk and thus controls the duration of the first stage of the decay profile observed in an X-ray light curve (see Methods for details). This (viscous)<|im_end|> <|im_start|>assistant New research shows the first evidence of strong winds around black holes throughout bright outburst events when a black hole rapidly consumes mass. The study, published in Nature, sheds new light on how mass transfers to black holes and how black holes can affect the environment around them. The research was conducted by an international team of researchers, led by scientists in the University of Alberta's Department of Physics. Using data from three international space agencies spanning 20 years, the scientists used new statistical techniques to study outbursts from stellar-mass black hole X-ray binary systems. Their results show evidence of consistent and strong winds surrounding black holes throughout outbursts. Until now, strong winds had only been seen in limited parts of these events. "Winds must blow away a large fraction of the matter a black hole could eat,'' described Bailey Tetarenko, PhD student and lead author on the study. "In one of our models, the winds removed 80 per cent of the black hole's potential meal." Depending on their size, stellar-mass black holes have the capacity to consume everything within a 3 to 150 kilometre radius. "Not even light can escape from this close to a black hole," explained Gregory Sivakoff, associate professor of physics and co-author. Other, much larger black holes, called supermassive black holes, appear to have affected the formation of entire galaxies. "But even supermassive black holes are smaller than our solar system. While they are small, black holes can have surprisingly large effects," explained Sivakoff. So, what exactly causes these winds in space? For now, it remains a mystery. "We think magnetic fields play a key role. But we'll need to do a great deal of future investigation to understand these winds," explained Craig Heinke, associate professor of physics and co-author. "Strong disk winds traced throughout outbursts in black-hole X-ray binaries" will be published online January 22 in Nature. <|im_end|>

