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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 liver is the most common site of metastatic disease 1 . Although this metastatic tropism may reflect the mechanical trapping of circulating tumour cells, liver metastasis is also dependent, at least in part, on the formation of a ‘pro-metastatic’ niche that supports the spread of tumour cells to the liver 2 , 3 . The mechanisms that direct the formation of this niche are poorly understood. Here we show that hepatocytes coordinate myeloid cell accumulation and fibrosis within the liver and, in doing so, increase the susceptibility of the liver to metastatic seeding and outgrowth. During early pancreatic tumorigenesis in mice, hepatocytes show activation of signal transducer and activator of transcription 3 (STAT3) signalling and increased production of serum amyloid A1 and A2 (referred to collectively as SAA). Overexpression of SAA by hepatocytes also occurs in patients with pancreatic and colorectal cancers that have metastasized to the liver, and many patients with locally advanced and metastatic disease show increases in circulating SAA. Activation of STAT3 in hepatocytes and the subsequent production of SAA depend on the release of interleukin 6 (IL-6) into the circulation by non-malignant cells. Genetic ablation or blockade of components of IL-6–STAT3–SAA signalling prevents the establishment of a pro-metastatic niche and inhibits liver metastasis. Our data identify an intercellular network underpinned by hepatocytes that forms the basis of a pro-metastatic niche in the liver, and identify new therapeutic targets. Main To understand the mechanisms that underlie the formation of a pro-metastatic niche in the liver, we used the LSL-Kras G12D /+ ;LSL-Trp53 R127H /+ ;Pdx1-cre (KPC) mouse model of pancreatic ductal adenocarcinoma (PDAC) 4 , 5 . We looked for features of a pro-metastatic niche in the livers of over-16-week-old tumour-bearing KPC mice and 8- to 10-week-old non-tumour-bearing (NTB) KPC control mice, which lack PDAC but harbour pancreatic intraepithelial neoplasia (PanIN) 6 . Compared to control mice, the livers of KPC mice contained increased numbers of myeloid cells, accompanied by an increase in the deposition and expression of fibronectin and type I collagen (COL1) (Fig. 1a , Extended Data Fig. 1a–d ). Orthotopic implantation of KPC-derived PDAC cells into wild-type mice recapitulated these changes (Extended Data Fig. 1e–i ). As shown previously 7 , 8 , matrix deposition did not require myeloid cells (Extended Data Fig. 1j–l ). These results are consistent with evidence that myeloid cell accumulation and extracellular matrix deposition are key components of a pro-metastatic niche 7 , 8 , 9 , 10 . Fig. 1: Primary PDAC development induces a pro-metastatic niche in the liver. a , Images and quantification of myeloid cells, fibronectin (FN), and COL1 in the liver. Arrows indicate Ly6G + cells. Numbers in parentheses on plots indicate the number ( n ) of mice. Data pooled from two experiments. TB, tumour-bearing; NTB, non-tumour-bearing. b , Images of the liver and quantification of PDAC–YFP cells. Control mice ( n = 14) and NTB KPC mice ( n = 10) were intrasplenically injected with PDAC–YFP cells, and the liver was analysed after 10 days. Data representative of two independent experiments. c , Scatter plot of transcriptome data. FPKM, fragments per kilobase of exon per million mapped fragments ( n = 5 for both groups). Scale bars, 50 μm ( a ) and 1 cm ( b ). Statistical significance calculated using one-way analysis of variance (ANOVA) with Dunnett’s test ( a ) and two-tailed Mann–Whitney test ( b ). Data represented as mean ± s.d. Source data Full size image We next evaluated the susceptibility of the liver to metastatic colonization. Yellow fluorescent protein (YFP)-labelled KPC-derived PDAC cells (PDAC–YFP) 6 were injected into control mice and KPC mice. The metastatic burden was threefold higher in KPC mice, and metastatic lesions were detected in the livers of KPC mice at increased frequency and size with enhanced proliferation (shown using Ki-67) (Fig. 1b , Extended Data Fig. 2a, b ). Similar findings were observed using a YFP-negative KPC-derived cell line (Extended Data Fig. 2c, d ). Orthotopic implantation of PDAC cells also increased the susceptibility of the liver to metastatic colonization, and this finding was independent of the presence of CD4 + and CD8 + T cells (Extended Data Fig. 2e–s ). We next performed mRNA sequencing on RNA isolated from the livers of control and KPC mice. We identified 275 differentially expressed genes (Extended Data Fig. 3a, b , Supplementary Data 1 ) and found that genes upregulated in KPC mice were associated with immune-related processes (Extended Data Fig. 3c ). Notably, genes encoding myeloid chemoattractants, including SAA and members of the S100 family, were upregulated in KPC mice 11 , 12 , 13 (Fig. 1c , Extended Data Fig. 3d, e ). We also found enrichment of immune-related pathways, particularly the IL-6–JAK–STAT3 signalling pathway (Extended Data Fig. 3f , Supplementary Table 1 ). We validated our results by examining the livers of KPC mice for the presence of phosphorylated STAT3 (pSTAT3). STAT3 was activated in 80–90% of hepatocytes from KPC mice, compared to less than 2% of hepatocytes in control mice (Extended Data Fig. 3g, h ). By contrast, we did not detect activation of STAT1 signalling (Extended Data Fig. 3i ). Orthotopic implantation of PDAC cells also induced phosphorylation of STAT3 in hepatocytes (Extended Data Fig. 3j, k ). As IL-6 is fundamental to STAT3 signalling in hepatocytes 14 , we examined the livers of control mice ( Il6 +/+ ) and IL-6 knockout mice ( Il6 −/− ) orthotopically injected with PBS or PDAC cells. Tumour-implanted Il6 −/− mice displayed a decrease in STAT3 activation, particularly in hepatocytes (Fig. 2a , Extended Data Fig. 4a ). This loss in STAT3 activation was accompanied by reductions in myeloid cell accumulation and extracellular matrix deposition without alterations in the morphology and density of liver sinusoids (Fig. 2a and Extended Data Fig. 4a-d ). We also observed reduced expression of SAA, other chemoattractants, and extracellular matrix proteins (Fig. 2b , Extended Data Fig. 4e ). Genetic ablation of Il6 ,", "role": "user" }, { "content": "When cancer spreads to another organ, it most commonly moves to the liver, and now researchers at the Abramson Cancer Center of the University of Pennsylvania say they know why. A new study, published today in Nature, shows hepatocytes—the chief functional cells of the liver—are at the center of a chain reaction that makes it particularly susceptible to cancer cells. These hepatocytes respond to inflammation by activating a protein called STAT3, which in turn increases their production of other proteins called SAA, which then remodel the liver and create the \"soil\" needed for cancer cells to \"seed.\" The researchers show that stopping this process by using antibodies that block IL-6—the inflammatory signal that drives this chain reaction—can limit the potential of cancer to spread to the liver. \"The seed-and-soil hypothesis is well-recognized, but our research now shows that hepatocytes are the major orchestrators of this process,\" said senior author Gregory L. Beatty, MD, Ph.D., an assistant professor of Hematology-Oncology at Penn's Perelman School of Medicine. Jae W. Lee, an MD/Ph.D. candidate in Beatty's laboratory, is the lead author. For this study, the team first used mouse models of pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer and currently the third leading cause of cancer death in the United States. They found that nearly all hepatocytes showed STAT3 activation in mice with cancer, compared to less than two percent of hepatocytes in mice without tumors. They then partnered with investigators at the Mayo Clinic Arizona and other Penn colleagues to show that this same biology could be seen in patients with pancreatic cancer as well colon and lung cancer. Genetically deleting STAT3 only in hepatocytes effectively blocked the increased susceptibility of the liver to cancer seeding in mice. The team collaborated further with investigators at the University of Kentucky to show that IL-6 controls STAT3 signaling in these cells and instructs hepatocytes to make SAA, which acts as an alarm to attract inflammatory cells and initiate a fibrotic reaction that together establish the \"soil.\" \"The liver is an important sensor in the body,\" Lee said. \"We show that hepatocytes sense inflammation and respond in a structured way that cancer uses to help it spread.\" The study also found that IL-6 drives changes in the liver whether there's a tumor present or not, implying that any condition associated with increased IL-6 levels—such as obesity or cardiovascular disease, among others—could affect the liver's receptiveness to cancer. Researchers say this provides evidence that therapies which target hepatocytes may be able to prevent cancer from spreading to the liver, a major cause of cancer mortality. ", "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 liver is the most common site of metastatic disease 1 . Although this metastatic tropism may reflect the mechanical trapping of circulating tumour cells, liver metastasis is also dependent, at least in part, on the formation of a ‘pro-metastatic’ niche that supports the spread of tumour cells to the liver 2 , 3 . The mechanisms that direct the formation of this niche are poorly understood. Here we show that hepatocytes coordinate myeloid cell accumulation and fibrosis within the liver and, in doing so, increase the susceptibility of the liver to metastatic seeding and outgrowth. During early pancreatic tumorigenesis in mice, hepatocytes show activation of signal transducer and activator of transcription 3 (STAT3) signalling and increased production of serum amyloid A1 and A2 (referred to collectively as SAA). Overexpression of SAA by hepatocytes also occurs in patients with pancreatic and colorectal cancers that have metastasized to the liver, and many patients with locally advanced and metastatic disease show increases in circulating SAA. Activation of STAT3 in hepatocytes and the subsequent production of SAA depend on the release of interleukin 6 (IL-6) into the circulation by non-malignant cells. Genetic ablation or blockade of components of IL-6–STAT3–SAA signalling prevents the establishment of a pro-metastatic niche and inhibits liver metastasis. Our data identify an intercellular network underpinned by hepatocytes that forms the basis of a pro-metastatic niche in the liver, and identify new therapeutic targets. Main To understand the mechanisms that underlie the formation of a pro-metastatic niche in the liver, we used the LSL-Kras G12D /+ ;LSL-Trp53 R127H /+ ;Pdx1-cre (KPC) mouse model of pancreatic ductal adenocarcinoma (PDAC) 4 , 5 . We looked for features of a pro-metastatic niche in the livers of over-16-week-old tumour-bearing KPC mice and 8- to 10-week-old non-tumour-bearing (NTB) KPC control mice, which lack PDAC but harbour pancreatic intraepithelial neoplasia (PanIN) 6 . Compared to control mice, the livers of KPC mice contained increased numbers of myeloid cells, accompanied by an increase in the deposition and expression of fibronectin and type I collagen (COL1) (Fig. 1a , Extended Data Fig. 1a–d ). Orthotopic implantation of KPC-derived PDAC cells into wild-type mice recapitulated these changes (Extended Data Fig. 1e–i ). As shown previously 7 , 8 , matrix deposition did not require myeloid cells (Extended Data Fig. 1j–l ). These results are consistent with evidence that myeloid cell accumulation and extracellular matrix deposition are key components of a pro-metastatic niche 7 , 8 , 9 , 10 . Fig. 1: Primary PDAC development induces a pro-metastatic niche in the liver. a , Images and quantification of myeloid cells, fibronectin (FN), and COL1 in the liver. Arrows indicate Ly6G + cells. Numbers in parentheses on plots indicate the number ( n ) of mice. Data pooled from two experiments. TB, tumour-bearing; NTB, non-tumour-bearing. b , Images of the liver and quantification of PDAC–YFP cells. Control mice ( n = 14) and NTB KPC mice ( n = 10) were intrasplenically injected with PDAC–YFP cells, and the liver was analysed after 10 days. Data