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1,771

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Over the last century, many shark populations have declined, primarily due to overexploitation in commercial, artisanal and recreational fisheries. In addition, in some locations the use of shark control programs also has had an impact on shark numbers. Still, there is a general perception that populations of large ocean predators cover wide areas and therefore their diversity is less susceptible to local anthropogenic disturbance. Here we report on temporal genomic analyses of tiger shark ( Galeocerdo cuvier ) DNA samples that were collected from eastern Australia over the past century. Using Single Nucleotide Polymorphism (SNP) loci, we documented a significant change in genetic composition of tiger sharks born between ~1939 and 2015. The change was most likely due to a shift over time in the relative contribution of two well-differentiated, but hitherto cryptic populations. Our data strongly indicate a dramatic shift in the relative contribution of these two populations to the overall tiger shark abundance on the east coast of Australia, possibly associated with differences in direct or indirect exploitation rates. Introduction Intraspecific genetic diversity is essential for long-term population persistence to avoid the negative effects of inbreeding 1 , to buffer against environmental variation in time and space 2 , and to ensure adaptability to a changing environment 3 . High genetic diversity may also have positive ecosystem effects by promoting productivity, abundance, and stability of community structure 4 , 5 , 6 . Thus, species with many discrete populations with different genetic adaptations, including life history strategies, are assumed better at withstanding exploitation and environmental variation, than a single panmictic population. Intraspecific diversity protection is a specified objective of the Convention on Biological Diversity (CBD; ), but is rarely an integral part of monitoring activities, in particular for species that are not critically endangered 7 , 8 . Indeed, the lack of dedicated sampling programs and the many species requiring monitoring makes it logistically impossible to oversee intra-specific diversity in most instances. In addition, the difficulties associated with the use of high-resolution genetic methods when sample sizes are low or when tissue samples vary in age, composition and provenance 9 also hinder our ability to assess intra-specific diversity. The use of DNA extracted from museum specimens, in combination with modern molecular analytical tools, has revolutionized the ability to assess genetic changes at contemporary time scales 10 , 11 . Studies on processes such as intra-population loss of diversity, adaptive change caused by evolutionary drivers in the environment, as well as the movement, decline, or extirpation of populations through time and space can now be undertaken 5 , 12 . In the marine realm, there are numerous examples of local population reductions and extinctions, in particular for large sharks and rays 13 , 14 , but closely coupling these incidences with genetic and genomic data is challenging due to the lack of temporal genetic data for elasmobranch species. Spatiotemporal genetic samples (i.e. obtained across several locations and years 15 ) can be used to test for changes in distribution of elasmobranch populations including potential extirpations and replacements, as well as intra-population changes in levels of genetic variability, and putative adaptive genetic changes in the timeframe of recent environmental changes or exploitation. This is of significant interest with respect to populations of large sharks, where there is a strong need for identification of genetic populations and their historical trajectories, as they represent both the relevant unit for evolution and management 9 , 16 in order to contribute significantly to short-term sustainable exploitation as well as long-term protection of intra-specific biodiversity. Failing to identify and incorporate biologically-discrete populations in management may cause overharvesting of particular (cryptic) populations or population segments, resulting in extinction or reduction of genetic diversity within populations 4 , 7 . The tiger shark ( Galeocerdo cuvier ) is one of the world’s largest sharks, with a circumglobal distribution in tropical and sub-tropical waters 17 , 18 . Throughout its range, the species is exploited by multiple users, from target and bycatch in commercial, artisanal, and recreational fisheries 19 , 20 , to shark control operations to improve bather safety 21 , 22 , which have been linked to on-going population decline and reduced average size of individuals 22 , 23 , 24 . The species is globally listed as Near Threatened on the International Union for the Conservation of Nature’s (IUCN) Red List of Threatened Species due to a suspected decline of ~ 30% over the past ~ 60 years 25 . This general decline covers variable regional population trends ranging from relatively stable abundances, e.g. North-western Atlantic 26 , to severe local depletions as observed in the Red Sea, Eritrea, Iranian Gulf, as well India and Pakistan 27 . In the Arabian Seas on-going local reported declines of 30–50% over three generations led the species to be locally assessed as Vulnerable 27 . Of greater concern, however, is the reported 74% decline in catch per unit effort (CPUE) for tiger sharks off Queensland (eastern Australia) over the past 25 years, which was accompanied by a 21% decline in the average size of individuals 24 . Thus, despite its cosmopolitan nature and dispersal potential, local depletions appear to be relatively common in the species, suggesting some degree of population isolation could occur. However, there is still a lack of adequate spatially resolved data to understand regional population trends of tiger sharks as they are commonly caught in unreported fisheries. Current assessments of the tiger shark population structure have been based on microsatellite and mitochondrial genetic markers, and have demonstrated a clear inter-basin genetic split between the Atlantic and Indo-Pacific Oceans, but a general lack of intra-basin population structuring 28 , 29 , 30 . Although this may be a true biological characteristic of the species, it could also reflect analytical challenges related to obtaining sufficient samples with good spatial coverage and the application of low-resolution genetic markers. Thus, in a recent review of research priorities, the development of high-resolution SNPs (Single Nucleotide Polymorphisms) to further resolve", "role": "user" }, { "content": "Jaws was the only word needed to give the iconic 1970's thriller about a great white with a preference for humans its eerie title. Though a strong and important player at the top of the foodchain, sharks face a range of enemies: overfishing, habitat loss, pollution, climate change and human fear resulting in the use of shark control programs in some locations. The fear and fascination for sharks have made people collect shark jaws for decades. These collections of shark jaws from museums, national fishery institutes and personal collections, including modern samples from fishery institutes represent a great opportunity for scientists. Using genomic data retrieved from historical tiger shark jaws, an international group of scientists including Professor Einar Eg from the Technical University of Denmark has found evidence of the disappearance of a local southeastern Australian population of tiger sharks. A disappearance associated with a documented local decline in abundance of tiger sharks, likely caused by the ongoing shark control program. An international study that highlights changes in genetic composition of tiger sharks (Galeocerdo cuvier) and potential loss of a south-eastern Australia population has just been published in the journal Scientific Reports \"Our study shows that tiger sharks can have local and genetically isolated populations at a restricted geographical scale—such as the south Eastern Australian coast—and that these local populations are vulnerable to direct exploitation and shark control programs,\" says Eg. Top predator controls the ecosystem balance The study shows that there are still tiger sharks in the area. However, these individuals belong to an, apparently, more widespread population found across the east/north coast of Australia. \"When we, through genetic analysis, better understand the distribution and migration of shark populations and their responses to human activities over historical time, we are better able to design proper management plans and actions at the appropriate geographical scale. Not only for the benefit of sharks, but for marine ecosystems as a whole,\" says Eg. \"Sharks are top predators. They control the abundance of other species below them, and sick fish, in the food chain, ensuring species diversity. I.e. they are important for maintaining ecosystem balance. They are generally long lived and slow reproducers, so a healthy shark fauna signals a healthy ocean and ecosystem.\" Genetic diversity is the fuel that drives future evolution Before the new study, it was believed that tiger sharks did not display local population structure. Thus, genetic differences among tiger shark populations were only found at a basin wide scale, such as between tiger sharks in the Pacific and Atlantic oceans. Accordingly, tiger sharks were expected to display low vulnerability towards local depletion. Therefore management of the species at a large geographical scale was in focus. \"From our samples alone, it appears that the historical local population has been extirpated or significantly reduced. This means that management of the species also has to focus on regional processes and exploitation patterns in order to protect local populations and biodiversity of the species as a whole,\" says Eg. \"Genetic diversity within a species, is the fuel that drives future evolution and adaptation to the environment, e.g. climate change. Without historical genetic/genomic data, there is no way of assessing the loss of genetic diversity within a species.\" Fear and facts—are sharks moving North? With regards to the shark control programs having an impact on shark numbers, the obvious question arises How afraid should one actually be to go swimming in Australia or South Africa? \"In 2021, there were 73 cases of unprovoked shark bites worldwide, with a total of 11 fatalities. Most attacks were related to surfing and board sports. In Australia, there were three fatalities and 1 in SA. So, the chance of being attacked and killed by a shark is almost non-existing. One should definitely be more afraid of driving in your car writing txt messages,\" says Eg. As climate change causes sea temperatures to rise, some researchers say that we may be looking into a future with large sharks entering Danish/European waters. However, Eg stresses that though changed temperature conditions could allow for more large sharks occurring in Danish/European waters, many other factors determine the distribution of a species. \"The Mediterranean, for instance, is very suitable for large sharks, but we do not see large assemblages of white, tiger, mako sharks there. If they come, it is highly unlikely that this would result in any bather-shark conflicts. As an example, there were no reported shark bites in Europe for 2021,\" says Eg. A future for sharks On a global scale, the tiger shark is near threatened. According to Professor Eg that covers a significant species depletion in some areas, while they're doing ok in other regions of the world: \"We need to shift tiger shark management conceptually from an exclusive species view to also include the local population aspect. For example, saving global populations has to go through protection and proper management of local populations,\" says Eg. \"Now, by having our temporal genetic data, we can study the genetic impact of anthropogenic pressure on marine species, enabling us to improve management in order to secure biodiversity.\" So, how can genetic research continue and help improve shark control and hunting in favor of sharks? \"Genetic research can help to elucidate the proper biological units (genetic populations), which should be the target for fisheries management, conservation and biodiversity protection,\" says Eg. \"Studies like ours can illustrate the likely consequences of local over-exploitation in relation to shark control and make us realize what we can lose by not paying attention to the distribution of genetic variation within a species.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Over the last century, many shark populations have declined, primarily due to overexploitation in commercial, artisanal and recreational fisheries. In addition, in some locations the use of shark control programs also has had an impact on shark numbers. Still, there is a general perception that populations of large ocean predators cover wide areas and therefore their diversity is less susceptible to local anthropogenic disturbance. Here we report on temporal genomic analyses of tiger shark ( Galeocerdo cuvier ) DNA samples that were collected from eastern Australia over the past century. Using Single Nucleotide Polymorphism (SNP) loci, we documented a significant change in genetic composition of tiger sharks born between ~1939 and 2015. The change was most likely due to a shift over time in the relative contribution of two well-differentiated, but hitherto cryptic populations. Our data strongly indicate a dramatic shift in the relative contribution of these two populations to the overall tiger shark abundance on the east coast of Australia, possibly associated with differences in direct or indirect exploitation rates. Introduction Intraspecific genetic diversity is essential for long-term population persistence to avoid the negative effects of inbreeding 1 , to buffer against environmental variation in time and space 2 , and to ensure adaptability to a changing environment 3 . High genetic diversity may also have positive ecosystem effects by promoting productivity, abundance, and stability of community structure 4 , 5 , 6 . Thus, species with many discrete populations with different genetic adaptations, including life history strategies, are assumed better at withstanding exploitation and environmental variation, than a single panmictic population. Intraspecific diversity protection is a specified objective of the Convention on Biological Diversity (CBD; ), but is rarely an integral part of monitoring activities, in particular for species that are not critically endangered 7 , 8 . Indeed, the lack of dedicated sampling programs and the many species requiring monitoring makes it logistically impossible to oversee intra-specific diversity in most instances. In addition, the difficulties associated with the use of high-resolution genetic methods when sample sizes are low or when tissue samples vary in age, composition and provenance 9 also hinder our ability to assess intra-specific diversity. The use of DNA extracted from museum specimens, in combination with modern molecular analytical tools, has revolutionized the ability to assess genetic changes at contemporary time scales 10 , 11 . Studies on processes such as intra-population loss of diversity, adaptive change caused by evolutionary drivers in the environment, as well as the movement, decline, or extirpation of populations through time and space can now be undertaken 5 , 12 . In the marine realm, there are numerous examples of local population reductions and extinctions, in particular for large sharks and rays 13 , 14 , but closely coupling these incidences with genetic and genomic data is challenging due to the lack of temporal genetic data for elasmobranch species. Spatiotemporal genetic samples (i.e. obtained across several locations and years 15 ) can be used to test for changes in distribution of elasmobranch populations including potential extirpations and replacements, as well as intra-population changes in levels of genetic variability, and putative adaptive genetic changes in the timeframe of recent environmental changes or exploitation. This is of significant interest with respect to populations of large sharks, where there is a strong need for identification of genetic populations and their historical trajectories, as they represent both the relevant unit for evolution and management 9 , 16 in order to contribute significantly to short-term sustainable exploitation as well as long-term protection of intra-specific biodiversity. Failing to identify and incorporate biologically-discrete populations in management may cause overharvesting of particular (cryptic) populations or population segments, resulting in extinction or reduction of genetic diversity within populations 4 , 7 . The tiger shark ( Galeocerdo cuvier ) is one of the world’s largest sharks, with a circumglobal distribution in tropical and sub-tropical waters 17 , 18 . Throughout its range, the species is exploited by multiple users, from target and bycatch in commercial, artisanal, and recreational fisheries 19 , 20 , to shark control operations to improve bather safety 21 , 22 , which have been linked to on-going population decline and reduced average size of individuals 22 , 23 , 24 . The species is globally listed as Near Threatened on the International Union for the Conservation of Nature’s (IUCN) Red List of Threatened Species due to a suspected decline of ~ 30% over the past ~ 60 years 25 . This general decline covers variable regional population trends ranging from relatively stable abundances, e.g. North-western Atlantic 26 , to severe local depletions as observed in the Red Sea, Eritrea, Iranian Gulf, as well India and Pakistan 27 . In the Arabian Seas on-going local reported declines of 30–50% over three generations led the species to be locally assessed as Vulnerable 27 . Of greater concern, however, is the reported 74% decline in catch per unit effort (CPUE) for tiger sharks off Queensland (eastern Australia) over the past 25 years, which was accompanied by a 21% decline in the average size of individuals 24 . Thus, despite its cosmopolitan nature and dispersal potential, local depletions appear to be relatively common in the species, suggesting some degree of population isolation could occur. However, there is still a lack of adequate spatially resolved data to understand regional population trends of tiger sharks as they are commonly caught in unreported fisheries. Current assessments of the tiger shark population structure have been based on microsatellite and mitochondrial genetic markers, and have demonstrated a clear inter-basin genetic split between the Atlantic and Indo-Pacific Oceans, but a general lack of intra-basin population structuring 28 , 29 , 30 . Although this may be a true biological characteristic of the species, it could also reflect analytical challenges related to obtaining sufficient samples with good spatial coverage and the application of low-resolution genetic markers. Thus, in a recent review of research priorities, the development of high-resolution SNPs (Single Nucleotide Polymorphisms) to further resolve<|im_end|> <|im_start|>assistant Jaws was the only word needed to give the iconic 1970's thriller about a great white with a preference for humans its eerie title. Though a strong and important player at the top of the foodchain, sharks face a range of enemies: overfishing, habitat loss, pollution, climate change and human fear resulting in the use of shark control programs in some locations. The fear and fascination for sharks have made people collect shark jaws for decades. These collections of shark jaws from museums, national fishery institutes and personal collections, including modern samples from fishery institutes represent a great opportunity for scientists. Using genomic data retrieved from historical tiger shark jaws, an international group of scientists including Professor Einar Eg from the Technical University of Denmark has found evidence of the disappearance of a local southeastern Australian population of tiger sharks. A disappearance associated with a documented local decline in abundance of tiger sharks, likely caused by the ongoing shark control program. An international study that highlights changes in genetic composition of tiger sharks (Galeocerdo cuvier) and potential loss of a south-eastern Australia population has just been published in the journal Scientific Reports "Our study shows that tiger sharks can have local and genetically isolated populations at a restricted geographical scale—such as the south Eastern Australian coast—and that these local populations are vulnerable to direct exploitation and shark control programs," says Eg. Top predator controls the ecosystem balance The study shows that there are still tiger sharks in the area. However, these individuals belong to an, apparently, more widespread population found across the east/north coast of Australia. "When we, through genetic analysis, better understand the distribution and migration of shark populations and their responses to human activities over historical time, we are better able to design proper management plans and actions at the appropriate geographical scale. Not only for the benefit of sharks, but for marine ecosystems as a whole," says Eg. "Sharks are top predators. They control the abundance of other species below them, and sick fish, in the food chain, ensuring species diversity. I.e. they are important for maintaining ecosystem balance. They are generally long lived and slow reproducers, so a healthy shark fauna signals a healthy ocean and ecosystem." Genetic diversity is the fuel that drives future evolution Before the new study, it was believed that tiger sharks did not display local population structure. Thus, genetic differences among tiger shark populations were only found at a basin wide scale, such as between tiger sharks in the Pacific and Atlantic oceans. Accordingly, tiger sharks were expected to display low vulnerability towards local depletion. Therefore management of the species at a large geographical scale was in focus. "From our samples alone, it appears that the historical local population has been extirpated or significantly reduced. This means that management of the species also has to focus on regional processes and exploitation patterns in order to protect local populations and biodiversity of the species as a whole," says Eg. "Genetic diversity within a species, is the fuel that drives future evolution and adaptation to the environment, e.g. climate change. Without historical genetic/genomic data, there is no way of assessing the loss of genetic diversity within a species." Fear and facts—are sharks moving North? With regards to the shark control programs having an impact on shark numbers, the obvious question arises How afraid should one actually be to go swimming in Australia or South Africa? "In 2021, there were 73 cases of unprovoked shark bites worldwide, with a total of 11 fatalities. Most attacks were related to surfing and board sports. In Australia, there were three fatalities and 1 in SA. So, the chance of being attacked and killed by a shark is almost non-existing. One should definitely be more afraid of driving in your car writing txt messages," says Eg. As climate change causes sea temperatures to rise, some researchers say that we may be looking into a future with large sharks entering Danish/European waters. However, Eg stresses that though changed temperature conditions could allow for more large sharks occurring in Danish/European waters, many other factors determine the distribution of a species. "The Mediterranean, for instance, is very suitable for large sharks, but we do not see large assemblages of white, tiger, mako sharks there. If they come, it is highly unlikely that this would result in any bather-shark conflicts. As an example, there were no reported shark bites in Europe for 2021," says Eg. A future for sharks On a global scale, the tiger shark is near threatened. According to Professor Eg that covers a significant species depletion in some areas, while they're doing ok in other regions of the world: "We need to shift tiger shark management conceptually from an exclusive species view to also include the local population aspect. For example, saving global populations has to go through protection and proper management of local populations," says Eg. "Now, by having our temporal genetic data, we can study the genetic impact of anthropogenic pressure on marine species, enabling us to improve management in order to secure biodiversity." So, how can genetic research continue and help improve shark control and hunting in favor of sharks? "Genetic research can help to elucidate the proper biological units (genetic populations), which should be the target for fisheries management, conservation and biodiversity protection," says Eg. "Studies like ours can illustrate the likely consequences of local over-exploitation in relation to shark control and make us realize what we can lose by not paying attention to the distribution of genetic variation within a species." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract During an inflammatory response, lymphocyte recruitment into tissue must be tightly controlled because dysregulated trafficking contributes to the pathogenesis of chronic disease. Here we show that during inflammation and in response to adiponectin, B cells tonically inhibit T cell trafficking by secreting a peptide (PEPITEM) proteolytically derived from 14.3.3 zeta delta (14.3.3.ζδ) protein. PEPITEM binds cadherin-15 on endothelial cells, promoting synthesis and release of sphingosine-1 phosphate, which inhibits trafficking of T cells without affecting recruitment of other leukocytes. Expression of adiponectin receptors on B cells and adiponectin-induced PEPITEM secretion wanes with age, implying immune senescence of the pathway. Additionally, these changes are evident in individuals with type 1 diabetes or rheumatoid arthritis, and circulating PEPITEM in patient serum is reduced compared to that of healthy age-matched donors. In both diseases, tonic inhibition of T cell trafficking across inflamed endothelium is lost. Control of patient T cell trafficking is re-established by treatment with exogenous PEPITEM. Moreover, in animal models of peritonitis, hepatic ischemia-reperfusion injury, Salmonella infection, uveitis and Sjögren's syndrome, PEPITEM reduced T cell recruitment into inflamed tissues. Main In vertebrates, a lymphocyte (T cell and B cell)-based adaptive immune system has evolved to augment innate immunity. Adaptive responses require lymphocyte trafficking between the bone marrow, lymphoid organs and peripheral tissues using blood as a vehicle for dispersal 1 . Our knowledge of the trafficking process is still incomplete. However, unregulated T cell recruitment during inflammation is pathogenic and contributes to chronic disease 2 , 3 . Here we reveal the function of a homeostatic pathway, which imposes a tonic inhibition on T cell trafficking during inflammation. Identification of this pathway arose through studies on the circulating adipokine adiponectin. Adiponectin affects both metabolic and immune pathways 4 , 5 , 6 , 7 , including the recruitment of leukocytes during an inflammatory response 6 , and plasma concentrations of adiponectin are low in a number of chronic diseases, including diabetes 4 . We tested the hypothesis that adiponectin might regulate lymphocyte trafficking and that changes in adiponectin function might contribute to pathogenic lymphocyte recruitment in chronic inflammatory and autoimmune diseases. We started by observing lymphocyte trafficking in vitro across isolated human endothelial cells, which are the gatekeepers to the tissues for circulating leukocytes. To enter inflamed tissue, T cells migrate through endothelial cells lining the post-capillary venules 8 , 9 , and this has been modeled both in vitro and in vivo 10 , 11 , 12 , 13 , 14 , 15 . Thus, memory T cells moving rapidly in the flowing blood are preferentially recruited by endothelial cells activated by cytokines (for example, tumor necrosis factor α (TNF-α) and/or interferon γ (IFN-γ)). Tethering from flow and rolling adhesion are supported by E-selectin and vascular cell adhesion molecule 1 (VCAM-1) 16 , whereas integrin-mediated stable adhesion and migration are supported by sequential signals from chemokines and prostaglandin D 2 (PGD 2 ; refs. 17 , 18 , 19 , 20 , 21 , 22 , 23 ). Here we show that in the presence of adiponectin, B cells recruited to the endothelial cell surface during inflammation reduce the efficiency of memory T cell migration by imposing a tonic inhibition on this process. Thus, we believe that the adaptive immune system has evolved a robust strategy for regulating inappropriate or excessive activity, thereby limiting the possibility of establishing a chronic inflammatory response that might contribute to disease. Results Adiponectin regulates T cell migration In vitro, adiponectin dose-dependently inhibited the TNF-α– and IFN-γ–induced trans-endothelial migration of human peripheral blood lymphocytes (PBLs) with a half-maximal effective concentration (EC 50 ) of 2.6 nM (0.94 μg/ml) ( Fig. 1a and Supplementary Fig. 1a ), with the most marked effects seen at physiological circulating levels observed in healthy humans (5−15 μg/ml). Although migration was reduced compared to the untreated control so that more cells were firmly adherent to the apical surface of the endothelium ( Supplementary Fig. 1b ), the number of lymphocytes recruited was unaffected by adiponectin ( Supplementary Fig. 1c ). The effects of adiponectin on PBL migration were seen in both a static system ( Fig. 1a ) and under conditions of flow ( Fig. 1b ), and they were evident on human umbilical vein endothelial cells (HUVECs) and human dermal microvascular endothelial cells (HDMECs) ( Fig. 1c ). The majority of transmigrating PBLs were CD3 + CD45RO + memory T cells, as expected for this model (ref. 17 and data not shown). Adiponectin did not alter the expression and/or function of lymphocyte integrins (α 4 β 1 and α L β 2 ), the chemokine receptor CXCR3, or the PGD 2 receptor DP-2 on PBLs ( Supplementary Fig. 1d ). Moreover, chemotactic responses to CXCL12, CXCL10, or PGD 2 were unaltered by adiponectin ( Supplementary Fig. 1e ). Fewer than 5% of T cells (CD3 + cells), including memory and naïve subsets, expressed adiponectin receptors (adipoR1 and adipoR2) ( Fig. 1d–f ). However, circulating B cells (CD19 + cells) expressed both receptors abundantly ( Fig. 1d–f ). We also found that endothelial cells expressed both adiponectin receptors ( Supplementary Fig. 2 ). However, adiponectin did not directly target endothelial cells in our system, as treated PBLs are washed to remove any adiponectin before their addition to the endothelial cells. To ensure that any residual carryover of this agent did not influence lymphocyte recruitment, we verified that adiponectin did not modulate the gene expression of adhesion molecules and chemokines in TNF-α– and IFN-γ–stimulated endothelial cells ( Supplementary Table 1 ). As T cells lack adiponectin receptors but show altered patterns of migration in response to adiponectin, we postulated that another lymphocyte population mediated the inhibition of T cell trafficking. Upon depleting B cells from the PBL mixture, T cells were released from the inhibitory effects of adiponectin ( Fig. 1g ). Adding back purified B cells to isolated T cells could reconstitute the adiponectin-dependent inhibition of T cell migration, and using supernatants from adiponectin-stimulated B cells was as effective as adding", "role": "user" }, { "content": "Researchers from the University of Birmingham have identified an important new way in which our immune systems are regulated, and hope that understanding it will help tackle the debilitating effects of type 1 diabetes, rheumatoid arthritis and other serious diseases. The team discovered a novel pathway that regulates the movement of pathogenic immune cells from the blood into tissue during an inflammatory response. A healthy, efficient immune system ordinarily works to damp down inflammation and carefully regulate the magnitude of the response to infection and disease. In diseases such as diabetes and arthritis, as well as when we age, our immune system becomes less stringently regulated and this can lead to an exaggerated inflammatory response - allowing inappropriate access of immune cells to vulnerable tissues. The new study shows that beneficial effects of the new pathway are lost in these diseases, as well as during normal ageing. The study, published in Nature Medicine, details how a key molecule regulates this aspect of our immune response. Importantly, the team were then able to show how the addition of this molecule to immune cells from patients with diabetes and arthritis could regain control of the movement of their immune cells, thereby reversing the pathogenic changes seen in these diseases. Professor Ed Rainger, from the University of Birmingham, explained, \"Our immune system becomes progressively less effective over the years and this can become harmful leading to disease. Being able to understand the link between ageing and pathology will help us to reduce the risk of ill health associated with increasing age.\" \"Our discovery of this new pathway is very exciting. Not only does it reveal new ways in which our bodies control inflammation, it also indicates that we may be able design new drugs to reverse the disease and age specific loss of this pathway.\" \"The fact that the new pathway is relevant to both diabetes and rheumatoid arthritis, which are quite different diseases, implies a broad applicability to many chronic inflammatory and autoimmune diseases. This is an area of research we are keen to follow, and will be working with doctors from other specialities to determine whether this is the case and whether new therapies might be more broadly applicable\" The global healthcare landscape is undergoing a significant shift, with some populations experiencing a sharp increase in life expectancy. However, an ageing population comes with a rise in the prevalence of debilitating diseases, which in turn passes on a significant burden to the patients, their families and their health service providers. Professor Rainger added, 'The link between the decline of this pathway and normal ageing is also very interesting, as this is a natural process. It means that patients with diseases such as rheumatoid arthritis may have accelerated decline of this pathway so that individuals as young as 20 have the immune function of 70 year olds. If we can identify patients at risk of developing this disease we may be able to artificially restore some vigour to their immune systems and reduce the burden of disease for the individual patient as well as their families and the NHS.'' The next step is to use the findings in clinical studies that will investigate the viability of treatments and therapies targeting this pathway. Professor Peter Weissberg, Medical Director at the British Heart Foundation, said: \"This is a superb piece of research that appears to have identified a new way to regulate chronic inflammation. It helps to explain why autoimmune diseases like rheumatoid arthritis become more common with age.\" \"It remains to be seen whether these findings will have any direct relevance to cardiovascular disease. However, coronary heart disease tends to be more common in people with chronic inflammatory conditions such as rheumatoid arthritis, so if this research leads to better treatments for these conditions, it might be expected that this will lead to fewer heart attacks in these patients.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract During an inflammatory response, lymphocyte recruitment into tissue must be tightly controlled because dysregulated trafficking contributes to the pathogenesis of chronic disease. Here we show that during inflammation and in response to adiponectin, B cells tonically inhibit T cell trafficking by secreting a peptide (PEPITEM) proteolytically derived from 14.3.3 zeta delta (14.3.3.ζδ) protein. PEPITEM binds cadherin-15 on endothelial cells, promoting synthesis and release of sphingosine-1 phosphate, which inhibits trafficking of T cells without affecting recruitment of other leukocytes. Expression of adiponectin receptors on B cells and adiponectin-induced PEPITEM secretion wanes with age, implying immune senescence of the pathway. Additionally, these changes are evident in individuals with type 1 diabetes or rheumatoid arthritis, and circulating PEPITEM in patient serum is reduced compared to that of healthy age-matched donors. In both diseases, tonic inhibition of T cell trafficking across inflamed endothelium is lost. Control of patient T cell trafficking is re-established by treatment with exogenous PEPITEM. Moreover, in animal models of peritonitis, hepatic ischemia-reperfusion injury, Salmonella infection, uveitis and Sjögren's syndrome, PEPITEM reduced T cell recruitment into inflamed tissues. Main In vertebrates, a lymphocyte (T cell and B cell)-based adaptive immune system has evolved to augment innate immunity. Adaptive responses require lymphocyte trafficking between the bone marrow, lymphoid organs and peripheral tissues using blood as a vehicle for dispersal 1 . Our knowledge of the trafficking process is still incomplete. However, unregulated T cell recruitment during inflammation is pathogenic and contributes to chronic disease 2 , 3 . Here we reveal the function of a homeostatic pathway, which imposes a tonic inhibition on T cell trafficking during inflammation. Identification of this pathway arose through studies on the circulating adipokine adiponectin. Adiponectin affects both metabolic and immune pathways 4 , 5 , 6 , 7 , including the recruitment of leukocytes during an inflammatory response 6 , and plasma concentrations of adiponectin are low in a number of chronic diseases, including diabetes 4 . We tested the hypothesis that adiponectin might regulate lymphocyte trafficking and that changes in adiponectin function might contribute to pathogenic lymphocyte recruitment in chronic inflammatory and autoimmune diseases. We started by observing lymphocyte trafficking in vitro across isolated human endothelial cells, which are the gatekeepers to the tissues for circulating leukocytes. To enter inflamed tissue, T cells migrate through endothelial cells lining the post-capillary venules 8 , 9 , and this has been modeled both in vitro and in vivo 10 , 11 , 12 , 13 , 14 , 15 . Thus, memory T cells moving rapidly in the flowing blood are preferentially recruited by endothelial cells activated by cytokines (for example, tumor necrosis factor α (TNF-α) and/or interferon γ (IFN-γ)). Tethering from flow and rolling adhesion are supported by E-selectin and vascular cell adhesion molecule 1 (VCAM-1) 16 , whereas integrin-mediated stable adhesion and migration are supported by sequential signals from chemokines and prostaglandin D 2 (PGD 2 ; refs. 17 , 18 , 19 , 20 , 21 , 22 , 23 ). Here we show that in the presence of adiponectin, B cells recruited to the endothelial cell surface during inflammation reduce the efficiency of memory T cell migration by imposing a tonic inhibition on this process. Thus, we believe that the adaptive immune system has evolved a robust strategy for regulating inappropriate or excessive activity, thereby limiting the possibility of establishing a chronic inflammatory response that might contribute to disease. Results Adiponectin regulates T cell migration In vitro, adiponectin dose-dependently inhibited the TNF-α– and IFN-γ–induced trans-endothelial migration of human peripheral blood lymphocytes (PBLs) with a half-maximal effective concentration (EC 50 ) of 2.6 nM (0.94 μg/ml) ( Fig. 1a and Supplementary Fig. 1a ), with the most marked effects seen at physiological circulating levels observed in healthy humans (5−15 μg/ml). Although migration was reduced compared to the untreated control so that more cells were firmly adherent to the apical surface of the endothelium ( Supplementary Fig. 1b ), the number of lymphocytes recruited was unaffected by adiponectin ( Supplementary Fig. 1c ). The effects of adiponectin on PBL migration were seen in both a static system ( Fig. 1a ) and under conditions of flow ( Fig. 1b ), and they were evident on human umbilical vein endothelial cells (HUVECs) and human dermal microvascular endothelial cells (HDMECs) ( Fig. 1c ). The majority of transmigrating PBLs were CD3 + CD45RO + memory T cells, as expected for this model (ref. 17 and data not shown). Adiponectin did not alter the expression and/or function of lymphocyte integrins (α 4 β 1 and α L β 2 ), the chemokine receptor CXCR3, or the PGD 2 receptor DP-2 on PBLs ( Supplementary Fig. 1d ). Moreover, chemotactic responses to CXCL12, CXCL10, or PGD 2 were unaltered by adiponectin ( Supplementary Fig. 1e ). Fewer than 5% of T cells (CD3 + cells), including memory and naïve subsets, expressed adiponectin receptors (adipoR1 and adipoR2) ( Fig. 1d–f ). However, circulating B cells (CD19 + cells) expressed both receptors abundantly ( Fig. 1d–f ). We also found that endothelial cells expressed both adiponectin receptors ( Supplementary Fig. 2 ). However, adiponectin did not directly target endothelial cells in our system, as treated PBLs are washed to remove any adiponectin before their addition to the endothelial cells. To ensure that any residual carryover of this agent did not influence lymphocyte recruitment, we verified that adiponectin did not modulate the gene expression of adhesion molecules and chemokines in TNF-α– and IFN-γ–stimulated endothelial cells ( Supplementary Table 1 ). As T cells lack adiponectin receptors but show altered patterns of migration in response to adiponectin, we postulated that another lymphocyte population mediated the inhibition of T cell trafficking. Upon depleting B cells from the PBL mixture, T cells were released from the inhibitory effects of adiponectin ( Fig. 1g ). Adding back purified B cells to isolated T cells could reconstitute the adiponectin-dependent inhibition of T cell migration, and using supernatants from adiponectin-stimulated B cells was as effective as adding<|im_end|> <|im_start|>assistant Researchers from the University of Birmingham have identified an important new way in which our immune systems are regulated, and hope that understanding it will help tackle the debilitating effects of type 1 diabetes, rheumatoid arthritis and other serious diseases. The team discovered a novel pathway that regulates the movement of pathogenic immune cells from the blood into tissue during an inflammatory response. A healthy, efficient immune system ordinarily works to damp down inflammation and carefully regulate the magnitude of the response to infection and disease. In diseases such as diabetes and arthritis, as well as when we age, our immune system becomes less stringently regulated and this can lead to an exaggerated inflammatory response - allowing inappropriate access of immune cells to vulnerable tissues. The new study shows that beneficial effects of the new pathway are lost in these diseases, as well as during normal ageing. The study, published in Nature Medicine, details how a key molecule regulates this aspect of our immune response. Importantly, the team were then able to show how the addition of this molecule to immune cells from patients with diabetes and arthritis could regain control of the movement of their immune cells, thereby reversing the pathogenic changes seen in these diseases. Professor Ed Rainger, from the University of Birmingham, explained, "Our immune system becomes progressively less effective over the years and this can become harmful leading to disease. Being able to understand the link between ageing and pathology will help us to reduce the risk of ill health associated with increasing age." "Our discovery of this new pathway is very exciting. Not only does it reveal new ways in which our bodies control inflammation, it also indicates that we may be able design new drugs to reverse the disease and age specific loss of this pathway." "The fact that the new pathway is relevant to both diabetes and rheumatoid arthritis, which are quite different diseases, implies a broad applicability to many chronic inflammatory and autoimmune diseases. This is an area of research we are keen to follow, and will be working with doctors from other specialities to determine whether this is the case and whether new therapies might be more broadly applicable" The global healthcare landscape is undergoing a significant shift, with some populations experiencing a sharp increase in life expectancy. However, an ageing population comes with a rise in the prevalence of debilitating diseases, which in turn passes on a significant burden to the patients, their families and their health service providers. Professor Rainger added, 'The link between the decline of this pathway and normal ageing is also very interesting, as this is a natural process. It means that patients with diseases such as rheumatoid arthritis may have accelerated decline of this pathway so that individuals as young as 20 have the immune function of 70 year olds. If we can identify patients at risk of developing this disease we may be able to artificially restore some vigour to their immune systems and reduce the burden of disease for the individual patient as well as their families and the NHS.'' The next step is to use the findings in clinical studies that will investigate the viability of treatments and therapies targeting this pathway. Professor Peter Weissberg, Medical Director at the British Heart Foundation, said: "This is a superb piece of research that appears to have identified a new way to regulate chronic inflammation. It helps to explain why autoimmune diseases like rheumatoid arthritis become more common with age." "It remains to be seen whether these findings will have any direct relevance to cardiovascular disease. However, coronary heart disease tends to be more common in people with chronic inflammatory conditions such as rheumatoid arthritis, so if this research leads to better treatments for these conditions, it might be expected that this will lead to fewer heart attacks in these patients." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Isolation of metastatic circulating tumor cells (CTCs) from cancer patients is of high value for disease monitoring and molecular characterization. Despite the development of many new CTC isolation platforms in the last decade, their isolation and detection has remained a challenge due to the lack of specific and sensitive markers. In this feasibility study, we present a method for CTC isolation based on the specific binding of the malaria rVAR2 protein to oncofetal chondroitin sulfate (ofCS). We show that rVAR2 efficiently captures CTCs from hepatic, lung, pancreatic, and prostate carcinoma patients with minimal contamination of peripheral blood mononuclear cells. Expression of ofCS is present on epithelial and mesenchymal cancer cells and is equally preserved during epithelial–mesenchymal transition of cancer cells. In 25 stage I–IV prostate cancer patient samples, CTC enumeration significantly correlates with disease stage. Lastly, rVAR2 targets a larger and more diverse population of CTCs compared to anti-EpCAM strategies. Introduction Metastasis, the process in which malignant cells spread from the primary tumor to distant sites, is of key importance in cancer. Up to 90% of cancer-related deaths are related to the metastatic spread of cancer cells 1 , 2 , 3 . This complex process is vital to cancer progression and involves intravasation of cancer cells into the blood stream 2 . The cancer cells traveling in the blood are called circulating tumor cells (CTCs) 4 , 5 , and a subset of these has increased metastatic capacity 6 . CTCs have spurred increasing clinical interest since their levels in the blood were shown to be predictive of overall outcome for patients with metastatic colorectal, breast, prostate, and lung carcinomas 7 , 8 , 9 , 10 . Furthermore, the detection and enumeration of CTCs in patient blood samples, also termed liquid biopsies, provide a non-invasive tool for real-time monitoring of treatment response and estimating risk for metastatic relapse 11 . Besides enumeration, isolation of viable CTCs from blood enables individual and longitudinal molecular characterization and downstream experimental analysis, irrespective of the availability of tumor tissue biopsies. The ability to perform cellular analysis of bulk CTCs, but also contained subpopulations of cells with enhanced metastatic capacity, may represent a major advantage over DNA-based approaches, such as the detection of circulating tumor DNA 12 . Several CTC detection and isolation platforms have been described 13 . Many recently developed systems are based on distinct biophysical properties of CTCs such as their theoretically larger size compared to peripheral blood mononuclear cells (PBMCs). However, studies have shown a large variation in CTC size and a considerable size overlap between CTCs and PBMCs 14 . Therefore, while these methods may provide viable CTCs, separation purely based on size could be too restrictive and introduce a considerable bias by missing important metastatic cells for the downstream analysis. Other systems for CTC isolation use antibodies to target epithelial markers, such as the epithelial cell adhesion molecule (EpCAM) cell surface protein. One of these is the CellSearch® CTC platform, which relies on detecting CTCs using anti-EpCAM antibody-coated magnetic ferrofluid nanoparticles followed by bulk magnetic enrichment 4 . In this platform, enriched cancer cells are identified as CTCs by their cytokeratin (CK) positivity using a fluorescent-labeled antibody, and potentially contaminating PBMCs are identified by a CD45 counterstain. This system represents the current gold standard for CTC enumeration and is approved by the US Food and Drug Administration (FDA) for monitoring patients with metastatic breast, colorectal, and prostate cancers 15 . Given the heterogeneous nature of CTCs, EpCAM-based capture approaches are inherently biased toward capturing CTCs with well-preserved epithelial traits and are rarely efficient in epithelial cancers with downregulated EpCAM expression, e.g., during epithelial–mesenchymal transition (EMT), or in cancers of mesenchymal origin (i.e., sarcomas) 16 , 17 , 18 . In an attempt to include these cells, many CTC isolation methods combine several antibodies in an antibody cocktail and thereby target a larger population of CTCs 19 , 20 , 21 . Such cocktails are, however, often only applicable to specific tumor types and prone to capture more non-cancer cells including white blood cells 22 , 23 . A similar contamination issue arises when the inverse approach is taken and CTCs are enriched by depletion of CD45-positive white blood cells, most likely due to a considerable fraction of leukocytes with low-level expression of surface marker 14 , 24 , 25 . Considering the limitations of the above-described methods, it is clear that the field would benefit greatly from a specific and universally expressed cancer marker for capturing and detecting CTCs. The isolation of CTCs requires a highly specific target, which is completely absent from normal cells. In line with this, we have recently described a uniquely modified form of chondroitin sulfate (CS), termed oncofetal chondroitin sulfate (ofCS), which is expressed by placental cells and cancer cells of both epithelial and mesenchymal origin 26 . CS belongs to the family of glycosaminoglycans (GAG), which are long, linear carbohydrates made up of repeated disaccharide units that can be differentially modified by disaccharide sulfations. CS can be attached to different proteins called chondroitin sulfate proteoglycans (CSPGs) on the cell membrane or in the extracellular matrix. We have shown that ofCS can be attached to more than 30 different proteoglycans 26 , 27 , 28 , 29 , 30 . A single cancer cell may display different combinations of these ofCS proteoglycans and thereby ofCS serves as a more robust cancer biomarker as it is not restricted to the expression of a single protein. CSPGs are often overexpressed in primary as well as metastatic tumors, which, in combination with the expression of the specific ofCS structure across a diverse array of tumor types as well as its strict cancer specificity, makes them an appealing target for the universal and efficient isolation and detection of CTCs 31 . We recently made the exciting discovery that the unique ofCS can be detected by the VAR2CSA malaria protein 26 . In placental malaria, parasite-infected erythrocytes adhere to ofCS in the placenta using the malaria", "role": "user" }, { "content": "In a spectacular new study, researchers from the University of Copenhagen have discovered a method of diagnosing a broad range of cancers at their early stages by utilising a particular malaria protein that sticks to cancer cells in blood samples. The researchers hope that this method can be used in cancer screenings in the near future. Each year, cancer kills approximately 9 million people worldwide, and early diagnosis is crucial to efficient treatment and survival. Now, researchers from the Faculty of Health and Medical Sciences at the University of Copenhagen have come up with a new method of diagnosing cancer in its early stages in humans by way of a malaria protein called VAR2CSA, which sticks to cancer cells. All the scientists need to determine whether or not a person has cancer is a blood sample. \"We have developed a method in which we take a blood sample, and with great sensitivity and specificity, we're able to retrieve the individual cancer cells from the blood. We catch the cancer cells in greater numbers than existing methods, which offers the opportunity to detect cancer earlier and thus improve outcome. You can use this method to diagnose broadly, as it's not dependent on cancer type. We have already detected various types of cancer cells in blood samples. And if there is a cancer cell in your blood, you have a tumour somewhere in your body,\" says Professor Ali Salanti from the Department of Immunology and Microbiology and joint author of the study, which has just been published in the scientific journal, Nature Communications. Today, there are several ways of detecting cancer cells in blood. Most of them are based on a particular marker, which is found on the surface of tumour cells. However, not all tumour cells display this marker, which renders these methods unable to detect tumour cells spread to other organs such the liver, lung and bones, as opposed to the method based on the malaria protein. A few years ago, Ali Salanti and his fellow researchers discovered a new method of treating cancer with the protein VAR2CSA, which is produced by malaria parasites. And these discoveries have formed the basis of the research group's new method of diagnosis. Among other things, they have shown that the malaria protein sticks to a specific sugar molecule, which is found in more than 95 percent of all types of cancer cells. In other words, this new method of diagnosis can be used to detect practically all types of cancer. Circulating tumour cells A cancerous tumour consists of several different cancer cell types, some of which spread by wandering through the tissue and into the blood. These cancer cells in the blood are called circulating tumour cells, and they can develop into metastases, which cause up to 90 percent of all cancer-related deaths. If cancer originating in the lungs spreads to the brain, it is called brain metastasis. The new method detects the circulating tumour cells in a blood sample by using the malaria protein. During the development of this new method, the researchers took 10 cancer cells and added them to five millilitres of blood, and were subsequently able to retrieve nine out of 10 cancer cells from the blood sample. \"We count the number of cancer cells, and based on that, we're able to make a prognosis. You can, for example, decide to change a given treatment if the number of circulating tumour cells does not change during the treatment the patient is currently undergoing. This method also enables us to retrieve live cancer cells, which we can then grow and use for testing treatments in order to determine which type of treatment the patient responds to,\" says Postdoc Mette Ørskov Agerbæk, Department of Immunology and Microbiology and joint author of the study. Future screening programme The researchers are following up on their results in a large clinical study in which many more patients with pancreatic cancer have been tested using this method. \"We found strikingly high numbers of circulating tumour cells in every single patient with pancreatic cancer, but none in the control group,\" says Professor Christopher Heeschen, School of Medical Sciences, UNSW, Sydney, Australia, and joint author of the study. The researchers envision using the method to screen people at high risk of developing cancer in the future. However, they also expect that this method can be used as a biomarker indicating whether a patient with mostly vague symptoms actually has cancer or not. This will enable doctors to determine the stage of the disease. \"Today, it's difficult to determine which stage cancer is at. Our method has enabled us to detect cancer at stages one, two, three and four. Based on the number of circulating tumour cells we find in someone's blood, we'll be able to determine whether it's a relatively aggressive cancer or not so then to adjust the treatment accordingly,\" explains Professor Ali Salanti who adds that a much larger clinical study is needed before firm correlations to tumour staging can be made. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Isolation of metastatic circulating tumor cells (CTCs) from cancer patients is of high value for disease monitoring and molecular characterization. Despite the development of many new CTC isolation platforms in the last decade, their isolation and detection has remained a challenge due to the lack of specific and sensitive markers. In this feasibility study, we present a method for CTC isolation based on the specific binding of the malaria rVAR2 protein to oncofetal chondroitin sulfate (ofCS). We show that rVAR2 efficiently captures CTCs from hepatic, lung, pancreatic, and prostate carcinoma patients with minimal contamination of peripheral blood mononuclear cells. Expression of ofCS is present on epithelial and mesenchymal cancer cells and is equally preserved during epithelial–mesenchymal transition of cancer cells. In 25 stage I–IV prostate cancer patient samples, CTC enumeration significantly correlates with disease stage. Lastly, rVAR2 targets a larger and more diverse population of CTCs compared to anti-EpCAM strategies. Introduction Metastasis, the process in which malignant cells spread from the primary tumor to distant sites, is of key importance in cancer. Up to 90% of cancer-related deaths are related to the metastatic spread of cancer cells 1 , 2 , 3 . This complex process is vital to cancer progression and involves intravasation of cancer cells into the blood stream 2 . The cancer cells traveling in the blood are called circulating tumor cells (CTCs) 4 , 5 , and a subset of these has increased metastatic capacity 6 . CTCs have spurred increasing clinical interest since their levels in the blood were shown to be predictive of overall outcome for patients with metastatic colorectal, breast, prostate, and lung carcinomas 7 , 8 , 9 , 10 . Furthermore, the detection and enumeration of CTCs in patient blood samples, also termed liquid biopsies, provide a non-invasive tool for real-time monitoring of treatment response and estimating risk for metastatic relapse 11 . Besides enumeration, isolation of viable CTCs from blood enables individual and longitudinal molecular characterization and downstream experimental analysis, irrespective of the availability of tumor tissue biopsies. The ability to perform cellular analysis of bulk CTCs, but also contained subpopulations of cells with enhanced metastatic capacity, may represent a major advantage over DNA-based approaches, such as the detection of circulating tumor DNA 12 . Several CTC detection and isolation platforms have been described 13 . Many recently developed systems are based on distinct biophysical properties of CTCs such as their theoretically larger size compared to peripheral blood mononuclear cells (PBMCs). However, studies have shown a large variation in CTC size and a considerable size overlap between CTCs and PBMCs 14 . Therefore, while these methods may provide viable CTCs, separation purely based on size could be too restrictive and introduce a considerable bias by missing important metastatic cells for the downstream analysis. Other systems for CTC isolation use antibodies to target epithelial markers, such as the epithelial cell adhesion molecule (EpCAM) cell surface protein. One of these is the CellSearch® CTC platform, which relies on detecting CTCs using anti-EpCAM antibody-coated magnetic ferrofluid nanoparticles followed by bulk magnetic enrichment 4 . In this platform, enriched cancer cells are identified as CTCs by their cytokeratin (CK) positivity using a fluorescent-labeled antibody, and potentially contaminating PBMCs are identified by a CD45 counterstain. This system represents the current gold standard for CTC enumeration and is approved by the US Food and Drug Administration (FDA) for monitoring patients with metastatic breast, colorectal, and prostate cancers 15 . Given the heterogeneous nature of CTCs, EpCAM-based capture approaches are inherently biased toward capturing CTCs with well-preserved epithelial traits and are rarely efficient in epithelial cancers with downregulated EpCAM expression, e.g., during epithelial–mesenchymal transition (EMT), or in cancers of mesenchymal origin (i.e., sarcomas) 16 , 17 , 18 . In an attempt to include these cells, many CTC isolation methods combine several antibodies in an antibody cocktail and thereby target a larger population of CTCs 19 , 20 , 21 . Such cocktails are, however, often only applicable to specific tumor types and prone to capture more non-cancer cells including white blood cells 22 , 23 . A similar contamination issue arises when the inverse approach is taken and CTCs are enriched by depletion of CD45-positive white blood cells, most likely due to a considerable fraction of leukocytes with low-level expression of surface marker 14 , 24 , 25 . Considering the limitations of the above-described methods, it is clear that the field would benefit greatly from a specific and universally expressed cancer marker for capturing and detecting CTCs. The isolation of CTCs requires a highly specific target, which is completely absent from normal cells. In line with this, we have recently described a uniquely modified form of chondroitin sulfate (CS), termed oncofetal chondroitin sulfate (ofCS), which is expressed by placental cells and cancer cells of both epithelial and mesenchymal origin 26 . CS belongs to the family of glycosaminoglycans (GAG), which are long, linear carbohydrates made up of repeated disaccharide units that can be differentially modified by disaccharide sulfations. CS can be attached to different proteins called chondroitin sulfate proteoglycans (CSPGs) on the cell membrane or in the extracellular matrix. We have shown that ofCS can be attached to more than 30 different proteoglycans 26 , 27 , 28 , 29 , 30 . A single cancer cell may display different combinations of these ofCS proteoglycans and thereby ofCS serves as a more robust cancer biomarker as it is not restricted to the expression of a single protein. CSPGs are often overexpressed in primary as well as metastatic tumors, which, in combination with the expression of the specific ofCS structure across a diverse array of tumor types as well as its strict cancer specificity, makes them an appealing target for the universal and efficient isolation and detection of CTCs 31 . We recently made the exciting discovery that the unique ofCS can be detected by the VAR2CSA malaria protein 26 . In placental malaria, parasite-infected erythrocytes adhere to ofCS in the placenta using the malaria<|im_end|> <|im_start|>assistant In a spectacular new study, researchers from the University of Copenhagen have discovered a method of diagnosing a broad range of cancers at their early stages by utilising a particular malaria protein that sticks to cancer cells in blood samples. The researchers hope that this method can be used in cancer screenings in the near future. Each year, cancer kills approximately 9 million people worldwide, and early diagnosis is crucial to efficient treatment and survival. Now, researchers from the Faculty of Health and Medical Sciences at the University of Copenhagen have come up with a new method of diagnosing cancer in its early stages in humans by way of a malaria protein called VAR2CSA, which sticks to cancer cells. All the scientists need to determine whether or not a person has cancer is a blood sample. "We have developed a method in which we take a blood sample, and with great sensitivity and specificity, we're able to retrieve the individual cancer cells from the blood. We catch the cancer cells in greater numbers than existing methods, which offers the opportunity to detect cancer earlier and thus improve outcome. You can use this method to diagnose broadly, as it's not dependent on cancer type. We have already detected various types of cancer cells in blood samples. And if there is a cancer cell in your blood, you have a tumour somewhere in your body," says Professor Ali Salanti from the Department of Immunology and Microbiology and joint author of the study, which has just been published in the scientific journal, Nature Communications. Today, there are several ways of detecting cancer cells in blood. Most of them are based on a particular marker, which is found on the surface of tumour cells. However, not all tumour cells display this marker, which renders these methods unable to detect tumour cells spread to other organs such the liver, lung and bones, as opposed to the method based on the malaria protein. A few years ago, Ali Salanti and his fellow researchers discovered a new method of treating cancer with the protein VAR2CSA, which is produced by malaria parasites. And these discoveries have formed the basis of the research group's new method of diagnosis. Among other things, they have shown that the malaria protein sticks to a specific sugar molecule, which is found in more than 95 percent of all types of cancer cells. In other words, this new method of diagnosis can be used to detect practically all types of cancer. Circulating tumour cells A cancerous tumour consists of several different cancer cell types, some of which spread by wandering through the tissue and into the blood. These cancer cells in the blood are called circulating tumour cells, and they can develop into metastases, which cause up to 90 percent of all cancer-related deaths. If cancer originating in the lungs spreads to the brain, it is called brain metastasis. The new method detects the circulating tumour cells in a blood sample by using the malaria protein. During the development of this new method, the researchers took 10 cancer cells and added them to five millilitres of blood, and were subsequently able to retrieve nine out of 10 cancer cells from the blood sample. "We count the number of cancer cells, and based on that, we're able to make a prognosis. You can, for example, decide to change a given treatment if the number of circulating tumour cells does not change during the treatment the patient is currently undergoing. This method also enables us to retrieve live cancer cells, which we can then grow and use for testing treatments in order to determine which type of treatment the patient responds to," says Postdoc Mette Ørskov Agerbæk, Department of Immunology and Microbiology and joint author of the study. Future screening programme The researchers are following up on their results in a large clinical study in which many more patients with pancreatic cancer have been tested using this method. "We found strikingly high numbers of circulating tumour cells in every single patient with pancreatic cancer, but none in the control group," says Professor Christopher Heeschen, School of Medical Sciences, UNSW, Sydney, Australia, and joint author of the study. The researchers envision using the method to screen people at high risk of developing cancer in the future. However, they also expect that this method can be used as a biomarker indicating whether a patient with mostly vague symptoms actually has cancer or not. This will enable doctors to determine the stage of the disease. "Today, it's difficult to determine which stage cancer is at. Our method has enabled us to detect cancer at stages one, two, three and four. Based on the number of circulating tumour cells we find in someone's blood, we'll be able to determine whether it's a relatively aggressive cancer or not so then to adjust the treatment accordingly," explains Professor Ali Salanti who adds that a much larger clinical study is needed before firm correlations to tumour staging can be made. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Understanding brain function requires technologies that can control the activity of large populations of neurons with high fidelity in space and time. We developed a multiphoton holographic approach to activate or suppress the activity of ensembles of cortical neurons with cellular resolution and sub-millisecond precision. Since existing opsins were inadequate, we engineered new soma-targeted (ST) optogenetic tools, ST-ChroME and IRES-ST-eGtACR1, optimized for multiphoton activation and suppression. Employing a three-dimensional all-optical read–write interface, we demonstrate the ability to simultaneously photostimulate up to 50 neurons distributed in three dimensions in a 550 × 550 × 100-µm 3 volume of brain tissue. This approach allows the synthesis and editing of complex neural activity patterns needed to gain insight into the principles of neural codes. Main Neural circuits can encode information in the rate 1 , timing 2 , number 3 , and synchrony of action potentials 4 , as well as in the identity of active neurons 5 . Yet the technical inability to create or edit custom patterns of spatiotemporal neural activity is a key impediment to understanding the logic and syntax of the neural code 6 . Experimental approaches that allow high-fidelity temporal control of neural activity 7 from specific groups of neurons would make it possible to systematically vary spike rate, timing, synchrony, and number and would permit definitive tests of how neural ensembles encode information. Similarly, deleting action potentials from functionally defined neurons will allow experimenters to probe the elements of endogenous activity patterns that contribute to neural computations and behaviors with unprecedented precision. Optogenetics offers the basis for such a technology, but many neural computations rely on genetically similar yet functionally distinct neurons that are physically intermixed 8 , 9 , and are thus beyond the reach of conventional approaches. Two-photon (2P) optogenetics 10 , 11 , 12 , 13 allows experimenters to stimulate neurons based on their precise spatial location as well as their genetic identity. Combined with 2P calcium imaging, this allows activation of specific neurons on the basis of any desired feature 14 , 15 , 16 , 17 , 18 . However, in vivo all-optical approaches in mice have suffered from low temporal precision (>10 ms jitter) 14 , 15 , 16 , or could only photostimulate several neurons simultaneously 15 , 19 and thus could not create precise neural activity patterns. Furthermore, until recently, in vivo multiphoton suppression of neural activity was not previously possible 20 , critically limiting the ability of experimenters to assess the necessity of spikes originating from specific, functionally defined neurons. Several optical methods can stimulate neurons using 2P excitation, although all have limitations. A standard 2P optogenetic technique is to scan a small laser spot over neurons that express variants of slow red-shifted opsins like C1V1 T/T 10 , 13 . While this approach effectively drives spiking, the slow kinetics of the scanning laser and the opsin preclude precise control of the specific sequence of neural activity, resulting in uncertain trial-to-trial reproducibility 12 , 14 , 16 . In contrast, scanless multiphoton stimulation using computer-generated holography (CGH) and temporal focusing allows simultaneous illumination of the entire somatic membrane and can provide higher temporal fidelity when used with a fast opsin 19 , 21 , 22 , 23 , 24 , 25 . However, existing excitatory opsins are too weak or too slow to drive precise neural activity patterns with scanless 2P optogenetics in vivo 15 , 20 . Additionally, only recent innovations have allowed scanless holographic optogenetics to function with high axial resolution in three dimensions (3D) 26 , 27 . Therefore, to synthesize and edit custom distributed patterns of neural ensemble activity, we engineered powerful new opsins optimized for multiphoton optogenetics. We developed ChroME, an ultrafast and highly potent opsin with 3–5× larger photocurrents than opsins commonly used for multiphoton optogenetics 12 , 13 , 28 . This allows high-fidelity sub-millisecond control of pyramidal neuron spiking. In vivo, we activated ensembles of neurons expressing ST-ChroME using 3D scanless holographic optogenetics with temporal focusing (3D-SHOT) 27 , synthesizing precise sequences of neural activity with cellular resolution and millisecond precision. By combining 3D-SHOT with volumetric 2P calcium imaging, we obtained all-optical control of distributed neural ensembles, simultaneously stimulating up to 50 neurons with high temporal precision and cellular resolution. Furthermore, to achieve all-optical suppression, we improved and employed the extremely potent inhibitory anion opsin, GtACR1 29 , which exhibits 80-fold increases in photocurrent over previously employed pump-based opsins for multiphoton optogenetic silencing 13 . Critically, we identified a strategy to prevent the cellular toxicity we observed when the transgene was expressed conventionally. Using this new construct, IRES-ST-eGtACR1, with 3D-SHOT, we provide electrophysiological and all-optical demonstration of high fidelity silencing of neural activity from identified neurons in vivo. Together, these data represent a novel technological approach for precise multimodal control of neural ensemble activity with high fidelity. Results Requirements for controlling neural activity with millisecond precision To control neural activity with sub-millisecond precision, we sought an opsin and a 2P stimulation approach capable of generating large currents with rapid kinetics 30 . Injecting current into patched neurons (layer (L) 2/3 pyramidal cells, used throughout this study unless otherwise noted) in brain slices, we could reliably evoke precise spike trains with brief, high-amplitude current steps. In contrast, long current injections, analogous to some spiral scanning approaches 14 , 16 , resulted in variable spike number and timing, but required lower current amplitudes (Fig. 1a,b and Supplementary Fig. 1 ). Fig. 1: ST-ChroME allows precise high-fidelity 2P activation. a , Overlay of 25 trials from a representative L2/3 pyramidal neuron showing the V m response to 5-ms current pulses or sustained current injection ( I inj ) near the neuron’s rheobase. b , Current needed to induce action potentials as a function of stimulus duration ( n = 8 L2/3 pyramidal neurons). c , Left: grand average photocurrent traces from neurons expressing ST-C1V1 T/T (black, n = 19), ST-ChrimsonR (red, n = 11), ST-Chronos (green, n = 25), or ST-ChroME (magenta,", "role": "user" }, { "content": "What if we could edit the sensations we feel; paste in our brain pictures that we never saw, cut out unwanted pain or insert non-existent scents into memory? University of California, Berkeley neuroscientists are building the equipment to do just that, using holographic projection into the brain to activate or suppress dozens and ultimately thousands of neurons at once, hundreds of times each second, copying real patterns of brain activity to fool the brain into thinking it has felt, seen or sensed something. The goal is to read neural activity constantly and decide, based on the activity, which sets of neurons to activate to simulate the pattern and rhythm of an actual brain response, so as to replace lost sensations after peripheral nerve damage, for example, or control a prosthetic limb. \"This has great potential for neural prostheses, since it has the precision needed for the brain to interpret the pattern of activation. If you can read and write the language of the brain, you can speak to it in its own language and it can interpret the message much better,\" said Alan Mardinly, a postdoctoral fellow in the UC Berkeley lab of Hillel Adesnik, an assistant professor of molecular and cell biology. \"This is one of the first steps in a long road to develop a technology that could be a virtual brain implant with additional senses or enhanced senses.\" Mardinly is one of three first authors of a paper appearing online April 30 in advance of publication in the journal Nature Neuroscience that describes the holographic brain modulator, which can activate up to 50 neurons at once in a three-dimensional chunk of brain containing several thousand neurons, and repeat that up to 300 times a second with different sets of 50 neurons. \"The ability to talk to the brain has the incredible potential to help compensate for neurological damage caused by degenerative diseases or injury,\" said Ehud Isacoff, a UC Berkeley professor of molecular and cell biology and director of the Helen Wills Neuroscience Institute, who was not involved in the research project. \"By encoding perceptions into the human cortex, you could allow the blind to see or the paralyzed to feel touch.\" Holographic projection Each of the 2,000 to 3,000 neurons in the chunk of brain was outfitted with a protein that, when hit by a flash of light, turns the cell on to create a brief spike of activity. One of the key breakthroughs was finding a way to target each cell individually without hitting all at once. To focus the light onto just the cell body - a target smaller than the width of a human hair - of nearly all cells in a chunk of brain, they turned to computer generated holography, a method of bending and focusing light to form a three-dimensional spatial pattern. The effect is as if a 3D image were floating in space. In this case, the holographic image was projected into a thin layer of brain tissue at the surface of the cortex, about a tenth of a millimeter thick, though a clear window into the brain. \"The major advance is the ability to control neurons precisely in space and time,\" said postdoc Nicolas Pégard, another first author who works both in Adesnik's lab and the lab of co-author Laura Waller, an associate professor of electrical engineering and computer sciences. \"In other words, to shoot the very specific sets of neurons you want to activate and do it at the characteristic scale and the speed at which they normally work.\" The researchers have already tested the prototype in the touch, vision and motor areas of the brains of mice as they walk on a treadmill with their heads immobilized. While they have not noted any behavior changes in the mice when their brain is stimulated, Mardinly said that their brain activity - which is measured in real-time with two-photon imaging of calcium levels in the neurons - shows patterns similar to a response to a sensory stimulus. They're now training mice so they can detect behavior changes after stimulation. Prosthetics and brain implants The area of the brain covered - now a slice one-half millimeter square and one-tenth of a millimeter thick - can be scaled up to read from and write to more neurons in the brain's outer layer, or cortex, Pégard said. And the laser holography setup could eventually be miniaturized to fit in a backpack a person could haul around. Mardinly, Pégard and the other first author, postdoc Ian Oldenburg, constructed the holographic brain modulator by making technological advances in a number of areas. Mardinly and Oldenburg, together with Savitha Sridharan, a research associate in the lab, developed better optogenetic switches to insert into cells to turn them on and off. The switches - light activated ion channels on the cell surface that open briefly when triggered - turn on strongly and then quickly shut off, all in about 3 milliseconds, so they're ready to be re-stimulated up to 50 or more times per second, consistent with normal firing rates in the cortex. Pégard developed the holographic projection system using a liquid crystal screen that acts like a holographic negative to sculpt the light from 40W lasers into the desired 3D pattern. The lasers are pulsed in 300 femtosecond-long bursts every microsecond. He, Mardinly, Oldenburg and their colleagues published a paper last year describing the device, which they call 3D-SHOT, for three-dimensional scanless holographic optogenetics with temporal focusing. \"This is the culmination of technologies that researchers have been working on for a while, but have been impossible to put together,\" Mardinly said. \"We solved numerous technical problems at the same time to bring it all together and finally realize the potential of this technology.\" As they improve their technology, they plan to start capturing real patterns of activity in the cortex in order to learn how to reproduce sensations and perceptions to play back through their holographic system. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Understanding brain function requires technologies that can control the activity of large populations of neurons with high fidelity in space and time. We developed a multiphoton holographic approach to activate or suppress the activity of ensembles of cortical neurons with cellular resolution and sub-millisecond precision. Since existing opsins were inadequate, we engineered new soma-targeted (ST) optogenetic tools, ST-ChroME and IRES-ST-eGtACR1, optimized for multiphoton activation and suppression. Employing a three-dimensional all-optical read–write interface, we demonstrate the ability to simultaneously photostimulate up to 50 neurons distributed in three dimensions in a 550 × 550 × 100-µm 3 volume of brain tissue. This approach allows the synthesis and editing of complex neural activity patterns needed to gain insight into the principles of neural codes. Main Neural circuits can encode information in the rate 1 , timing 2 , number 3 , and synchrony of action potentials 4 , as well as in the identity of active neurons 5 . Yet the technical inability to create or edit custom patterns of spatiotemporal neural activity is a key impediment to understanding the logic and syntax of the neural code 6 . Experimental approaches that allow high-fidelity temporal control of neural activity 7 from specific groups of neurons would make it possible to systematically vary spike rate, timing, synchrony, and number and would permit definitive tests of how neural ensembles encode information. Similarly, deleting action potentials from functionally defined neurons will allow experimenters to probe the elements of endogenous activity patterns that contribute to neural computations and behaviors with unprecedented precision. Optogenetics offers the basis for such a technology, but many neural computations rely on genetically similar yet functionally distinct neurons that are physically intermixed 8 , 9 , and are thus beyond the reach of conventional approaches. Two-photon (2P) optogenetics 10 , 11 , 12 , 13 allows experimenters to stimulate neurons based on their precise spatial location as well as their genetic identity. Combined with 2P calcium imaging, this allows activation of specific neurons on the basis of any desired feature 14 , 15 , 16 , 17 , 18 . However, in vivo all-optical approaches in mice have suffered from low temporal precision (>10 ms jitter) 14 , 15 , 16 , or could only photostimulate several neurons simultaneously 15 , 19 and thus could not create precise neural activity patterns. Furthermore, until recently, in vivo multiphoton suppression of neural activity was not previously possible 20 , critically limiting the ability of experimenters to assess the necessity of spikes originating from specific, functionally defined neurons. Several optical methods can stimulate neurons using 2P excitation, although all have limitations. A standard 2P optogenetic technique is to scan a small laser spot over neurons that express variants of slow red-shifted opsins like C1V1 T/T 10 , 13 . While this approach effectively drives spiking, the slow kinetics of the scanning laser and the opsin preclude precise control of the specific sequence of neural activity, resulting in uncertain trial-to-trial reproducibility 12 , 14 , 16 . In contrast, scanless multiphoton stimulation using computer-generated holography (CGH) and temporal focusing allows simultaneous illumination of the entire somatic membrane and can provide higher temporal fidelity when used with a fast opsin 19 , 21 , 22 , 23 , 24 , 25 . However, existing excitatory opsins are too weak or too slow to drive precise neural activity patterns with scanless 2P optogenetics in vivo 15 , 20 . Additionally, only recent innovations have allowed scanless holographic optogenetics to function with high axial resolution in three dimensions (3D) 26 , 27 . Therefore, to synthesize and edit custom distributed patterns of neural ensemble activity, we engineered powerful new opsins optimized for multiphoton optogenetics. We developed ChroME, an ultrafast and highly potent opsin with 3–5× larger photocurrents than opsins commonly used for multiphoton optogenetics 12 , 13 , 28 . This allows high-fidelity sub-millisecond control of pyramidal neuron spiking. In vivo, we activated ensembles of neurons expressing ST-ChroME using 3D scanless holographic optogenetics with temporal focusing (3D-SHOT) 27 , synthesizing precise sequences of neural activity with cellular resolution and millisecond precision. By combining 3D-SHOT with volumetric 2P calcium imaging, we obtained all-optical control of distributed neural ensembles, simultaneously stimulating up to 50 neurons with high temporal precision and cellular resolution. Furthermore, to achieve all-optical suppression, we improved and employed the extremely potent inhibitory anion opsin, GtACR1 29 , which exhibits 80-fold increases in photocurrent over previously employed pump-based opsins for multiphoton optogenetic silencing 13 . Critically, we identified a strategy to prevent the cellular toxicity we observed when the transgene was expressed conventionally. Using this new construct, IRES-ST-eGtACR1, with 3D-SHOT, we provide electrophysiological and all-optical demonstration of high fidelity silencing of neural activity from identified neurons in vivo. Together, these data represent a novel technological approach for precise multimodal control of neural ensemble activity with high fidelity. Results Requirements for controlling neural activity with millisecond precision To control neural activity with sub-millisecond precision, we sought an opsin and a 2P stimulation approach capable of generating large currents with rapid kinetics 30 . Injecting current into patched neurons (layer (L) 2/3 pyramidal cells, used throughout this study unless otherwise noted) in brain slices, we could reliably evoke precise spike trains with brief, high-amplitude current steps. In contrast, long current injections, analogous to some spiral scanning approaches 14 , 16 , resulted in variable spike number and timing, but required lower current amplitudes (Fig. 1a,b and Supplementary Fig. 1 ). Fig. 1: ST-ChroME allows precise high-fidelity 2P activation. a , Overlay of 25 trials from a representative L2/3 pyramidal neuron showing the V m response to 5-ms current pulses or sustained current injection ( I inj ) near the neuron’s rheobase. b , Current needed to induce action potentials as a function of stimulus duration ( n = 8 L2/3 pyramidal neurons). c , Left: grand average photocurrent traces from neurons expressing ST-C1V1 T/T (black, n = 19), ST-ChrimsonR (red, n = 11), ST-Chronos (green, n = 25), or ST-ChroME (magenta,<|im_end|> <|im_start|>assistant What if we could edit the sensations we feel; paste in our brain pictures that we never saw, cut out unwanted pain or insert non-existent scents into memory? University of California, Berkeley neuroscientists are building the equipment to do just that, using holographic projection into the brain to activate or suppress dozens and ultimately thousands of neurons at once, hundreds of times each second, copying real patterns of brain activity to fool the brain into thinking it has felt, seen or sensed something. The goal is to read neural activity constantly and decide, based on the activity, which sets of neurons to activate to simulate the pattern and rhythm of an actual brain response, so as to replace lost sensations after peripheral nerve damage, for example, or control a prosthetic limb. "This has great potential for neural prostheses, since it has the precision needed for the brain to interpret the pattern of activation. If you can read and write the language of the brain, you can speak to it in its own language and it can interpret the message much better," said Alan Mardinly, a postdoctoral fellow in the UC Berkeley lab of Hillel Adesnik, an assistant professor of molecular and cell biology. "This is one of the first steps in a long road to develop a technology that could be a virtual brain implant with additional senses or enhanced senses." Mardinly is one of three first authors of a paper appearing online April 30 in advance of publication in the journal Nature Neuroscience that describes the holographic brain modulator, which can activate up to 50 neurons at once in a three-dimensional chunk of brain containing several thousand neurons, and repeat that up to 300 times a second with different sets of 50 neurons. "The ability to talk to the brain has the incredible potential to help compensate for neurological damage caused by degenerative diseases or injury," said Ehud Isacoff, a UC Berkeley professor of molecular and cell biology and director of the Helen Wills Neuroscience Institute, who was not involved in the research project. "By encoding perceptions into the human cortex, you could allow the blind to see or the paralyzed to feel touch." Holographic projection Each of the 2,000 to 3,000 neurons in the chunk of brain was outfitted with a protein that, when hit by a flash of light, turns the cell on to create a brief spike of activity. One of the key breakthroughs was finding a way to target each cell individually without hitting all at once. To focus the light onto just the cell body - a target smaller than the width of a human hair - of nearly all cells in a chunk of brain, they turned to computer generated holography, a method of bending and focusing light to form a three-dimensional spatial pattern. The effect is as if a 3D image were floating in space. In this case, the holographic image was projected into a thin layer of brain tissue at the surface of the cortex, about a tenth of a millimeter thick, though a clear window into the brain. "The major advance is the ability to control neurons precisely in space and time," said postdoc Nicolas Pégard, another first author who works both in Adesnik's lab and the lab of co-author Laura Waller, an associate professor of electrical engineering and computer sciences. "In other words, to shoot the very specific sets of neurons you want to activate and do it at the characteristic scale and the speed at which they normally work." The researchers have already tested the prototype in the touch, vision and motor areas of the brains of mice as they walk on a treadmill with their heads immobilized. While they have not noted any behavior changes in the mice when their brain is stimulated, Mardinly said that their brain activity - which is measured in real-time with two-photon imaging of calcium levels in the neurons - shows patterns similar to a response to a sensory stimulus. They're now training mice so they can detect behavior changes after stimulation. Prosthetics and brain implants The area of the brain covered - now a slice one-half millimeter square and one-tenth of a millimeter thick - can be scaled up to read from and write to more neurons in the brain's outer layer, or cortex, Pégard said. And the laser holography setup could eventually be miniaturized to fit in a backpack a person could haul around. Mardinly, Pégard and the other first author, postdoc Ian Oldenburg, constructed the holographic brain modulator by making technological advances in a number of areas. Mardinly and Oldenburg, together with Savitha Sridharan, a research associate in the lab, developed better optogenetic switches to insert into cells to turn them on and off. The switches - light activated ion channels on the cell surface that open briefly when triggered - turn on strongly and then quickly shut off, all in about 3 milliseconds, so they're ready to be re-stimulated up to 50 or more times per second, consistent with normal firing rates in the cortex. Pégard developed the holographic projection system using a liquid crystal screen that acts like a holographic negative to sculpt the light from 40W lasers into the desired 3D pattern. The lasers are pulsed in 300 femtosecond-long bursts every microsecond. He, Mardinly, Oldenburg and their colleagues published a paper last year describing the device, which they call 3D-SHOT, for three-dimensional scanless holographic optogenetics with temporal focusing. "This is the culmination of technologies that researchers have been working on for a while, but have been impossible to put together," Mardinly said. "We solved numerous technical problems at the same time to bring it all together and finally realize the potential of this technology." As they improve their technology, they plan to start capturing real patterns of activity in the cortex in order to learn how to reproduce sensations and perceptions to play back through their holographic system. <|im_end|>