representative of two independent experiments. c , Scatter plot of transcriptome data. FPKM, fragments per kilobase of exon per million mapped fragments ( n = 5 for both groups). Scale bars, 50 μm ( a ) and 1 cm ( b ). Statistical significance calculated using one-way analysis of variance (ANOVA) with Dunnett’s test ( a ) and two-tailed Mann–Whitney test ( b ). Data represented as mean ± s.d. Source data Full size image We next evaluated the susceptibility of the liver to metastatic colonization. Yellow fluorescent protein (YFP)-labelled KPC-derived PDAC cells (PDAC–YFP) 6 were injected into control mice and KPC mice. The metastatic burden was threefold higher in KPC mice, and metastatic lesions were detected in the livers of KPC mice at increased frequency and size with enhanced proliferation (shown using Ki-67) (Fig. 1b , Extended Data Fig. 2a, b ). Similar findings were observed using a YFP-negative KPC-derived cell line (Extended Data Fig. 2c, d ). Orthotopic implantation of PDAC cells also increased the susceptibility of the liver to metastatic colonization, and this finding was independent of the presence of CD4 + and CD8 + T cells (Extended Data Fig. 2e–s ). We next performed mRNA sequencing on RNA isolated from the livers of control and KPC mice. We identified 275 differentially expressed genes (Extended Data Fig. 3a, b , Supplementary Data 1 ) and found that genes upregulated in KPC mice were associated with immune-related processes (Extended Data Fig. 3c ). Notably, genes encoding myeloid chemoattractants, including SAA and members of the S100 family, were upregulated in KPC mice 11 , 12 , 13 (Fig. 1c , Extended Data Fig. 3d, e ). We also found enrichment of immune-related pathways, particularly the IL-6–JAK–STAT3 signalling pathway (Extended Data Fig. 3f , Supplementary Table 1 ). We validated our results by examining the livers of KPC mice for the presence of phosphorylated STAT3 (pSTAT3). STAT3 was activated in 80–90% of hepatocytes from KPC mice, compared to less than 2% of hepatocytes in control mice (Extended Data Fig. 3g, h ). By contrast, we did not detect activation of STAT1 signalling (Extended Data Fig. 3i ). Orthotopic implantation of PDAC cells also induced phosphorylation of STAT3 in hepatocytes (Extended Data Fig. 3j, k ). As IL-6 is fundamental to STAT3 signalling in hepatocytes 14 , we examined the livers of control mice ( Il6 +/+ ) and IL-6 knockout mice ( Il6 −/− ) orthotopically injected with PBS or PDAC cells. Tumour-implanted Il6 −/− mice displayed a decrease in STAT3 activation, particularly in hepatocytes (Fig. 2a , Extended Data Fig. 4a ). This loss in STAT3 activation was accompanied by reductions in myeloid cell accumulation and extracellular matrix deposition without alterations in the morphology and density of liver sinusoids (Fig. 2a and Extended Data Fig. 4a-d ). We also observed reduced expression of SAA, other chemoattractants, and extracellular matrix proteins (Fig. 2b , Extended Data Fig. 4e ). Genetic ablation of Il6 ,<|im_end|> <|im_start|>assistant When cancer spreads to another organ, it most commonly moves to the liver, and now researchers at the Abramson Cancer Center of the University of Pennsylvania say they know why. A new study, published today in Nature, shows hepatocytes—the chief functional cells of the liver—are at the center of a chain reaction that makes it particularly susceptible to cancer cells. These hepatocytes respond to inflammation by activating a protein called STAT3, which in turn increases their production of other proteins called SAA, which then remodel the liver and create the "soil" needed for cancer cells to "seed." The researchers show that stopping this process by using antibodies that block IL-6—the inflammatory signal that drives this chain reaction—can limit the potential of cancer to spread to the liver. "The seed-and-soil hypothesis is well-recognized, but our research now shows that hepatocytes are the major orchestrators of this process," said senior author Gregory L. Beatty, MD, Ph.D., an assistant professor of Hematology-Oncology at Penn's Perelman School of Medicine. Jae W. Lee, an MD/Ph.D. candidate in Beatty's laboratory, is the lead author. For this study, the team first used mouse models of pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer and currently the third leading cause of cancer death in the United States. They found that nearly all hepatocytes showed STAT3 activation in mice with cancer, compared to less than two percent of hepatocytes in mice without tumors. They then partnered with investigators at the Mayo Clinic Arizona and other Penn colleagues to show that this same biology could be seen in patients with pancreatic cancer as well colon and lung cancer. Genetically deleting STAT3 only in hepatocytes effectively blocked the increased susceptibility of the liver to cancer seeding in mice. The team collaborated further with investigators at the University of Kentucky to show that IL-6 controls STAT3 signaling in these cells and instructs hepatocytes to make SAA, which acts as an alarm to attract inflammatory cells and initiate a fibrotic reaction that together establish the "soil." "The liver is an important sensor in the body," Lee said. "We show that hepatocytes sense inflammation and respond in a structured way that cancer uses to help it spread." The study also found that IL-6 drives changes in the liver whether there's a tumor present or not, implying that any condition associated with increased IL-6 levels—such as obesity or cardiovascular disease, among others—could affect the liver's receptiveness to cancer. Researchers say this provides evidence that therapies which target hepatocytes may be able to prevent cancer from spreading to the liver, a major cause of cancer mortality. <|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 Magnetic resonance imaging and spectroscopy are versatile methods for probing brain physiology, but their intrinsically low sensitivity limits the achievable spatial and temporal resolution. Here, we introduce a monolithically integrated NMR-on-a-chip needle that combines an ultra-sensitive 300 µm NMR coil with a complete NMR transceiver, enabling in vivo measurements of blood oxygenation and flow in nanoliter volumes at a sampling rate of 200 Hz. Main Methods based on nuclear magnetic resonance (NMR) are powerful analytical techniques in the life sciences, using nuclear spins as specific nanoscopic probes. Despite substantial advances in magnetic resonance (MR) hardware and methodology, NMR is still limited by its poor sensitivity (compared, for example, with optical methods), hindering in particular its use in the study of brain physiology and pathology. Recently, integrated circuit (IC)-based NMR systems have been introduced 1 , 2 , 3 , 4 , 5 to simplify the hardware complexity of MR experiments and to boost sensitivity. Integration of the MR detection coil with the transceiver on a single IC 4 , 5 laid the foundation for millimeter-size, sensitive MR systems for in situ and in vivo applications such as palm-size NMR spectrometry 1 and NMR spectroscopy of single cells 5 . Here, we present a monolithic needle-shaped NMR-on-a-chip transceiver (Fig. 1a,b ) that makes the advantages of IC-based NMR available for various applications in neuroscience. With its miniaturized on-chip coil, low-noise performance and compact, 450 µm-wide needle design, our NMR-on-a-chip transceiver simultaneously improves sensitivity as well as spatial and temporal resolution. In contrast to conventional microcoils 6 , 7 , the micrometer-scale interconnecting wires between the on-chip coil and the electronics combined with the fully differential design reduce the pickup of parasitic MR signals and electromagnetic interference. This enables interference-free in vivo experiments in a defined region of interest. Compared to conventional functional MR imaging (fMRI), the on-chip microcoil removes the need for time-consuming spatial encoding and allows for a continuous recording of MR signals in a nanoliter volume with millisecond resolution. Fig. 1: Schematic overview of the target application of the needle-shaped NMR-on-a-chip transceiver, the ASIC design and the experimental setup. a , The NMR needle is inserted into the target brain area, for example the somatosensory cortex, to perform localized and fast functional MR experiments. b , Fully integrated NMR-on-a-chip spectrometer with an on-chip planar broadband detection coil. The transceiver electronics include a low-noise receiver with quadrature demodulation, an H-bridge-based PA and a frequency synthesizer (containing a phase-frequency detector (PFD), a charge pump (CP) and a quadrature signal generator (IQ)). c , Experimental setup around the NMR needle: the ASIC is glued and bonded on a small carrier PCB and connected via a ribbon cable to the signal conditioning PCB. This setup can be mounted either on a carrier with a sample container and a conventional 8 mm surface coil as reference for system characterization, such as linewidth, sensitivity and SNR, and MR imaging (in vitro setup) or on an animal bed for neuronal experiments to measure changes in blood oxygenation and flow in rats (in vivo setup). The bed or carrier is placed inside a 14.1 T small-animal scanner and the system is completed by a commercial data-acquisition card and a LabVIEW-based console located in the control room. Full size image To achieve the required detection sensitivity in a form factor that is suitable for localized in vivo experiments in brain tissue, we realized a complete NMR spectrometer as a complementary metal-oxide-semiconductor (CMOS) application-specific integrated circuit (ASIC) (Fig. 1b ). This low-power (20 mW) NMR-on-a-chip transceiver features an on-chip, 24-turn, 300 µm outer diameter, transmit/receive (TX/RX) NMR coil. The RX path contains a complete quadrature receiver with an overall noise figure of 0.7 dB including a phase-locked loop (PLL)-based frequency synthesizer and protection switches for the low-noise amplifier (LNA). The TX path features an H-bridge power amplifier (PA) operating from a 3.3 V supply and driven by the on-chip PLL that produces a maximum coil current of 15 mA at 600 MHz. Owing to its amplitude and phase modulation capabilities, the on-chip electronics allow for the use of standard imaging sequences and spectroscopy techniques. In mechanical postprocessing, we first ground the manufactured chips down to a thickness of 100 µm and then shaped them as a needle with a wafer dicer. We used two different setups for in vitro characterization and for in vivo neuronal rat experiments in a 14.1 T small-animal scanner (Fig. 1c ). After first-order manual shimming, the NMR needle achieves a spectral linewidth of 12 Hz in a water phantom (Supplementary Fig. 1 ) and 53 Hz for in vivo experiments (Supplementary Fig. 2 ). We determined the sensitivity of the NMR needle using a three-dimensional gradient echo (3DGRE) sequence, resulting in a sensitive volume of 9.8 nl (Fig. 2a and Supplementary Fig. 3 ) and a time-domain spin sensitivity of \\(2.0 \\times 10^{13}{\\,\\mathrm{spins}}\\,\\mathrm{per}\\,\\sqrt {{\\mathrm{Hz}}}\\) . Compared to a conventional 8 mm surface coil, the NMR needle’s signal-to-noise ratio (SNR) per spin is 40 times higher ( Methods ). We obtained 3DGRE images of a polyimide phantom with an isotropic resolution of 13 µm in less than 15 min, demonstrating the excellent MR imaging capabilities of the NMR needle (Supplementary Fig. 4 ). Fig. 2: In vitro measurement of the sensitive volume and representative experimental results from in vivo rat forepaw stimulation experiments. a , Single-shot (that is, no averaging) 3DGRE image of the sensitive volume V sens of the NMR needle immersed in 10 mM Gd-doped water ( N = 1). b , Coronal anatomical MR image recorded with a conventional surface coil, showing the precise needle location (no averaging, N = 1). The inset shows an overlay from EPI fMRI with a contralateral activation from the stimulation of the left paw in the implantation region of the needle (average of N = 20 stimulation blocks). c , Axial anatomical MR image showing the precise needle location and implantation depth ( N = 1). The inset shows an overlay from EPI fMRI (", "role": "user" }, { "content": "A team of neuroscientists and electrical engineers from Germany and Switzerland developed a highly sensitive implant that enables to probe brain physiology with unparalleled spatial and temporal resolution. They introduce an ultra-fine needle with an integrated chip that is capable of detecting and transmitting nuclear magnetic resonance (NMR) data from nanoliter volumes of brain oxygen metabolism. The breakthrough design will allow entirely new applications in the life sciences. The group of researchers led by Klaus Scheffler from the Max Planck Institute for Biological Cybernetics and the University of Tübingen as well as by Jens Anders from the University of Stuttgart identified a technical bypass that bridges the electrophysical limits of contemporary brain scan methods. Their development of a capillary monolithic nuclear magnetic resonance (NMR) needle combines the versatility of brain imaging with the accuracy of a very localized and fast technique to analyze the specific neuronal activity of the brain. \"The integrated design of a nuclear magnetic resonance detector on a single chip supremely reduces the typical electromagnetic interference of magnetic resonance signals. This enables neuroscientists to gather precise data from minuscule areas of the brain and to combine them with information from spatial and temporal data of the brain´s physiology,\" explains principal investigator Klaus Scheffler. \"With this method, we can now better understand specific activity and functionalities in the brain.