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311, 4546, 433, 682, 3871, 323, 5616, 13383, 279, 4754, 315, 420, 5557, 1210, 1666, 814, 7417, 872, 5557, 11, 814, 3197, 311, 1212, 40880, 1972, 12912, 315, 5820, 304, 279, 49370, 304, 2015, 311, 4048, 1268, 311, 23645, 72597, 323, 51866, 311, 1514, 1203, 1555, 872, 72927, 79173, 1887, 13, 220, 128257, 198 ]

2,682

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract The electronic correlations (e.g. unconventional superconductivity (SC), chiral charge order and nematic order) and giant anomalous Hall effect (AHE) in topological kagome metals AV 3 Sb 5 (A = K, Rb, and Cs) have attracted great interest. Electrical control of those correlated electronic states and AHE allows us to resolve their own nature and origin and to discover new quantum phenomena. Here, we show that electrically controlled proton intercalation has significant impacts on striking quantum phenomena in CsV 3 Sb 5 nanodevices mainly through inducing disorders in thinner nanoflakes and carrier density modulation in thicker ones. Specifically, in disordered thin nanoflakes (below 25 nm), we achieve a quantum phase transition from a superconductor to a “failed insulator” with a large saturated sheet resistance for T → 0 K. Meanwhile, the carrier density modulation in thicker nanoflakes shifts the Fermi level across the charge density wave (CDW) gap and gives rise to an extrinsic-intrinsic transition of AHE. With the first-principles calculations, the extrinsic skew scattering of holes in the nearly flat bands with finite Berry curvature by multiple impurities would account for the giant AHE. Our work uncovers a distinct disorder-driven bosonic superconductor-insulator transition (SIT), outlines a global picture of the giant AHE and reveals its correlation with the unconventional CDW in the AV 3 Sb 5 family. Introduction The layered kagome metals AV 3 Sb 5 (A = K, Rb and Cs) that possess topological electron bands and geometrical frustration of vanadium lattices are of great interests 1 , 2 , 3 . This is in no small part due to the many quantum phenomena that they support including unconventional SC 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , novel nematic order 12 , chiral charge density order 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , giant anomalous Hall effect 23 , 24 , 25 as well as the interplay between two-gap SC and CDW in CsV 3 Sb 5 26 . The unique coexistence of electronic correlations and band topology in AV 3 Sb 5 allows for investigating intriguing transitions of these correlated states, such as the superconductor-insulator transition (SIT), a protocol quantum phase transition (QPT) that is usually tuned by disorders, magnetic fields and electric gating 27 , 28 . Moreover, the origin of giant AHE in AV 3 Sb 5 and its correlation with chiral CDW remain elusive 29 , 30 , in spite of several recently proposed mechanisms including the extrinsic skew scattering of Dirac quasiparticles with frustrated magnetic sublattice 23 , the orbital currents of novel chiral charge order 13 or the chiral flux phase in the CDW phase 31 . Thus the ability to tune the carrier density and the corresponding Fermi surfaces would play a vital role in understanding and manipulating these novel quantum states and further realizing exotic QPTs. In this work, we find that electrically controlled proton intercalation 32 , 33 exhibits crucial impacts on the superconducting state, CDW state and the associated AHE in CsV 3 Sb 5 nanoflakes via disorders and carrier density modulation. In thinner nanoflakes (below 25 nm) with large gate voltages (e.g. with an amplitude above 15 V), the enhanced disorders from intercalated protons suppressed both CDW and superconducting phase coherence and gave rise to a SIT associated with the localized Cooper pairs, featuring a saturated sheet resistance reaching up to 10 6 Ω for T → 0, dubbed a “failed insulator”. While in thicker CsV 3 Sb 5 nanoflakes with much lower gate voltages (within 7 V), the superconducting transition instead retained with nearly unchanged sheet resistance in normal state at 5 K, indicating very limited impact of disorder. However, the Hall measurements demonstrate a large modulation of carrier density (with the modulation up to 10 22 cm −3 ) and the relevant Fermi surface topology changes from a hole pocket to an electron pocket. Consequently, we find that the giant anomalous Hall conductivity (AHC) with a maximal amplitude exceeding 10 4 Ω −1 cm −1 mainly pinned down to a narrow hole-carrier-density window around \$p=\\left(2.5\\pm 1.2\\right)\\times {10}^{22}\\,{{{{{{\\rm{cm}}}}}}}^{-3}\$ at low temperatures. Meanwhile, the AHE exhibits a clear extrinsic-intrinsic transition as the Fermi level shifts across the CDW gap near the saddle point. The observed giant AHE can be ascribed to the extrinsic skew scattering of the holes in the flat bands with nonzero Berry curvature by V vacancies and magnetic field tilted paramagnetic (PM) impurities. Results The layered material CsV 3 Sb 5 has a hexagonal crystal structure with space group P6/mmm (No. 191). As shown in the upper panel of Fig. 1a , the V 3 Sb layers are sandwiched by antimonene layers and Cs layers. X-ray diffraction (XRD) (see Supplementary Fig. 1 ), reveals a sharp (001) diffraction peak, indicating a single crystal possessing (001) preferred orientation, in line with previous work 4 . The striking feature of CsV 3 Sb 5 is that the V atoms form a 2D kagome network. This frustrated magnetic sublattice of V was expected to induce novel correlation effects, such as spin-liquid states 34 , 35 . The lower panel of Fig. 1a illustrates a schematic of the gating device. A CsV 3 Sb 5 nanoflake is mounted on the solid proton conductor with an underlying Pt electrode to form a solid proton field effect transistor (SP-FET). Next we demonstrate how the proton intercalation significantly affects the SC state, CDW state and the giant AHE in CsV 3 Sb 5 nanoflakes with distinct thicknesses. Fig. 1: Temperature-dependent longitudinal resistance curves under various gating voltages in device #5 (21 nm). a Schematic of proton gating on CsV 3 Sb 5 nanoflakes (upper) and Hall-bar device (lower). b Temperature dependence of sheet resistance at various gate voltages in device #5. c Sheet resistance as a function of charge density n e near SIT. The critical resistance R c ~ 316 Ω is obtained with carrier density \\({{{{{{\\rm{n}}}}}}}_{{{{{{\\rm{c}}}}}}} \\sim", "role": "user" }, { "content": "A new RMIT-led international collaboration published in February has uncovered, for the first time, a distinct disorder-driven bosonic superconductor-insulator transition. The discovery outlines a global picture of the giant anomalous Hall effect and reveals its correlation with the unconventional charge density wave in the AV3Sb5 kagome metal family, with potential applications in future ultra-low energy electronics. Superconductors, which can transmit electricity without energy dissipation, hold great promise for the development of future low-energy electronics technologies, and are already applied in diverse fields such as hover trains and high-strength magnets (such as medical MRIs). However, precisely how the superconductivity forms and works in many materials remains an unsolved issue and limits its applications. Recently, a new kagome superconductor family AV3Sb5 has attracted intensive interest for their novel properties. \"Kagome\" materials feature an unusual lattice named for a Japanese basket-weave pattern with corner-sharing triangles. The AV3Sb5 materials (where A refers to cesium, rubidium, or potassium) provide ideal platforms for physics studies such as topology and strong correlations, but despite many recent investigations, the origin of the material's giant anomalous Hall effect and superconductivity remain in debate. The FLEET-led collaboration of researchers at RMIT University (Australia) and partner organization the High Magnetic Field Laboratory (China) confirm for the first time the electric control of superconductivity and AHE in a van der Waals kagome metal CsV3Sb5. Manipulating giant anomalous Hall effect via reversible proton intercalation Possessing topological electron bands and geometrical frustration of vanadium lattices, the layered kagome metals AV3Sb5 have attracted great interests in condensed matter physics due to the many quantum phenomena that they support including: unconventional, novel nematic orderchiral charge density ordergiant anomalous Hall effect (AHE), andthe interplay between two-gap superconductivity and charge density wave (CDW) in AV3Sb5. Moreover, the origin of giant AHE in AV3Sb5 and its correlation with chiral CDW remain elusive, in spite of several recently proposed mechanisms including the extrinsic skew scattering of Dirac quasiparticles with frustrated magnetic sublattice, the orbital currents of novel chiral charge order and the chiral flux phase in the CDW phase. \"Up to now, we had obtained many intriguing results with proton gate technique in vdW spintronic devices. Since this technique can effectively modulate the carrier density up to 1021 cm-3, we would like to apply it on AV3Sb5, which harbors a similar carrier density level,\" says the new study's first author, FLEET Research Fellow Dr. Guolin Zheng (RMIT). \"The ability to tune the carrier density and the corresponding Fermi surfaces would play a vital role in understanding and manipulating these novel quantum states and would potentially realize some exotic quantum phase transitions.\" The team chose to test this theory on CsV3Sb5 which potentially has the largest spare atom space for proton intercalation. The devices were easily designed and fabricated based on the team's rich experience in this field. Their subsequent results with CsV3Sb5 depended strongly on material thickness. \"It was very difficult to effectively modulate the 'thicker' nanoflakes (more than 100 nm),\" says co-first author, FLEET Research Fellow Dr. Cheng Tan (RMIT). \"But when the thickness went down to around 40 nm, the injection of the proton became quite easy,\" says Cheng. \"We even found that the injection is highly reversible. Indeed, we have seldom met such a proton-friendly material.\" Interestingly, with the evolving proton intercalation, the carrier type (or the \"sign\" of the Hall effect) could be modulated to either hole or electron type and the amplitude of the AHEs achieved were effectively tuned as well. Further experimental and theoretical investigations indicate that this dramatic modulation of giant AHE originates from the Fermi level shift in the reconstructed band structures. \"The results of the gated AHE also revealed that the most possible origin of the AHE is skew scattering and this further improves our understanding on the kagome metal,\" explains Guolin. \"But we have not yet observed superconductor-insulator transition in 40 nm nanoflakes.\" \"We must further try thinner CsV3Sb5 nanoflakes to explore this.\" Proton intercalation induced superconductor-to-'failed insulator' transition The unique coexistence of electronic correlations and band topology in AV3Sb5 allows for investigating intriguing transitions of these correlated states, such as superconductor-insulator transition, a quantum phase transition usually tuned by disorders, magnetic fields and electric gating. By decreasing the number of atomic layers, the team took further steps to explore the potential quantum phase transitions in CsV3Sb5. \"At first I directly tried some <10 nm ultrathin nanoflakes,\" says Cheng. \"I did observe that the critical temperatures of the superconductivity phase decreased with the increasing proton intercalation, but I could not definitively confirm that the superconductivity disappeared, as it might still exist at milliKelvin temperatures, where we cannot reach. Also, the devices were very fragile when I tried to further increase the proton intercalation.\" So Cheng changed the strategy and dealt with the 10~20nm thicker nanoflakes, as well as trying different electrode materials to seek a better electrical contact. This strategy met with success. The team, surprisingly, observed that the critical temperature of the CDW phase decreased and the temperature-dependent resistance curves exhibit a clear superconductor-to-insulator transition under increasing proton injection. \"The proton intercalation introduced the disorder and suppressed both CDW and superconducting phase coherence,\" says contributing-author A/Prof Lan Wang (also at RMIT). \"And this gave rise to a superconductor-insulator transition associated with localized Cooper pairs and featuring a saturated sheet resistance reaching up to 106 Ω for temperature approaching zero, dubbed a 'failed insulator.'\" \"Our work uncovers a distinct disorder-driven bosonic superconductor-insulator transition, outlines a global picture of the giant AHE and reveals its correlation with the unconventional CDW in the AV3Sb5 family.\" \"This significant and electrically-controlled superconductor-insulator transition and anomalous Hall effect in kagome metals should inspire more investigations of the relevant intriguing physics, with promise for energy-saving nanoelectronic devices.\" \"Electrically controlled superconductor-to-failed insulator transition and giant anomalous Hall effect in kagome metal CsV3Sb5 nanoflakes\" was published in Nature Communications in February 2023. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract The electronic correlations (e.g. unconventional superconductivity (SC), chiral charge order and nematic order) and giant anomalous Hall effect (AHE) in topological kagome metals AV 3 Sb 5 (A = K, Rb, and Cs) have attracted great interest. Electrical control of those correlated electronic states and AHE allows us to resolve their own nature and origin and to discover new quantum phenomena. Here, we show that electrically controlled proton intercalation has significant impacts on striking quantum phenomena in CsV 3 Sb 5 nanodevices mainly through inducing disorders in thinner nanoflakes and carrier density modulation in thicker ones. Specifically, in disordered thin nanoflakes (below 25 nm), we achieve a quantum phase transition from a superconductor to a “failed insulator” with a large saturated sheet resistance for T → 0 K. Meanwhile, the carrier density modulation in thicker nanoflakes shifts the Fermi level across the charge density wave (CDW) gap and gives rise to an extrinsic-intrinsic transition of AHE. With the first-principles calculations, the extrinsic skew scattering of holes in the nearly flat bands with finite Berry curvature by multiple impurities would account for the giant AHE. Our work uncovers a distinct disorder-driven bosonic superconductor-insulator transition (SIT), outlines a global picture of the giant AHE and reveals its correlation with the unconventional CDW in the AV 3 Sb 5 family. Introduction The layered kagome metals AV 3 Sb 5 (A = K, Rb and Cs) that possess topological electron bands and geometrical frustration of vanadium lattices are of great interests 1 , 2 , 3 . This is in no small part due to the many quantum phenomena that they support including unconventional SC 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , novel nematic order 12 , chiral charge density order 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , giant anomalous Hall effect 23 , 24 , 25 as well as the interplay between two-gap SC and CDW in CsV 3 Sb 5 26 . The unique coexistence of electronic correlations and band topology in AV 3 Sb 5 allows for investigating intriguing transitions of these correlated states, such as the superconductor-insulator transition (SIT), a protocol quantum phase transition (QPT) that is usually tuned by disorders, magnetic fields and electric gating 27 , 28 . Moreover, the origin of giant AHE in AV 3 Sb 5 and its correlation with chiral CDW remain elusive 29 , 30 , in spite of several recently proposed mechanisms including the extrinsic skew scattering of Dirac quasiparticles with frustrated magnetic sublattice 23 , the orbital currents of novel chiral charge order 13 or the chiral flux phase in the CDW phase 31 . Thus the ability to tune the carrier density and the corresponding Fermi surfaces would play a vital role in understanding and manipulating these novel quantum states and further realizing exotic QPTs. In this work, we find that electrically controlled proton intercalation 32 , 33 exhibits crucial impacts on the superconducting state, CDW state and the associated AHE in CsV 3 Sb 5 nanoflakes via disorders and carrier density modulation. In thinner nanoflakes (below 25 nm) with large gate voltages (e.g. with an amplitude above 15 V), the enhanced disorders from intercalated protons suppressed both CDW and superconducting phase coherence and gave rise to a SIT associated with the localized Cooper pairs, featuring a saturated sheet resistance reaching up to 10 6 Ω for T → 0, dubbed a “failed insulator”. While in thicker CsV 3 Sb 5 nanoflakes with much lower gate voltages (within 7 V), the superconducting transition instead retained with nearly unchanged sheet resistance in normal state at 5 K, indicating very limited impact of disorder. However, the Hall measurements demonstrate a large modulation of carrier density (with the modulation up to 10 22 cm −3 ) and the relevant Fermi surface topology changes from a hole pocket to an electron pocket. Consequently, we find that the giant anomalous Hall conductivity (AHC) with a maximal amplitude exceeding 10 4 Ω −1 cm −1 mainly pinned down to a narrow hole-carrier-density window around $p=\left(2.5\pm 1.2\right)\times {10}^{22}\,{{{{{{\rm{cm}}}}}}}^{-3}$ at low temperatures. Meanwhile, the AHE exhibits a clear extrinsic-intrinsic transition as the Fermi level shifts across the CDW gap near the saddle point. The observed giant AHE can be ascribed to the extrinsic skew scattering of the holes in the flat bands with nonzero Berry curvature by V vacancies and magnetic field tilted paramagnetic (PM) impurities. Results The layered material CsV 3 Sb 5 has a hexagonal crystal structure with space group P6/mmm (No. 191). As shown in the upper panel of Fig. 1a , the V 3 Sb layers are sandwiched by antimonene layers and Cs layers. X-ray diffraction (XRD) (see Supplementary Fig. 1 ), reveals a sharp (001) diffraction peak, indicating a single crystal possessing (001) preferred orientation, in line with previous work 4 . The striking feature of CsV 3 Sb 5 is that the V atoms form a 2D kagome network. This frustrated magnetic sublattice of V was expected to induce novel correlation effects, such as spin-liquid states 34 , 35 . The lower panel of Fig. 1a illustrates a schematic of the gating device. A CsV 3 Sb 5 nanoflake is mounted on the solid proton conductor with an underlying Pt electrode to form a solid proton field effect transistor (SP-FET). Next we demonstrate how the proton intercalation significantly affects the SC state, CDW state and the giant AHE in CsV 3 Sb 5 nanoflakes with distinct thicknesses. Fig. 1: Temperature-dependent longitudinal resistance curves under various gating voltages in device #5 (21 nm). a Schematic of proton gating on CsV 3 Sb 5 nanoflakes (upper) and Hall-bar device (lower). b Temperature dependence of sheet resistance at various gate voltages in device #5. c Sheet resistance as a function of charge density n e near SIT. The critical resistance R c ~ 316 Ω is obtained with carrier density \({{{{{{\rm{n}}}}}}}_{{{{{{\rm{c}}}}}}} \sim<|im_end|> <|im_start|>assistant A new RMIT-led international collaboration published in February has uncovered, for the first time, a distinct disorder-driven bosonic superconductor-insulator transition. The discovery outlines a global picture of the giant anomalous Hall effect and reveals its correlation with the unconventional charge density wave in the AV3Sb5 kagome metal family, with potential applications in future ultra-low energy electronics. Superconductors, which can transmit electricity without energy dissipation, hold great promise for the development of future low-energy electronics technologies, and are already applied in diverse fields such as hover trains and high-strength magnets (such as medical MRIs). However, precisely how the superconductivity forms and works in many materials remains an unsolved issue and limits its applications. Recently, a new kagome superconductor family AV3Sb5 has attracted intensive interest for their novel properties. "Kagome" materials feature an unusual lattice named for a Japanese basket-weave pattern with corner-sharing triangles. The AV3Sb5 materials (where A refers to cesium, rubidium, or potassium) provide ideal platforms for physics studies such as topology and strong correlations, but despite many recent investigations, the origin of the material's giant anomalous Hall effect and superconductivity remain in debate. The FLEET-led collaboration of researchers at RMIT University (Australia) and partner organization the High Magnetic Field Laboratory (China) confirm for the first time the electric control of superconductivity and AHE in a van der Waals kagome metal CsV3Sb5. Manipulating giant anomalous Hall effect via reversible proton intercalation Possessing topological electron bands and geometrical frustration of vanadium lattices, the layered kagome metals AV3Sb5 have attracted great interests in condensed matter physics due to the many quantum phenomena that they support including: unconventional, novel nematic orderchiral charge density ordergiant anomalous Hall effect (AHE), andthe interplay between two-gap superconductivity and charge density wave (CDW) in AV3Sb5. Moreover, the origin of giant AHE in AV3Sb5 and its correlation with chiral CDW remain elusive, in spite of several recently proposed mechanisms including the extrinsic skew scattering of Dirac quasiparticles with frustrated magnetic sublattice, the orbital currents of novel chiral charge order and the chiral flux phase in the CDW phase. "Up to now, we had obtained many intriguing results with proton gate technique in vdW spintronic devices. Since this technique can effectively modulate the carrier density up to 1021 cm-3, we would like to apply it on AV3Sb5, which harbors a similar carrier density level," says the new study's first author, FLEET Research Fellow Dr. Guolin Zheng (RMIT). "The ability to tune the carrier density and the corresponding Fermi surfaces would play a vital role in understanding and manipulating these novel quantum states and would potentially realize some exotic quantum phase transitions." The team chose to test this theory on CsV3Sb5 which potentially has the largest spare atom space for proton intercalation. The devices were easily designed and fabricated based on the team's rich experience in this field. Their subsequent results with CsV3Sb5 depended strongly on material thickness. "It was very difficult to effectively modulate the 'thicker' nanoflakes (more than 100 nm)," says co-first author, FLEET Research Fellow Dr. Cheng Tan (RMIT). "But when the thickness went down to around 40 nm, the injection of the proton became quite easy," says Cheng. "We even found that the injection is highly reversible. Indeed, we have seldom met such a proton-friendly material." Interestingly, with the evolving proton intercalation, the carrier type (or the "sign" of the Hall effect) could be modulated to either hole or electron type and the amplitude of the AHEs achieved were effectively tuned as well. Further experimental and theoretical investigations indicate that this dramatic modulation of giant AHE originates from the Fermi level shift in the reconstructed band structures. "The results of the gated AHE also revealed that the most possible origin of the AHE is skew scattering and this further improves our understanding on the kagome metal," explains Guolin. "But we have not yet observed superconductor-insulator transition in 40 nm nanoflakes." "We must further try thinner CsV3Sb5 nanoflakes to explore this." Proton intercalation induced superconductor-to-'failed insulator' transition The unique coexistence of electronic correlations and band topology in AV3Sb5 allows for investigating intriguing transitions of these correlated states, such as superconductor-insulator transition, a quantum phase transition usually tuned by disorders, magnetic fields and electric gating. By decreasing the number of atomic layers, the team took further steps to explore the potential quantum phase transitions in CsV3Sb5. "At first I directly tried some <10 nm ultrathin nanoflakes," says Cheng. "I did observe that the critical temperatures of the superconductivity phase decreased with the increasing proton intercalation, but I could not definitively confirm that the superconductivity disappeared, as it might still exist at milliKelvin temperatures, where we cannot reach. Also, the devices were very fragile when I tried to further increase the proton intercalation." So Cheng changed the strategy and dealt with the 10~20nm thicker nanoflakes, as well as trying different electrode materials to seek a better electrical contact. This strategy met with success. The team, surprisingly, observed that the critical temperature of the CDW phase decreased and the temperature-dependent resistance curves exhibit a clear superconductor-to-insulator transition under increasing proton injection. "The proton intercalation introduced the disorder and suppressed both CDW and superconducting phase coherence," says contributing-author A/Prof Lan Wang (also at RMIT). "And this gave rise to a superconductor-insulator transition associated with localized Cooper pairs and featuring a saturated sheet resistance reaching up to 106 Ω for temperature approaching zero, dubbed a 'failed insulator.'" "Our work uncovers a distinct disorder-driven bosonic superconductor-insulator transition, outlines a global picture of the giant AHE and reveals its correlation with the unconventional CDW in the AV3Sb5 family." "This significant and electrically-controlled superconductor-insulator transition and anomalous Hall effect in kagome metals should inspire more investigations of the relevant intriguing physics, with promise for energy-saving nanoelectronic devices." "Electrically controlled superconductor-to-failed insulator transition and giant anomalous Hall effect in kagome metal CsV3Sb5 nanoflakes" was published in Nature Communications in February 2023. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Guidelines Hypothesis Interesting Images Letter New Book Received Obituary Opinion Perspective Proceeding Paper Project Report Protocol Registered Report Reply Retraction Short Note Study Protocol Systematic Review Technical Note Tutorial Viewpoint All Article Types Advanced Search Section All Sections AI Remote Sensing Atmospheric Remote Sensing Biogeosciences Remote Sensing Coral Reefs Remote Sensing Discoveries in Remote Sensing Earth Observation Data Earth Observation for Emergency Management Ecological Remote Sensing Engineering Remote Sensing Environmental Remote Sensing Forest Remote Sensing Ocean Remote Sensing Remote Sensing and Geo-Spatial Science Remote Sensing Communications Remote Sensing Image Processing Remote Sensing in Agriculture and Vegetation Remote Sensing in Geology, Geomorphology and Hydrology Remote Sensing of the Water Cycle Satellite Missions for Earth and Planetary Exploration Urban Remote Sensing All Sections Special Issue All Special Issues Remote Sensing: 15th Anniversary 100 Years ISPRS - Advancing Remote Sensing Science 2nd Edition Advances in Remote Sensing for Archaeological Heritage 3D Point Clouds in Rock Mechanics Applications Accuracy Assessment of UAS Lidar Active-Passive Microwave Sensing for Earth System Parameters Advanced Communication and Networking Techniques for Remote Sensing Advanced Machine Learning and Big Data Analytics in Remote Sensing for Natural Hazards Management Advanced Machine Learning Approaches for Hyperspectral Data Analysis Advanced Radar Signal Processing and Applications Advanced Remote Sensing Methods for 3D Vegetation Mapping and Characterization Advanced Satellite-Terrestrial Networks Advanced Topics in Remote Sensing Advancement of Remote Sensing and UAS in Cartography and Visualisation Advancements in Remote Sensing and GIS in Mobile Computing and Location-Based Services Advances and Innovative Applications of Unmanned Aerial Vehicles Advances in Applications of Volunteered Geographic Information Advances in Climate and Geophysics Advances in Geographic Object-Based Image Analysis (GEOBIA) Advances in Mobile Laser Scanning and Mobile Mapping Advances in Object and Activity Detection in Remote Sensing Imagery Advances in Object and Activity Detection in Remote Sensing Imagery II Advances in Object-Based Image Analysis—Linking with Computer Vision and Machine Learning Advances in Quantitative Remote Sensing in China – In Memory of Prof. Xiaowen Li Advances in Real Aperture and Synthetic Aperture Ground-Based Interferometry Advances in Remote Sensing and Geographic Information Science and Their Uses in Geointelligence Advances in Remote Sensing Applications for the Detection of Biological Invasions Advances in Remote Sensing for Archaeological Heritage Advances in Remote Sensing in Coastal Geomorphology Advances in Remote Sensing of Agriculture Advances in Remote Sensing of Crop Water Use Estimation Advances in Remote Sensing of Forestry Advances in Remote Sensing of Wildland Fires Advances in Remote Sensing-based Disaster Monitoring and Assessment Advances in SAR: Sensors, Methodologies, and Applications Advances in Satellite Altimetry Advances in Satellite Altimetry and Its Application Advances in Synthetic Aperture Radar Remote Sensing Advances in the Remote Sensing of Terrestrial Evaporation Advances in VIIRS Data Advances of Remote Sensing in Environmental Geoscience Aerosol and Cloud Remote Sensing Airborne Laser Scanning Analysis of Remote Sensing Image Data Application of Machine Learning in Volcano Monitoring Application of Multi-Sensor Fusion Technology in Target Detection and Recognition Application of Remote Sensing in Hydrological Modeling and Watershed Management Applications and New Trends in Metrology for Radar/LiDAR-Based Systems Applications of Deep Learning in Smart Agriculture Applications of Full Waveform Lidar Applications of GNSS Reflectometry for Earth Observation Applications of Micro- and Nano-Satellites for Earth Observation Applications of Remote Sensing in Landscape Ecology in Latin America Applications of Remote Sensing in Rangelands Research Applications of Synthetic Aperture Radar (SAR) for Land Cover Analysis Approaches for Monitoring Land Degradation with Remote Sensing Archaeological Prospecting and Remote Sensing Artifacts in Remote Sensing Data Analysis: An Ecological Perspective Artificial Intelligence and Automation in Sustainable Smart Farming Artificial Neural Networks and Evolutionary Computation in Remote Sensing Assessment of Renewable Energy Resources with Remote Sensing Assimilation of Remote Sensing Data into Earth System Models Atmospheric Remote Sensing Baltic Sea Remote Sensing Big Data Analytics for Secure and Smart Environmental Services Big Earth Observation Data: From Cloud Technologies to Insights and Foresight Bistatic HF Radar Calibration and Validation of Synthetic Aperture Radar Calibration and Verification of Remote Sensing Instruments and Observations Carbon Cycle, Global Change, and Multi-Sensor Remote Sensing Cartography of the Solar System: Remote Sensing beyond Earth Celebrating the 50th Anniversary of the Moon Landing with Views of Earth from Satellite and Apollo Missions Citizen Science and Earth Observation Climate Modelling and Monitoring Using GNSS Close Range Remote Sensing Close-Range Remote Sensing by Ground Penetrating Radar Compact Polarimetric SAR Concurrent Positioning, Mapping and Perception of Multi-source Data Fusion for Smart Applications Contemporary Microwave and Radar Techniques in Remote Sensing—MIKON 2022, IRS 2022 CORINE Land Cover System: Limits and Challenges for Territorial Studies and Planning Cross-Calibration and Interoperability of Remote Sensing Instruments Cryospheric Remote Sensing Data Mining in Multi-Platform Remote Sensing Data Science in Remote Sensing Data Science, Artificial Intelligence and Remote Sensing Deep Learning for Intelligent Synthetic Aperture Radar Systems Deep Learning for Target Object Detection and Identification in Remote Sensing Data Deep Learning in Remote Sensing: Sample Datasets, Algorithms and Applications Dense Image Time Series Analysis for Ecosystem Monitoring Design and Calibration of Microwave Radiometers and Scatterometers for Remote Sensing of the Earth Designing and Managing the Next Generation of Transportation Infrastructure Digital Forest Resource Monitoring and Uncertainty Analysis Discovering A More Diverse Remote Sensing Discipline Drone-Based Ecological Conservation Earth Environment Monitoring with Advanced Spaceborne Synthetic Aperture Radar: New Architectures, Operational Modes, and Processing Techniques Earth Monitoring from A New Generation of Geostationary Satellites Earth Observation and Sustainable Development in Marine and Freshwater Systems Earth Observation for Ecosystems Monitoring in Space and Time Earth Observation for Water Resource Management in Africa Earth Observation in Planning for Sustainable Urban Development Earth Observation Technology Cluster: Innovative Sensor Systems for Advanced Land Surface Studies Earth Observation to Support Disaster Preparedness and Disaster Risk Management Earth Observation with AVHRR Data and Interconsistency Earth Observations for a Better Future Earth Earth Observations for Addressing Global Challenges Earth Observations for Geohazards Earth Observations for the Sustainable Development Ecogeomorphological Research Using Satellite Images Ecological Status and Change by Remote Sensing Environmental Research with Global Navigation Satellite System (GNSS) EO Solutions to Support Countries Implementing the SDGs ESA - NRSCC", "role": "user" }, { "content": "German cities emit several times less light per capita than comparably sized American cities, according to a recent publication in the journal Remote Sensing. The size of the gap grew with city size, as light per capita increased with city size in the USA but decreased with city size in Germany. The study also examined regional differences, and surprisingly found that light emission per capita was higher in cities in the former East of Germany than from those in the former West. The lead author, Dr. Christopher Kyba, studies visible light at night as a member of the Remote Sensing section of the German Research Center for Geosciences (GFZ). \"The size of the difference in light emission is surprisingly large. This work will allow us to identify comparable cities in order to uncover the reasons behind the differences.\" These could include differences in the type of lamps, but also architectural factors like the width of the streets and the amount of trees. The LED lamps currently being installed in many cities are expected to greatly change the nighttime environment, for example by reducing the amount of light that shines upwards. A main point of the study is to emphasize the great improvement in the quality of nighttime imagery of Earth since 2012. The European Space Agency's NightPod instrument has allowed astronauts to take high resolution images of individual cities. In addition, the entire world is now imaged nightly at 750 meter resolution by the Visible Infrared Imaging Radiometer Suite Day-Night Band onboard the Suomi National Polar-Orbiting Program weather satellite. This new imagery has made it possible to identify and measure the output of individual bright sources of light pollution for the first time. The study found that in Megacities in developing countries, the brightest light sources were typically airports or harbors. In contrast, the brightest areas in the capital cities of Europe are often associated with leisure, for example stadiums and city centers. While artificial light at night is a problem for astronomers and nocturnal animals, it has the potential to be an important tool in understanding human activity. In order to make the most use out of it, the researchers say they will need to study urban light emissions in detail, including their spectrum, the directions in which light is emitted, and changes in light use and lit area over time. The study demonstrated one practical use of the new data: since maps of nighttime light emission highlight the areas where light pollution is especially prevalent, they provide information about which areas can best be targeted for energy savings. Coauthor Dr. Franz Hölker from the Leibniz Institute for Freshwater Ecology and Inland Fisheries (IGB) explains, \"artificial light is responsible for a sizable portion of all nighttime electricity consumption. Identifying areas where light could be more efficiently used will make it possible to save energy, reduce costs, and reduce the impact of artificial light on the nighttime environment.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Guidelines Hypothesis Interesting Images Letter New Book Received Obituary Opinion Perspective Proceeding Paper Project Report Protocol Registered Report Reply Retraction Short Note Study Protocol Systematic Review Technical Note Tutorial Viewpoint All Article Types Advanced Search Section All Sections AI Remote Sensing Atmospheric Remote Sensing Biogeosciences Remote Sensing Coral Reefs Remote Sensing Discoveries in Remote Sensing Earth Observation Data Earth Observation for Emergency Management Ecological Remote Sensing Engineering Remote Sensing Environmental Remote Sensing Forest Remote Sensing Ocean Remote Sensing Remote Sensing and Geo-Spatial Science Remote Sensing Communications Remote Sensing Image Processing Remote Sensing in Agriculture and Vegetation Remote Sensing in Geology, Geomorphology and Hydrology Remote Sensing of the Water Cycle Satellite Missions for Earth and Planetary Exploration Urban Remote Sensing All Sections Special Issue All Special Issues Remote Sensing: 15th Anniversary 100 Years ISPRS - Advancing Remote Sensing Science 2nd Edition Advances in Remote Sensing for Archaeological Heritage 3D Point Clouds in Rock Mechanics Applications Accuracy Assessment of UAS Lidar Active-Passive Microwave Sensing for Earth System Parameters Advanced Communication and Networking Techniques for Remote Sensing Advanced Machine Learning and Big Data Analytics in Remote Sensing for Natural Hazards Management Advanced Machine Learning Approaches for Hyperspectral Data Analysis Advanced Radar Signal Processing and Applications Advanced Remote Sensing Methods for 3D Vegetation Mapping and Characterization Advanced Satellite-Terrestrial Networks Advanced Topics in Remote Sensing Advancement of Remote Sensing and UAS in Cartography and Visualisation Advancements in Remote Sensing and GIS in Mobile Computing and Location-Based Services Advances and Innovative Applications of Unmanned Aerial Vehicles Advances in Applications of Volunteered Geographic Information Advances in Climate and Geophysics Advances in Geographic Object-Based Image Analysis (GEOBIA) Advances in Mobile Laser Scanning and Mobile Mapping Advances in Object and Activity Detection in Remote Sensing Imagery Advances in Object and Activity Detection in Remote Sensing Imagery II Advances in Object-Based Image Analysis—Linking with Computer Vision and Machine Learning Advances in Quantitative Remote Sensing in China – In Memory of Prof. Xiaowen Li Advances in Real Aperture and Synthetic Aperture Ground-Based Interferometry Advances in Remote Sensing and Geographic Information Science and Their Uses in Geointelligence Advances in Remote Sensing Applications for the Detection of Biological Invasions Advances in Remote Sensing for Archaeological Heritage Advances in Remote Sensing in Coastal Geomorphology Advances in Remote Sensing of Agriculture Advances in Remote Sensing of Crop Water Use Estimation Advances in Remote Sensing of Forestry Advances in Remote Sensing of Wildland Fires Advances in Remote Sensing-based Disaster Monitoring and Assessment Advances in SAR: Sensors, Methodologies, and Applications Advances in Satellite Altimetry Advances in Satellite Altimetry and Its Application Advances in Synthetic Aperture Radar Remote Sensing Advances in the Remote Sensing of Terrestrial Evaporation Advances in VIIRS Data Advances of Remote Sensing in Environmental Geoscience Aerosol and Cloud Remote Sensing Airborne Laser Scanning Analysis of Remote Sensing Image Data Application of Machine Learning in Volcano Monitoring Application of Multi-Sensor Fusion Technology in Target Detection and Recognition Application of Remote Sensing in Hydrological Modeling and Watershed Management Applications and New Trends in Metrology for Radar/LiDAR-Based Systems Applications of Deep Learning in Smart Agriculture Applications of Full Waveform Lidar Applications of GNSS Reflectometry for Earth Observation Applications of Micro- and Nano-Satellites for Earth Observation Applications of Remote Sensing in Landscape Ecology in Latin America Applications of Remote Sensing in Rangelands Research Applications of Synthetic Aperture Radar (SAR) for Land Cover Analysis Approaches for Monitoring Land Degradation with Remote Sensing Archaeological Prospecting and Remote Sensing Artifacts in Remote Sensing Data Analysis: An Ecological Perspective Artificial Intelligence and Automation in Sustainable Smart Farming Artificial Neural Networks and Evolutionary Computation in Remote Sensing Assessment of Renewable Energy Resources with Remote Sensing Assimilation of Remote Sensing Data into Earth System Models Atmospheric Remote Sensing Baltic Sea Remote Sensing Big Data Analytics for Secure and Smart Environmental Services Big Earth Observation Data: From Cloud Technologies to Insights and Foresight Bistatic HF Radar Calibration and Validation of Synthetic Aperture Radar Calibration and Verification of Remote Sensing Instruments and Observations Carbon Cycle, Global Change, and Multi-Sensor Remote Sensing Cartography of the Solar System: Remote Sensing beyond Earth Celebrating the 50th Anniversary of the Moon Landing with Views of Earth from Satellite and Apollo Missions Citizen Science and Earth Observation Climate Modelling and Monitoring Using GNSS Close Range Remote Sensing Close-Range Remote Sensing by Ground Penetrating Radar Compact Polarimetric SAR Concurrent Positioning, Mapping and Perception of Multi-source Data Fusion for Smart Applications Contemporary Microwave and Radar Techniques in Remote Sensing—MIKON 2022, IRS 2022 CORINE Land Cover System: Limits and Challenges for Territorial Studies and Planning Cross-Calibration and Interoperability of Remote Sensing Instruments Cryospheric Remote Sensing Data Mining in Multi-Platform Remote Sensing Data Science in Remote Sensing Data Science, Artificial Intelligence and Remote Sensing Deep Learning for Intelligent Synthetic Aperture Radar Systems Deep Learning for Target Object Detection and Identification in Remote Sensing Data Deep Learning in Remote Sensing: Sample Datasets, Algorithms and Applications Dense Image Time Series Analysis for Ecosystem Monitoring Design and Calibration of Microwave Radiometers and Scatterometers for Remote Sensing of the Earth Designing and Managing the Next Generation of Transportation Infrastructure Digital Forest Resource Monitoring and Uncertainty Analysis Discovering A More Diverse Remote Sensing Discipline Drone-Based Ecological Conservation Earth Environment Monitoring with Advanced Spaceborne Synthetic Aperture Radar: New Architectures, Operational Modes, and Processing Techniques Earth Monitoring from A New Generation of Geostationary Satellites Earth Observation and Sustainable Development in Marine and Freshwater Systems Earth Observation for Ecosystems Monitoring in Space and Time Earth Observation for Water Resource Management in Africa Earth Observation in Planning for Sustainable Urban Development Earth Observation Technology Cluster: Innovative Sensor Systems for Advanced Land Surface Studies Earth Observation to Support Disaster Preparedness and Disaster Risk Management Earth Observation with AVHRR Data and Interconsistency Earth Observations for a Better Future Earth Earth Observations for Addressing Global Challenges Earth Observations for Geohazards Earth Observations for the Sustainable Development Ecogeomorphological Research Using Satellite Images Ecological Status and Change by Remote Sensing Environmental Research with Global Navigation Satellite System (GNSS) EO Solutions to Support Countries Implementing the SDGs ESA - NRSCC<|im_end|> <|im_start|>assistant German cities emit several times less light per capita than comparably sized American cities, according to a recent publication in the journal Remote Sensing. The size of the gap grew with city size, as light per capita increased with city size in the USA but decreased with city size in Germany. The study also examined regional differences, and surprisingly found that light emission per capita was higher in cities in the former East of Germany than from those in the former West. The lead author, Dr. Christopher Kyba, studies visible light at night as a member of the Remote Sensing section of the German Research Center for Geosciences (GFZ). "The size of the difference in light emission is surprisingly large. This work will allow us to identify comparable cities in order to uncover the reasons behind the differences." These could include differences in the type of lamps, but also architectural factors like the width of the streets and the amount of trees. The LED lamps currently being installed in many cities are expected to greatly change the nighttime environment, for example by reducing the amount of light that shines upwards. A main point of the study is to emphasize the great improvement in the quality of nighttime imagery of Earth since 2012. The European Space Agency's NightPod instrument has allowed astronauts to take high resolution images of individual cities. In addition, the entire world is now imaged nightly at 750 meter resolution by the Visible Infrared Imaging Radiometer Suite Day-Night Band onboard the Suomi National Polar-Orbiting Program weather satellite. This new imagery has made it possible to identify and measure the output of individual bright sources of light pollution for the first time. The study found that in Megacities in developing countries, the brightest light sources were typically airports or harbors. In contrast, the brightest areas in the capital cities of Europe are often associated with leisure, for example stadiums and city centers. While artificial light at night is a problem for astronomers and nocturnal animals, it has the potential to be an important tool in understanding human activity. In order to make the most use out of it, the researchers say they will need to study urban light emissions in detail, including their spectrum, the directions in which light is emitted, and changes in light use and lit area over time. The study demonstrated one practical use of the new data: since maps of nighttime light emission highlight the areas where light pollution is especially prevalent, they provide information about which areas can best be targeted for energy savings. Coauthor Dr. Franz Hölker from the Leibniz Institute for Freshwater Ecology and Inland Fisheries (IGB) explains, "artificial light is responsible for a sizable portion of all nighttime electricity consumption. Identifying areas where light could be more efficiently used will make it possible to save energy, reduce costs, and reduce the impact of artificial light on the nighttime environment." <|im_end|>

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1,941

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Quantum entanglement between spatially separated objects is one of the most intriguing phenomena in physics. The outcomes of independent measurements on entangled objects show correlations that cannot be explained by classical physics. As well as being of fundamental interest, entanglement is a unique resource for quantum information processing and communication. Entangled quantum bits (qubits) can be used to share private information or implement quantum logical gates 1 , 2 . Such capabilities are particularly useful when the entangled qubits are spatially separated 3 , 4 , 5 , providing the opportunity to create highly connected quantum networks 6 or extend quantum cryptography to long distances 7 , 8 . Here we report entanglement of two electron spin qubits in diamond with a spatial separation of three metres. We establish this entanglement using a robust protocol based on creation of spin–photon entanglement at each location and a subsequent joint measurement of the photons. Detection of the photons heralds the projection of the spin qubits onto an entangled state. We verify the resulting non-local quantum correlations by performing single-shot readout 9 on the qubits in different bases. The long-distance entanglement reported here can be combined with recently achieved initialization, readout and entanglement operations 9 , 10 , 11 , 12 , 13 on local long-lived nuclear spin registers, paving the way for deterministic long-distance teleportation, quantum repeaters and extended quantum networks. Main A quantum network can be constructed by using entanglement to connect local processing nodes, each containing a register of well-controlled and long-lived qubits 6 . Solids are an attractive platform for such registers, as the use of nanofabrication and material design may enable well-controlled and scalable qubit systems 14 . The potential impact of quantum networks on science and technology has recently spurred research efforts towards generating entangled states of distant solid-state qubits 15 , 16 , 17 , 18 , 19 , 20 , 21 . A prime candidate for a solid-state quantum register is the nitrogen–vacancy (NV) defect centre in diamond. The NV centre combines a long-lived electronic spin ( S = 1) with a robust optical interface, enabling measurement and high-fidelity control of the spin qubit 15 , 22 , 23 , 24 . Furthermore, the NV electron spin can be used to access and manipulate nearby nuclear spins 9 , 10 , 11 , 12 , 13 , 25 , thereby forming a multi-qubit register. To use such registers in a quantum network requires a mechanism to coherently connect remote NV centres. Here we demonstrate the generation of entanglement between NV centre spin qubits in distant set-ups. We achieve this by combining recently established spin initialization and single-shot readout techniques 9 with efficient resonant optical detection and feedback-based control over the optical transitions, all in a single experiment and executed with high fidelity. These results put solid-state qubits on a par with trapped atomic qubits 3 , 4 , 5 as highly promising candidates for implementing quantum networks. Our experiment makes use of two NV spin qubits located in independent low-temperature set-ups separated by 3 m ( Fig. 1a ). We encode the qubit basis states |↑〉 and |↓〉 in the NV spin sublevels m S = 0 and m S = −1, respectively. Each qubit can be independently read out by detecting spin-dependent fluorescence in the NV phonon sideband (non-resonant detection) 9 . The qubits are individually controlled with microwave pulses applied to on-chip striplines 23 . Quantum states encoded in the qubits are extremely long-lived: using dynamical decoupling techniques 23 , we obtain a coherence time exceeding 10 ms ( Fig. 1b ), which is the longest coherence time measured so far for a single electron spin in a solid. Figure 1: Experimental set-up and protocol for generating long-distance entanglement between two solid-state spin qubits. a , Experimental set-up. Each nitrogen–vacancy (NV) centre resides in a synthetic ultrapure diamond oriented in the <111> direction. The two diamonds are located in two independent low-temperature confocal microscope set-ups separated by 3 m. The NV centres can be individually excited resonantly by red lasers and off-resonantly by a green laser. The emission (dashed arrows) is spectrally separated into an off-resonant part (phonon sideband, PSB) and a resonant part (zero-phonon line, ZPL). The PSB emission is used for independent single-shot readout of the spin qubits 9 . The ZPL photons from the two NV centres are overlapped on a fibre-coupled beamsplitter. Microwave pulses for spin control are applied via on-chip microwave striplines. An applied magnetic field of 17.5 G splits the m S = ±1 levels in energy. The optical frequencies of NV B are tuned by a d.c. electric field applied to the gate electrodes (inset, scanning electron microscope image of a similar device). To enhance the collection efficiency, solid immersion lenses have been milled around the two NV centres 9 . b , The coherence of the NV B spin qubit as a function of total free evolution time t FE during an N -pulse dynamical decoupling sequence 23 . Curves are fitted to A exp[−( t FE / T coh ) 3 ] + 0.5. For N = 64 we find T coh = 14.3 ± 0.4 ms. Error bars are 2 s.e. c , Entanglement protocol (details in main text), illustrating the pulse sequence applied simultaneously to both NV centres. Both NV centres are initially prepared in a superposition 1/√2(|↑〉+|↓〉). A short 2 ns spin-selective resonant laser pulse creates spin–photon entanglement 1/√2(|↑1〉+|↓0〉). The photons are overlapped on the beamsplitter and detected in the two output ports. Both spins are then flipped, and the NV centres are excited a second time. The detection of one photon in each excitation round heralds the entanglement and triggers individual spin readout. PowerPoint slide Full size image We generate and herald entanglement between these distant qubits by detecting the resonance fluorescence of the NV centres. The specific entanglement protocol we use is based on the proposal of ref. 26 , and is schematically drawn in Fig. 1c .", "role": "user" }, { "content": "(Phys.org) —Researchers at TU Delft in the Netherlands have managed to bring two electrons, three meters from each other, into a quantum- entangled state. This result marks a major step towards realizing a quantum network that can be used to connect future quantum computers and to send information in a completely secure way by means of 'teleportation'. The results have been published online on April 24 in Nature. Entanglement is arguably the most intriguing consequence of the laws of quantum mechanics. When two particles become entangled, their identities merge: their collective state is precisely determined but the individual identity of each of the particles has disappeared. The entangled particles behave as one, even when separated by a large distance. Einstein doubted this prediction, which he called 'spooky action at a distance', but experiments have proven its existance. Entangled states are interesting for computers as they allow a huge number of calculations to be carried out simultaneously. A quantum computer with 400 basic units ('quantum bits') could, for example, already process more bits of information simultaneously than there are atoms in the universe. In recent years, scientists have succeeded in entangling quantum bits within a single chip. Now, for the first time, this has been successfully achieved with quantum bits on different chips. Prof. Ronald Hanson's research group at TU Delft's Kavli Institute of Nanoscience makes quantum bits from electrons in diamonds. 'We use diamonds because they form 'mini-prisons' for electrons if there is a nitrogen atom in the position of one of the carbon atoms. As we can examine these mini-prisons individually, we can study and monitor an individual electron and even a single atomic nucleus. We can prepare the spin (direction of rotation) of these particles in a previously determined state, control the spin and subsequently read it out. We do all this using a material from which chips can be made. That is important it is believed that only chip-based systems can be scaled up to a practical technology', Hanson explains. The two electrons are stimulated by a laser pulse to emit a photon (particle of light). This photon carries with it information on the state of the electron. Both photons pass at the same time through a semi-transparant mirror. Following the laws of quantum physics, a photon detected behind the mirror came from both electrons at the same time. This way detection of a photon entangles the two electrons. Measurement of the state (‘spin’) of one of the electrons then instantaneously determines the state of the other electron. Compare this to tossing a coin. Tossing a single coin yields a random outcome. But for entangled coins, whenever one of the coins shows “heads”, the other one always yields “tails”, and vice versa. Entanglement over a distance of three metres Co-financed by the FOM Foundation and in cooperation entity. 'Incidentally, the three-metre distance between the electrons was chosen quite arbitrarily. We could conduct this experiment over much larger distances', Hanson adds.with the British firm Element Six, Hanson and his colleagues succeeded in bringing two electrons in different diamonds, situated at several metres' distance from each other, into an entangled state. As the two electrons do not feel each other at this large distance, the researchers used light particles to mediate the required interaction. To prove the resulting entanglement, the spin orientation of both electrons was read out and compared. Although the spin orientation of each electron individually was completely random, exactly as predicted by quantum mechanics, the researchers found that the two orientations were always exactly opposite to each other. This proves that the two electrons are entangled and behave as a single entity. 'Incidentally, the three-metre distance between the electrons was chosen quite arbitrarily. We could conduct this experiment over much larger distances', Hanson adds. TeleportationThe next step for the research is the teleportation of electrons. Hanson: 'In theory it is possible to 'teleport' the state of a particle over a large distance to another particle by making smart use of entanglement. Quantum teleportation does not relocate the material itself, but only the state of that material. But given the fact that all elementary particles are identical, quantum teleportation of one electron to another has the same effect as relocating the electron.' According to Hanson, in addition to new fundamental insights, there are two further reasons why the publication in Nature is likely to be an important impulse for the development of new technologies. 'Firstly, because this is an important step towards creating a quantum network for communication between future quantum computers – a quantum internet. We are already working on expanding the experiments using more quantum bits per chip. Entanglement could be used to link such a network of quantum computers.' 'Secondly, teleportation offers the possibility of sending information in a completely secure way. With teleportation, the information does not travel through the intermediate space and therefore cannot be intercepted.' ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Quantum entanglement between spatially separated objects is one of the most intriguing phenomena in physics. The outcomes of independent measurements on entangled objects show correlations that cannot be explained by classical physics. As well as being of fundamental interest, entanglement is a unique resource for quantum information processing and communication. Entangled quantum bits (qubits) can be used to share private information or implement quantum logical gates 1 , 2 . Such capabilities are particularly useful when the entangled qubits are spatially separated 3 , 4 , 5 , providing the opportunity to create highly connected quantum networks 6 or extend quantum cryptography to long distances 7 , 8 . Here we report entanglement of two electron spin qubits in diamond with a spatial separation of three metres. We establish this entanglement using a robust protocol based on creation of spin–photon entanglement at each location and a subsequent joint measurement of the photons. Detection of the photons heralds the projection of the spin qubits onto an entangled state. We verify the resulting non-local quantum correlations by performing single-shot readout 9 on the qubits in different bases. The long-distance entanglement reported here can be combined with recently achieved initialization, readout and entanglement operations 9 , 10 , 11 , 12 , 13 on local long-lived nuclear spin registers, paving the way for deterministic long-distance teleportation, quantum repeaters and extended quantum networks. Main A quantum network can be constructed by using entanglement to connect local processing nodes, each containing a register of well-controlled and long-lived qubits 6 . Solids are an attractive platform for such registers, as the use of nanofabrication and material design may enable well-controlled and scalable qubit systems 14 . The potential impact of quantum networks on science and technology has recently spurred research efforts towards generating entangled states of distant solid-state qubits 15 , 16 , 17 , 18 , 19 , 20 , 21 . A prime candidate for a solid-state quantum register is the nitrogen–vacancy (NV) defect centre in diamond. The NV centre combines a long-lived electronic spin ( S = 1) with a robust optical interface, enabling measurement and high-fidelity control of the spin qubit 15 , 22 , 23 , 24 . Furthermore, the NV electron spin can be used to access and manipulate nearby nuclear spins 9 , 10 , 11 , 12 , 13 , 25 , thereby forming a multi-qubit register. To use such registers in a quantum network requires a mechanism to coherently connect remote NV centres. Here we demonstrate the generation of entanglement between NV centre spin qubits in distant set-ups. We achieve this by combining recently established spin initialization and single-shot readout techniques 9 with efficient resonant optical detection and feedback-based control over the optical transitions, all in a single experiment and executed with high fidelity. These results put solid-state qubits on a par with trapped atomic qubits 3 , 4 , 5 as highly promising candidates for implementing quantum networks. Our experiment makes use of two NV spin qubits located in independent low-temperature set-ups separated by 3 m ( Fig. 1a ). We encode the qubit basis states |↑〉 and |↓〉 in the NV spin sublevels m S = 0 and m S = −1, respectively. Each qubit can be independently read out by detecting spin-dependent fluorescence in the NV phonon sideband (non-resonant detection) 9 . The qubits are individually controlled with microwave pulses applied to on-chip striplines 23 . Quantum states encoded in the qubits are extremely long-lived: using dynamical decoupling techniques 23 , we obtain a coherence time exceeding 10 ms ( Fig. 1b ), which is the longest coherence time measured so far for a single electron spin in a solid. Figure 1: Experimental set-up and protocol for generating long-distance entanglement between two solid-state spin qubits. a , Experimental set-up. Each nitrogen–vacancy (NV) centre resides in a synthetic ultrapure diamond oriented in the <111> direction. The two diamonds are located in two independent low-temperature confocal microscope set-ups separated by 3 m. The NV centres can be individually excited resonantly by red lasers and off-resonantly by a green laser. The emission (dashed arrows) is spectrally separated into an off-resonant part (phonon sideband, PSB) and a resonant part (zero-phonon line, ZPL). The PSB emission is used for independent single-shot readout of the spin qubits 9 . The ZPL photons from the two NV centres are overlapped on a fibre-coupled beamsplitter. Microwave pulses for spin control are applied via on-chip microwave striplines. An applied magnetic field of 17.5 G splits the m S = ±1 levels in energy. The optical frequencies of NV B are tuned by a d.c. electric field applied to the gate electrodes (inset, scanning electron microscope image of a similar device). To enhance the collection efficiency, solid immersion lenses have been milled around the two NV centres 9 . b , The coherence of the NV B spin qubit as a function of total free evolution time t FE during an N -pulse dynamical decoupling sequence 23 . Curves are fitted to A exp[−( t FE / T coh ) 3 ] + 0.5. For N = 64 we find T coh = 14.3 ± 0.4 ms. Error bars are 2 s.e. c , Entanglement protocol (details in main text), illustrating the pulse sequence applied simultaneously to both NV centres. Both NV centres are initially prepared in a superposition 1/√2(|↑〉+|↓〉). A short 2 ns spin-selective resonant laser pulse creates spin–photon entanglement 1/√2(|↑1〉+|↓0〉). The photons are overlapped on the beamsplitter and detected in the two output ports. Both spins are then flipped, and the NV centres are excited a second time. The detection of one photon in each excitation round heralds the entanglement and triggers individual spin readout. PowerPoint slide Full size image We generate and herald entanglement between these distant qubits by detecting the resonance fluorescence of the NV centres. The specific entanglement protocol we use is based on the proposal of ref. 26 , and is schematically drawn in Fig. 1c .<|im_end|> <|im_start|>assistant (Phys.org) —Researchers at TU Delft in the Netherlands have managed to bring two electrons, three meters from each other, into a quantum- entangled state. This result marks a major step towards realizing a quantum network that can be used to connect future quantum computers and to send information in a completely secure way by means of 'teleportation'. The results have been published online on April 24 in Nature. Entanglement is arguably the most intriguing consequence of the laws of quantum mechanics. When two particles become entangled, their identities merge: their collective state is precisely determined but the individual identity of each of the particles has disappeared. The entangled particles behave as one, even when separated by a large distance. Einstein doubted this prediction, which he called 'spooky action at a distance', but experiments have proven its existance. Entangled states are interesting for computers as they allow a huge number of calculations to be carried out simultaneously. A quantum computer with 400 basic units ('quantum bits') could, for example, already process more bits of information simultaneously than there are atoms in the universe. In recent years, scientists have succeeded in entangling quantum bits within a single chip. Now, for the first time, this has been successfully achieved with quantum bits on different chips. Prof. Ronald Hanson's research group at TU Delft's Kavli Institute of Nanoscience makes quantum bits from electrons in diamonds. 'We use diamonds because they form 'mini-prisons' for electrons if there is a nitrogen atom in the position of one of the carbon atoms. As we can examine these mini-prisons individually, we can study and monitor an individual electron and even a single atomic nucleus. We can prepare the spin (direction of rotation) of these particles in a previously determined state, control the spin and subsequently read it out. We do all this using a material from which chips can be made. That is important it is believed that only chip-based systems can be scaled up to a practical technology', Hanson explains. The two electrons are stimulated by a laser pulse to emit a photon (particle of light). This photon carries with it information on the state of the electron. Both photons pass at the same time through a semi-transparant mirror. Following the laws of quantum physics, a photon detected behind the mirror came from both electrons at the same time. This way detection of a photon entangles the two electrons. Measurement of the state (‘spin’) of one of the electrons then instantaneously determines the state of the other electron. Compare this to tossing a coin. Tossing a single coin yields a random outcome. But for entangled coins, whenever one of the coins shows “heads”, the other one always yields “tails”, and vice versa. Entanglement over a distance of three metres Co-financed by the FOM Foundation and in cooperation entity. 'Incidentally, the three-metre distance between the electrons was chosen quite arbitrarily. We could conduct this experiment over much larger distances', Hanson adds.with the British firm Element Six, Hanson and his colleagues succeeded in bringing two electrons in different diamonds, situated at several metres' distance from each other, into an entangled state. As the two electrons do not feel each other at this large distance, the researchers used light particles to mediate the required interaction. To prove the resulting entanglement, the spin orientation of both electrons was read out and compared. Although the spin orientation of each electron individually was completely random, exactly as predicted by quantum mechanics, the researchers found that the two orientations were always exactly opposite to each other. This proves that the two electrons are entangled and behave as a single entity. 'Incidentally, the three-metre distance between the electrons was chosen quite arbitrarily. We could conduct this experiment over much larger distances', Hanson adds. TeleportationThe next step for the research is the teleportation of electrons. Hanson: 'In theory it is possible to 'teleport' the state of a particle over a large distance to another particle by making smart use of entanglement. Quantum teleportation does not relocate the material itself, but only the state of that material. But given the fact that all elementary particles are identical, quantum teleportation of one electron to another has the same effect as relocating the electron.' According to Hanson, in addition to new fundamental insights, there are two further reasons why the publication in Nature is likely to be an important impulse for the development of new technologies. 'Firstly, because this is an important step towards creating a quantum network for communication between future quantum computers – a quantum internet. We are already working on expanding the experiments using more quantum bits per chip. Entanglement could be used to link such a network of quantum computers.' 'Secondly, teleportation offers the possibility of sending information in a completely secure way. With teleportation, the information does not travel through the intermediate space and therefore cannot be intercepted.' <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Manned submersible dives discovered plastic litter accumulations in a submarine canyon located in the northwestern South China Sea, ∼150 km from the nearest coast. These plastic-dominated litter accumulations were mostly concentrated in two large scours in the steeper middle reach of the canyon. Plastic particles and fragments generally occurred on the upstream-facing sides of large boulders and other topographic obstacles, indicating obstruction during down-valley transportation. Most of the litter accumulations were distributed in the up-valley dipping slopes downstream of the scour centers. This pattern is tentatively linked to turbidity currents, which accelerated down the steep upstream slopes of the scours and underwent a hydraulic jump toward the scour centers before decelerating on the upstream-facing flank. Associated seabed sediment consisted of clayey and sandy silts, with unimodal or bimodal grain-size distributions, which are typical for turbidites. The focused distribution of the litter accumulations is therefore linked to turbidity currents that episodically flush the canyon. Our findings provide evidence that litter dispersion in the deep sea may initially be governed by gravity flows, and that turbidity currents efficiently transfer plastic litter to the deeper ocean floor. INTRODUCTION Marine plastic pollution is a pressing global challenge because of its deleterious impact on the environment and its ecosystems, on human health, and on social economy ( U.N. Environment, 2019 ). It has been estimated that ∼4.8–12.7 million tons of plastics enter the oceans each year ( Jambeck et al., 2015 ), and 70% of this amount would reach the seafloor ( Pham et al., 2014 ). Compared to waste floating on the sea surface, benthic litter has received considerably less attention, primarily due to the difficulty of access. Limited studies have nevertheless shown that benthic litter is ubiquitous in the ocean ( Tekman et al., 2017 ; Chiba et al., 2018 ). Submarine canyons not only serve as conduits delivering vast amounts of sediments, nutrients, and pollutants into the deep sea, but also as sinks (permanent and/or transient) of large volumes of such materials ( Fildani, 2017 ). Litter density in submarine canyons has been reported to be 2–3 times higher than that on adjacent open shelves and slopes ( Pham et al., 2014 ; Cau et al., 2017 ; Kane et al., 2020 ). The mechanisms by which benthic litter is dispersed in submarine canyons are, however, largely unknown. It has been suggested that certain underflows, including internal tides ( Schlining et al., 2013 ; van den Beld et al., 2017 ) and various types of gravity flows ( Wei et al., 2012 ; Tubau et al., 2015 ; Daly et al., 2018 ; Kane and Clare, 2019 ; Pierdomenico et al., 2019 ; Pohl et al., 2020 ), might be responsible. Here, we report the results of manned submersible dives that found focused accumulations of benthic litter in a submarine canyon of the South China Sea (SCS). We investigated the transport and depositional processes that formed these accumulations by documenting litter distribution together with grain-size and morphodynamic analyses. BACKGROUND AND METHODS Located in the northwestern SCS, the studied submarine canyon (18.10–18.64°N, 111.86–112.10°E) is headed at 350 m water depth on the outer shelf, ∼150 km from the nearest coast, and it terminates at ∼2350 m depth on the continental slope. At its distal end, it merges with the Xisha Trough, a large submarine canyon in the SCS ( Fig. 1A ). The shelf-indented canyon consists of a 20-km-long, relatively gentle upper reach, followed by an 8-km-long, steep and rugged middle reach, and a 32-km-long flat lower reach. The middle reach of the canyon, the focus of this study, consists of a long stepped chute leading into two successive large scours at the chute toe ( Fig. 1B ; Fig. S1 in the Supplemental Material 1 ). Circulation on the northern SCS margin is characterized by three layers of western boundary currents (WBCs), i.e., the upper layer cyclonic (<500–1000 m water depth), the intermediate anticyclonic, and the deep cyclonic (>2000 m water depth) WBCs ( Wang et al., 2011 ; Zhou et al., 2017 ; Zhu et al., 2019 ). Shelf-parallel currents also occur, including the Guangdong Coastal Current in the nearshore area, and the SCS Warm Current (SCSWC) mainly between the 200 and 400 m isobaths in the outer shelf to shelf-break zone ( Fig. 1A ; Guan and Fang, 2006 ). In addition, the margin is subject to frequent typhoons and strong internal waves ( Alford et al., 2015 ). We conducted seven manned submersible dives in May 2018 (dive 78), July 2019 (dives 159 and 172–173), and March 2020 (dives 227–229; Figs. 1 – 3 ). The initial purpose of these dives was to investigate the step-like morphology in the canyon’s middle reach. However, we encountered unexpectedly large litter accumulations in our first dive ( Fig. 2 ; Fig. S1; Peng et al., 2019 ). These accumulations became the focus of the present study. We used visual observations and video footage collected during the dives to investigate the occurrence of the benthic litter, locate the litter piles, and measure their sizes. The video footage was clear enough to allow us to identify litter items larger than 10 cm in size. The scattered litter items were individually counted along the dive tracks on each photographic snapshot, with density denoted by number of litter items per snapshot (nlps, Fig. 3 ). Areas of high density (≥4 nlps) in litter items were delineated ( Figs. 2A , 2B , and 3 ). The length, width, height, and orientation of the litter piles were measured (Table S1). These estimates may have an error of up to 20%–30% as evaluated by repeat observations of individual litter piles. One 27-cm-long piston core was sampled at 1 cm intervals for grain-size analysis using a laser particle-size analyzer to understand the nature of the bottom sediment ( Fig. 1C ). Details of the background and methods are provided in the Supplemental Material. RESULTS Benthic litter in the canyon occurred either as scattered items or in piles (", "role": "user" }, { "content": "Benthic plastic litter is a main source of pollutants in oceans, but how it disperses is largely unknown. This study by Guangfa Zhong and Xiaotong Peng, published today in Geology, presents novel findings on the distribution patterns and dispersion mechanisms of deep-sea plastic waste in a submarined canyon located in the northwestern South China Sea. Evidence collected from a series of manned submersible dives indicate that the plastic litter items transported and deposited in the canyon are most likely controlled by turbidity currents. Here the plastic litter items are highly heterogeneously distributed: Up to 89% of them occur in a few scours of the canyon. The plastic items are mostly accumulated in longitudinal litter piles of 2-61 m long, 0.5-8 m wide, and 0.1-1.2 m high on average. Plastic particles and fragments generally occurred on the upstream-facing sides of large boulders and other topographic obstacles, indicating obstruction during down-valley transportation. Furthermore, the litter piles were mostly distributed in the up-valley dipping slopes downstream of the scour centers, which is tentatively linked to the deceleration of turbidity currents after shedding down the steep upstream slopes of the scours and undergoing a hydraulic jump at the scour centers. This interpretation is supported by the sedimentological evidence from grain-size analysis of associated seabed sediment. The results of this study lend support to the hypothesis of turbidity-current-controlled dispersion of plastic litter and bear implications on deep-sea environmental protection and surveillance. The focused and patterned distribution of benthic plastics in the canyon that can be reasonably explained by morphodynamic interactions sheds light on monitoring or even removal of deep-sea macro-plastic pollutants. Photo showing plastic particles and fragments occurred on the upstream-facing side of a large boulder. Upstream is on the right side. A higher-resolution photo is available. Credit: Guangfa Zhong and Xiaotong Peng Bathymetric contour maps in the upper (A) and lower (B) scours at the downstream end of the steeper middle reach of the canyon, showing distribution of the plastic litter piles in the up-valley (northward) dipping slopes downstream of local scour centers. Color dotted lines indicate litter piles, with dots denoting locations and lines indicating orientations. Color dashed lines show dive tracks. Thin solid black lines represent isobaths. A higher-resolution version of this figure is available. Credit: Guangfa Zhong and Xiaotong Peng ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Manned submersible dives discovered plastic litter accumulations in a submarine canyon located in the northwestern South China Sea, ∼150 km from the nearest coast. These plastic-dominated litter accumulations were mostly concentrated in two large scours in the steeper middle reach of the canyon. Plastic particles and fragments generally occurred on the upstream-facing sides of large boulders and other topographic obstacles, indicating obstruction during down-valley transportation. Most of the litter accumulations were distributed in the up-valley dipping slopes downstream of the scour centers. This pattern is tentatively linked to turbidity currents, which accelerated down the steep upstream slopes of the scours and underwent a hydraulic jump toward the scour centers before decelerating on the upstream-facing flank. Associated seabed sediment consisted of clayey and sandy silts, with unimodal or bimodal grain-size distributions, which are typical for turbidites. The focused distribution of the litter accumulations is therefore linked to turbidity currents that episodically flush the canyon. Our findings provide evidence that litter dispersion in the deep sea may initially be governed by gravity flows, and that turbidity currents efficiently transfer plastic litter to the deeper ocean floor. INTRODUCTION Marine plastic pollution is a pressing global challenge because of its deleterious impact on the environment and its ecosystems, on human health, and on social economy ( U.N. Environment, 2019 ). It has been estimated that ∼4.8–12.7 million tons of plastics enter the oceans each year ( Jambeck et al., 2015 ), and 70% of this amount would reach the seafloor ( Pham et al., 2014 ). Compared to waste floating on the sea surface, benthic litter has received considerably less attention, primarily due to the difficulty of access. Limited studies have nevertheless shown that benthic litter is ubiquitous in the ocean ( Tekman et al., 2017 ; Chiba et al., 2018 ). Submarine canyons not only serve as conduits delivering vast amounts of sediments, nutrients, and pollutants into the deep sea, but also as sinks (permanent and/or transient) of large volumes of such materials ( Fildani, 2017 ). Litter density in submarine canyons has been reported to be 2–3 times higher than that on adjacent open shelves and slopes ( Pham et al., 2014 ; Cau et al., 2017 ; Kane et al., 2020 ). The mechanisms by which benthic litter is dispersed in submarine canyons are, however, largely unknown. It has been suggested that certain underflows, including internal tides ( Schlining et al., 2013 ; van den Beld et al., 2017 ) and various types of gravity flows ( Wei et al., 2012 ; Tubau et al., 2015 ; Daly et al., 2018 ; Kane and Clare, 2019 ; Pierdomenico et al., 2019 ; Pohl et al., 2020 ), might be responsible. Here, we report the results of manned submersible dives that found focused accumulations of benthic litter in a submarine canyon of the South China Sea (SCS). We investigated the transport and depositional processes that formed these accumulations by documenting litter distribution together with grain-size and morphodynamic analyses. BACKGROUND AND METHODS Located in the northwestern SCS, the studied submarine canyon (18.10–18.64°N, 111.86–112.10°E) is headed at 350 m water depth on the outer shelf, ∼150 km from the nearest coast, and it terminates at ∼2350 m depth on the continental slope. At its distal end, it merges with the Xisha Trough, a large submarine canyon in the SCS ( Fig. 1A ). The shelf-indented canyon consists of a 20-km-long, relatively gentle upper reach, followed by an 8-km-long, steep and rugged middle reach, and a 32-km-long flat lower reach. The middle reach of the canyon, the focus of this study, consists of a long stepped chute leading into two successive large scours at the chute toe ( Fig. 1B ; Fig. S1 in the Supplemental Material 1 ). Circulation on the northern SCS margin is characterized by three layers of western boundary currents (WBCs), i.e., the upper layer cyclonic (<500–1000 m water depth), the intermediate anticyclonic, and the deep cyclonic (>2000 m water depth) WBCs ( Wang et al., 2011 ; Zhou et al., 2017 ; Zhu et al., 2019 ). Shelf-parallel currents also occur, including the Guangdong Coastal Current in the nearshore area, and the SCS Warm Current (SCSWC) mainly between the 200 and 400 m isobaths in the outer shelf to shelf-break zone ( Fig. 1A ; Guan and Fang, 2006 ). In addition, the margin is subject to frequent typhoons and strong internal waves ( Alford et al., 2015 ). We conducted seven manned submersible dives in May 2018 (dive 78), July 2019 (dives 159 and 172–173), and March 2020 (dives 227–229; Figs. 1 – 3 ). The initial purpose of these dives was to investigate the step-like morphology in the canyon’s middle reach. However, we encountered unexpectedly large litter accumulations in our first dive ( Fig. 2 ; Fig. S1; Peng et al., 2019 ). These accumulations became the focus of the present study. We used visual observations and video footage collected during the dives to investigate the occurrence of the benthic litter, locate the litter piles, and measure their sizes. The video footage was clear enough to allow us to identify litter items larger than 10 cm in size. The scattered litter items were individually counted along the dive tracks on each photographic snapshot, with density denoted by number of litter items per snapshot (nlps, Fig. 3 ). Areas of high density (≥4 nlps) in litter items were delineated ( Figs. 2A , 2B , and 3 ). The length, width, height, and orientation of the litter piles were measured (Table S1). These estimates may have an error of up to 20%–30% as evaluated by repeat observations of individual litter piles. One 27-cm-long piston core was sampled at 1 cm intervals for grain-size analysis using a laser particle-size analyzer to understand the nature of the bottom sediment ( Fig. 1C ). Details of the background and methods are provided in the Supplemental Material. RESULTS Benthic litter in the canyon occurred either as scattered items or in piles (<|im_end|> <|im_start|>assistant Benthic plastic litter is a main source of pollutants in oceans, but how it disperses is largely unknown. This study by Guangfa Zhong and Xiaotong Peng, published today in Geology, presents novel findings on the distribution patterns and dispersion mechanisms of deep-sea plastic waste in a submarined canyon located in the northwestern South China Sea. Evidence collected from a series of manned submersible dives indicate that the plastic litter items transported and deposited in the canyon are most likely controlled by turbidity currents. Here the plastic litter items are highly heterogeneously distributed: Up to 89% of them occur in a few scours of the canyon. The plastic items are mostly accumulated in longitudinal litter piles of 2-61 m long, 0.5-8 m wide, and 0.1-1.2 m high on average. Plastic particles and fragments generally occurred on the upstream-facing sides of large boulders and other topographic obstacles, indicating obstruction during down-valley transportation. Furthermore, the litter piles were mostly distributed in the up-valley dipping slopes downstream of the scour centers, which is tentatively linked to the deceleration of turbidity currents after shedding down the steep upstream slopes of the scours and undergoing a hydraulic jump at the scour centers. This interpretation is supported by the sedimentological evidence from grain-size analysis of associated seabed sediment. The results of this study lend support to the hypothesis of turbidity-current-controlled dispersion of plastic litter and bear implications on deep-sea environmental protection and surveillance. The focused and patterned distribution of benthic plastics in the canyon that can be reasonably explained by morphodynamic interactions sheds light on monitoring or even removal of deep-sea macro-plastic pollutants. Photo showing plastic particles and fragments occurred on the upstream-facing side of a large boulder. Upstream is on the right side. A higher-resolution photo is available. Credit: Guangfa Zhong and Xiaotong Peng Bathymetric contour maps in the upper (A) and lower (B) scours at the downstream end of the steeper middle reach of the canyon, showing distribution of the plastic litter piles in the up-valley (northward) dipping slopes downstream of local scour centers. Color dotted lines indicate litter piles, with dots denoting locations and lines indicating orientations. Color dashed lines show dive tracks. Thin solid black lines represent isobaths. A higher-resolution version of this figure is available. Credit: Guangfa Zhong and Xiaotong Peng <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Nanowire -based field-effect transistors are among the most promising means of overcoming the limits of today's planar silicon electronic devices, in part because of their suitability for gate-all-around architectures, which provide perfect electrostatic control and facilitate further reductions in “ultimate” transistor size while maintaining low leakage currents. However, an architecture combining a scalable and reproducible structure with good electrical performance has yet to be demonstrated. Here, we report a high performance field-effect transistor implemented on massively parallel dense vertical nanowire arrays with silicided source/drain contacts and scaled metallic gate length fabricated using a simple process. The proposed architecture offers several advantages including better immunity to short channel effects, reduction of device-to-device variability, and nanometer gate length patterning without the need for high-resolution lithography . These benefits are important in the large-scale manufacture of low-power transistors and memory devices. Introduction The development of electronics and the continuous improvement in circuit performance have historically been driven by the “simple” downscaling of the basic circuit building block: the MOS transistor. Today, the physical limitations of nanoscale transistor operation (in particular the increasing power consumption per chip) have led to the development of innovative MOS architectures, such as multi-gate devices (FinFET and tri-gate approaches) to improve electrostatic control of the channel. The natural evolution of these architectures is the gate-all-around (GAA) transistor 1,2 fabricated on a semiconductor nanowire (NW). These devices represent an ideal design for electrostatic control of charge inversion and permit further reductions in transistor size. However, the current flowing through such devices in the “on” state (current drive) remains low due to the small cross-sectional area of the NW. It is therefore essential to implement these transistors on nanowire arrays rather than on single NWs in order to combine excellent electrostatic control with increased current capability and an improved signal/noise ratio. The numerous methods for fabricating NWs may be grouped into bottom-up (B-U) and top-down (T-D) approaches. In B-U methods, the NWs are grown on a substrate using chemical deposition techniques, whereas nanostructure formation in T-D fabrication is based on the selective etching of a patterned planar material. Each method has its own advantages and drawbacks: the B-U route enables NWs to be grown using a large variety of materials, while the T-D approach may be quickly integrated into standard CMOS processes with a very good reproducibility and NW control (position, diameter, and pitch). From an integration point of view, NWs may be processed horizontally (planar) or vertically. Horizontal NW approaches are limited in terms of NW density. NWs fabricated using etching processes (T-D) have, in the best case, a density slightly higher than those fabricated using conventional planar technology, 3 while high-density arrays are very difficult to achieve using horizontal growth techniques (B-U). In order to obtain a planar orientation, horizontal growth must be guided in cavities 4 or the NWs must be grown separate from the substrate and then relocated 5,6 in a complex, contamination-prone, and poorly reproducible process. Multi-layer horizontally stacked NWs 7 require extremely complex processes, and achieving the desired device miniaturization is fraught with difficulty. On the other hand, vertical integration is a particularly attractive approach because its 3-D character is directly compatible with both T-D and B-U growth methods and the process results in extremely high integration densities 8 (70% surface shrink compared to planar architecture 3 ), opening the way to new integration approaches. Despite this promising potential, a vertical approach has not yet been used to demonstrate an outstanding scaled architecture because of challenges such as contact formation at the bottom of the wires, 9 and perfect control of the thickness and flatness of spacer layers. 10–13 In this work, we realize a FET device implemented on a vertical NW array with a sub-14 nm gate length ( L g ) that demonstrates excellent electrostatic behavior and promising scaling properties in view of reaching sub-5 nm architecture. An easy-to-manufacture nano-transistor The proposed architecture was implemented on dense Si NW arrays obtained using a top-down approach that couples e-beam lithography with plasma etching and sacrificial self-limited oxidation. 14 The process is based on the stress retarded oxidation phenomenon 15 and enables fabrication of very reproducible NWs with perfectly controlled diameter and position and much lower dimensional variability than other top-down approaches. Free standing NWs with diameters as small as 16 nm 14 have been patterned starting from a (100) bulk wafer with a p-type doping level of 8 × 10 18 at. cm −3 . The diameter dimension is taken at the middle part of the nanowire. Fig. 1a is a schematic view of the device in which terminals embedded in a dielectric matrix are positioned at the bottom, center, and top of the NW for use as the source, gate and drain contacts. Fabrication begins with formation of a thin gate oxide (5 nm) using dry oxidation followed by an anisotropic plasma etch to remove the oxide layer at each nanowire termination. A 15 nm platinum layer is anisotropically deposited using e-beam evaporation, and temperature activation (RTP N 2 H 2 , 500 °C/3 min) is used to create silicided contacts at the bottom and the top of each NW (the source and drain contacts). The greatest technological challenge in fabricating competitive 3D vertical devices is obtaining nanometer-scale control of the layer engineering using conventional methods rather than high-resolution lithography. A key step is the construction of the insulating layer between the contact electrodes (source, gate, and drain, Fig. 1a ) in order to achieve symmetrical ultra-small scale devices. Previous attempts 11–13 exhibited sloping layers (up- or down-slope depending on the process conditions). The corresponding gate layers, which necessarily reproduce the shape of the underlying insulator, therefore induced high parasitic capacitances and prevented successful downscaling. By employing a spin-on glass filling step followed by a chemical etch-back, we achieved perfect control of the insulator layer planarization to obtain a flat topology as well as nanometer-scale thickness control. An inorganic flowable resist with a chemical structure (hydrogen silsesquioxane) similar to silicon dioxide was", "role": "user" }, { "content": "(Phys.org) —Two French researchers, Guilhem Larrieu and Xiang‑Lei Han, may have succeeded in possibly setting back the date to which Moore's Law would no longer apply by creating a new kind of nanowire Field-Effect Transistor (FET). In their paper published in the journal Nanoscale, the two describe how they built a \"gate-all-around\" made of 225 nanowires, each with its own 14nm-thick chromium layer that serves as a gate. In their search to find new ways to cram more electronics onto the same size chips, researchers have turned to FETs. Transistors on chips are the parts that control the flow of electricity—figuring out a way to make them smaller is a vital part of keeping Moore's Law alive. One way to do this is to do away with wires and instead use nanowires. However, because of their small size, nanowires aren't capable of carrying enough current to do the work necessary on a chip. To get around that, researchers have tried creating bundles of nanowires; but thus far, the gates to control them have been too unwieldy. In this new effort, the researchers tried a different approach. First they created a forest of 225 nanowires by etching a slab of silicon—the bottom half of each nanowire is submersed in a material that serves as a source. Just up from that base, the researchers applied a chromium layer wrapped all the way around the nanowire to serve as the gate. Above that was another layer of material that serves as the sink. This simple design allows each nanowire to be controlled by its individual gate, and the researchers report the thickness of the gate is what makes it all work. At 14nm, the gate can be made short enough to continue to allow for the control of the current. The result is a transistor that thus far appears to be a workable way for increasingly more circuitry to be added to a computer chip. Top surface topography of the low-k dielectric layer that covers the Si NW array using Atomic Force Microscopy (AFM). Credit: Nanoscale, 2013,5, 2437-2441. Should the new design pan out, it won't keep Moore's Law alive forever, of course. One day, researchers will reach a point where it's no longer possible—due to the laws of physics—to add more processing power to a computer chip. As such, new research will necessarily be focused on ways to build smarter computers using different ideas, rather than new materials. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Nanowire -based field-effect transistors are among the most promising means of overcoming the limits of today's planar silicon electronic devices, in part because of their suitability for gate-all-around architectures, which provide perfect electrostatic control and facilitate further reductions in “ultimate” transistor size while maintaining low leakage currents. However, an architecture combining a scalable and reproducible structure with good electrical performance has yet to be demonstrated. Here, we report a high performance field-effect transistor implemented on massively parallel dense vertical nanowire arrays with silicided source/drain contacts and scaled metallic gate length fabricated using a simple process. The proposed architecture offers several advantages including better immunity to short channel effects, reduction of device-to-device variability, and nanometer gate length patterning without the need for high-resolution lithography . These benefits are important in the large-scale manufacture of low-power transistors and memory devices. Introduction The development of electronics and the continuous improvement in circuit performance have historically been driven by the “simple” downscaling of the basic circuit building block: the MOS transistor. Today, the physical limitations of nanoscale transistor operation (in particular the increasing power consumption per chip) have led to the development of innovative MOS architectures, such as multi-gate devices (FinFET and tri-gate approaches) to improve electrostatic control of the channel. The natural evolution of these architectures is the gate-all-around (GAA) transistor 1,2 fabricated on a semiconductor nanowire (NW). These devices represent an ideal design for electrostatic control of charge inversion and permit further reductions in transistor size. However, the current flowing through such devices in the “on” state (current drive) remains low due to the small cross-sectional area of the NW. It is therefore essential to implement these transistors on nanowire arrays rather than on single NWs in order to combine excellent electrostatic control with increased current capability and an improved signal/noise ratio. The numerous methods for fabricating NWs may be grouped into bottom-up (B-U) and top-down (T-D) approaches. In B-U methods, the NWs are grown on a substrate using chemical deposition techniques, whereas nanostructure formation in T-D fabrication is based on the selective etching of a patterned planar material. Each method has its own advantages and drawbacks: the B-U route enables NWs to be grown using a large variety of materials, while the T-D approach may be quickly integrated into standard CMOS processes with a very good reproducibility and NW control (position, diameter, and pitch). From an integration point of view, NWs may be processed horizontally (planar) or vertically. Horizontal NW approaches are limited in terms of NW density. NWs fabricated using etching processes (T-D) have, in the best case, a density slightly higher than those fabricated using conventional planar technology, 3 while high-density arrays are very difficult to achieve using horizontal growth techniques (B-U). In order to obtain a planar orientation, horizontal growth must be guided in cavities 4 or the NWs must be grown separate from the substrate and then relocated 5,6 in a complex, contamination-prone, and poorly reproducible process. Multi-layer horizontally stacked NWs 7 require extremely complex processes, and achieving the desired device miniaturization is fraught with difficulty. On the other hand, vertical integration is a particularly attractive approach because its 3-D character is directly compatible with both T-D and B-U growth methods and the process results in extremely high integration densities 8 (70% surface shrink compared to planar architecture 3 ), opening the way to new integration approaches. Despite this promising potential, a vertical approach has not yet been used to demonstrate an outstanding scaled architecture because of challenges such as contact formation at the bottom of the wires, 9 and perfect control of the thickness and flatness of spacer layers. 10–13 In this work, we realize a FET device implemented on a vertical NW array with a sub-14 nm gate length ( L g ) that demonstrates excellent electrostatic behavior and promising scaling properties in view of reaching sub-5 nm architecture. An easy-to-manufacture nano-transistor The proposed architecture was implemented on dense Si NW arrays obtained using a top-down approach that couples e-beam lithography with plasma etching and sacrificial self-limited oxidation. 14 The process is based on the stress retarded oxidation phenomenon 15 and enables fabrication of very reproducible NWs with perfectly controlled diameter and position and much lower dimensional variability than other top-down approaches. Free standing NWs with diameters as small as 16 nm 14 have been patterned starting from a (100) bulk wafer with a p-type doping level of 8 × 10 18 at. cm −3 . The diameter dimension is taken at the middle part of the nanowire. Fig. 1a is a schematic view of the device in which terminals embedded in a dielectric matrix are positioned at the bottom, center, and top of the NW for use as the source, gate and drain contacts. Fabrication begins with formation of a thin gate oxide (5 nm) using dry oxidation followed by an anisotropic plasma etch to remove the oxide layer at each nanowire termination. A 15 nm platinum layer is anisotropically deposited using e-beam evaporation, and temperature activation (RTP N 2 H 2 , 500 °C/3 min) is used to create silicided contacts at the bottom and the top of each NW (the source and drain contacts). The greatest technological challenge in fabricating competitive 3D vertical devices is obtaining nanometer-scale control of the layer engineering using conventional methods rather than high-resolution lithography. A key step is the construction of the insulating layer between the contact electrodes (source, gate, and drain, Fig. 1a ) in order to achieve symmetrical ultra-small scale devices. Previous attempts 11–13 exhibited sloping layers (up- or down-slope depending on the process conditions). The corresponding gate layers, which necessarily reproduce the shape of the underlying insulator, therefore induced high parasitic capacitances and prevented successful downscaling. By employing a spin-on glass filling step followed by a chemical etch-back, we achieved perfect control of the insulator layer planarization to obtain a flat topology as well as nanometer-scale thickness control. An inorganic flowable resist with a chemical structure (hydrogen silsesquioxane) similar to silicon dioxide was<|im_end|> <|im_start|>assistant (Phys.org) —Two French researchers, Guilhem Larrieu and Xiang‑Lei Han, may have succeeded in possibly setting back the date to which Moore's Law would no longer apply by creating a new kind of nanowire Field-Effect Transistor (FET). In their paper published in the journal Nanoscale, the two describe how they built a "gate-all-around" made of 225 nanowires, each with its own 14nm-thick chromium layer that serves as a gate. In their search to find new ways to cram more electronics onto the same size chips, researchers have turned to FETs. Transistors on chips are the parts that control the flow of electricity—figuring out a way to make them smaller is a vital part of keeping Moore's Law alive. One way to do this is to do away with wires and instead use nanowires. However, because of their small size, nanowires aren't capable of carrying enough current to do the work necessary on a chip. To get around that, researchers have tried creating bundles of nanowires; but thus far, the gates to control them have been too unwieldy. In this new effort, the researchers tried a different approach. First they created a forest of 225 nanowires by etching a slab of silicon—the bottom half of each nanowire is submersed in a material that serves as a source. Just up from that base, the researchers applied a chromium layer wrapped all the way around the nanowire to serve as the gate. Above that was another layer of material that serves as the sink. This simple design allows each nanowire to be controlled by its individual gate, and the researchers report the thickness of the gate is what makes it all work. At 14nm, the gate can be made short enough to continue to allow for the control of the current. The result is a transistor that thus far appears to be a workable way for increasingly more circuitry to be added to a computer chip. Top surface topography of the low-k dielectric layer that covers the Si NW array using Atomic Force Microscopy (AFM). Credit: Nanoscale, 2013,5, 2437-2441. Should the new design pan out, it won't keep Moore's Law alive forever, of course. One day, researchers will reach a point where it's no longer possible—due to the laws of physics—to add more processing power to a computer chip. As such, new research will necessarily be focused on ways to build smarter computers using different ideas, rather than new materials. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Gene expression is tightly regulated, with many genes exhibiting cell-specific silencing when their protein product would disrupt normal cellular function 1 . This silencing is largely controlled by non-coding elements, and their disruption might cause human disease 2 . We performed gene-agnostic screening of the non-coding regions to discover new molecular causes of congenital hyperinsulinism. This identified 14 non-coding de novo variants affecting a 42-bp conserved region encompassed by a regulatory element in intron 2 of the hexokinase 1 gene ( HK1 ). HK1 is widely expressed across all tissues except in the liver and pancreatic beta cells and is thus termed a ‘disallowed gene’ in these specific tissues. We demonstrated that the variants result in a loss of repression of HK1 in pancreatic beta cells, thereby causing insulin secretion and congenital hyperinsulinism. Using epigenomic data accessed from public repositories, we demonstrated that these variants reside within a regulatory region that we determine to be critical for cell-specific silencing. Importantly, this has revealed a disease mechanism for non-coding variants that cause inappropriate expression of a disallowed gene. Main Genetic discovery in Mendelian disease has focused on identifying highly penetrant variants affecting the function of genes expressed in clinically affected tissue(s). While this approach has proven successful, the underlying etiology of over 3,000 presumed monogenic diseases remains undefined 2 , 3 , 4 , 5 , of which many have notable clinical and genetic heterogeneity 6 , 7 . Congenital hyperinsulinism (CHI) is characterized by inappropriate insulin secretion during hypoglycemia. It is a clinically and genetically heterogeneous disease for which, despite extensive sequencing efforts, the underlying etiology is not known in up to 50% of individuals 8 , 9 . To identify new etiologies, we performed whole-genome sequencing of 135 individuals with biochemically confirmed, persistent CHI without an identified disease-causing variant in a known gene (Supplementary Table 1 ). We initially searched for genes containing new coding de novo or biallelic variants in two or more individuals. When no such genes were found, we turned to the non-coding genome and searched for de novo copy number variants. This identified a single locus within intron 2 of HK1 containing two heterozygous ~4.5-kb deletions with a 2,787-bp overlap in two unrelated individuals (Extended Data Fig. 1 ). Digital droplet PCR confirmed the deletions in both probands and an affected twin. We next searched for de novo single-nucleotide variants and indels within the minimal deleted region in our whole-genome-sequencing discovery cohort and in a replication cohort of 27 individuals with CHI who had undergone pancreatectomy as part of routine clinical care (Supplementary Table 1 ). This identified seven different de novo variants in 12 probands. In two cases, the variants had been inherited by similarly affected offspring (Fig. 1 ). All variants were new 10 , 11 and within a 42-bp conserved region constrained against variation in the Genome Aggregation Database (gnomAD) 12 . Fig. 1: Schematic representation of the HK1 gene and the identified variants. a , Schematic representation of the HK1 gene (GRCh37/hg19 chromosome 10, 71,029,756–71,161,637). The full-length testis-specific isoform ( ENST00000448642 ) and the shorter ubiquitously expressed isoform ( ENST00000359426 ) are depicted. The positions of the two ~4.5-kb deletions within intron 2 of the shorter isoform and the seven different heterozygous single-nucleotide variants and indels within the minimal deleted region identified in 14 probands are shown. The number of probands with each variant is provided. An asterisk (*) denotes a single proband with two de novo variants (Extended Data Fig. 8 ). The variant positions are given according to the GRCh37/hg19 genomic coordinates. b , Partial pedigrees showing inherited HK1 variants in three families. Filled symbols represent individuals with CHI. ‡ Haplotype analysis confirmed that the HK1 variant had arisen de novo in patient 3.2. M, HK1 variant; N, no variant; NA, DNA not available. Pedigrees for the 11 probands with de novo HK1 variants are not shown. Full size image Overall, the finding of nine different de novo variants in 14 probands, co-segregating with disease in three additional family members, provides overwhelming evidence of disease causality. All 17 individuals with a HK1 non-coding variant had severe early-onset CHI (median age at diagnosis: birth (interquartile range (IQR), 0–14 d)). These variants were not associated with macrosomia at birth (median birthweight z score, 0.61 (IQR, 0.10–1.84)). This suggests that insulin secretion was not markedly increased in utero, given its role as a potent growth factor during fetal development. In all cases, the hyperinsulinism persisted; the eldest individual still known to be affected was 18 years of age. These findings suggest that the variants act to disrupt glucose-induced insulin secretion throughout post-natal life and into adulthood but have less impact during fetal development. The HK1 variants caused a beta cell-specific defect with no common additional features between patients. In five individuals, medical management was ineffective, leading to pancreatic resection. Of these, the only case that had resolution of CHI developed insulin-dependent diabetes following near-total pancreatectomy. Histopathological analysis of resected pancreatic tissue ( n = 2) demonstrated a discrete pathology, distinguishable from diffuse disease resulting from ABCC8 variants, the most common cause of CHI (Extended Data Fig. 2 ). An overview of the clinical features is provided in Supplementary Tables 2 and 3 . HK1 encodes a glycolytic enzyme that is silenced in the pancreas and liver but expressed in all other mature tissues (Extended Data Fig. 3a–c ), where it supports glucose metabolism, ensuring cell survival 13 . Within the pancreatic beta cell, glucose is phosphorylated to glucose 6-phosphate by glucokinase (GCK; hexokinase 4), which, due to a low binding affinity ( K m ~8 mM), acts as the pancreatic glucose sensor coupling insulin release to the prevailing glucose concentration 14 . Hexokinase 1 has a markedly higher affinity for glucose ( K m < 50 µM) 14 . Silencing of HK1 in favor of GCK in the beta cell therefore ensures appropriate glucose sensing, minimizing insulin release at low glucose levels. While biallelic loss-of-function HK1 variants have been reported to", "role": "user" }, { "content": "Scientists have discovered the cause of a rare condition within a part of the genome that has been largely unexplored in medical genetics. A team at the University of Exeter has found genetic changes in a region that controls the activity of the genome, turning on or off genes, and in doing so they have found a key that could unlock other causes of rare conditions. The finding, published in Nature Genetics, is a very rare case of a cause of disease that only results from changes outside the exome, the region of the genome that codes for genes . It is also the first time that changes have been shown to affect a gene—known as HK1—that does not normally have a role in the relevant body tissue—in this case, the pancreas. Until now, scientists have typically sequenced the part of the genome that describes the genetic code of all genes in individuals with a rare disease. They do this looking for variants in the DNA that affects a protein known to have an important role in the disease-relevant organ. A good example is observed in neonatal diabetes, where genetic variants disrupt the function of the pancreatic protein insulin, causing high blood sugar levels. The team at the University of Exeter's search for a genetic cause of Congenital Hyperinsulinism took a more complex path. In contrast to diabetes, this condition causes babies to secrete too much insulin from their pancreas. That means babies can be born very large, and suffer from problems associated with low blood sugar. If the condition is not treated appropriately, the brain can be starved of vital fuels, which can cause learning difficulties, or even death. Until now, scientists have been unable to find the genetic cause of the condition in up to half of babies with Congenital Hyperinsulinism—one reason why treatments are scarce. The limited medications available often fail to work, sometimes meaning the patient has to endure their pancreas being removed. This often fails to cure the disease or in some cases can cause diabetes. Now, a team led by Dr. Sarah Flanagan, at the University of Exeter, has broken new ground—providing answers for families, and unlocking a new way of investigating the causes of many elusive rare diseases. Dr. Flanagan explained: \"We've really struggled to work out what's going on in these 50 percent of babies with no known genetic cause of Congenital Hyperinsulinism. We've been looking for defects in genes for years, but it remained frustratingly elusive.\" Using state-of-the-art technology enabled the team to sequence the genomes of 17 individuals with Congenital Hyperinsulinism with an unexplained cause, revealing a revelation—the genetic variants that were causing the disease did not occur within a protein but within a 'regulatory switch' which is important for turning on and off a protein in the pancreas. The impact of the genetic variants was that HK1 was turned on in the pancreas' of patients with Congenital Hyperinsulinism. The gene, which leads to insulin being produced even when blood sugar levels are low, is usually turned off in the pancreas. But the team found it was active—meaning it was working to lower blood sugar to dangerous levels. Studying a unique collection of pancreatic tissue confirmed this hypothesis. \"It's incredibly important to be able to provide answers to parents who have been desperate to know the cause of their child's condition,\" said Dr. Flanagan. \"Now that the HK1 variants have been discovered, routine genome sequencing in sick children would be the perfect method to detect them at clinical diagnosis allowing for improved outcomes. These findings also pave the way for improved treatment of this condition with the development of drugs that inhibit HK1, and consequently insulin production, being a real possibility.\" \"Even more exciting is the potential for this approach to unlock causes of other genetic conditions. We now know that we need to look across the whole genome to find genetic changes that may affect regulatory switches. We need to specifically turn our attention to the proteins that are turned off in the disease-relevant organ tissue and study how and why they are turned off. That approach could rapidly advance genetics and provide answers, and better treatments.\" The paper is entitled \"Non-coding variants disrupting a tissue-specific regulatory element in HK1 cause congenital hyperinsulinism,\" published in Nature Genetics. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Gene expression is tightly regulated, with many genes exhibiting cell-specific silencing when their protein product would disrupt normal cellular function 1 . This silencing is largely controlled by non-coding elements, and their disruption might cause human disease 2 . We performed gene-agnostic screening of the non-coding regions to discover new molecular causes of congenital hyperinsulinism. This identified 14 non-coding de novo variants affecting a 42-bp conserved region encompassed by a regulatory element in intron 2 of the hexokinase 1 gene ( HK1 ). HK1 is widely expressed across all tissues except in the liver and pancreatic beta cells and is thus termed a ‘disallowed gene’ in these specific tissues. We demonstrated that the variants result in a loss of repression of HK1 in pancreatic beta cells, thereby causing insulin secretion and congenital hyperinsulinism. Using epigenomic data accessed from public repositories, we demonstrated that these variants reside within a regulatory region that we determine to be critical for cell-specific silencing. Importantly, this has revealed a disease mechanism for non-coding variants that cause inappropriate expression of a disallowed gene. Main Genetic discovery in Mendelian disease has focused on identifying highly penetrant variants affecting the function of genes expressed in clinically affected tissue(s). While this approach has proven successful, the underlying etiology of over 3,000 presumed monogenic diseases remains undefined 2 , 3 , 4 , 5 , of which many have notable clinical and genetic heterogeneity 6 , 7 . Congenital hyperinsulinism (CHI) is characterized by inappropriate insulin secretion during hypoglycemia. It is a clinically and genetically heterogeneous disease for which, despite extensive sequencing efforts, the underlying etiology is not known in up to 50% of individuals 8 , 9 . To identify new etiologies, we performed whole-genome sequencing of 135 individuals with biochemically confirmed, persistent CHI without an identified disease-causing variant in a known gene (Supplementary Table 1 ). We initially searched for genes containing new coding de novo or biallelic variants in two or more individuals. When no such genes were found, we turned to the non-coding genome and searched for de novo copy number variants. This identified a single locus within intron 2 of HK1 containing two heterozygous ~4.5-kb deletions with a 2,787-bp overlap in two unrelated individuals (Extended Data Fig. 1 ). Digital droplet PCR confirmed the deletions in both probands and an affected twin. We next searched for de novo single-nucleotide variants and indels within the minimal deleted region in our whole-genome-sequencing discovery cohort and in a replication cohort of 27 individuals with CHI who had undergone pancreatectomy as part of routine clinical care (Supplementary Table 1 ). This identified seven different de novo variants in 12 probands. In two cases, the variants had been inherited by similarly affected offspring (Fig. 1 ). All variants were new 10 , 11 and within a 42-bp conserved region constrained against variation in the Genome Aggregation Database (gnomAD) 12 . Fig. 1: Schematic representation of the HK1 gene and the identified variants. a , Schematic representation of the HK1 gene (GRCh37/hg19 chromosome 10, 71,029,756–71,161,637). The full-length testis-specific isoform ( ENST00000448642 ) and the shorter ubiquitously expressed isoform ( ENST00000359426 ) are depicted. The positions of the two ~4.5-kb deletions within intron 2 of the shorter isoform and the seven different heterozygous single-nucleotide variants and indels within the minimal deleted region identified in 14 probands are shown. The number of probands with each variant is provided. An asterisk (*) denotes a single proband with two de novo variants (Extended Data Fig. 8 ). The variant positions are given according to the GRCh37/hg19 genomic coordinates. b , Partial pedigrees showing inherited HK1 variants in three families. Filled symbols represent individuals with CHI. ‡ Haplotype analysis confirmed that the HK1 variant had arisen de novo in patient 3.2. M, HK1 variant; N, no variant; NA, DNA not available. Pedigrees for the 11 probands with de novo HK1 variants are not shown. Full size image Overall, the finding of nine different de novo variants in 14 probands, co-segregating with disease in three additional family members, provides overwhelming evidence of disease causality. All 17 individuals with a HK1 non-coding variant had severe early-onset CHI (median age at diagnosis: birth (interquartile range (IQR), 0–14 d)). These variants were not associated with macrosomia at birth (median birthweight z score, 0.61 (IQR, 0.10–1.84)). This suggests that insulin secretion was not markedly increased in utero, given its role as a potent growth factor during fetal development. In all cases, the hyperinsulinism persisted; the eldest individual still known to be affected was 18 years of age. These findings suggest that the variants act to disrupt glucose-induced insulin secretion throughout post-natal life and into adulthood but have less impact during fetal development. The HK1 variants caused a beta cell-specific defect with no common additional features between patients. In five individuals, medical management was ineffective, leading to pancreatic resection. Of these, the only case that had resolution of CHI developed insulin-dependent diabetes following near-total pancreatectomy. Histopathological analysis of resected pancreatic tissue ( n = 2) demonstrated a discrete pathology, distinguishable from diffuse disease resulting from ABCC8 variants, the most common cause of CHI (Extended Data Fig. 2 ). An overview of the clinical features is provided in Supplementary Tables 2 and 3 . HK1 encodes a glycolytic enzyme that is silenced in the pancreas and liver but expressed in all other mature tissues (Extended Data Fig. 3a–c ), where it supports glucose metabolism, ensuring cell survival 13 . Within the pancreatic beta cell, glucose is phosphorylated to glucose 6-phosphate by glucokinase (GCK; hexokinase 4), which, due to a low binding affinity ( K m ~8 mM), acts as the pancreatic glucose sensor coupling insulin release to the prevailing glucose concentration 14 . Hexokinase 1 has a markedly higher affinity for glucose ( K m < 50 µM) 14 . Silencing of HK1 in favor of GCK in the beta cell therefore ensures appropriate glucose sensing, minimizing insulin release at low glucose levels. While biallelic loss-of-function HK1 variants have been reported to<|im_end|> <|im_start|>assistant Scientists have discovered the cause of a rare condition within a part of the genome that has been largely unexplored in medical genetics. A team at the University of Exeter has found genetic changes in a region that controls the activity of the genome, turning on or off genes, and in doing so they have found a key that could unlock other causes of rare conditions. The finding, published in Nature Genetics, is a very rare case of a cause of disease that only results from changes outside the exome, the region of the genome that codes for genes . It is also the first time that changes have been shown to affect a gene—known as HK1—that does not normally have a role in the relevant body tissue—in this case, the pancreas. Until now, scientists have typically sequenced the part of the genome that describes the genetic code of all genes in individuals with a rare disease. They do this looking for variants in the DNA that affects a protein known to have an important role in the disease-relevant organ. A good example is observed in neonatal diabetes, where genetic variants disrupt the function of the pancreatic protein insulin, causing high blood sugar levels. The team at the University of Exeter's search for a genetic cause of Congenital Hyperinsulinism took a more complex path. In contrast to diabetes, this condition causes babies to secrete too much insulin from their pancreas. That means babies can be born very large, and suffer from problems associated with low blood sugar. If the condition is not treated appropriately, the brain can be starved of vital fuels, which can cause learning difficulties, or even death. Until now, scientists have been unable to find the genetic cause of the condition in up to half of babies with Congenital Hyperinsulinism—one reason why treatments are scarce. The limited medications available often fail to work, sometimes meaning the patient has to endure their pancreas being removed. This often fails to cure the disease or in some cases can cause diabetes. Now, a team led by Dr. Sarah Flanagan, at the University of Exeter, has broken new ground—providing answers for families, and unlocking a new way of investigating the causes of many elusive rare diseases. Dr. Flanagan explained: "We've really struggled to work out what's going on in these 50 percent of babies with no known genetic cause of Congenital Hyperinsulinism. We've been looking for defects in genes for years, but it remained frustratingly elusive." Using state-of-the-art technology enabled the team to sequence the genomes of 17 individuals with Congenital Hyperinsulinism with an unexplained cause, revealing a revelation—the genetic variants that were causing the disease did not occur within a protein but within a 'regulatory switch' which is important for turning on and off a protein in the pancreas. The impact of the genetic variants was that HK1 was turned on in the pancreas' of patients with Congenital Hyperinsulinism. The gene, which leads to insulin being produced even when blood sugar levels are low, is usually turned off in the pancreas. But the team found it was active—meaning it was working to lower blood sugar to dangerous levels. Studying a unique collection of pancreatic tissue confirmed this hypothesis. "It's incredibly important to be able to provide answers to parents who have been desperate to know the cause of their child's condition," said Dr. Flanagan. "Now that the HK1 variants have been discovered, routine genome sequencing in sick children would be the perfect method to detect them at clinical diagnosis allowing for improved outcomes. These findings also pave the way for improved treatment of this condition with the development of drugs that inhibit HK1, and consequently insulin production, being a real possibility." "Even more exciting is the potential for this approach to unlock causes of other genetic conditions. We now know that we need to look across the whole genome to find genetic changes that may affect regulatory switches. We need to specifically turn our attention to the proteins that are turned off in the disease-relevant organ tissue and study how and why they are turned off. That approach could rapidly advance genetics and provide answers, and better treatments." The paper is entitled "Non-coding variants disrupting a tissue-specific regulatory element in HK1 cause congenital hyperinsulinism," published in Nature Genetics. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract It is widely recognized that collisional mountain belt topography is generated by crustal thickening and lowered by river bedrock erosion, linking climate and tectonics 1 , 2 , 3 , 4 . However, whether surface processes or lithospheric strength control mountain belt height, shape and longevity remains uncertain. Additionally, how to reconcile high erosion rates in some active orogens with long-term survival of mountain belts for hundreds of millions of years remains enigmatic. Here we investigate mountain belt growth and decay using a new coupled surface process 5 , 6 and mantle-scale tectonic model 7 . End-member models and the new non-dimensional Beaumont number, Bm, quantify how surface processes and tectonics control the topographic evolution of mountain belts, and enable the definition of three end-member types of growing orogens: type 1, non-steady state, strength controlled (Bm > 0.5); type 2, flux steady state 8 , strength controlled (Bm ≈ 0.4−0.5); and type 3, flux steady state, erosion controlled (Bm < 0.4). Our results indicate that tectonics dominate in Himalaya–Tibet and the Central Andes (both type 1), efficient surface processes balance high convergence rates in Taiwan (probably type 2) and surface processes dominate in the Southern Alps of New Zealand (type 3). Orogenic decay is determined by erosional efficiency and can be subdivided into two phases with variable isostatic rebound characteristics and associated timescales. The results presented here provide a unified framework explaining how surface processes and lithospheric strength control the height, shape, and longevity of mountain belts. Main Mountain belt evolution in collisional settings comprises crustal thickening and surface uplift, followed by tectonic quiescence and isostatic rebound that may include extensional collapse. Surface processes shape mountain belt surface morphology by counteracting tectonic growth and by causing topographic decay. End-member collisional mountain belt types 9 include (1) active, narrow orogens with high rock uplift and erosion rates, such as those in Taiwan and the Southern Alps of New Zealand (SANZ), (2) active, wide orogens with orogenic plateaus and overall low erosion rates, such as in Himalaya–Tibet and the Andes, and (3) inactive orogens with slowly decaying topography surviving tens to several hundreds of millions of years, such as the Urals or the Appalachians. High erosion rates in small orogens, co-existence on Earth of large and small orogens of variable height, and the long-term survival of orogenic topography raise fundamental questions about the factors controlling the width, height and longevity of mountain belts during their growth and decay phases. In non-glaciated mountain belts, rainfall and river incision control the erosional efficiency, denudation rate and sediment yield 2 , 10 , 11 , implying that climate may set the width, height and relief in growing orogens 2 , 3 , 12 , 13 , 14 , 15 , 16 , 17 , 18 . Erosional efficiency is also thought to control the longevity of mountainous relief 19 , 20 . However, others have shown 21 , 22 , 23 , 24 that finite crustal strength may be the main factor limiting the maximum elevation of orogens under some circumstances, demonstrating the need for a proper representation of tectonic deformation to study the effect of the erosional efficiency on mountain growth and decay, which includes isostasy, mantle lithosphere subduction, discrete faulting, and proper earth-like rheologies. Coupled tectonic–surface process model We use the thermo-mechanical tectonic model FANTOM 7 , 25 coupled to the landscape evolution model FastScape 5 , 6 , resolving the interaction between upper mantle scale tectonic deformation and surface processes at high resolution. FANTOM computes deformation of earth-like materials with frictional-plastic and non-linear thermally activated viscous flow, whereas FastScape solves for river erosion, hillslope processes, sediment transport and deposition (Methods; Extended Data Fig. 1 ). The erosional efficiency depends mostly on fluvial erodibility K f , which spans several orders of magnitude owing to its dependence on rainfall, rainfall variability, lithology, fracturation, vegetation cover, and abrasive agents 14 , 20 , 26 , 27 , 28 , 29 . We present three end-member models with low (model 1), high (model 2), and very high (model 3) fluvial erodibility (Figs. 1 and 2 ). Fig. 1: Key stages for models 1–3. One model per column (model 1, a , d , g ; model 2, b , e , h ; model 3, c , f , i ). a–c , Model snapshots at the end of shortening. From bottom to top: enlarged view of the model domain showing material distribution (sed, sediments; uc, upper crust; mc, middle crust; lc, lower crust; lm, lithospheric mantle) and temperature contours from the thermo-mechanical tectonic model, map-view landscape, swath elevation profile of the landscape, and profiles of uplift ( U ) and average erosion rate ( ė ). t is the model time, Δ x is the amount of convergence, and v c is the convergence rate (1 cm yr –1 ). d – i , Swath profile and corresponding uplift and average erosion rates during the orogenic decay phase I ( d – f ) and phase II ( g – i ). Full size image Fig. 2: Evolution of mountain belt topography. a , Evolution of the mean elevation at the main drainage divide (solid line) with the corresponding shaded swath profile. The mean elevation of the main drainage divide coincides with the maximum mean elevation of the orogens. In model 1 these measures do not coincide around 20–30 Myr, and the maximum mean elevation is additionally shown as a stippled line. The grey shaded area frames the growth phase; the decay phase has a white background. Capped black bars show typical swath profiles of several orogens on Earth; the dot indicates mean elevation. Swath profiles of growing orogens (Andes (And), Himalaya (Him), Taiwan (Tw), SANZ, see Fig. 3 ) are placed with ascending height; Pyrenees and West Alps (W Alps) are placed according to their orogenic decay time 17 , 51 . Note that the swath profiles of natural systems can be explained by a combination of surface process efficiency and crustal", "role": "user" }, { "content": "Scientists have come up with a new classification scheme for mountain belts that uses just a single number to describe whether the elevation of the mountain belt is controlled mainly by weathering and erosion or by properties of the Earth's crust, i.e., the lithospheric strength: the \"Beaumont number\" (Bm). It's named after Chris Beaumont, a scientist who, together with his team, developed coupled models of surface processes and tectonic forces. The scientists report about their findings in the current issue of Nature. A Beaumont number between 0.4 and 0.5 means that the mountains are in a so-called flux steady state in which the controlling factors of mountain growth are tectonic forces and the lithospheric strength, balanced by weathering processes as, for example, in Taiwan. With a Bm value lower than 0.4, mountains are also in a flux steady state but with erosion as controlling factor like the Southern Alps of New Zealand. A Beaumont number above 0.5 means that the mountains still grow (non-steady state) with lithospheric strength controlling the process. Examples for this type are the Himalaya-Tibet mountains and the Central Andes. This classification is resolving a long-standing question whether tectonic forces and strength of the Earth's crust are the controlling factors of mountain elevation or whether weathering processes are in control. The new study says it can be one or the other—depending on geographic location, climate and underground properties. The team of scientists led by Sebastian G. Wolf of Bergen University in Norway used a new coupled surface process and mantle-scale tectonic model for their study by combining the thermomechanical tectonic model FANTOM with the landscape evolution model FastScape. Thus, they were able to reconcile high erosion rates in some active orogens with long-term survival of mountain belts for hundreds of millions of years. Jean Braun of the GFZ German Research Centre for Geosciences, who co-authored the paper, says that \"with our Beaumont number we can determine to which proportion tectonics, climate, and crustal strength control the height of mountain belts. And, for most mountain belts, this can be done without complex measurements or assumptions; all that is needed is a knowledge of the rate of convergence obtained from present-day plate velocities or plate reconstructions, the height of the mountain obtained from a topographic map and the widening rate obtained from the geological record. In a nutshell: Whether a mountain is short or tall is the product of slow or fast convergence, wet or dry climate, or strong or weak crust.\" The Beaumont number shows which of these three factors is dominating. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract It is widely recognized that collisional mountain belt topography is generated by crustal thickening and lowered by river bedrock erosion, linking climate and tectonics 1 , 2 , 3 , 4 . However, whether surface processes or lithospheric strength control mountain belt height, shape and longevity remains uncertain. Additionally, how to reconcile high erosion rates in some active orogens with long-term survival of mountain belts for hundreds of millions of years remains enigmatic. Here we investigate mountain belt growth and decay using a new coupled surface process 5 , 6 and mantle-scale tectonic model 7 . End-member models and the new non-dimensional Beaumont number, Bm, quantify how surface processes and tectonics control the topographic evolution of mountain belts, and enable the definition of three end-member types of growing orogens: type 1, non-steady state, strength controlled (Bm > 0.5); type 2, flux steady state 8 , strength controlled (Bm ≈ 0.4−0.5); and type 3, flux steady state, erosion controlled (Bm < 0.4). Our results indicate that tectonics dominate in Himalaya–Tibet and the Central Andes (both type 1), efficient surface processes balance high convergence rates in Taiwan (probably type 2) and surface processes dominate in the Southern Alps of New Zealand (type 3). Orogenic decay is determined by erosional efficiency and can be subdivided into two phases with variable isostatic rebound characteristics and associated timescales. The results presented here provide a unified framework explaining how surface processes and lithospheric strength control the height, shape, and longevity of mountain belts. Main Mountain belt evolution in collisional settings comprises crustal thickening and surface uplift, followed by tectonic quiescence and isostatic rebound that may include extensional collapse. Surface processes shape mountain belt surface morphology by counteracting tectonic growth and by causing topographic decay. End-member collisional mountain belt types 9 include (1) active, narrow orogens with high rock uplift and erosion rates, such as those in Taiwan and the Southern Alps of New Zealand (SANZ), (2) active, wide orogens with orogenic plateaus and overall low erosion rates, such as in Himalaya–Tibet and the Andes, and (3) inactive orogens with slowly decaying topography surviving tens to several hundreds of millions of years, such as the Urals or the Appalachians. High erosion rates in small orogens, co-existence on Earth of large and small orogens of variable height, and the long-term survival of orogenic topography raise fundamental questions about the factors controlling the width, height and longevity of mountain belts during their growth and decay phases. In non-glaciated mountain belts, rainfall and river incision control the erosional efficiency, denudation rate and sediment yield 2 , 10 , 11 , implying that climate may set the width, height and relief in growing orogens 2 , 3 , 12 , 13 , 14 , 15 , 16 , 17 , 18 . Erosional efficiency is also thought to control the longevity of mountainous relief 19 , 20 . However, others have shown 21 , 22 , 23 , 24 that finite crustal strength may be the main factor limiting the maximum elevation of orogens under some circumstances, demonstrating the need for a proper representation of tectonic deformation to study the effect of the erosional efficiency on mountain growth and decay, which includes isostasy, mantle lithosphere subduction, discrete faulting, and proper earth-like rheologies. Coupled tectonic–surface process model We use the thermo-mechanical tectonic model FANTOM 7 , 25 coupled to the landscape evolution model FastScape 5 , 6 , resolving the interaction between upper mantle scale tectonic deformation and surface processes at high resolution. FANTOM computes deformation of earth-like materials with frictional-plastic and non-linear thermally activated viscous flow, whereas FastScape solves for river erosion, hillslope processes, sediment transport and deposition (Methods; Extended Data Fig. 1 ). The erosional efficiency depends mostly on fluvial erodibility K f , which spans several orders of magnitude owing to its dependence on rainfall, rainfall variability, lithology, fracturation, vegetation cover, and abrasive agents 14 , 20 , 26 , 27 , 28 , 29 . We present three end-member models with low (model 1), high (model 2), and very high (model 3) fluvial erodibility (Figs. 1 and 2 ). Fig. 1: Key stages for models 1–3. One model per column (model 1, a , d , g ; model 2, b , e , h ; model 3, c , f , i ). a–c , Model snapshots at the end of shortening. From bottom to top: enlarged view of the model domain showing material distribution (sed, sediments; uc, upper crust; mc, middle crust; lc, lower crust; lm, lithospheric mantle) and temperature contours from the thermo-mechanical tectonic model, map-view landscape, swath elevation profile of the landscape, and profiles of uplift ( U ) and average erosion rate ( ė ). t is the model time, Δ x is the amount of convergence, and v c is the convergence rate (1 cm yr –1 ). d – i , Swath profile and corresponding uplift and average erosion rates during the orogenic decay phase I ( d – f ) and phase II ( g – i ). Full size image Fig. 2: Evolution of mountain belt topography. a , Evolution of the mean elevation at the main drainage divide (solid line) with the corresponding shaded swath profile. The mean elevation of the main drainage divide coincides with the maximum mean elevation of the orogens. In model 1 these measures do not coincide around 20–30 Myr, and the maximum mean elevation is additionally shown as a stippled line. The grey shaded area frames the growth phase; the decay phase has a white background. Capped black bars show typical swath profiles of several orogens on Earth; the dot indicates mean elevation. Swath profiles of growing orogens (Andes (And), Himalaya (Him), Taiwan (Tw), SANZ, see Fig. 3 ) are placed with ascending height; Pyrenees and West Alps (W Alps) are placed according to their orogenic decay time 17 , 51 . Note that the swath profiles of natural systems can be explained by a combination of surface process efficiency and crustal<|im_end|> <|im_start|>assistant Scientists have come up with a new classification scheme for mountain belts that uses just a single number to describe whether the elevation of the mountain belt is controlled mainly by weathering and erosion or by properties of the Earth's crust, i.e., the lithospheric strength: the "Beaumont number" (Bm). It's named after Chris Beaumont, a scientist who, together with his team, developed coupled models of surface processes and tectonic forces. The scientists report about their findings in the current issue of Nature. A Beaumont number between 0.4 and 0.5 means that the mountains are in a so-called flux steady state in which the controlling factors of mountain growth are tectonic forces and the lithospheric strength, balanced by weathering processes as, for example, in Taiwan. With a Bm value lower than 0.4, mountains are also in a flux steady state but with erosion as controlling factor like the Southern Alps of New Zealand. A Beaumont number above 0.5 means that the mountains still grow (non-steady state) with lithospheric strength controlling the process. Examples for this type are the Himalaya-Tibet mountains and the Central Andes. This classification is resolving a long-standing question whether tectonic forces and strength of the Earth's crust are the controlling factors of mountain elevation or whether weathering processes are in control. The new study says it can be one or the other—depending on geographic location, climate and underground properties. The team of scientists led by Sebastian G. Wolf of Bergen University in Norway used a new coupled surface process and mantle-scale tectonic model for their study by combining the thermomechanical tectonic model FANTOM with the landscape evolution model FastScape. Thus, they were able to reconcile high erosion rates in some active orogens with long-term survival of mountain belts for hundreds of millions of years. Jean Braun of the GFZ German Research Centre for Geosciences, who co-authored the paper, says that "with our Beaumont number we can determine to which proportion tectonics, climate, and crustal strength control the height of mountain belts. And, for most mountain belts, this can be done without complex measurements or assumptions; all that is needed is a knowledge of the rate of convergence obtained from present-day plate velocities or plate reconstructions, the height of the mountain obtained from a topographic map and the widening rate obtained from the geological record. In a nutshell: Whether a mountain is short or tall is the product of slow or fast convergence, wet or dry climate, or strong or weak crust." The Beaumont number shows which of these three factors is dominating. <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract While rich medical, behavioral, and socio-demographic data are key to modern data-driven research, their collection and use raise legitimate privacy concerns. Anonymizing datasets through de-identification and sampling before sharing them has been the main tool used to address those concerns. We here propose a generative copula-based method that can accurately estimate the likelihood of a specific person to be correctly re-identified, even in a heavily incomplete dataset. On 210 populations, our method obtains AUC scores for predicting individual uniqueness ranging from 0.84 to 0.97, with low false-discovery rate. Using our model, we find that 99.98% of Americans would be correctly re-identified in any dataset using 15 demographic attributes. Our results suggest that even heavily sampled anonymized datasets are unlikely to satisfy the modern standards for anonymization set forth by GDPR and seriously challenge the technical and legal adequacy of the de-identification release-and-forget model. Introduction In the last decade, the ability to collect and store personal data has exploded. With two thirds of the world population having access to the Internet 1 , electronic medical records becoming the norm 2 , and the rise of the Internet of Things, this is unlikely to stop anytime soon. Collected at scale from financial or medical services, when filling in online surveys or liking pages, this data has an incredible potential for good. It drives scientific advancements in medicine 3 , social science 4 , 5 , and AI 6 and promises to revolutionize the way businesses and governments function 7 , 8 . However, the large-scale collection and use of detailed individual-level data raise legitimate privacy concerns. The recent backlashes against the sharing of NHS [UK National Health Service] medical data with DeepMind 9 and the collection and subsequent sale of Facebook data to Cambridge Analytica 10 are the latest evidences that people are concerned about the confidentiality, privacy, and ethical use of their data. In a recent survey, >72% of U.S. citizens reported being worried about sharing personal information online 11 . In the wrong hands, sensitive data can be exploited for blackmailing, mass surveillance, social engineering, or identity theft. De-identification, the process of anonymizing datasets before sharing them, has been the main paradigm used in research and elsewhere to share data while preserving people’s privacy 12 , 13 , 14 . Data protection laws worldwide consider anonymous data as not personal data anymore 15 , 16 allowing it to be freely used, shared, and sold. Academic journals are, e.g., increasingly requiring authors to make anonymous data available to the research community 17 . While standards for anonymous data vary, modern data protection laws, such as the European General Data Protection Regulation (GDPR) and the California Consumer Privacy Act (CCPA), consider that each and every person in a dataset has to be protected for the dataset to be considered anonymous 18 , 19 , 20 . This new higher standard for anonymization is further made clear by the introduction in GDPR of pseudonymous data: data that does not contain obvious identifiers but might be re-identifiable and is therefore within the scope of the law 16 , 18 . Yet numerous supposedly anonymous datasets have recently been released and re-identified 15 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 . In 2016, journalists re-identified politicians in an anonymized browsing history dataset of 3 million German citizens, uncovering their medical information and their sexual preferences 23 . A few months before, the Australian Department of Health publicly released de-identified medical records for 10% of the population only for researchers to re-identify them 6 weeks later 24 . Before that, studies had shown that de-identified hospital discharge data could be re-identified using basic demographic attributes 25 and that diagnostic codes, year of birth, gender, and ethnicity could uniquely identify patients in genomic studies data 26 . Finally, researchers were able to uniquely identify individuals in anonymized taxi trajectories in NYC 27 , bike sharing trips in London 28 , subway data in Riga 29 , and mobile phone and credit card datasets 30 , 31 . Statistical disclosure control researchers and some companies are disputing the validity of these re-identifications: as datasets are always incomplete, journalists and researchers can never be sure they have re-identified the right person even if they found a match 32 , 33 , 34 , 35 . They argue that this provides strong plausible deniability to participants and reduce the risks, making such de-identified datasets anonymous including according to GDPR 36 , 37 , 38 , 39 . De-identified datasets can be intrinsically incomplete, e.g., because the dataset only covers patients of one of the hospital networks in a country or because they have been subsampled as part of the de-identification process. For example, the U.S. Census Bureau releases only 1% of their decennial census and sampling fractions for international census range from 0.07% in India to 10% in South American countries 40 . Companies are adopting similar approaches with, e.g., the Netflix Prize dataset including <10% of their users 41 . Imagine a health insurance company who decides to run a contest to predict breast cancer and publishes a de-identified dataset of 1000 people, 1% of their 100,000 insureds in California, including people’s birth date, gender, ZIP code, and breast cancer diagnosis. John Doe’s employer downloads the dataset and finds one (and only one) record matching Doe’s information: male living in Berkeley, CA (94720), born on January 2 nd 1968, and diagnosed with breast cancer (self-disclosed by John Doe). This record also contains the details of his recent (failed) stage IV treatments. When contacted, the insurance company argues that matching does not equal re-identification: the record could belong to 1 of the 99,000 other people they insure or, if the employer does not know whether Doe is insured by this company or not, to anyone else of the 39.5M people living in California. Our paper shows how the likelihood of a specific individual to", "role": "user" }, { "content": "With the first large fines for breaching EU General Data Protection Regulation (GDPR) regulations upon us, and the UK government about to review GDPR guidelines, researchers have shown how even anonymised datasets can be traced back to individuals using machine learning. The researchers say their paper, published today in Nature Communications, demonstrates that allowing data to be used—to train AI algorithms, for example—while preserving people's privacy, requires much more than simply adding noise, sampling datasets, and other de-identification techniques. They have also published a demonstration tool that allows people to understand just how likely they are to be traced, even if the dataset they are in is anonymised and just a small fraction of it shared. They say their findings should be a wake-up call for policymakers on the need to tighten the rules for what constitutes truly anonymous data. Companies and governments both routinely collect and use our personal data. Our data and the way it's used is protected under relevant laws like GDPR or the US's California Consumer Privacy Act (CCPA). Data is 'sampled' and anonymised, which includes stripping the data of identifying characteristics like names and email addresses, so that individuals cannot, in theory, be identified. After this process, the data's no longer subject to data protection regulations, so it can be freely used and sold to third parties like advertising companies and data brokers. The new research shows that once bought, the data can often be reverse engineered using machine learning to re-identify individuals, despite the anonymisation techniques. This could expose sensitive information about personally identified individuals, and allow buyers to build increasingly comprehensive personal profiles of individuals. The research demonstrates for the first time how easily and accurately this can be done—even with incomplete datasets. In the research, 99.98 per cent of Americans were correctly re-identified in any available 'anonymised' dataset by using just 15 characteristics, including age, gender, and marital status. First author Dr. Luc Rocher of UCLouvain said: \"While there might be a lot of people who are in their thirties, male, and living in New York City, far fewer of them were also born on 5 January, are driving a red sports car, and live with two kids (both girls) and one dog.\" To demonstrate this, the researchers developed a machine learning model to evaluate the likelihood for an individual's characteristics to be precise enough to describe only one person in a population of billions. They also developed an online tool, which doesn't save data and is for demonstration purposes only, to help people see which characteristics make them unique in datasets. The tool first asks you put in the first part of their post (UK) or ZIP (US) code, gender, and date of birth, before giving them a probability that their profile could be re-identified in any anonymised dataset. It then asks your marital status, number of vehicles, house ownership status, and employment status, before recalculating. By adding more characteristics, the likelihood of a match to be correct dramatically increases. Senior author Dr. Yves-Alexandre de Montjoye, of Imperial's Department of Computing, and Data Science Institute, said: \"This is pretty standard information for companies to ask for. Although they are bound by GDPR guidelines, they're free to sell the data to anyone once it's anonymised. Our research shows just how easily—and how accurately—individuals can be traced once this happens. He added: \"Companies and governments have downplayed the risk of re-identification by arguing that the datasets they sell are always incomplete. \"Our findings contradict this and demonstrate that an attacker could easily and accurately estimate the likelihood that the record they found belongs to the person they are looking for.\" Re-identifying anonymised data is how journalists exposed Donald Trump's 1985-94 tax returns in May 2019. Co-author Dr. Julien Hendrickx from UCLouvain said: \"We're often assured that anonymisation will keep our personal information safe. Our paper shows that de-identification is nowhere near enough to protect the privacy of people's data.\" The researchers say policymakers must do more to protect individuals from such attacks, which could have serious ramifications for careers as well as personal and financial lives. Dr. Hendrickx added: \"It is essential for anonymisation standards to be robust and account for new threats like the one demonstrated in this paper.\" Dr. de Montjoye said: \"The goal of anonymisation is so we can use data to benefit society. This is extremely important but should not and does not have to happen at the expense of people's privacy.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract While rich medical, behavioral, and socio-demographic data are key to modern data-driven research, their collection and use raise legitimate privacy concerns. Anonymizing datasets through de-identification and sampling before sharing them has been the main tool used to address those concerns. We here propose a generative copula-based method that can accurately estimate the likelihood of a specific person to be correctly re-identified, even in a heavily incomplete dataset. On 210 populations, our method obtains AUC scores for predicting individual uniqueness ranging from 0.84 to 0.97, with low false-discovery rate. Using our model, we find that 99.98% of Americans would be correctly re-identified in any dataset using 15 demographic attributes. Our results suggest that even heavily sampled anonymized datasets are unlikely to satisfy the modern standards for anonymization set forth by GDPR and seriously challenge the technical and legal adequacy of the de-identification release-and-forget model. Introduction In the last decade, the ability to collect and store personal data has exploded. With two thirds of the world population having access to the Internet 1 , electronic medical records becoming the norm 2 , and the rise of the Internet of Things, this is unlikely to stop anytime soon. Collected at scale from financial or medical services, when filling in online surveys or liking pages, this data has an incredible potential for good. It drives scientific advancements in medicine 3 , social science 4 , 5 , and AI 6 and promises to revolutionize the way businesses and governments function 7 , 8 . However, the large-scale collection and use of detailed individual-level data raise legitimate privacy concerns. The recent backlashes against the sharing of NHS [UK National Health Service] medical data with DeepMind 9 and the collection and subsequent sale of Facebook data to Cambridge Analytica 10 are the latest evidences that people are concerned about the confidentiality, privacy, and ethical use of their data. In a recent survey, >72% of U.S. citizens reported being worried about sharing personal information online 11 . In the wrong hands, sensitive data can be exploited for blackmailing, mass surveillance, social engineering, or identity theft. De-identification, the process of anonymizing datasets before sharing them, has been the main paradigm used in research and elsewhere to share data while preserving people’s privacy 12 , 13 , 14 . Data protection laws worldwide consider anonymous data as not personal data anymore 15 , 16 allowing it to be freely used, shared, and sold. Academic journals are, e.g., increasingly requiring authors to make anonymous data available to the research community 17 . While standards for anonymous data vary, modern data protection laws, such as the European General Data Protection Regulation (GDPR) and the California Consumer Privacy Act (CCPA), consider that each and every person in a dataset has to be protected for the dataset to be considered anonymous 18 , 19 , 20 . This new higher standard for anonymization is further made clear by the introduction in GDPR of pseudonymous data: data that does not contain obvious identifiers but might be re-identifiable and is therefore within the scope of the law 16 , 18 . Yet numerous supposedly anonymous datasets have recently been released and re-identified 15 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 . In 2016, journalists re-identified politicians in an anonymized browsing history dataset of 3 million German citizens, uncovering their medical information and their sexual preferences 23 . A few months before, the Australian Department of Health publicly released de-identified medical records for 10% of the population only for researchers to re-identify them 6 weeks later 24 . Before that, studies had shown that de-identified hospital discharge data could be re-identified using basic demographic attributes 25 and that diagnostic codes, year of birth, gender, and ethnicity could uniquely identify patients in genomic studies data 26 . Finally, researchers were able to uniquely identify individuals in anonymized taxi trajectories in NYC 27 , bike sharing trips in London 28 , subway data in Riga 29 , and mobile phone and credit card datasets 30 , 31 . Statistical disclosure control researchers and some companies are disputing the validity of these re-identifications: as datasets are always incomplete, journalists and researchers can never be sure they have re-identified the right person even if they found a match 32 , 33 , 34 , 35 . They argue that this provides strong plausible deniability to participants and reduce the risks, making such de-identified datasets anonymous including according to GDPR 36 , 37 , 38 , 39 . De-identified datasets can be intrinsically incomplete, e.g., because the dataset only covers patients of one of the hospital networks in a country or because they have been subsampled as part of the de-identification process. For example, the U.S. Census Bureau releases only 1% of their decennial census and sampling fractions for international census range from 0.07% in India to 10% in South American countries 40 . Companies are adopting similar approaches with, e.g., the Netflix Prize dataset including <10% of their users 41 . Imagine a health insurance company who decides to run a contest to predict breast cancer and publishes a de-identified dataset of 1000 people, 1% of their 100,000 insureds in California, including people’s birth date, gender, ZIP code, and breast cancer diagnosis. John Doe’s employer downloads the dataset and finds one (and only one) record matching Doe’s information: male living in Berkeley, CA (94720), born on January 2 nd 1968, and diagnosed with breast cancer (self-disclosed by John Doe). This record also contains the details of his recent (failed) stage IV treatments. When contacted, the insurance company argues that matching does not equal re-identification: the record could belong to 1 of the 99,000 other people they insure or, if the employer does not know whether Doe is insured by this company or not, to anyone else of the 39.5M people living in California. Our paper shows how the likelihood of a specific individual to<|im_end|> <|im_start|>assistant With the first large fines for breaching EU General Data Protection Regulation (GDPR) regulations upon us, and the UK government about to review GDPR guidelines, researchers have shown how even anonymised datasets can be traced back to individuals using machine learning. The researchers say their paper, published today in Nature Communications, demonstrates that allowing data to be used—to train AI algorithms, for example—while preserving people's privacy, requires much more than simply adding noise, sampling datasets, and other de-identification techniques. They have also published a demonstration tool that allows people to understand just how likely they are to be traced, even if the dataset they are in is anonymised and just a small fraction of it shared. They say their findings should be a wake-up call for policymakers on the need to tighten the rules for what constitutes truly anonymous data. Companies and governments both routinely collect and use our personal data. Our data and the way it's used is protected under relevant laws like GDPR or the US's California Consumer Privacy Act (CCPA). Data is 'sampled' and anonymised, which includes stripping the data of identifying characteristics like names and email addresses, so that individuals cannot, in theory, be identified. After this process, the data's no longer subject to data protection regulations, so it can be freely used and sold to third parties like advertising companies and data brokers. The new research shows that once bought, the data can often be reverse engineered using machine learning to re-identify individuals, despite the anonymisation techniques. This could expose sensitive information about personally identified individuals, and allow buyers to build increasingly comprehensive personal profiles of individuals. The research demonstrates for the first time how easily and accurately this can be done—even with incomplete datasets. In the research, 99.98 per cent of Americans were correctly re-identified in any available 'anonymised' dataset by using just 15 characteristics, including age, gender, and marital status. First author Dr. Luc Rocher of UCLouvain said: "While there might be a lot of people who are in their thirties, male, and living in New York City, far fewer of them were also born on 5 January, are driving a red sports car, and live with two kids (both girls) and one dog." To demonstrate this, the researchers developed a machine learning model to evaluate the likelihood for an individual's characteristics to be precise enough to describe only one person in a population of billions. They also developed an online tool, which doesn't save data and is for demonstration purposes only, to help people see which characteristics make them unique in datasets. The tool first asks you put in the first part of their post (UK) or ZIP (US) code, gender, and date of birth, before giving them a probability that their profile could be re-identified in any anonymised dataset. It then asks your marital status, number of vehicles, house ownership status, and employment status, before recalculating. By adding more characteristics, the likelihood of a match to be correct dramatically increases. Senior author Dr. Yves-Alexandre de Montjoye, of Imperial's Department of Computing, and Data Science Institute, said: "This is pretty standard information for companies to ask for. Although they are bound by GDPR guidelines, they're free to sell the data to anyone once it's anonymised. Our research shows just how easily—and how accurately—individuals can be traced once this happens. He added: "Companies and governments have downplayed the risk of re-identification by arguing that the datasets they sell are always incomplete. "Our findings contradict this and demonstrate that an attacker could easily and accurately estimate the likelihood that the record they found belongs to the person they are looking for." Re-identifying anonymised data is how journalists exposed Donald Trump's 1985-94 tax returns in May 2019. Co-author Dr. Julien Hendrickx from UCLouvain said: "We're often assured that anonymisation will keep our personal information safe. Our paper shows that de-identification is nowhere near enough to protect the privacy of people's data." The researchers say policymakers must do more to protect individuals from such attacks, which could have serious ramifications for careers as well as personal and financial lives. Dr. Hendrickx added: "It is essential for anonymisation standards to be robust and account for new threats like the one demonstrated in this paper." Dr. de Montjoye said: "The goal of anonymisation is so we can use data to benefit society. This is extremely important but should not and does not have to happen at the expense of people's privacy." <|im_end|>