\" According to Scheffler and his group, their invention may unveil the possibility of discovering novel effects or typical fingerprints of neuronal activation, up to specific neuronal events in brain tissue. \"Our design setup will allow scalable solutions, meaning the possibility of expanding the collection of data from more than from a single area—but on the same device. The scalability of our approach will allow us to extend our platform by additional sensing modalities such as electrophysiological and optogenetic measurements,\" adds the second principal investigator Jens Anders. The teams of Scheffler and Anders are very confident that their technical approach may help demerge the complex physiologic processes within the neural networks of the brain and that it may uncover additional benefits that can provide even deeper insights into the functionality of the brain. With their primary goal to develop new techniques that are able to specifically probe the structural and biochemical composition of living brain tissue, their latest innovation paves the way for future highly specific and quantitative mapping techniques of neuronal activity and bioenergetic processes in the brain cells. ", "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 Magnetic resonance imaging and spectroscopy are versatile methods for probing brain physiology, but their intrinsically low sensitivity limits the achievable spatial and temporal resolution. Here, we introduce a monolithically integrated NMR-on-a-chip needle that combines an ultra-sensitive 300 µm NMR coil with a complete NMR transceiver, enabling in vivo measurements of blood oxygenation and flow in nanoliter volumes at a sampling rate of 200 Hz. Main Methods based on nuclear magnetic resonance (NMR) are powerful analytical techniques in the life sciences, using nuclear spins as specific nanoscopic probes. Despite substantial advances in magnetic resonance (MR) hardware and methodology, NMR is still limited by its poor sensitivity (compared, for example, with optical methods), hindering in particular its use in the study of brain physiology and pathology. Recently, integrated circuit (IC)-based NMR systems have been introduced 1 , 2 , 3 , 4 , 5 to simplify the hardware complexity of MR experiments and to boost sensitivity. Integration of the MR detection coil with the transceiver on a single IC 4 , 5 laid the foundation for millimeter-size, sensitive MR systems for in situ and in vivo applications such as palm-size NMR spectrometry 1 and NMR spectroscopy of single cells 5 . Here, we present a monolithic needle-shaped NMR-on-a-chip transceiver (Fig. 1a,b ) that makes the advantages of IC-based NMR available for various applications in neuroscience. With its miniaturized on-chip coil, low-noise performance and compact, 450 µm-wide needle design, our NMR-on-a-chip transceiver simultaneously improves sensitivity as well as spatial and temporal resolution. In contrast to conventional microcoils 6 , 7 , the micrometer-scale interconnecting wires between the on-chip coil and the electronics combined with the fully differential design reduce the pickup of parasitic MR signals and electromagnetic interference. This enables interference-free in vivo experiments in a defined region of interest. Compared to conventional functional MR imaging (fMRI), the on-chip microcoil removes the need for time-consuming spatial encoding and allows for a continuous recording of MR signals in a nanoliter volume with millisecond resolution. Fig. 1: Schematic overview of the target application of the needle-shaped NMR-on-a-chip transceiver, the ASIC design and the experimental setup. a , The NMR needle is inserted into the target brain area, for example the somatosensory cortex, to perform localized and fast functional MR experiments. b , Fully integrated NMR-on-a-chip spectrometer with an on-chip planar broadband detection coil. The transceiver electronics include a low-noise receiver with quadrature demodulation, an H-bridge-based PA and a frequency synthesizer (containing a phase-frequency detector (PFD), a charge pump (CP) and a quadrature signal generator (IQ)). c , Experimental setup around the NMR needle: the ASIC is glued and bonded on a small carrier PCB and connected via a ribbon cable to the signal conditioning PCB. This setup can be mounted either on a carrier with a sample container and a conventional 8 mm surface coil as reference for system characterization, such as linewidth, sensitivity and SNR, and MR imaging (in vitro setup) or on an animal bed for neuronal experiments to measure changes in blood oxygenation and flow in rats (in vivo setup). The bed or carrier is placed inside a 14.1 T small-animal scanner and the system is completed by a commercial data-acquisition card and a LabVIEW-based console located in the control room. Full size image To achieve the required detection sensitivity in a form factor that is suitable for localized in vivo experiments in brain tissue, we realized a complete NMR spectrometer as a complementary metal-oxide-semiconductor (CMOS) application-specific integrated circuit (ASIC) (Fig. 1b ). This low-power (20 mW) NMR-on-a-chip transceiver features an on-chip, 24-turn, 300 µm outer diameter, transmit/receive (TX/RX) NMR coil. The RX path contains a complete quadrature receiver with an overall noise figure of 0.7 dB including a phase-locked loop (PLL)-based frequency synthesizer and protection switches for the low-noise amplifier (LNA). The TX path features an H-bridge power amplifier (PA) operating from a 3.3 V supply and driven by the on-chip PLL that produces a maximum coil current of 15 mA at 600 MHz. Owing to its amplitude and phase modulation capabilities, the on-chip electronics allow for the use of standard imaging sequences and spectroscopy techniques. In mechanical postprocessing, we first ground the manufactured chips down to a thickness of 100 µm and then shaped them as a needle with a wafer dicer. We used two different setups for in vitro characterization and for in vivo neuronal rat experiments in a 14.1 T small-animal scanner (Fig. 1c ). After first-order manual shimming, the NMR needle achieves a spectral linewidth of 12 Hz in a water phantom (Supplementary Fig. 1 ) and 53 Hz for in vivo experiments (Supplementary Fig. 2 ). We determined the sensitivity of the NMR needle using a three-dimensional gradient echo (3DGRE) sequence, resulting in a sensitive volume of 9.8 nl (Fig. 2a and Supplementary Fig. 3 ) and a time-domain spin sensitivity of \(2.0 \times 10^{13}{\,\mathrm{spins}}\,\mathrm{per}\,\sqrt {{\mathrm{Hz}}}\) . Compared to a conventional 8 mm surface coil, the NMR needle’s signal-to-noise ratio (SNR) per spin is 40 times higher ( Methods ). We obtained 3DGRE images of a polyimide phantom with an isotropic resolution of 13 µm in less than 15 min, demonstrating the excellent MR imaging capabilities of the NMR needle (Supplementary Fig. 4 ). Fig. 2: In vitro measurement of the sensitive volume and representative experimental results from in vivo rat forepaw stimulation experiments. a , Single-shot (that is, no averaging) 3DGRE image of the sensitive volume V sens of the NMR needle immersed in 10 mM Gd-doped water ( N = 1). b , Coronal anatomical MR image recorded with a conventional surface coil, showing the precise needle location (no averaging, N = 1). The inset shows an overlay from EPI fMRI with a contralateral activation from the stimulation of the left paw in the implantation region of the needle (average of N = 20 stimulation blocks). c , Axial anatomical MR image showing the precise needle location and implantation depth ( N = 1). The inset shows an overlay from EPI fMRI (<|im_end|> <|im_start|>assistant A team of neuroscientists and electrical engineers from Germany and Switzerland developed a highly sensitive implant that enables to probe brain physiology with unparalleled spatial and temporal resolution. They introduce an ultra-fine needle with an integrated chip that is capable of detecting and transmitting nuclear magnetic resonance (NMR) data from nanoliter volumes of brain oxygen metabolism. The breakthrough design will allow entirely new applications in the life sciences. The group of researchers led by Klaus Scheffler from the Max Planck Institute for Biological Cybernetics and the University of Tübingen as well as by Jens Anders from the University of Stuttgart identified a technical bypass that bridges the electrophysical limits of contemporary brain scan methods. Their development of a capillary monolithic nuclear magnetic resonance (NMR) needle combines the versatility of brain imaging with the accuracy of a very localized and fast technique to analyze the specific neuronal activity of the brain. "The integrated design of a nuclear magnetic resonance detector on a single chip supremely reduces the typical electromagnetic interference of magnetic resonance signals. This enables neuroscientists to gather precise data from minuscule areas of the brain and to combine them with information from spatial and temporal data of the brain´s physiology," explains principal investigator Klaus Scheffler. "With this method, we can now better understand specific activity and functionalities in the brain." According to Scheffler and his group, their invention may unveil the possibility of discovering novel effects or typical fingerprints of neuronal activation, up to specific neuronal events in brain tissue. "Our design setup will allow scalable solutions, meaning the possibility of expanding the collection of data from more than from a single area—but on the same device. The scalability of our approach will allow us to extend our platform by additional sensing modalities such as electrophysiological and optogenetic measurements," adds the second principal investigator Jens Anders. The teams of Scheffler and Anders are very confident that their technical approach may help demerge the complex physiologic processes within the neural networks of the brain and that it may uncover additional benefits that can provide even deeper insights into the functionality of the brain. With their primary goal to develop new techniques that are able to specifically probe the structural and biochemical composition of living brain tissue, their latest innovation paves the way for future highly specific and quantitative mapping techniques of neuronal activity and bioenergetic processes in the brain cells. <|im_end|>
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1,937