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[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Microglia are highly motile glial cells that are proposed to mediate synaptic pruning during neuronal circuit formation. Disruption of signaling between microglia and neurons leads to an excess of immature synaptic connections, thought to be the result of impaired phagocytosis of synapses by microglia. However, until now the direct phagocytosis of synapses by microglia has not been reported and fundamental questions remain about the precise synaptic structures and phagocytic mechanisms involved. Here we used light sheet fluorescence microscopy to follow microglia–synapse interactions in developing organotypic hippocampal cultures, complemented by a 3D ultrastructural characterization using correlative light and electron microscopy (CLEM). Our findings define a set of dynamic microglia–synapse interactions, including the selective partial phagocytosis, or trogocytosis ( trogo -: nibble), of presynaptic structures and the induction of postsynaptic spine head filopodia by microglia. These findings allow us to propose a mechanism for the facilitatory role of microglia in synaptic circuit remodeling and maturation. Introduction Microglia are glial cells that derive from the myeloid hematopoietic lineage and take up long-lived residence in the developing brain. In response to brain injury, microglia migrate to the site of damage and participate in the phagocytic removal of cellular debris 1 . The recent discovery that microglia are also highly motile in the uninjured brain 2 , 3 , continuously extending and retracting processes through the extracellular space, suggests that they may monitor and contribute to synaptic maturation and function. Clues to this activity come from observations that during early postnatal development microglia undergo morphological maturation that matches synaptic maturation 4 , and that they express receptors for neuronal signaling factors that are upregulated during this period 5 . These data, combined with the known phagocytic capacity of myeloid cells, led to the hypothesis that microglia may have a role in the phagocytic elimination of synapses as part of the widespread pruning of exuberant synaptic connections during development 6 , 7 . This hypothesis was supported by two studies that reported the selective engulfment of synaptic structures by microglia and the appearance of excess immature synapses in mice lacking either the fractalkine 8 (Cx3cl1/Cx3cr1) or complement component 9 (C1q/C3/CR3) microglia signaling pathways. Numerous studies have confirmed an important role for microglia in promoting synapse and circuit maturation. Knockout (KO) mice lacking complement factors show cortical excitatory hyperconnectivity 10 , supporting a role for microglia in the elimination of excess synapses in the mammalian neocortex. KO mice lacking fractalkine receptor show transient excitatory hyperconnectivity followed by weak synaptic multiplicity and reduced functional brain connectivity in adulthood 11 , 12 , suggesting that a failure to eliminate synapses at the correct developmental time prevents the normal strengthening of synaptic connections. Notably, inhibitory synapses in hippocampus appear to be unaffected by disruptions of neuron–microglia signaling 11 (but see ref. 13 ). Microglia are also likely to be required for environment-induced brain plasticity as mice lacking microglia P2Y 12 receptors show deficits in early monocular deprivation-associated visual cortical plasticity 14 . At the same time, studies have pointed to a role for microglia in synapse formation in the adult brain, showing that they can elicit calcium transients and the formation of filopodia from dendritic branches 15 , and that they are required for learning-induced synapse formation 16 . Together, these studies suggest that microglia have a complex role in shaping maturing circuits. An important question raised by these studies is whether synaptic phagocytosis by microglia underlies some or all of these phenotypes. Unfortunately, support for a role of microglia in the phagocytic elimination of synapses is based entirely on indirect evidence—localization of synaptic material within microglia in fixed specimens and increased synapse density following the disruption of microglia function. In this study, we set out to test the hypothesis that microglia engulf and eliminate synapses during mouse hippocampal development. First, we carried out quantitative confocal microscopy analysis of microglia–synapse interactions in fixed hippocampal tissue. Microglia were found to contact dendritic spines, but contrary to previous reports we found no evidence for the elimination of postsynaptic material. Second, we confirmed these data at the ultrastructural level by correlative light and electron microscopy (CLEM) using focused ion beam scanning electron microscopy (FIB-SEM) and discovered evidence for the partial elimination, or trogocytosis, of presynaptic boutons and axons by microglia. Trogocytosis has been described in the immune system as a non-apoptotic mechanism for the rapid capture of membrane components and differs from phagocytosis, which involves the engulfment and elimination of larger cellular structures (> 1 µm) 17 , 18 , 19 . Third, we carried out time-lapse light sheet microscopy of microglia–synapse interactions in organotypic hippocampal cultures and observed the trogocytosis of exclusively presynaptic material. Time-lapse microscopy also revealed the frequent induction of spine head filopodia at sites of microglia–synapse contacts and these were confirmed at the ultrastructural level. Our findings provide the first direct evidence for the elimination of synaptic material by microglia in living brain tissue and suggest that microglia facilitate circuit maturation by a combination of trogocytosis of the axonal compartment and the remodeling of postsynaptic sites. Results No evidence for phagocytosis of spines by microglia To identify the period of maximal microglia phagocytic activity in postnatal hippocampal development, we performed immunocolocalization analysis of Iba1-labelled microglia with CD68, a phagosomal marker, in fixed sections at postnatal day 8 (P8), P15, P28, and P40 (Supplementary Fig. 1a, b ). CD68 immunoreactivity was high at P8–P15 with a peak at P15 and a gradual decrease in the following weeks. The CD68 immunoreactivity pattern at P15 was confirmed in genetically labeled microglia (Supplementary Fig. 1c, d ). These findings indicate that the second postnatal week of mouse hippocampal development is likely to be a period of active microglia phagocytosis and suggested that this period may be most relevant to search for evidence of phagocytic elimination of synapses by microglia. Previous studies have presented indirect evidence for the phagocytic engulfment of dendritic spines in hippocampus and visual cortex 8 , 14 , 20 . For example, immunoreactivity for postsynaptic density 95 (PSD95) protein", "role": "user" }, { "content": "For the first time, EMBL researchers have captured microglia pruning synaptic connections between brain cells. Their findings show that the special glial cells help synapses grow and rearrange, demonstrating the essential role of microglia in brain development. Nature Communications will publish the results on March 26. Around one in 10 brain cells are microglia. Cousins of macrophages, they act as the first and main contact in the central nervous system's active immune defense. They also guide healthy brain development. Researchers have proposed that microglia prune synapses as an essential step during early circuit refinement. But until now, no one had observed this activity. Microglia make synapses stronger Laetitia Weinhard from the Gross group at EMBL Rome set out on a massive imaging study to observe this process in action in the mouse brain, in collaboration with the Schwab team at EMBL Heidelberg. \"Our findings suggest that microglia are nibbling synapses as a way to make them stronger, rather than weaker,\" says Cornelius Gross, who led the work. Around half of the time, microglia contact a synapse, and the synapse head sends out thin projections called filopodia to contact them. In one particularly dramatic case—as seen in the accompanying image—15 synapse heads extended filopodia toward a single microglia as it picked on a synapse. \"As we were trying to see how microglia eliminate synapses, we realised that microglia actually induce their growth most of the time,\" Laetitia Weinhard explains. It turns out that microglia might underly the formation of double synapses, in which the terminal end of a neuron releases neurotransmitters onto two neighboring partners instead of one. This process can support effective connectivity between neurons. Weinhard says, \"This shows that microglia are broadly involved in structural plasticity and might induce the rearrangement of synapses, a mechanism underlying learning and memory.\" Perseverance Since this was the first attempt to visualise this process in the brain, the current paper entails five years of technological development. The team tried three different state-of-the-art imaging systems before succeeding. Finally, by combining correlative light and electron microscopy (CLEM) and light sheet fluorescence microscopy—a technique developed at EMBL—they were able to make the first movie of microglia eating synapses. \"This is what neuroscientists have fantasised about for years, but nobody had ever seen before,\" says Cornelius Gross. \"These findings allow us to propose a mechanism for the role of microglia in the remodeling and evolution of brain circuits during development.\" In the future, he plans to investigate the role of microglia in brain development during adolescence and the possible link to the onset of schizophrenia and depression. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Microglia are highly motile glial cells that are proposed to mediate synaptic pruning during neuronal circuit formation. Disruption of signaling between microglia and neurons leads to an excess of immature synaptic connections, thought to be the result of impaired phagocytosis of synapses by microglia. However, until now the direct phagocytosis of synapses by microglia has not been reported and fundamental questions remain about the precise synaptic structures and phagocytic mechanisms involved. Here we used light sheet fluorescence microscopy to follow microglia–synapse interactions in developing organotypic hippocampal cultures, complemented by a 3D ultrastructural characterization using correlative light and electron microscopy (CLEM). Our findings define a set of dynamic microglia–synapse interactions, including the selective partial phagocytosis, or trogocytosis ( trogo -: nibble), of presynaptic structures and the induction of postsynaptic spine head filopodia by microglia. These findings allow us to propose a mechanism for the facilitatory role of microglia in synaptic circuit remodeling and maturation. Introduction Microglia are glial cells that derive from the myeloid hematopoietic lineage and take up long-lived residence in the developing brain. In response to brain injury, microglia migrate to the site of damage and participate in the phagocytic removal of cellular debris 1 . The recent discovery that microglia are also highly motile in the uninjured brain 2 , 3 , continuously extending and retracting processes through the extracellular space, suggests that they may monitor and contribute to synaptic maturation and function. Clues to this activity come from observations that during early postnatal development microglia undergo morphological maturation that matches synaptic maturation 4 , and that they express receptors for neuronal signaling factors that are upregulated during this period 5 . These data, combined with the known phagocytic capacity of myeloid cells, led to the hypothesis that microglia may have a role in the phagocytic elimination of synapses as part of the widespread pruning of exuberant synaptic connections during development 6 , 7 . This hypothesis was supported by two studies that reported the selective engulfment of synaptic structures by microglia and the appearance of excess immature synapses in mice lacking either the fractalkine 8 (Cx3cl1/Cx3cr1) or complement component 9 (C1q/C3/CR3) microglia signaling pathways. Numerous studies have confirmed an important role for microglia in promoting synapse and circuit maturation. Knockout (KO) mice lacking complement factors show cortical excitatory hyperconnectivity 10 , supporting a role for microglia in the elimination of excess synapses in the mammalian neocortex. KO mice lacking fractalkine receptor show transient excitatory hyperconnectivity followed by weak synaptic multiplicity and reduced functional brain connectivity in adulthood 11 , 12 , suggesting that a failure to eliminate synapses at the correct developmental time prevents the normal strengthening of synaptic connections. Notably, inhibitory synapses in hippocampus appear to be unaffected by disruptions of neuron–microglia signaling 11 (but see ref. 13 ). Microglia are also likely to be required for environment-induced brain plasticity as mice lacking microglia P2Y 12 receptors show deficits in early monocular deprivation-associated visual cortical plasticity 14 . At the same time, studies have pointed to a role for microglia in synapse formation in the adult brain, showing that they can elicit calcium transients and the formation of filopodia from dendritic branches 15 , and that they are required for learning-induced synapse formation 16 . Together, these studies suggest that microglia have a complex role in shaping maturing circuits. An important question raised by these studies is whether synaptic phagocytosis by microglia underlies some or all of these phenotypes. Unfortunately, support for a role of microglia in the phagocytic elimination of synapses is based entirely on indirect evidence—localization of synaptic material within microglia in fixed specimens and increased synapse density following the disruption of microglia function. In this study, we set out to test the hypothesis that microglia engulf and eliminate synapses during mouse hippocampal development. First, we carried out quantitative confocal microscopy analysis of microglia–synapse interactions in fixed hippocampal tissue. Microglia were found to contact dendritic spines, but contrary to previous reports we found no evidence for the elimination of postsynaptic material. Second, we confirmed these data at the ultrastructural level by correlative light and electron microscopy (CLEM) using focused ion beam scanning electron microscopy (FIB-SEM) and discovered evidence for the partial elimination, or trogocytosis, of presynaptic boutons and axons by microglia. Trogocytosis has been described in the immune system as a non-apoptotic mechanism for the rapid capture of membrane components and differs from phagocytosis, which involves the engulfment and elimination of larger cellular structures (> 1 µm) 17 , 18 , 19 . Third, we carried out time-lapse light sheet microscopy of microglia–synapse interactions in organotypic hippocampal cultures and observed the trogocytosis of exclusively presynaptic material. Time-lapse microscopy also revealed the frequent induction of spine head filopodia at sites of microglia–synapse contacts and these were confirmed at the ultrastructural level. Our findings provide the first direct evidence for the elimination of synaptic material by microglia in living brain tissue and suggest that microglia facilitate circuit maturation by a combination of trogocytosis of the axonal compartment and the remodeling of postsynaptic sites. Results No evidence for phagocytosis of spines by microglia To identify the period of maximal microglia phagocytic activity in postnatal hippocampal development, we performed immunocolocalization analysis of Iba1-labelled microglia with CD68, a phagosomal marker, in fixed sections at postnatal day 8 (P8), P15, P28, and P40 (Supplementary Fig. 1a, b ). CD68 immunoreactivity was high at P8–P15 with a peak at P15 and a gradual decrease in the following weeks. The CD68 immunoreactivity pattern at P15 was confirmed in genetically labeled microglia (Supplementary Fig. 1c, d ). These findings indicate that the second postnatal week of mouse hippocampal development is likely to be a period of active microglia phagocytosis and suggested that this period may be most relevant to search for evidence of phagocytic elimination of synapses by microglia. Previous studies have presented indirect evidence for the phagocytic engulfment of dendritic spines in hippocampus and visual cortex 8 , 14 , 20 . For example, immunoreactivity for postsynaptic density 95 (PSD95) protein<|im_end|> <|im_start|>assistant For the first time, EMBL researchers have captured microglia pruning synaptic connections between brain cells. Their findings show that the special glial cells help synapses grow and rearrange, demonstrating the essential role of microglia in brain development. Nature Communications will publish the results on March 26. Around one in 10 brain cells are microglia. Cousins of macrophages, they act as the first and main contact in the central nervous system's active immune defense. They also guide healthy brain development. Researchers have proposed that microglia prune synapses as an essential step during early circuit refinement. But until now, no one had observed this activity. Microglia make synapses stronger Laetitia Weinhard from the Gross group at EMBL Rome set out on a massive imaging study to observe this process in action in the mouse brain, in collaboration with the Schwab team at EMBL Heidelberg. "Our findings suggest that microglia are nibbling synapses as a way to make them stronger, rather than weaker," says Cornelius Gross, who led the work. Around half of the time, microglia contact a synapse, and the synapse head sends out thin projections called filopodia to contact them. In one particularly dramatic case—as seen in the accompanying image—15 synapse heads extended filopodia toward a single microglia as it picked on a synapse. "As we were trying to see how microglia eliminate synapses, we realised that microglia actually induce their growth most of the time," Laetitia Weinhard explains. It turns out that microglia might underly the formation of double synapses, in which the terminal end of a neuron releases neurotransmitters onto two neighboring partners instead of one. This process can support effective connectivity between neurons. Weinhard says, "This shows that microglia are broadly involved in structural plasticity and might induce the rearrangement of synapses, a mechanism underlying learning and memory." Perseverance Since this was the first attempt to visualise this process in the brain, the current paper entails five years of technological development. The team tried three different state-of-the-art imaging systems before succeeding. Finally, by combining correlative light and electron microscopy (CLEM) and light sheet fluorescence microscopy—a technique developed at EMBL—they were able to make the first movie of microglia eating synapses. "This is what neuroscientists have fantasised about for years, but nobody had ever seen before," says Cornelius Gross. "These findings allow us to propose a mechanism for the role of microglia in the remodeling and evolution of brain circuits during development." In the future, he plans to investigate the role of microglia in brain development during adolescence and the possible link to the onset of schizophrenia and depression. <|im_end|>

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2,091

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract We report a deep learning-enabled field-portable and cost-effective imaging flow cytometer that automatically captures phase-contrast color images of the contents of a continuously flowing water sample at a throughput of 100 mL/h. The device is based on partially coherent lens-free holographic microscopy and acquires the diffraction patterns of flowing micro-objects inside a microfluidic channel. These holographic diffraction patterns are reconstructed in real time using a deep learning-based phase-recovery and image-reconstruction method to produce a color image of each micro-object without the use of external labeling. Motion blur is eliminated by simultaneously illuminating the sample with red, green, and blue light-emitting diodes that are pulsed. Operated by a laptop computer, this portable device measures 15.5 cm × 15 cm × 12.5 cm, weighs 1 kg, and compared to standard imaging flow cytometers, it provides extreme reductions of cost, size and weight while also providing a high volumetric throughput over a large object size range. We demonstrated the capabilities of this device by measuring ocean samples at the Los Angeles coastline and obtaining images of its micro- and nanoplankton composition. Furthermore, we measured the concentration of a potentially toxic alga ( Pseudo-nitzschia ) in six public beaches in Los Angeles and achieved good agreement with measurements conducted by the California Department of Public Health. The cost-effectiveness, compactness, and simplicity of this computational platform might lead to the creation of a network of imaging flow cytometers for large-scale and continuous monitoring of the ocean microbiome, including its plankton composition. Introduction Plankton form the base of the oceanic food chain, and thus they are important components of the whole marine ecosystem. Phytoplankton are responsible for approximately half of the global photoautotrophic primary production 1 , 2 . High-resolution mapping of the composition of phytoplankton over extended periods is very important and but rather challenging because the concentration and composition of species rapidly change as a function of space and time 3 . Furthermore, the factors governing these changes are not fully understood 4 , and phytoplankton population dynamics are chaotic 5 . The changes in the seasonal bloom cycle can also have major environmental 6 and economic effects 7 . The vast majority of phytoplankton species are not harmful, but some species produce neurotoxins that can enter the food chain, accumulate, and poison fish, mammals, and ultimately humans. Notable examples include Karenia brevis , which produces brevetoxin and causes neurotoxic shellfish poisoning 8 ; Alexandrium fundyense , which generates saxitoxin and causes paralytic shellfish poisoning; Dinophysis acuminata , which produces okadaic acid and results in diarrhetic shellfish poisoning 9 ; and Pseudo-nitzschia , which produces domoic acid and is responsible for amnesiac shellfish poisoning, potentially even leading to death 10 , 11 . Currently, monitoring of the concentrations of these species in coastal regions, including in California (USA), is usually performed by manual sample collection from coastal waters using plankton nets, followed by transportation of the sample to a central laboratory for light microscopy-based analysis 12 , which is very tedious, slow, and expensive and requires several manual steps performed by professionals. As an alternative to light microscopy-based analysis, flow cytometry has been used to analyze phytoplankton samples for more than 35 years 13 . The technique relies on using a sheath flow to confine the plankton sample to the focal point of an illuminating laser beam and measuring the forward and side scattering intensities of each individual object/particle inside the sample volume. To aid classification, flow cytometry is usually coupled with a fluorescence readout to detect the autofluorescence of chlorophyll, phycocyanin, and phycoerythrin found in algae and cyanobacteria. Several field-portable devices based on flow cytometry have been successfully used for analyzing nano- and pico-phytoplankton distributions in natural water samples 14 , 15 , 16 . However, taxonomic identification based solely on scattering and fluorescence data is usually not feasible in flow cytometry, and thus these devices are coupled with additional microscopic image analysis 17 or need to be enhanced with some form of imaging 18 , 19 . Consequently, imaging flow cytometry has become a widely used technique 20 in which a microscope objective is used to image the sample (e.g., algae) within a fluidic flow. The image capture is triggered by a fluorescence detector, and thus objects with detectable autofluorescence are imaged. Some of the widely utilized and commercially available imaging flow cytometers include the Flowcam 21 (Fluid Imaging Technologies), Imaging Flowcytobot 22 (McLane Research Laboratories), and CytoSense 23 (Cytobouy b.v.). Although these systems are able to perform imaging of the plankton in a flow, they still have some important limitations. The use of a microscope objective lens provides a strong trade-off between the image resolution and volumetric throughput of these systems; therefore, to obtain high-quality images, the measured sample volume is limited to a few milliliters per hour (e.g., 3–15 mL/h). Using lower-magnification objective lenses can scale up this low throughput by approximately tenfold at the expense of image quality. In addition, the shallow depth-of-field of the microscope objective necessitates hydrodynamic focusing of the liquid sample into a few-µm-thick layer using a stable sheath flow. This also restricts the size of the objects that can be imaged (e.g., to <150 µm) as well as the flow velocity and throughput of the system, thus requiring the use of additional expensive techniques such as acoustic focusing 22 . As a result of these factors, currently existing imaging flow cytometers used in environmental microbiology are fairly bulky (weighing, e.g., 9–30 kg) and costly (>$40,000–$100,000), limiting their widespread use. Holographic imaging of plankton samples provides a label-free alternative to these existing fluorescence-based approaches; in fact, its use in environmental microbiology started more than 40 years ago using photographic films 24 and subsequently continued via digital cameras and reconstruction techniques 25 . Holography provides a volumetric imaging technique that uses coherent or partially coherent light to record the interference intensity pattern of an object 26 . This hologram can subsequently be reconstructed to digitally bring the object into focus. The hologram contains information on the", "role": "user" }, { "content": "In the past 10 years, harmful algal blooms—sudden increases in the population of algae, typically in coastal regions and freshwater systems—have become a more serious problem for marine life throughout the U.S. The blooms are made up of phytoplankton, which naturally produce biotoxins, and those toxins can affect not only fish and plant life in the water, but also mammals, birds and humans who live near those areas. According to the National Oceanic and Atmospheric Administration, the events have become more common and are occurring in more regions around the world than ever before. The ability to forecast harmful algal blooms and their locations, size and severity could help scientists prevent their dangerous effects. But it has been difficult to predict when and where the blooms will occur. Now, UCLA researchers have developed an inexpensive and portable device that can analyze water samples immediately, which would provide marine biologists with real-time insight about the possibility that the algal blooms could occur in the area they're testing. That, in turn, would allow officials who manage coastal areas to make better, faster decisions about, for example, closing beaches and shellfish beds before algal blooms cause serious damage. UCLA researchers created a new flow cytometer—which detects and measures the physical and chemical characteristics of tiny objects within a sample—based on holographic imaging and artificial intelligence. It can quickly analyze the composition of various plankton species within a matter of seconds, much faster than the current standard method, which involves collecting water samples manually and running them through several steps. The research, which was published online by Light: Science & Applications and will appear in the journal's print edition, was led by Aydogan Ozcan, the UCLA Chancellor's Professor of Electrical and Computer Engineering and associate director of the California NanoSystems Institute at UCLA. The growing threat from blooms is being caused in part by higher water temperature due to climate change, and in part by high levels of nutrients (mainly phosphorus, nitrogen and carbon) from fertilizers used for lawns and farmland. The toxic compounds produced by the blooms can deplete oxygen from the water and can block sunlight from reaching fish and aquatic plants, which cause them to die or migrate elsewhere. In addition, fish and nearby wildlife can even ingest the toxins; and in some rare cases, if they are close enough to the blooms, humans can inhale them which can affect the nervous system, brain and liver, and eventually lead to death. Scientists have generally tried to understand algal blooms through manual sampling and traditional light microscopy, which they use to create high-resolution maps showing a phytoplankton composition in that area over extended periods of time. To build those maps, technicians have to collect water samples by hand using plankton nets and then bring them to a lab for analysis. The process is challenging in part because the concentration and composition of algae in a given body of water can change quickly—even in the time it takes to analyze samples. The device created by Ozcan and his colleagues speeds up the entire process and, because it does not use lenses or other optical components, it performs the testing at a much lower cost. It images algae samples—and is capable of scanning a wide range of other substances, too —using holography and artificial intelligence. Commercially available imaging flow cytometers used in environmental microbiology can cost from $40,000 to $100,000, which has limited their widespread use. The UCLA cytometer is compact and lightweight, and it can be assembled from parts costing less than $2,500. One challenge the researchers had to overcome was ensuring the device would have enough light to create well-lit, high-speed images without motion blur. \"It's similar to taking a picture of a Formula 1 race car,\" Ozcan said. \"The cameraman needs a very short exposure to avoid motion blur. In our case, that means using a very bright, pulsed light source with a pulse length about one-thousandth the duration of the blink of an eye.\" To test the device, the scientists measured ocean samples along the Los Angeles coastline and obtained images of its phytoplankton composition. They also measured the concentration of a potentially toxic alga called Pseudo-nitzschia along six public beaches in the region. The UCLA researchers' measurements were comparable to those in a recent study by the California Department of Public Health's Marine Biotoxin Monitoring Program. Zoltán Gӧrӧcs, a UCLA postdoctoral scholar and the study's first author, said the researchers are in the process of discussing their new device with marine biologists to determine where it would be most useful. \"Our device can be adapted to look at larger organisms with a higher throughput or look at smaller ones with a better image quality while sacrificing some of the throughput,\" he said. ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract We report a deep learning-enabled field-portable and cost-effective imaging flow cytometer that automatically captures phase-contrast color images of the contents of a continuously flowing water sample at a throughput of 100 mL/h. The device is based on partially coherent lens-free holographic microscopy and acquires the diffraction patterns of flowing micro-objects inside a microfluidic channel. These holographic diffraction patterns are reconstructed in real time using a deep learning-based phase-recovery and image-reconstruction method to produce a color image of each micro-object without the use of external labeling. Motion blur is eliminated by simultaneously illuminating the sample with red, green, and blue light-emitting diodes that are pulsed. Operated by a laptop computer, this portable device measures 15.5 cm × 15 cm × 12.5 cm, weighs 1 kg, and compared to standard imaging flow cytometers, it provides extreme reductions of cost, size and weight while also providing a high volumetric throughput over a large object size range. We demonstrated the capabilities of this device by measuring ocean samples at the Los Angeles coastline and obtaining images of its micro- and nanoplankton composition. Furthermore, we measured the concentration of a potentially toxic alga ( Pseudo-nitzschia ) in six public beaches in Los Angeles and achieved good agreement with measurements conducted by the California Department of Public Health. The cost-effectiveness, compactness, and simplicity of this computational platform might lead to the creation of a network of imaging flow cytometers for large-scale and continuous monitoring of the ocean microbiome, including its plankton composition. Introduction Plankton form the base of the oceanic food chain, and thus they are important components of the whole marine ecosystem. Phytoplankton are responsible for approximately half of the global photoautotrophic primary production 1 , 2 . High-resolution mapping of the composition of phytoplankton over extended periods is very important and but rather challenging because the concentration and composition of species rapidly change as a function of space and time 3 . Furthermore, the factors governing these changes are not fully understood 4 , and phytoplankton population dynamics are chaotic 5 . The changes in the seasonal bloom cycle can also have major environmental 6 and economic effects 7 . The vast majority of phytoplankton species are not harmful, but some species produce neurotoxins that can enter the food chain, accumulate, and poison fish, mammals, and ultimately humans. Notable examples include Karenia brevis , which produces brevetoxin and causes neurotoxic shellfish poisoning 8 ; Alexandrium fundyense , which generates saxitoxin and causes paralytic shellfish poisoning; Dinophysis acuminata , which produces okadaic acid and results in diarrhetic shellfish poisoning 9 ; and Pseudo-nitzschia , which produces domoic acid and is responsible for amnesiac shellfish poisoning, potentially even leading to death 10 , 11 . Currently, monitoring of the concentrations of these species in coastal regions, including in California (USA), is usually performed by manual sample collection from coastal waters using plankton nets, followed by transportation of the sample to a central laboratory for light microscopy-based analysis 12 , which is very tedious, slow, and expensive and requires several manual steps performed by professionals. As an alternative to light microscopy-based analysis, flow cytometry has been used to analyze phytoplankton samples for more than 35 years 13 . The technique relies on using a sheath flow to confine the plankton sample to the focal point of an illuminating laser beam and measuring the forward and side scattering intensities of each individual object/particle inside the sample volume. To aid classification, flow cytometry is usually coupled with a fluorescence readout to detect the autofluorescence of chlorophyll, phycocyanin, and phycoerythrin found in algae and cyanobacteria. Several field-portable devices based on flow cytometry have been successfully used for analyzing nano- and pico-phytoplankton distributions in natural water samples 14 , 15 , 16 . However, taxonomic identification based solely on scattering and fluorescence data is usually not feasible in flow cytometry, and thus these devices are coupled with additional microscopic image analysis 17 or need to be enhanced with some form of imaging 18 , 19 . Consequently, imaging flow cytometry has become a widely used technique 20 in which a microscope objective is used to image the sample (e.g., algae) within a fluidic flow. The image capture is triggered by a fluorescence detector, and thus objects with detectable autofluorescence are imaged. Some of the widely utilized and commercially available imaging flow cytometers include the Flowcam 21 (Fluid Imaging Technologies), Imaging Flowcytobot 22 (McLane Research Laboratories), and CytoSense 23 (Cytobouy b.v.). Although these systems are able to perform imaging of the plankton in a flow, they still have some important limitations. The use of a microscope objective lens provides a strong trade-off between the image resolution and volumetric throughput of these systems; therefore, to obtain high-quality images, the measured sample volume is limited to a few milliliters per hour (e.g., 3–15 mL/h). Using lower-magnification objective lenses can scale up this low throughput by approximately tenfold at the expense of image quality. In addition, the shallow depth-of-field of the microscope objective necessitates hydrodynamic focusing of the liquid sample into a few-µm-thick layer using a stable sheath flow. This also restricts the size of the objects that can be imaged (e.g., to <150 µm) as well as the flow velocity and throughput of the system, thus requiring the use of additional expensive techniques such as acoustic focusing 22 . As a result of these factors, currently existing imaging flow cytometers used in environmental microbiology are fairly bulky (weighing, e.g., 9–30 kg) and costly (>$40,000–$100,000), limiting their widespread use. Holographic imaging of plankton samples provides a label-free alternative to these existing fluorescence-based approaches; in fact, its use in environmental microbiology started more than 40 years ago using photographic films 24 and subsequently continued via digital cameras and reconstruction techniques 25 . Holography provides a volumetric imaging technique that uses coherent or partially coherent light to record the interference intensity pattern of an object 26 . This hologram can subsequently be reconstructed to digitally bring the object into focus. The hologram contains information on the<|im_end|> <|im_start|>assistant In the past 10 years, harmful algal blooms—sudden increases in the population of algae, typically in coastal regions and freshwater systems—have become a more serious problem for marine life throughout the U.S. The blooms are made up of phytoplankton, which naturally produce biotoxins, and those toxins can affect not only fish and plant life in the water, but also mammals, birds and humans who live near those areas. According to the National Oceanic and Atmospheric Administration, the events have become more common and are occurring in more regions around the world than ever before. The ability to forecast harmful algal blooms and their locations, size and severity could help scientists prevent their dangerous effects. But it has been difficult to predict when and where the blooms will occur. Now, UCLA researchers have developed an inexpensive and portable device that can analyze water samples immediately, which would provide marine biologists with real-time insight about the possibility that the algal blooms could occur in the area they're testing. That, in turn, would allow officials who manage coastal areas to make better, faster decisions about, for example, closing beaches and shellfish beds before algal blooms cause serious damage. UCLA researchers created a new flow cytometer—which detects and measures the physical and chemical characteristics of tiny objects within a sample—based on holographic imaging and artificial intelligence. It can quickly analyze the composition of various plankton species within a matter of seconds, much faster than the current standard method, which involves collecting water samples manually and running them through several steps. The research, which was published online by Light: Science & Applications and will appear in the journal's print edition, was led by Aydogan Ozcan, the UCLA Chancellor's Professor of Electrical and Computer Engineering and associate director of the California NanoSystems Institute at UCLA. The growing threat from blooms is being caused in part by higher water temperature due to climate change, and in part by high levels of nutrients (mainly phosphorus, nitrogen and carbon) from fertilizers used for lawns and farmland. The toxic compounds produced by the blooms can deplete oxygen from the water and can block sunlight from reaching fish and aquatic plants, which cause them to die or migrate elsewhere. In addition, fish and nearby wildlife can even ingest the toxins; and in some rare cases, if they are close enough to the blooms, humans can inhale them which can affect the nervous system, brain and liver, and eventually lead to death. Scientists have generally tried to understand algal blooms through manual sampling and traditional light microscopy, which they use to create high-resolution maps showing a phytoplankton composition in that area over extended periods of time. To build those maps, technicians have to collect water samples by hand using plankton nets and then bring them to a lab for analysis. The process is challenging in part because the concentration and composition of algae in a given body of water can change quickly—even in the time it takes to analyze samples. The device created by Ozcan and his colleagues speeds up the entire process and, because it does not use lenses or other optical components, it performs the testing at a much lower cost. It images algae samples—and is capable of scanning a wide range of other substances, too —using holography and artificial intelligence. Commercially available imaging flow cytometers used in environmental microbiology can cost from $40,000 to $100,000, which has limited their widespread use. The UCLA cytometer is compact and lightweight, and it can be assembled from parts costing less than $2,500. One challenge the researchers had to overcome was ensuring the device would have enough light to create well-lit, high-speed images without motion blur. "It's similar to taking a picture of a Formula 1 race car," Ozcan said. "The cameraman needs a very short exposure to avoid motion blur. In our case, that means using a very bright, pulsed light source with a pulse length about one-thousandth the duration of the blink of an eye." To test the device, the scientists measured ocean samples along the Los Angeles coastline and obtained images of its phytoplankton composition. They also measured the concentration of a potentially toxic alga called Pseudo-nitzschia along six public beaches in the region. The UCLA researchers' measurements were comparable to those in a recent study by the California Department of Public Health's Marine Biotoxin Monitoring Program. Zoltán Gӧrӧcs, a UCLA postdoctoral scholar and the study's first author, said the researchers are in the process of discussing their new device with marine biologists to determine where it would be most useful. "Our device can be adapted to look at larger organisms with a higher throughput or look at smaller ones with a better image quality while sacrificing some of the throughput," he said. <|im_end|>