[ { "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 Clonal haematopoiesis involves the expansion of certain blood cell lineages and has been associated with ageing and adverse health outcomes 1 , 2 , 3 , 4 , 5 . Here we use exome sequence data on 628,388 individuals to identify 40,208 carriers of clonal haematopoiesis of indeterminate potential (CHIP). Using genome-wide and exome-wide association analyses, we identify 24 loci (21 of which are novel) where germline genetic variation influences predisposition to CHIP, including missense variants in the lymphocytic antigen coding gene LY75 , which are associated with reduced incidence of CHIP. We also identify novel rare variant associations with clonal haematopoiesis and telomere length. Analysis of 5,041 health traits from the UK Biobank (UKB) found relationships between CHIP and severe COVID-19 outcomes, cardiovascular disease, haematologic traits, malignancy, smoking, obesity, infection and all-cause mortality. Longitudinal and Mendelian randomization analyses revealed that CHIP is associated with solid cancers, including non-melanoma skin cancer and lung cancer, and that CHIP linked to DNMT3A is associated with the subsequent development of myeloid but not lymphoid leukaemias. Additionally, contrary to previous findings from the initial 50,000 UKB exomes 6 , our results in the full sample do not support a role for IL-6 inhibition in reducing the risk of cardiovascular disease among CHIP carriers. Our findings demonstrate that CHIP represents a complex set of heterogeneous phenotypes with shared and unique germline genetic causes and varied clinical implications. Main As humans age, somatic alterations accrue in the DNA of haematopoietic stem cells (HSCs) due to mitotic errors and DNA damage. Alterations that confer a selective growth advantage can lead to the expansion of particular cell lineages, a phenomenon called clonal haematopoiesis. The presence of clonal haematopoiesis has been associated with an increased risk of haematological neoplasms, cytopaenias, cardiovascular disease (CVD), infection and all-cause mortality 1 , 2 , 3 , 4 , 5 . For this reason, identifying germline causes of clonal haematopoiesis has the potential to improve our understanding of initiating events in the development of these common diseases. Large-scale studies of the germline causes of clonal haematopoiesis have used samples from the UKB and other large cohorts, but those studies have been limited mostly to clonal haematopoiesis phenotypes that can be assessed using single nucleotide polymorphism (SNP) array genotype data, such as mosaic chromosomal alternations (mCA) and mosaic loss of sex chromosomes 4 , 7 , 8 (mLOX and mLOY). Identifying individuals with CHIP, which is defined by somatic protein-altering mutations in genes that are recurrently mutated in clonal haematopoiesis, requires sequencing of blood 1 , 2 . Once a clone has expanded sufficiently, the somatic variants from this clone can be captured along with germline variants by exome sequencing. Since exome sequencing captures protein-altering variants, its large-scale application enables the detection of readily interpretable rare variant association signals, and can elucidate critical genes and pathways and potential therapeutic targeting 9 , 10 . So far, the largest genetic association study of CHIP has included 3,831 CHIP mutation carriers in a sample of 65,405 individuals and has identified four common variant loci 11 . Here, we use exome sequencing data to characterize CHIP status in 454,803 UKB 10 and 173,585 Geisinger MyCode Community Health Initiative (GHS) participants. We then conduct a common variant genome-wide association study (GWAS) and rare variant and gene burden exome-wide association study (ExWAS) of CHIP by leveraging 27,331 CHIP mutation carriers from the UKB. We perform a replication analysis using 12,877 CHIP mutation carriers from the GHS cohort. To identify germline predictors of specific clonal haematopoiesis driver mutations, we also conduct GWAS and ExWAS in carriers of CHIP mutations from individual CHIP genes. We then compare genetic association findings for CHIP to those from analyses of other clonal haematopoiesis phenotypes determined from somatic alterations in the blood, including mCA, mLOX, mLOY and telomere length. Although GWAS of these non-CHIP clonal haematopoiesis phenotypes have been conducted 4 , 7 , 12 , none have evaluated the effect of rare variation. The ExWAS we perform here represents the first systematic large-scale exploration of the effect of rare variants on the genetic susceptibility of these phenotypes. Finally, we examine the clinical consequences of somatic CHIP mutations and germline predictors of CHIP in several ways. We first conduct a PheWAS 13 of germline predictors of CHIP to understand their biological functions, and test cross-sectional phenotype associations of CHIP carrier status across 5,194 traits in the UKB. We then test the risk of incident cancer, CVD and all-cause mortality among specific CHIP gene mutation carriers and use Mendelian randomization to test for evidence of causal associations between CHIP and phenotypes of interest. Calling CHIP We used exome sequencing data from 454,803 and 173,585 individuals from the UKB and GHS cohorts, respectively, to generate large callsets of CHIP carrier status ( Methods ). In brief, we called somatic mutations using Mutect2 in a pipeline that included custom QC filtering (Extended Data Fig. 1a ), and ultimately restricted our analysis to 23 well defined and recurrent CHIP-associated genes. This focused analysis identified 29,669 variants across 27,331 individuals in the UKB (6%), and 14,766 variants across 12,877 individuals in the GHS (7.4%). DNMT3A , TET2 , ASXL1 , PPM1D and TP53 were the most commonly mutated genes in both cohorts (Extended Data Fig. 2a ). Although the GHS cohort had a wider age range, and therefore a larger number of older individuals, the prevalence by age was similar across cohorts, and reached approximately 15% by 75 years of age (Extended Data Fig. 1b,c ). Prevalence of CHIP gene-specific mutations was consistent with recurrence patterns, with mutations in the most commonly mutated CHIP genes beginning to increase in prevalence at younger ages (Extended Data Fig. 1d,e and Supplementary Note 1 ). Somatic mutations within the IDH2 and SRSF2 genes co-occurred significantly more frequently than expected in both the UKB and GHS cohorts, whereas DNMT3A mutations co-occurred less frequently with other mutations than expected (Extended Data Fig. 2b,c and Supplementary Table 1 ). Among individuals with multiple CHIP mutations", "role": "user" }, { "content": "A team of researchers at Regeneron Pharmaceuticals has identified new genomic variants associated with clonal hematopoiesis of indeterminate potential (CHIP). In their paper published in the journal Nature, the group describes how they used exome-wide and genome-wide association analyses to study differences in the blood of some people with somatic mutations. Nature has also published a Research Highlights piece in the same journal issue, discussing the work done by the New York team. Hematopoiesis is a process that results in the formation of cellular blood components. And clonal hematopoiesis is the part of the process that is involved in the development of cell lineages. The importance of the overall process is highlighted by the fact that every person produces approximately 300 billion new blood cells every single day of their life. Prior research has suggested that there are variants associated with clonal hematopoiesis of indeterminate potential in certain people—each of which can have a unique impact. In this new effort, the team at Regeneron sought to find some of them by studying information held in very large datasets, such as the UK Biobank and the Geisinger MyCode Community Health Initiative. To find the variants they were after, the researchers focused their search efforts on 23 genes that have already been associated with CHIP. By searching through data on 628,388 individuals, they were able to identify 40,208 carriers of at least one variant associated with CHIP. They then conducted exome-wide and genome-wide studies of the carriers they had identified. In so doing, they were able to identify 24 loci—21 of which had not been seen before. The researchers also found that they were able to identify some variants that could be associated with clonal hematopoiesis and the length of telomeres in certain individuals. In another part of their study, the team analyzed health traits of people listed in the UK Biobank looking for associations between people who had CHIP variants and other issues. In so doing, they found associations between people who had clonal hematopoiesis variants and diseases such as COVID-19, heart problems, obesity and problems clearing infections of various types. They also found associations between individuals with CHIP and development of cancerous tumors and myeloid leukemias. ", "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 Clonal haematopoiesis involves the expansion of certain blood cell lineages and has been associated with ageing and adverse health outcomes 1 , 2 , 3 , 4 , 5 . Here we use exome sequence data on 628,388 individuals to identify 40,208 carriers of clonal haematopoiesis of indeterminate potential (CHIP). Using genome-wide and exome-wide association analyses, we identify 24 loci (21 of which are novel) where germline genetic variation influences predisposition to CHIP, including missense variants in the lymphocytic antigen coding gene LY75 , which are associated with reduced incidence of CHIP. We also identify novel rare variant associations with clonal haematopoiesis and telomere length. Analysis of 5,041 health traits from the UK Biobank (UKB) found relationships between CHIP and severe COVID-19 outcomes, cardiovascular disease, haematologic traits, malignancy, smoking, obesity, infection and all-cause mortality. Longitudinal and Mendelian randomization analyses revealed that CHIP is associated with solid cancers, including non-melanoma skin cancer and lung cancer, and that CHIP linked to DNMT3A is associated with the subsequent development of myeloid but not lymphoid leukaemias. Additionally, contrary to previous findings from the initial 50,000 UKB exomes 6 , our results in the full sample do not support a role for IL-6 inhibition in reducing the risk of cardiovascular disease among CHIP carriers. Our findings demonstrate that CHIP represents a complex set of heterogeneous phenotypes with shared and unique germline genetic causes and varied clinical implications. Main As humans age, somatic alterations accrue in the DNA of haematopoietic stem cells (HSCs) due to mitotic errors and DNA damage. Alterations that confer a selective growth advantage can lead to the expansion of particular cell lineages, a phenomenon called clonal haematopoiesis. The presence of clonal haematopoiesis has been associated with an increased risk of haematological neoplasms, cytopaenias, cardiovascular disease (CVD), infection and all-cause mortality 1 , 2 , 3 , 4 , 5 . For this reason, identifying germline causes of clonal haematopoiesis has the potential to improve our understanding of initiating events in the development of these common diseases. Large-scale studies of the germline causes of clonal haematopoiesis have used samples from the UKB and other large cohorts, but those studies have been limited mostly to clonal haematopoiesis phenotypes that can be assessed using single nucleotide polymorphism (SNP) array genotype data, such as mosaic chromosomal alternations (mCA) and mosaic loss of sex chromosomes 4 , 7 , 8 (mLOX and mLOY). Identifying individuals with CHIP, which is defined by somatic protein-altering mutations in genes that are recurrently mutated in clonal haematopoiesis, requires sequencing of blood 1 , 2 . Once a clone has expanded sufficiently, the somatic variants from this clone can be captured along with germline variants by exome sequencing. Since exome sequencing captures protein-altering variants, its large-scale application enables the detection of readily interpretable rare variant association signals, and can elucidate critical genes and pathways and potential therapeutic targeting 9 , 10 . So far, the largest genetic association study of CHIP has included 3,831 CHIP mutation carriers in a sample of 65,405 individuals and has identified four common variant loci 11 . Here, we use exome sequencing data to characterize CHIP status in 454,803 UKB 10 and 173,585 Geisinger MyCode Community Health Initiative (GHS) participants. We then conduct a common variant genome-wide association study (GWAS) and rare variant and gene burden exome-wide association study (ExWAS) of CHIP by leveraging 27,331 CHIP mutation carriers from the UKB. We perform a replication analysis using 12,877 CHIP mutation carriers from the GHS cohort. To identify germline predictors of specific clonal haematopoiesis driver mutations, we also conduct GWAS and ExWAS in carriers of CHIP mutations from individual CHIP genes. We then compare genetic association findings for CHIP to those from analyses of other clonal haematopoiesis phenotypes determined from somatic alterations in the blood, including mCA, mLOX, mLOY and telomere length. Although GWAS of these non-CHIP clonal haematopoiesis phenotypes have been conducted 4 , 7 , 12 , none have evaluated the effect of rare variation. The ExWAS we perform here represents the first systematic large-scale exploration of the effect of rare variants on the genetic susceptibility of these phenotypes. Finally, we examine the clinical consequences of somatic CHIP mutations and germline predictors of CHIP in several ways. We first conduct a PheWAS 13 of germline predictors of CHIP to understand their biological functions, and test cross-sectional phenotype associations of CHIP carrier status across 5,194 traits in the UKB. We then test the risk of incident cancer, CVD and all-cause mortality among specific CHIP gene mutation carriers and use Mendelian randomization to test for evidence of causal associations between CHIP and phenotypes of interest. Calling CHIP We used exome sequencing data from 454,803 and 173,585 individuals from the UKB and GHS cohorts, respectively, to generate large callsets of CHIP carrier status ( Methods ). In brief, we called somatic mutations using Mutect2 in a pipeline that included custom QC filtering (Extended Data Fig. 1a ), and ultimately restricted our analysis to 23 well defined and recurrent CHIP-associated genes. This focused analysis identified 29,669 variants across 27,331 individuals in the UKB (6%), and 14,766 variants across 12,877 individuals in the GHS (7.4%). DNMT3A , TET2 , ASXL1 , PPM1D and TP53 were the most commonly mutated genes in both cohorts (Extended Data Fig. 2a ). Although the GHS cohort had a wider age range, and therefore a larger number of older individuals, the prevalence by age was similar across cohorts, and reached approximately 15% by 75 years of age (Extended Data Fig. 1b,c ). Prevalence of CHIP gene-specific mutations was consistent with recurrence patterns, with mutations in the most commonly mutated CHIP genes beginning to increase in prevalence at younger ages (Extended Data Fig. 1d,e and Supplementary Note 1 ). Somatic mutations within the IDH2 and SRSF2 genes co-occurred significantly more frequently than expected in both the UKB and GHS cohorts, whereas DNMT3A mutations co-occurred less frequently with other mutations than expected (Extended Data Fig. 2b,c and Supplementary Table 1 ). Among individuals with multiple CHIP mutations<|im_end|> <|im_start|>assistant A team of researchers at Regeneron Pharmaceuticals has identified new genomic variants associated with clonal hematopoiesis of indeterminate potential (CHIP). In their paper published in the journal Nature, the group describes how they used exome-wide and genome-wide association analyses to study differences in the blood of some people with somatic mutations. Nature has also published a Research Highlights piece in the same journal issue, discussing the work done by the New York team. Hematopoiesis is a process that results in the formation of cellular blood components. And clonal hematopoiesis is the part of the process that is involved in the development of cell lineages. The importance of the overall process is highlighted by the fact that every person produces approximately 300 billion new blood cells every single day of their life. Prior research has suggested that there are variants associated with clonal hematopoiesis of indeterminate potential in certain people—each of which can have a unique impact. In this new effort, the team at Regeneron sought to find some of them by studying information held in very large datasets, such as the UK Biobank and the Geisinger MyCode Community Health Initiative. To find the variants they were after, the researchers focused their search efforts on 23 genes that have already been associated with CHIP. By searching through data on 628,388 individuals, they were able to identify 40,208 carriers of at least one variant associated with CHIP. They then conducted exome-wide and genome-wide studies of the carriers they had identified. In so doing, they were able to identify 24 loci—21 of which had not been seen before. The researchers also found that they were able to identify some variants that could be associated with clonal hematopoiesis and the length of telomeres in certain individuals. In another part of their study, the team analyzed health traits of people listed in the UK Biobank looking for associations between people who had CHIP variants and other issues. In so doing, they found associations between people who had clonal hematopoiesis variants and diseases such as COVID-19, heart problems, obesity and problems clearing infections of various types. They also found associations between individuals with CHIP and development of cancerous tumors and myeloid leukemias. <|im_end|>
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1,954
[ { "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 COVID-19 pandemic triggered a surge in demand for facemasks to protect against disease transmission. In response to shortages, many public health authorities have recommended homemade masks as acceptable alternatives to surgical masks and N95 respirators. Although mask wearing is intended, in part, to protect others from exhaled, virus-containing particles, few studies have examined particle emission by mask-wearers into the surrounding air. Here, we measured outward emissions of micron-scale aerosol particles by healthy humans performing various expiratory activities while wearing different types of medical-grade or homemade masks. Both surgical masks and unvented KN95 respirators, even without fit-testing, reduce the outward particle emission rates by 90% and 74% on average during speaking and coughing, respectively, compared to wearing no mask, corroborating their effectiveness at reducing outward emission. These masks similarly decreased the outward particle emission of a coughing superemitter, who for unclear reasons emitted up to two orders of magnitude more expiratory particles via coughing than average. In contrast, shedding of non-expiratory micron-scale particulates from friable cellulosic fibers in homemade cotton-fabric masks confounded explicit determination of their efficacy at reducing expiratory particle emission. Audio analysis of the speech and coughing intensity confirmed that people speak more loudly, but do not cough more loudly, when wearing a mask. Further work is needed to establish the efficacy of cloth masks at blocking expiratory particles for speech and coughing at varied intensity and to assess whether virus-contaminated fabrics can generate aerosolized fomites, but the results strongly corroborate the efficacy of medical-grade masks and highlight the importance of regular washing of homemade masks. Introduction Airborne transmission of infectious respiratory diseases involves the emission of microorganism-containing aerosols and droplets during various expiratory activities (e.g., breathing, talking, coughing, and sneezing). Transmission of viruses in emitted droplets and aerosols to susceptible individuals may occur via physical contact after deposition on surfaces, reaerosolization after deposition, direct deposition of emitted droplets on mucosal surfaces (e.g., mouth, eyes), or direct inhalation of virus-laden aerosols 1 , 2 . Uncertainty remains regarding the role and spatial scale of these different transmission modes (contact, droplet spray, or aerosol inhalation) for specific respiratory diseases, including for COVID-19 3 , 4 , 5 , 6 , 7 , in particular settings, but airborne transmission stems from the initial expiratory emission of aerosols or droplets. Consequently, the wearing of masks—in addition to vigilant hand hygiene—has been put forth as a means to mitigate disease transmission, especially in healthcare settings 8 , 9 , 10 , 11 . Much research has indicated that masks can provide significant protection to the wearer, although proper mask fitting is critical to realizing such benefits 12 , 13 , 14 , 15 . Alternatively, masks can potentially reduce outward transmission by infected individuals, providing protection to others 7 , 16 , 17 . There have been indications of asymptomatic carriers of COVID-19 infecting others 18 , 19 , 20 , leading to increasing, albeit inconsistent 21 , 22 , 23 , 24 , calls for more universal wearing of masks or face coverings by the general public to help control disease transmission during pandemics. It is therefore important to understand the efficacy of masks and face coverings of different types in reducing outward transmission of aerosols and droplets from expiratory activities. Results from epidemiological and clinical studies assessing the effectiveness of masks in reducing disease transmission suggest that mask wearing can provide some benefits 10 , 11 , especially with early interventions, but often the results lack statistical significance 25 , 26 , 27 , 28 , 29 , 30 , 31 . Laboratory studies provide another means to assess or infer mask effectiveness. Measurement of material filtration efficiencies can provide initial guidance on potential mask effectiveness for preventing outward transmission 15 , 32 , 33 , 34 , 35 , but do not directly address mask performance when worn. Early photographic evidence indicates masks can limit the spread of cough-generated particles 36 . Measurements using simulated breathing with an artificial test head showed the concentration of particles between 0.02 μm-1 μm decreases across masks of different types 37 . Also using simulated breathing, Green et al. 38 found surgical masks effectively reduced outward transmission of endospores and vegetative cells, with seemingly greater reduction of particles > 0.7 μm compared to smaller particles. Using volunteers, Davies et al. 32 found that surgical and home-made cotton masks substantially reduce emission of culturable microorganisms from coughing by healthy volunteers, with similar reduction observed over a range of particle sizes (from 0.65 μm to > 7 μm). Milton et al. 16 found that surgical masks substantially reduced viral copy numbers in exhaled “fine” aerosol (≤ 5 μm) and “coarse” droplets (> 5 μm) from volunteers having influenza, with greater reduction in the coarse fraction. This result differs somewhat from very recent measurements by Leung et al. 13 , who showed a statistically significant reduction in shedding of influenza from breathing in coarse but not fine particles with participants wearing surgical masks. They did, however, find that masks reduced shedding of seasonal coronavirus from breathing for both coarse and fine particles, although viral RNA was observed in less than half of the samples even with no mask, complicating the assessment. The above studies all indicate a strong potential for masks to help reduce transmission of respiratory illnesses. To date, however, none have investigated the effectiveness of masks across a range of expiratory activities, and limited consideration has been given to different mask types. Furthermore, no studies to date have considered the masks themselves as potential sources of aerosol particles. It is well established that fibrous cellulosic materials, like cotton and paper, can release large quantities of micron-scale particles (i.e., dust) into the air 39 , 40 , 41 , 42 . Traditionally, these particles have not been considered a potential concern for respiratory viral diseases like influenza or now COVID-19, since these diseases have been thought to be transmitted via expiratory particles emitted directly from the respiratory tract of infected individuals 43 . Early", "role": "user" }, { "content": "Laboratory tests of surgical and N95 masks by researchers at the University of California, Davis, show that they do cut down the amount of aerosolized particles emitted during breathing, talking and coughing. Tests of homemade cloth face coverings, however, show