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2,366

[ { "content": "You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it", "role": "system" }, { "content": "Abstract Activation of the RIG-I-like receptors, retinoic-acid inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5), establishes an antiviral state by upregulating interferon (IFN)-stimulated genes (ISGs). Among these is ISG15, the mechanistic roles of which in innate immunity still remain enigmatic. In the present study, we report that ISG15 conjugation is essential for antiviral IFN responses mediated by the viral RNA sensor MDA5. ISGylation of the caspase activation and recruitment domains of MDA5 promotes its oligomerization and thereby triggers activation of innate immunity against a range of viruses, including coronaviruses, flaviviruses and picornaviruses. The ISG15-dependent activation of MDA5 is antagonized through direct de-ISGylation mediated by the papain-like protease of SARS-CoV-2, a recently emerged coronavirus that has caused the COVID-19 pandemic. Our work demonstrates a crucial role for ISG15 in the MDA5-mediated antiviral response, and also identifies a key immune evasion mechanism of SARS-CoV-2, which may be targeted for the development of new antivirals and vaccines to combat COVID-19. Main Viral perturbation of host immune homoeostasis is monitored by the innate immune system, which relies on receptors that sense danger- or pathogen-associated molecular patterns (PAMPs) 1 , 2 , 3 . The RIG-I-like receptors (RLRs) RIG-I and MDA5 are pivotal for virus detection by surveying the cytoplasm for viral or host-derived immunostimulatory RNAs 4 . Binding of RNA to the C-terminal domain (CTD) and helicase of RIG-I and MDA5 leads to their signalling-primed conformation that allows for the recruitment of several enzymes 5 . These enzymes modify RLRs at multiple domains and sites, and post-translational modifications (PTMs) are particularly well studied for the caspase activation and recruitment domains (CARDs), the signalling modules. Protein phosphatase 1 (PP1)α/γ dephosphorylates the RIG-I and MDA5 CARDs 6 . In the case of RIG-I, dephosphorylation promotes Lys63-linked polyubiquitination of the CARDs by TRIM25 (tripartite motif containing 25) and other E3 ligases 7 , 8 , which stabilizes the oligomeric form of RIG-I, thereby enabling mitochondrial antiviral-signalling protein (MAVS) binding. Compared with those of RIG-I, the individual steps of MDA5 activation and critical PTMs involved are less well understood. RLR activation induces the production of type I and III IFNs which, in turn, propagate antiviral signalling by upregulating ISGs 9 , 10 . Among those is ISG15, a ubiquitin-like protein that can be covalently conjugated to lysine residues of target proteins, a PTM process termed ISGylation 11 . Although ISG15 conjugation has been widely recognized to act antivirally 12 , mechanisms of host protein ISGylation that could explain the broad antiviral restriction activity of ISG15 are currently unknown. The causative agent of the ongoing COVID-19 pandemic, severe acute respiratory syndrome coronavirus 2 (SCoV2), belongs to the Coronaviridae family that contains several other human pathogens. Coronaviruses have an exceptional capability to suppress IFN-mediated antiviral responses, and low IFN production in SCoV2-infected patients correlated with severe disease 13 . Among the coronaviral IFN antagonists is the papain-like protease (PLpro) which has deubiquitinating and de-ISGylating activities 14 , 15 . In the present study, we identify an essential role for ISGylation in MDA5 activation. We further show that SCoV2 PLpro interacts with MDA5 and antagonizes ISG15-dependent MDA5 activation via active de-ISGylation, unveiling that SCoV2 has already evolved to escape immune surveillance by MDA5. Results MDA5, but not RIG-I, signalling requires ISG15 To identify PTMs of the MDA5 CARDs that may regulate MDA5 activation, we subjected affinity-purified MDA5–2CARD fused to glutathione- S -transferase (GST–MDA5–2CARD), or GST alone, to liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS), and found that, specifically, GST–MDA5–2CARD co-purified with ISG15, which appeared as two bands that migrated more slowly (by ~15 and 30 kDa) than unmodified GST–MDA5–2CARD (Extended Data Fig. 1a ). Immunoblotting (IB) confirmed that GST–MDA5–2CARD is modified by ISG15 (Extended Data Fig. 1b ). We next determined the relevance of ISG15 for MDA5-induced signalling. Whereas FLAG–MDA5 expression in wild-type (WT) mouse embryonic fibroblasts (MEFs) induced IFN-β messenger RNA and protein as well as Ccl5 transcripts in a dose-dependent manner, FLAG–MDA5 expression in Isg15 −/− MEFs led to ablated antiviral gene and protein expression (Fig. 1a and Extended Data Fig. 1c ). Similarly, antiviral gene induction by FLAG–MDA5 was strongly diminished in ISG15 knockout (KO) HeLa (human) cells compared with WT control cells (Fig. 1b and Extended Data Fig. 1d ), ruling out a species-specific effect. In contrast, FLAG–RIG-I induced comparable amounts of secreted IFN-β protein as well as Ifnb1 and Ccl5 transcripts in Isg15 −/− and WT MEFs (Fig. 1a and Extended Data Fig. 1c ). IFNB1 and CCL5 transcripts as well as IFN-β protein production by FLAG–RIG-I were similar or slightly enhanced in ISG15 KO HeLa cells compared with WT cells (Fig. 1b and Extended Data Fig. 1d ), consistent with previous reports that ISGylation negatively impacts RIG-I signalling 16 , 17 . Fig. 1: ISGylation is required for MDA5, but not RIG-I, signalling. a , b , ELISA of IFN-β from supernatants of MEFs (WT or Isg15 −/− ) ( a ) and HeLa cells (WT or ISG15 KO) ( b ) transiently transfected with increasing amounts of FLAG-tagged MDA5 or RIG-I for 40 h. Whole-cell lysates (WCLs) were probed by IB with anti-ISG15, anti-FLAG and anti-actin (loading control). c , ELISA of IFN-β from supernatants of WT or Isg15 −/− MEFs that were mock stimulated or transfected with EMCV RNA (0.1 or 0.4 µg ml −1 ), HMW-poly(I:C) (0.5 µg ml −1 ) or RABV Le (1 pmol ml −1 ), or infected with SeV (10 haemagglutination units (HAU) ml −1 ) for 24 h. d , RT–qPCR analysis of Ifnb1 , Ccl5 and Tnf mRNA in WT and Isg15 −/− MEFs stimulated as in c . e , IRF3 phosphorylation in the WCLs of NHLFs that were transfected with the indicated siRNAs for 30 h and then mock stimulated or transfected with EMCV RNA (0.4 µg ml −1 ) or RABV Le (1 pmol ml −1 ) for 6 h, assessed by IB with anti-pSer396-IRF3 and anti-IRF3. f , ELISA of IFN-β from supernatants of NHLFs that were transfected with", "role": "user" }, { "content": "Researchers from Cleveland Clinic's Florida Research and Innovation Center (FRIC) have identified a potential new target for anti-COVID-19 therapies. Their findings were published in Nature Microbiology. Led by FRIC scientific director Michaela Gack, Ph.D., the team discovered that a coronavirus enzyme called PLpro (papain-like protease) blocks the body's immune response to the infection. More research is necessary, but the findings suggest that therapeutics that inhibit the enzyme may help treat COVID-19. \"SARS-CoV-2—the virus that causes COVID-19—has evolved quickly against many of the body's well-known defense mechanisms,\" Gack said. \"Our findings, however, offer insights into a never-before characterized mechanism of immune activation and how PLpro disrupts this response, enabling SARS-CoV-2 to freely replicate and wreak havoc throughout the host. We discovered that inhibiting PLpro may help rescue the early immune response that is key to limiting viral replication and spread.\" One of the body's frontline immune defenses is a class of receptor proteins, including one called MDA5, that identify invaders by foreign patterns in their genetic material. When the receptors recognize a foreign pattern, they become activated and kick-start the immune system into antiviral mode. This is done in part by increasing the downstream expression of proteins encoded by interferon-stimulated genes (ISGs). In this study, Gack and her team identified a novel mechanism that leads to MDA5 activation during virus infection. They found that ISG15 must physically bind to specific regions in the MDA5 receptor—a process termed ISGylation—in order for MDA5 to effectively activate and unleash antiviral actors against invaders. They showed that ISGylation helps to promote the formation of larger MDA5 protein complexes, which ultimately results in a more robust immune response against a range of viruses. \"While discovery of a novel mechanism of immune activation is exciting on its own,\" Gack said, \"we also discovered a bit of bad news, which is that SARS-CoV-2 also understands how the mechanism works, considering it has already developed a strategy to block it.\" The research team shows that the coronavirus enzyme PLpro physically interacts with the receptor MDA5 and inhibits the ISGylation process. \"We're already looking forward to the next phase of study to investigate whether blocking PLpro's enzymatic function, or its interaction with MDA5, will help strengthen the human immune response against the virus,\" Gack said. \"If so, PLpro would certainly be an attractive target for future anti-COVID-19 therapeutics.\" ", "role": "assistant" } ]

<|im_start|>system You are a great journalist. Users will give you a scientific paper paper and ask you to write down a journalistic report of it<|im_end|> <|im_start|>user Abstract Activation of the RIG-I-like receptors, retinoic-acid inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5), establishes an antiviral state by upregulating interferon (IFN)-stimulated genes (ISGs). Among these is ISG15, the mechanistic roles of which in innate immunity still remain enigmatic. In the present study, we report that ISG15 conjugation is essential for antiviral IFN responses mediated by the viral RNA sensor MDA5. ISGylation of the caspase activation and recruitment domains of MDA5 promotes its oligomerization and thereby triggers activation of innate immunity against a range of viruses, including coronaviruses, flaviviruses and picornaviruses. The ISG15-dependent activation of MDA5 is antagonized through direct de-ISGylation mediated by the papain-like protease of SARS-CoV-2, a recently emerged coronavirus that has caused the COVID-19 pandemic. Our work demonstrates a crucial role for ISG15 in the MDA5-mediated antiviral response, and also identifies a key immune evasion mechanism of SARS-CoV-2, which may be targeted for the development of new antivirals and vaccines to combat COVID-19. Main Viral perturbation of host immune homoeostasis is monitored by the innate immune system, which relies on receptors that sense danger- or pathogen-associated molecular patterns (PAMPs) 1 , 2 , 3 . The RIG-I-like receptors (RLRs) RIG-I and MDA5 are pivotal for virus detection by surveying the cytoplasm for viral or host-derived immunostimulatory RNAs 4 . Binding of RNA to the C-terminal domain (CTD) and helicase of RIG-I and MDA5 leads to their signalling-primed conformation that allows for the recruitment of several enzymes 5 . These enzymes modify RLRs at multiple domains and sites, and post-translational modifications (PTMs) are particularly well studied for the caspase activation and recruitment domains (CARDs), the signalling modules. Protein phosphatase 1 (PP1)α/γ dephosphorylates the RIG-I and MDA5 CARDs 6 . In the case of RIG-I, dephosphorylation promotes Lys63-linked polyubiquitination of the CARDs by TRIM25 (tripartite motif containing 25) and other E3 ligases 7 , 8 , which stabilizes the oligomeric form of RIG-I, thereby enabling mitochondrial antiviral-signalling protein (MAVS) binding. Compared with those of RIG-I, the individual steps of MDA5 activation and critical PTMs involved are less well understood. RLR activation induces the production of type I and III IFNs which, in turn, propagate antiviral signalling by upregulating ISGs 9 , 10 . Among those is ISG15, a ubiquitin-like protein that can be covalently conjugated to lysine residues of target proteins, a PTM process termed ISGylation 11 . Although ISG15 conjugation has been widely recognized to act antivirally 12 , mechanisms of host protein ISGylation that could explain the broad antiviral restriction activity of ISG15 are currently unknown. The causative agent of the ongoing COVID-19 pandemic, severe acute respiratory syndrome coronavirus 2 (SCoV2), belongs to the Coronaviridae family that contains several other human pathogens. Coronaviruses have an exceptional capability to suppress IFN-mediated antiviral responses, and low IFN production in SCoV2-infected patients correlated with severe disease 13 . Among the coronaviral IFN antagonists is the papain-like protease (PLpro) which has deubiquitinating and de-ISGylating activities 14 , 15 . In the present study, we identify an essential role for ISGylation in MDA5 activation. We further show that SCoV2 PLpro interacts with MDA5 and antagonizes ISG15-dependent MDA5 activation via active de-ISGylation, unveiling that SCoV2 has already evolved to escape immune surveillance by MDA5. Results MDA5, but not RIG-I, signalling requires ISG15 To identify PTMs of the MDA5 CARDs that may regulate MDA5 activation, we subjected affinity-purified MDA5–2CARD fused to glutathione- S -transferase (GST–MDA5–2CARD), or GST alone, to liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS), and found that, specifically, GST–MDA5–2CARD co-purified with ISG15, which appeared as two bands that migrated more slowly (by ~15 and 30 kDa) than unmodified GST–MDA5–2CARD (Extended Data Fig. 1a ). Immunoblotting (IB) confirmed that GST–MDA5–2CARD is modified by ISG15 (Extended Data Fig. 1b ). We next determined the relevance of ISG15 for MDA5-induced signalling. Whereas FLAG–MDA5 expression in wild-type (WT) mouse embryonic fibroblasts (MEFs) induced IFN-β messenger RNA and protein as well as Ccl5 transcripts in a dose-dependent manner, FLAG–MDA5 expression in Isg15 −/− MEFs led to ablated antiviral gene and protein expression (Fig. 1a and Extended Data Fig. 1c ). Similarly, antiviral gene induction by FLAG–MDA5 was strongly diminished in ISG15 knockout (KO) HeLa (human) cells compared with WT control cells (Fig. 1b and Extended Data Fig. 1d ), ruling out a species-specific effect. In contrast, FLAG–RIG-I induced comparable amounts of secreted IFN-β protein as well as Ifnb1 and Ccl5 transcripts in Isg15 −/− and WT MEFs (Fig. 1a and Extended Data Fig. 1c ). IFNB1 and CCL5 transcripts as well as IFN-β protein production by FLAG–RIG-I were similar or slightly enhanced in ISG15 KO HeLa cells compared with WT cells (Fig. 1b and Extended Data Fig. 1d ), consistent with previous reports that ISGylation negatively impacts RIG-I signalling 16 , 17 . Fig. 1: ISGylation is required for MDA5, but not RIG-I, signalling. a , b , ELISA of IFN-β from supernatants of MEFs (WT or Isg15 −/− ) ( a ) and HeLa cells (WT or ISG15 KO) ( b ) transiently transfected with increasing amounts of FLAG-tagged MDA5 or RIG-I for 40 h. Whole-cell lysates (WCLs) were probed by IB with anti-ISG15, anti-FLAG and anti-actin (loading control). c , ELISA of IFN-β from supernatants of WT or Isg15 −/− MEFs that were mock stimulated or transfected with EMCV RNA (0.1 or 0.4 µg ml −1 ), HMW-poly(I:C) (0.5 µg ml −1 ) or RABV Le (1 pmol ml −1 ), or infected with SeV (10 haemagglutination units (HAU) ml −1 ) for 24 h. d , RT–qPCR analysis of Ifnb1 , Ccl5 and Tnf mRNA in WT and Isg15 −/− MEFs stimulated as in c . e , IRF3 phosphorylation in the WCLs of NHLFs that were transfected with the indicated siRNAs for 30 h and then mock stimulated or transfected with EMCV RNA (0.4 µg ml −1 ) or RABV Le (1 pmol ml −1 ) for 6 h, assessed by IB with anti-pSer396-IRF3 and anti-IRF3. f , ELISA of IFN-β from supernatants of NHLFs that were transfected with<|im_end|> <|im_start|>assistant Researchers from Cleveland Clinic's Florida Research and Innovation Center (FRIC) have identified a potential new target for anti-COVID-19 therapies. Their findings were published in Nature Microbiology. Led by FRIC scientific director Michaela Gack, Ph.D., the team discovered that a coronavirus enzyme called PLpro (papain-like protease) blocks the body's immune response to the infection. More research is necessary, but the findings suggest that therapeutics that inhibit the enzyme may help treat COVID-19. "SARS-CoV-2—the virus that causes COVID-19—has evolved quickly against many of the body's well-known defense mechanisms," Gack said. "Our findings, however, offer insights into a never-before characterized mechanism of immune activation and how PLpro disrupts this response, enabling SARS-CoV-2 to freely replicate and wreak havoc throughout the host. We discovered that inhibiting PLpro may help rescue the early immune response that is key to limiting viral replication and spread." One of the body's frontline immune defenses is a class of receptor proteins, including one called MDA5, that identify invaders by foreign patterns in their genetic material. When the receptors recognize a foreign pattern, they become activated and kick-start the immune system into antiviral mode. This is done in part by increasing the downstream expression of proteins encoded by interferon-stimulated genes (ISGs). In this study, Gack and her team identified a novel mechanism that leads to MDA5 activation during virus infection. They found that ISG15 must physically bind to specific regions in the MDA5 receptor—a process termed ISGylation—in order for MDA5 to effectively activate and unleash antiviral actors against invaders. They showed that ISGylation helps to promote the formation of larger MDA5 protein complexes, which ultimately results in a more robust immune response against a range of viruses. "While discovery of a novel mechanism of immune activation is exciting on its own," Gack said, "we also discovered a bit of bad news, which is that SARS-CoV-2 also understands how the mechanism works, considering it has already developed a strategy to block it." The research team shows that the coronavirus enzyme PLpro physically interacts with the receptor MDA5 and inhibits the ISGylation process. "We're already looking forward to the next phase of study to investigate whether blocking PLpro's enzymatic function, or its interaction with MDA5, will help strengthen the human immune response against the virus," Gack said. "If so, PLpro would certainly be an attractive target for future anti-COVID-19 therapeutics." <|im_end|>

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449, 386, 6486, 20, 323, 43215, 4861, 3507, 38, 868, 43918, 386, 6486, 20, 15449, 4669, 4642, 409, 98618, 38, 79933, 11, 92588, 430, 328, 7489, 53, 17, 706, 2736, 28995, 311, 12731, 22852, 22156, 555, 386, 6486, 20, 13, 18591, 386, 6486, 20, 11, 719, 539, 432, 1953, 22197, 11, 91977, 7612, 3507, 38, 868, 2057, 10765, 19932, 22365, 315, 279, 386, 6486, 20, 42800, 82, 430, 1253, 37377, 386, 6486, 20, 15449, 11, 584, 38126, 51552, 2320, 324, 1908, 386, 6486, 20, 4235, 17, 60319, 75754, 311, 35169, 589, 6473, 12, 328, 482, 25163, 521, 320, 76620, 4235, 6204, 32, 20, 4235, 17, 60319, 705, 477, 33934, 7636, 11, 311, 14812, 98284, 5814, 34356, 449, 67042, 3148, 9618, 442, 15501, 320, 8724, 4235, 4931, 14, 4931, 705, 323, 1766, 430, 11, 11951, 11, 33934, 4235, 6204, 32, 20, 4235, 17, 60319, 1080, 2320, 324, 1908, 449, 3507, 38, 868, 11, 902, 9922, 439, 1403, 21562, 430, 73691, 810, 14297, 320, 1729, 4056, 868, 323, 220, 966, 597, 31516, 8, 1109, 653, 28261, 33934, 4235, 6204, 32, 20, 4235, 17, 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59199, 2585, 7917, 320, 30035, 13, 220, 16, 65, 323, 41665, 2956, 23966, 13, 220, 16, 67, 7026, 17864, 704, 264, 9606, 19440, 2515, 13, 763, 13168, 11, 31479, 4235, 49, 1953, 22197, 36572, 30139, 15055, 315, 6367, 291, 11812, 45, 12, 52355, 13128, 439, 1664, 439, 1442, 18571, 16, 323, 356, 566, 20, 61412, 304, 358, 2034, 868, 25173, 14, 34363, 323, 59199, 386, 15229, 82, 320, 30035, 13, 220, 16, 64, 323, 41665, 2956, 23966, 13, 220, 16, 66, 7609, 11812, 34442, 16, 323, 356, 3218, 20, 61412, 439, 1664, 439, 11812, 45, 12, 52355, 13128, 5788, 555, 31479, 4235, 49, 1953, 22197, 1051, 4528, 477, 10284, 24872, 304, 3507, 38, 868, 38612, 1283, 8921, 7917, 7863, 449, 59199, 7917, 320, 30035, 13, 220, 16, 65, 323, 41665, 2956, 23966, 13, 220, 16, 67, 7026, 13263, 449, 3766, 6821, 430, 3507, 38, 79933, 48291, 25949, 432, 1953, 22197, 91977, 220, 845, 1174, 220, 1114, 662, 23966, 13, 220, 16, 25, 3507, 38, 79933, 374, 2631, 369, 386, 6486, 20, 11, 719, 539, 432, 1953, 22197, 11, 91977, 13, 264, 1174, 293, 1174, 17705, 35301, 315, 11812, 45, 12, 52355, 505, 39887, 266, 1821, 315, 386, 15229, 82, 320, 18961, 477, 358, 2034, 868, 25173, 14, 34363, 883, 320, 264, 883, 323, 1283, 8921, 7917, 320, 18961, 477, 3507, 38, 868, 38612, 8, 320, 293, 883, 41658, 398, 20429, 1599, 449, 7859, 15055, 315, 31479, 39304, 3640, 386, 6486, 20, 477, 432, 1953, 22197, 369, 220, 1272, 305, 13, 41593, 33001, 84495, 988, 320, 54, 3218, 82, 8, 1051, 463, 2788, 555, 12373, 449, 7294, 98618, 38, 868, 11, 7294, 12, 23358, 323, 7294, 12, 533, 258, 320, 10853, 2585, 570, 272, 1174, 17705, 35301, 315, 11812, 45, 12, 52355, 505, 39887, 266, 1821, 315, 59199, 477, 358, 2034, 868, 25173, 14, 34363, 386, 15229, 82, 430, 1051, 8018, 81471, 477, 20429, 1599, 449, 74804, 53, 41214, 320, 15, 13, 16, 477, 220, 15, 13, 19, 64012, 70, 16116, 25173, 16, 7026, 46514, 54, 2320, 5849, 9149, 57092, 8, 320, 15, 13, 20, 64012, 70, 16116, 25173, 16, 883, 477, 432, 1905, 53, 2009, 320, 16, 9012, 337, 16116, 25173, 16, 7026, 477, 29374, 449, 1369, 53, 320, 605, 6520, 336, 351, 6200, 332, 2617, 8316, 320, 17455, 52, 8, 16116, 25173, 16, 883, 369, 220, 1187, 305, 13, 294, 1174, 10860, 4235, 80, 74256, 6492, 315, 1442, 18571, 16, 1174, 356, 566, 20, 323, 350, 32837, 78872, 304, 59199, 323, 358, 2034, 868, 25173, 14, 34363, 386, 15229, 82, 81471, 439, 304, 272, 662, 384, 1174, 16646, 37, 18, 95089, 2354, 304, 279, 468, 3218, 82, 315, 24603, 49400, 430, 1051, 20429, 1599, 449, 279, 16717, 4502, 51295, 2170, 369, 220, 966, 305, 323, 1243, 8018, 81471, 477, 20429, 1599, 449, 74804, 53, 41214, 320, 15, 13, 19, 64012, 70, 16116, 25173, 16, 883, 477, 432, 1905, 53, 2009, 320, 16, 9012, 337, 16116, 25173, 16, 883, 369, 220, 21, 305, 11, 32448, 555, 12373, 449, 7294, 2320, 32845, 19615, 12, 2871, 37, 18, 323, 7294, 12, 2871, 37, 18, 13, 282, 1174, 17705, 35301, 315, 11812, 45, 12, 52355, 505, 39887, 266, 1821, 315, 24603, 49400, 430, 1051, 20429, 1599, 449, 128257, 198, 128256, 78191, 198, 60210, 505, 24372, 40324, 596, 9784, 8483, 323, 38710, 5955, 320, 10725, 1341, 8, 617, 11054, 264, 4754, 502, 2218, 369, 7294, 7813, 110985, 12, 777, 52312, 13, 11205, 14955, 1051, 4756, 304, 22037, 18654, 81162, 13, 32755, 555, 17067, 1341, 12624, 7690, 8096, 64, 480, 474, 11, 2405, 920, 2637, 279, 2128, 11352, 430, 264, 33333, 49242, 2663, 10528, 782, 320, 79, 391, 467, 12970, 5541, 521, 8, 10215, 279, 2547, 596, 22852, 2077, 311, 279, 19405, 13, 4497, 3495, 374, 5995, 11, 719, 279, 14955, 4284, 430, 9139, 88886, 430, 69033, 279, 49242, 1253, 1520, 4322, 20562, 12, 777, 13, 330, 50, 17485, 87271, 53, 12, 17, 22416, 17188, 430, 11384, 20562, 12, 777, 2345, 4752, 28995, 6288, 2403, 1690, 315, 279, 2547, 596, 1664, 22015, 9232, 24717, 1359, 480, 474, 1071, 13, 330, 8140, 14955, 11, 4869, 11, 3085, 26793, 1139, 264, 2646, 70547, 32971, 17383, 315, 22852, 15449, 323, 1268, 10528, 782, 24927, 82, 420, 2077, 11, 28462, 328, 17485, 87271, 53, 12, 17, 311, 26662, 46113, 323, 83675, 66592, 6957, 279, 3552, 13, 1226, 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7813, 110985, 12, 777, 9139, 88886, 1210, 220, 128257, 198 ]

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