that the fabric itself releases a large amount of fibers into the air, underscoring the importance of washing them. The work is published today (Sept. 24) in Scientific Reports. As the COVID-19 pandemic continues, the use of masks and other face coverings has emerged as an important tool alongside contact tracing and isolation, hand-washing and social distancing to reduce the spread of coronavirus. The Centers for Disease Control and Prevention, or CDC, and the World Health Organization endorse the use of face coverings, and masks or face coverings are required by many state and local governments, including the state of California. The goal of wearing face coverings is to prevent people who are infected with COVID-19 but asymptomatic from transmitting the virus to others. But while evidence shows that face coverings generally reduce the spread of airborne particles, there is limited information on how well they compare with each other. Sima Asadi, a graduate student working with Professor William Ristenpart in the UC Davis Department of Chemical Engineering, and colleagues at UC Davis and Icahn School of Medicine at Mount Sinai, New York, set up experiments to measure the flow of particles from volunteers wearing masks while they performed \"expiratory activities\" including breathing, talking, coughing and moving their jaw as if chewing gum. Asadi and Ristenpart have previously studied how people emit small particles, or aerosols, during speech. These particles are small enough to float through the air over a considerable distance, but large enough to carry viruses such as influenza or coronavirus. They have found that a fraction of people are \"superemitters\" who give off many more particles than average. The 10 volunteers sat in front of a funnel in a laminar flow cabinet. The funnel drew air from in front of their faces into a device that measured the size and number of particles exhaled. They wore either no mask, a medical-grade surgical mask, two types of N95 mask (vented or not), a homemade paper mask or homemade one- or two-layer cloth mask made from a cotton T-shirt according to CDC directions. Credit: UC Davis Up to 90 percent of particles blocked The tests only measured outward transmission—whether the masks could block an infected person from giving off particles that might carry viruses. Without a mask, talking (reading a passage of text) gave off about 10 times more particles than simple breathing. Forced coughing produced a variable amount of particles. One of the volunteers in the study was a superemitter who consistently produced nearly 100 times as many particles as the others when coughing. In all the test scenarios, surgical and N95 masks blocked as much as 90 percent of particles, compared to not wearing a mask. Face coverings also reduced airborne particles from the superemitter. Homemade cotton masks actually produced more particles than not wearing a mask. These appeared to be tiny fibers released from the fabric. Because the cotton masks produced particles themselves, it's difficult to tell if they also blocked exhaled particles. They did seem to at least reduce the number of larger particles. The results confirm that masks and face coverings are effective in reducing the spread of airborne particles, Ristenpart said, and also the importance of regularly washing cloth masks. ", "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 COVID-19 pandemic triggered a surge in demand for facemasks to protect against disease transmission. In response to shortages, many public health authorities have recommended homemade masks as acceptable alternatives to surgical masks and N95 respirators. Although mask wearing is intended, in part, to protect others from exhaled, virus-containing particles, few studies have examined particle emission by mask-wearers into the surrounding air. Here, we measured outward emissions of micron-scale aerosol particles by healthy humans performing various expiratory activities while wearing different types of medical-grade or homemade masks. Both surgical masks and unvented KN95 respirators, even without fit-testing, reduce the outward particle emission rates by 90% and 74% on average during speaking and coughing, respectively, compared to wearing no mask, corroborating their effectiveness at reducing outward emission. These masks similarly decreased the outward particle emission of a coughing superemitter, who for unclear reasons emitted up to two orders of magnitude more expiratory particles via coughing than average. In contrast, shedding of non-expiratory micron-scale particulates from friable cellulosic fibers in homemade cotton-fabric masks confounded explicit determination of their efficacy at reducing expiratory particle emission. Audio analysis of the speech and coughing intensity confirmed that people speak more loudly, but do not cough more loudly, when wearing a mask. Further work is needed to establish the efficacy of cloth masks at blocking expiratory particles for speech and coughing at varied intensity and to assess whether virus-contaminated fabrics can generate aerosolized fomites, but the results strongly corroborate the efficacy of medical-grade masks and highlight the importance of regular washing of homemade masks. Introduction Airborne transmission of infectious respiratory diseases involves the emission of microorganism-containing aerosols and droplets during various expiratory activities (e.g., breathing, talking, coughing, and sneezing). Transmission of viruses in emitted droplets and aerosols to susceptible individuals may occur via physical contact after deposition on surfaces, reaerosolization after deposition, direct deposition of emitted droplets on mucosal surfaces (e.g., mouth, eyes), or direct inhalation of virus-laden aerosols 1 , 2 . Uncertainty remains regarding the role and spatial scale of these different transmission modes (contact, droplet spray, or aerosol inhalation) for specific respiratory diseases, including for COVID-19 3 , 4 , 5 , 6 , 7 , in particular settings, but airborne transmission stems from the initial expiratory emission of aerosols or droplets. Consequently, the wearing of masks—in addition to vigilant hand hygiene—has been put forth as a means to mitigate disease transmission, especially in healthcare settings 8 , 9 , 10 , 11 . Much research has indicated that masks can provide significant protection to the wearer, although proper mask fitting is critical to realizing such benefits 12 , 13 , 14 , 15 . Alternatively, masks can potentially reduce outward transmission by infected individuals, providing protection to others 7 , 16 , 17 . There have been indications of asymptomatic carriers of COVID-19 infecting others 18 , 19 , 20 , leading to increasing, albeit inconsistent 21 , 22 , 23 , 24 , calls for more universal wearing of masks or face coverings by the general public to help control disease transmission during pandemics. It is therefore important to understand the efficacy of masks and face coverings of different types in reducing outward transmission of aerosols and droplets from expiratory activities. Results from epidemiological and clinical studies assessing the effectiveness of masks in reducing disease transmission suggest that mask wearing can provide some benefits 10 , 11 , especially with early interventions, but often the results lack statistical significance 25 , 26 , 27 , 28 , 29 , 30 , 31 . Laboratory studies provide another means to assess or infer mask effectiveness. Measurement of material filtration efficiencies can provide initial guidance on potential mask effectiveness for preventing outward transmission 15 , 32 , 33 , 34 , 35 , but do not directly address mask performance when worn. Early photographic evidence indicates masks can limit the spread of cough-generated particles 36 . Measurements using simulated breathing with an artificial test head showed the concentration of particles between 0.02 μm-1 μm decreases across masks of different types 37 . Also using simulated breathing, Green et al. 38 found surgical masks effectively reduced outward transmission of endospores and vegetative cells, with seemingly greater reduction of particles > 0.7 μm compared to smaller particles. Using volunteers, Davies et al. 32 found that surgical and home-made cotton masks substantially reduce emission of culturable microorganisms from coughing by healthy volunteers, with similar reduction observed over a range of particle sizes (from 0.65 μm to > 7 μm). Milton et al. 16 found that surgical masks substantially reduced viral copy numbers in exhaled “fine” aerosol (≤ 5 μm) and “coarse” droplets (> 5 μm) from volunteers having influenza, with greater reduction in the coarse fraction. This result differs somewhat from very recent measurements by Leung et al. 13 , who showed a statistically significant reduction in shedding of influenza from breathing in coarse but not fine particles with participants wearing surgical masks. They did, however, find that masks reduced shedding of seasonal coronavirus from breathing for both coarse and fine particles, although viral RNA was observed in less than half of the samples even with no mask, complicating the assessment. The above studies all indicate a strong potential for masks to help reduce transmission of respiratory illnesses. To date, however, none have investigated the effectiveness of masks across a range of expiratory activities, and limited consideration has been given to different mask types. Furthermore, no studies to date have considered the masks themselves as potential sources of aerosol particles. It is well established that fibrous cellulosic materials, like cotton and paper, can release large quantities of micron-scale particles (i.e., dust) into the air 39 , 40 , 41 , 42 . Traditionally, these particles have not been considered a potential concern for respiratory viral diseases like influenza or now COVID-19, since these diseases have been thought to be transmitted via expiratory particles emitted directly from the respiratory tract of infected individuals 43 . Early<|im_end|> <|im_start|>assistant Laboratory tests of surgical and N95 masks by researchers at the University of California, Davis, show that they do cut down the amount of aerosolized particles emitted during breathing, talking and coughing. Tests of homemade cloth face coverings, however, show that the fabric itself releases a large amount of fibers into the air, underscoring the importance of washing them. The work is published today (Sept. 24) in Scientific Reports. As the COVID-19 pandemic continues, the use of masks and other face coverings has emerged as an important tool alongside contact tracing and isolation, hand-washing and social distancing to reduce the spread of coronavirus. The Centers for Disease Control and Prevention, or CDC, and the World Health Organization endorse the use of face coverings, and masks or face coverings are required by many state and local governments, including the state of California. The goal of wearing face coverings is to prevent people who are infected with COVID-19 but asymptomatic from transmitting the virus to others. But while evidence shows that face coverings generally reduce the spread of airborne particles, there is limited information on how well they compare with each other. Sima Asadi, a graduate student working with Professor William Ristenpart in the UC Davis Department of Chemical Engineering, and colleagues at UC Davis and Icahn School of Medicine at Mount Sinai, New York, set up experiments to measure the flow of particles from volunteers wearing masks while they performed "expiratory activities" including breathing, talking, coughing and moving their jaw as if chewing gum. Asadi and Ristenpart have previously studied how people emit small particles, or aerosols, during speech. These particles are small enough to float through the air over a considerable distance, but large enough to carry viruses such as influenza or coronavirus. They have found that a fraction of people are "superemitters" who give off many more particles than average. The 10 volunteers sat in front of a funnel in a laminar flow cabinet. The funnel drew air from in front of their faces into a device that measured the size and number of particles exhaled. They wore either no mask, a medical-grade surgical mask, two types of N95 mask (vented or not), a homemade paper mask or homemade one- or two-layer cloth mask made from a cotton T-shirt according to CDC directions. Credit: UC Davis Up to 90 percent of particles blocked The tests only measured outward transmission—whether the masks could block an infected person from giving off particles that might carry viruses. Without a mask, talking (reading a passage of text) gave off about 10 times more particles than simple breathing. Forced coughing produced a variable amount of particles. One of the volunteers in the study was a superemitter who consistently produced nearly 100 times as many particles as the others when coughing. In all the test scenarios, surgical and N95 masks blocked as much as 90 percent of particles, compared to not wearing a mask. Face coverings also reduced airborne particles from the superemitter. Homemade cotton masks actually produced more particles than not wearing a mask. These appeared to be tiny fibers released from the fabric. Because the cotton masks produced particles themselves, it's difficult to tell if they also blocked exhaled particles. They did seem to at least reduce the number of larger particles. The results confirm that masks and face coverings are effective in reducing the spread of airborne particles, Ristenpart said, and also the importance of regularly washing cloth masks. <|im_end|>
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2,049
[ { "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 inertial sliding of physisorbed submonolayer islands on crystal surfaces contains unexpected information on the exceptionally smooth sliding state associated with incommensurate superlubricity and on the mechanisms of its disappearance. Here, in a joint quartz crystal microbalance and molecular dynamics simulation case study of Xe on Cu(111), we show how superlubricity emerges in the large size limit of naturally incommensurate Xe islands. As coverage approaches a full monolayer, theory also predicts an abrupt adhesion-driven two-dimensional density compression on the order of several per cent, implying a hysteretic jump from superlubric free islands to a pressurized commensurate immobile monolayer. This scenario is fully supported by the quartz crystal microbalance data, which show remarkably large slip times with increasing submonolayer coverage, signalling superlubricity, followed by a dramatic drop to zero for the dense commensurate monolayer. Careful analysis of this variety of island sliding phenomena will be essential in future applications of friction at crystal/adsorbate interfaces. Main Systems achieving low values of dry sliding friction are of great physical and, potentially, technological interest 1 , 2 , 3 , 4 . Superlubricity—the vanishing of static friction—and the consequent ultra-low dynamic friction between crystal faces that are sufficiently hard and mutually incommensurate 5 , 6 , is experimentally rare and has been demonstrated or implied in only a relatively small number of cases, including telescopic sliding among carbon nanotubes 7 , 8 , sliding graphite flakes on a graphite substrate 9 , 10 , 11 , cluster nanomanipulation 12 , 13 and sliding colloidal layers 14 , 15 . It is essential that we increase the understanding of this phenomenon and, in view of potential nanotechnology applications, examine new and more generic systems beyond these. Submonolayer islands of rare gas atoms adsorbed on crystal surfaces offer an excellent platform to address friction at crystalline interfaces. Despite much experimental 16 , 17 , 18 , 19 , 20 , 21 , 22 and theoretical 23 , 24 , 25 , 26 , 27 work, superlubricity is a phenomenon that remains poorly explored in such systems. In the submonolayer range (0 < θ < 1, where θ is the coverage) and at low temperatures, adsorbate phase diagrams versus coverage θ are well known to display phase-separated two-dimensional (2D) solid islands, usually incommensurate with the surface lattice, coexisting with the 2D adatom vapour 28 , 29 . Using a quartz crystal microbalance (QCM), the inertial sliding friction of these islands is measured by the inverse of the slip time τ s = (1/4π)[δ( Q −1 )/δ f ], the ratio of the adsorbate-induced change in inverse quality factor over the respective change in the substrate oscillation frequency 30 . The peak of the inertial force acting on an island deposited on the QCM is expressed as F in = ρ isl SA (2π f ) 2 (where ρ isl is the 2D density at the centre of an adsorbed island of area S , and A and f are the oscillation amplitude and frequency, respectively), and equals the viscous frictional force F visc = Mv / τ s, (where M is the mass of the island and v is speed). This means that superlubricity should indirectly show up as an unusually large slip time. For over two decades, QCM work has shown that physisorbed atoms or molecules condense and generally slide above a submonolayer coverage θ sf , and τ s may typically reach values from hundreds of picoseconds to a nanosecond. These results 17 , 19 , 30 and the corresponding pioneering atomistic simulations 23 , 31 have provided much valuable initial information about the temperature and system dependence of inertial friction. So far, however, crucial aspects that specifically address the island structure of the adsorbate, the edge-originated pinning and in particular the change in commensurability and superlubricity with coverage (issues that, in our view, are important to nanofriction) have not yet come under scrutiny. Here, we present a joint experimental and theoretical study of the sliding of adsorbate islands on a crystalline substrate, and reveal surprising information about the exceptionally easy sliding suggestive of superlubricity, about its limiting factors (caused by edges and defects), and its eventual spontaneous demise at full coverage. Our chosen example is physisorbed Xe on Cu(111), a system for which the phase diagram is well studied (as is the case for other rare gas adsorbates on graphite and metal surfaces) 28 . Between ∼ 50 and 90 K, Xe monolayers condense on Cu(111) as a commensurate 2D solid. We conventionally designate this as unit coverage θ = 1, characterized by a density where is the commensurate adatom spacing. Low-energy electron diffraction at 50 K locates the Xe atoms on top of surface Cu atoms 32 , the planar distance ( a 0 ) of which is close to the Xe–Xe spacing in bulk Xe ( a Xe = 0.439 nm). At lower temperatures, the full Xe monolayer is known from surface extended X-ray measurements to shrink into an ‘overdense’ ( ρ > ρ 0 ) incommensurate structure, reaching commensurability only at 50 K following thermal expansion 33 . Conversely, the 2D atom density in Xe monatomic islands, which coexist with the adatom 2D vapour at submonolayer coverage, is not specifically known, but is often assumed to be equal to ρ 0 . Our results in fact show that the 2D crystalline Xe islands ( θ < 1) are slightly ‘underdense’ ( ρ isl < ρ 0 ) and increasingly incommensurate with thermal expansion, reaching a 2D density 4% below ρ 0 near 50 K. In this incommensurate state, the 2D lattice inside the Xe islands should slide superlubrically over the Cu(111) substrate, as expected for a ‘hard’ slider. Indeed, even though the Xe–Xe attraction V Xe−Xe ≈ 20 meV is an order of magnitude smaller than the Xe–Cu(111) adhesion energy E a ≈ 190 meV (ref. 28 ), it is an order of magnitude larger, and thus harder, than the weak Cu(111) surface corrugation, E c ≈ 1–2 meV (ref.", "role": "user" }, { "content": "It's possible to vary (even dramatically) the sliding properties of atoms on a surface by changing the size and \"compression\" of their aggregates: an experimental and theoretical study conducted with the collaboration of SISSA, the Istituto Officina dei Materiali of the CNR (Iom-Cnr-Democritos), ICTP in Trieste, the University of Padua, the University of Modena e Reggio Emilia, and the Istituto Nanoscienze of the CNR (Nano-Cnr) in Modena, has just been published in Nature Nanotechnology. (Nano)islands that slide freely on a sea of copper, but when they become too large (and too dense) they end up getting stuck: that nicely sums up the system investigated in a study just published in Nature Nanotechnology. \"We can suddenly switch from a state of superlubricity to one of extremely high friction by varying some parameters of the system being investigated. In this study, we used atoms of the noble gas xenon bound to one another to form two-dimensional islands, deposited on a copper surface (Cu 111). At low temperatures these aggregates slide with virtually no friction,\" explains Giampaolo Mistura of the University of Padua. \"We increased the size of the islands by adding xenon atoms and until the whole available surface was covered the friction decreased gradually. Instead, when the available space ran out and the addition of atoms caused the islands to compress, then we saw an exceptional increase in friction.\" The study was divided into an experimental part (mainly carried out by the University of Padua and Nano-Cnr/University of Modena and Reggio Emilia) and a theoretical part (based on computer models and simulations) conducted by SISSA/Iom-Cnr-Democritos/ICTP. \"To understand what happens when the islands are compressed, we need to appreciate the concept of 'interface commensurability',\" explains Roberto Guerra, researcher at the International School for Advanced Studies (SISSA) in Trieste and among the authors of the study. \"We can think of the system we studied as one made up of Lego bricks. The copper substrate is like a horizontal assembly of bricks and the xenon islands like single loose bricks,\" comments Guido Paolicelli of the CNR Nanoscience Institute. \"If the substrate and the islands consist of different bricks (in terms of width and distance between the studs), the islands will never get stuck on the substrate. This situation reproduces our system at temperatures slightly above absolute zero where we observe a state of superlubricity with virtually no friction. However, the increase in surface of the islands and the resulting compression of the material causes the islands to become commensurate to the substrate – like Lego bricks having the same pitch – and when that happens they suddenly get stuck.\" sample of crystalline copper used as a ‘sliding’ substrate. Credit: Nano-Cnr, Modena The study is the first to demonstrate that it is possible to dramatically vary the sliding properties of nano-objects. \"We can imagine a number of applications for this,\" concludes Guerra. \"For example, nanobearings could be developed that, under certain conditions, are capable of blocking their motion, in a completely reversible manner.\" ", "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 inertial sliding of physisorbed submonolayer islands on crystal surfaces contains unexpected information on the exceptionally smooth sliding state associated with incommensurate superlubricity and on the mechanisms of its disappearance. Here, in a joint quartz crystal microbalance and molecular dynamics simulation case study of Xe on Cu(111), we show how superlubricity emerges in the large size limit of naturally incommensurate Xe islands. As coverage approaches a full monolayer, theory also predicts an abrupt adhesion-driven two-dimensional density compression on the order of several per cent, implying a hysteretic jump from superlubric free islands to a pressurized commensurate immobile monolayer. This scenario is fully supported by the quartz crystal microbalance data, which show remarkably large slip times with increasing submonolayer coverage, signalling superlubricity, followed by a dramatic drop to zero for the dense commensurate monolayer. Careful analysis of this variety of island sliding phenomena will be essential in future applications of friction at crystal/adsorbate interfaces. Main Systems achieving low values of dry sliding friction are of great physical and, potentially, technological interest 1 , 2 , 3 , 4 . Superlubricity—the vanishing of static friction—and the consequent ultra-low dynamic friction between crystal faces that are sufficiently hard and mutually incommensurate 5 , 6 , is experimentally rare and has been demonstrated or implied in only a relatively small number of cases, including telescopic sliding among carbon nanotubes 7 , 8 , sliding graphite flakes on a graphite substrate 9 , 10 , 11 , cluster nanomanipulation 12 , 13 and sliding colloidal layers 14 , 15 . It is essential that we increase the understanding of this phenomenon and, in view of potential nanotechnology applications, examine new and more generic systems beyond these. Submonolayer islands of rare gas atoms adsorbed on crystal surfaces offer an excellent platform to address friction at crystalline interfaces. Despite much experimental 16 , 17 , 18 , 19 , 20 , 21 , 22 and theoretical 23 , 24 , 25 , 26 , 27 work, superlubricity is a phenomenon that remains poorly explored in such systems. In the submonolayer range (0 < θ < 1, where θ is the coverage) and at low temperatures, adsorbate phase diagrams versus coverage θ are well known to display phase-separated two-dimensional (2D) solid islands, usually incommensurate with the surface lattice, coexisting with the 2D adatom vapour 28 , 29 . Using a quartz crystal microbalance (QCM), the inertial sliding friction of these islands is measured by the inverse of the slip time τ s = (1/4π)[δ( Q −1 )/δ f ], the ratio of the adsorbate-induced change in inverse quality factor over the respective change in the substrate oscillation frequency 30 . The peak of the inertial force acting on an island deposited on the QCM is expressed as F in = ρ isl SA (2π f ) 2 (where ρ isl is the 2D density at the centre of an adsorbed island of area S , and A and f are the oscillation amplitude and frequency, respectively), and equals the viscous frictional force F visc = Mv / τ s, (where M is the mass of the island and v is speed). This means that superlubricity should indirectly show up as an unusually large slip time. For over two decades, QCM work has shown that physisorbed atoms or molecules condense and generally slide above a submonolayer coverage θ sf , and τ s may typically reach values from hundreds of picoseconds to a nanosecond. These results 17 , 19 , 30 and the corresponding pioneering atomistic simulations 23 , 31 have provided much valuable initial information about the temperature and system dependence of inertial friction. So far, however, crucial aspects that specifically address the island structure of the adsorbate, the edge-originated pinning and in particular the change in commensurability and superlubricity with coverage (issues that, in our view, are important to nanofriction) have not yet come under scrutiny. Here, we present a joint experimental and theoretical study of the sliding of adsorbate islands on a crystalline substrate, and reveal surprising information about the exceptionally easy sliding suggestive of superlubricity, about its limiting factors (caused by edges and defects), and its eventual spontaneous demise at full coverage. Our chosen example is physisorbed Xe on Cu(111), a system for which the phase diagram is well studied (as is the case for other rare gas adsorbates on graphite and metal surfaces) 28 . Between ∼ 50 and 90 K, Xe monolayers condense on Cu(111) as a commensurate 2D solid. We conventionally designate this as unit coverage θ = 1, characterized by a density where is the commensurate adatom spacing. Low-energy electron diffraction at 50 K locates the Xe atoms on top of surface Cu atoms 32 , the planar distance ( a 0 ) of which is close to the Xe–Xe spacing in bulk Xe ( a Xe = 0.439 nm). At lower temperatures, the full Xe monolayer is known from surface extended X-ray measurements to shrink into an ‘overdense’ ( ρ > ρ 0 ) incommensurate structure, reaching commensurability only at 50 K following thermal expansion 33 . Conversely, the 2D atom density in Xe monatomic islands, which coexist with the adatom 2D vapour at submonolayer coverage, is not specifically known, but is often assumed to be equal to ρ 0 . Our results in fact show that the 2D crystalline Xe islands ( θ < 1) are slightly ‘underdense’ ( ρ isl < ρ 0 ) and increasingly incommensurate with thermal expansion, reaching a 2D density 4% below ρ 0 near 50 K. In this incommensurate state, the 2D lattice inside the Xe islands should slide superlubrically over the Cu(111) substrate, as expected for a ‘hard’ slider. Indeed, even though the Xe–Xe attraction V Xe−Xe ≈ 20 meV is an order of magnitude smaller than the Xe–Cu(111) adhesion energy E a ≈ 190 meV (ref. 28 ), it is an order of magnitude larger, and thus harder, than the weak Cu(111) surface corrugation, E c ≈ 1–2 meV (ref.<|im_end|> <|im_start|>assistant It's possible to vary (even dramatically) the sliding properties of atoms on a surface by changing the size and "compression" of their aggregates: an experimental and theoretical study conducted with the collaboration of SISSA, the Istituto Officina dei Materiali of the CNR (Iom-Cnr-Democritos), ICTP in Trieste, the University of Padua, the University of Modena e Reggio Emilia, and the Istituto Nanoscienze of the CNR (Nano-Cnr) in Modena, has just been published in Nature Nanotechnology. (Nano)islands that slide freely on a sea of copper, but when they become too large (and too dense) they end up getting stuck: that nicely sums up the system investigated in a study just published in Nature Nanotechnology. "We can suddenly switch from a state of superlubricity to one of extremely high friction by varying some parameters of the system being investigated. In this study, we used atoms of the noble gas xenon bound to one another to form two-dimensional islands, deposited on a copper surface (Cu 111). At low temperatures these aggregates slide with virtually no friction," explains Giampaolo Mistura of the University of Padua. "We increased the size of the islands by adding xenon atoms and until the whole available surface was covered the friction decreased gradually. Instead, when the available space ran out and the addition of atoms caused the islands to compress, then we saw an exceptional increase in friction." The study was divided into an experimental part (mainly carried out by the University of Padua and Nano-Cnr/University of Modena and Reggio Emilia) and a theoretical part (based on computer models and simulations) conducted by SISSA/Iom-Cnr-Democritos/ICTP. "To understand what happens when the islands are compressed, we need to appreciate the concept of 'interface commensurability'," explains Roberto Guerra, researcher at the International School for Advanced Studies (SISSA) in Trieste and among the authors of the study. "We can think of the system we studied as one made up of Lego bricks. The copper substrate is like a horizontal assembly of bricks and the xenon islands like single loose bricks," comments Guido Paolicelli of the CNR Nanoscience Institute. "If the substrate and the islands consist of different bricks (in terms of width and distance between the studs), the islands will never get stuck on the substrate. This situation reproduces our system at temperatures slightly above absolute zero where we observe a state of superlubricity with virtually no friction. However, the increase in surface of the islands and the resulting compression of the material causes the islands to become commensurate to the substrate – like Lego bricks having the same pitch – and when that happens they suddenly get stuck." sample of crystalline copper used as a ‘sliding’ substrate. Credit: Nano-Cnr, Modena The study is the first to demonstrate that it is possible to dramatically vary the sliding properties of nano-objects. "We can imagine a number of applications for this," concludes Guerra. "For example, nanobearings could be developed that, under certain conditions, are capable of blocking their motion, in a completely reversible manner." <|im_end|>
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2,137
[ { "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 Objective To evaluate if induction of labour at 41 weeks improves perinatal and maternal outcomes in women with a low risk pregnancy compared with expectant management and induction of labour at 42 weeks. Design Multicentre, open label, randomised controlled superiority trial. Setting 14 hospitals in Sweden, 2016-18. Participants 2760 women with a low risk uncomplicated singleton pregnancy randomised (1:1) by the Swedish Pregnancy Register. 1381 women were assigned to the induction group and 1379 were assigned to the expectant management group. Interventions Induction of labour at 41 weeks and expectant management and induction of labour at 42 weeks. Main outcome measures The primary outcome was a composite perinatal outcome including one or more of stillbirth, neonatal mortality, Apgar score less than 7 at five minutes, pH less than 7.00 or metabolic acidosis (pH <7.05 and base deficit >12 mmol/L) in the umbilical artery, hypoxic ischaemic encephalopathy, intracranial haemorrhage, convulsions, meconium aspiration syndrome, mechanical ventilation within 72 hours, or obstetric brachial plexus injury. Primary analysis was by intention to treat. Results The study was stopped early owing to a significantly higher rate of perinatal mortality in the expectant management group. The composite primary perinatal outcome did not differ between the groups: 2.4% (33/1381) in the induction group and 2.2% (31/1379) in the expectant management group (relative risk 1.06, 95% confidence interval 0.65 to 1.73; P=0.90). No perinatal deaths occurred in the induction group but six (five stillbirths and one early neonatal death) occurred in the expectant management group (P=0.03). The proportion of caesarean delivery, instrumental vaginal delivery, or any major maternal morbidity did not differ between the groups. Conclusions This study comparing induction of labour at 41 weeks with expectant management and induction at 42 weeks does not show any significant difference in the primary composite adverse perinatal outcome. However, a reduction of the secondary outcome perinatal mortality is observed without increasing adverse maternal outcomes. Although these results should be interpreted cautiously, induction of labour ought to be offered to women no later than at 41 weeks and could be one (of few) interventions that reduces the rate of stillbirths. Trial registration Current Controlled Trials ISRCTN26113652 . Introduction Adverse perinatal outcomes gradually increase after 40 gestational weeks and are substantially increased post-term (≥42 weeks (≥294 days)). 1 2 The risk of stillbirth has been shown to increase after term, 1 2 3 4 5 and worldwide as much as 14% of stillbirths are associated with prolonged pregnancy. 2 Furthermore, maternal complications also increase with duration of pregnancy after 40 weeks. 1 To date, no agreement exists on how to manage late term (41 weeks+0 days to 42 weeks+0 days) pregnancies. The World Health Organization recommends induction of labour at 41 weeks, 6 and many countries offer induction of labour between 41 and 42 weeks to avoid prolonged pregnancy. 7 8 Randomised controlled trials have compared induction of labour with expectant management in prolonged pregnancies, most with inconclusive results for perinatal mortality and major morbidity. 9 The results from the latest Cochrane review (2018) showed lower rates of caesarean delivery and perinatal death but a higher rate of operative vaginal delivery in the induction group compared with the expectant management group. 9 After the latest Cochrane review and after the initiation of the present study, 10 two large randomised controlled trials examining low risk pregnancies have been published. A large trial from the United States, ARRIVE (A Randomized Trial of Induction Versus Expectant Management), compared induction of labour in nulliparous women at 39 weeks+0 days to 39 weeks+4 days with expectant management until 41 weeks+0 days. 11 No significant difference was found in perinatal outcome between groups, whereas the frequency of caesarean delivery was significantly lower in the early induction group. Another large recent trial from the Netherlands, INDEX (INDuction of labour at 41 weeks with a policy of EXpectant management until 42 weeks), compared induction of labour at 41 weeks+0 days to 41 weeks+1 day with expectant management until 42 weeks+0 days. 12 The results could not confirm non-inferiority for adverse perinatal outcome of expectant management, instead a significantly higher risk of adverse perinatal outcome was found in the expectant management group. No significant difference in the rate of caesarean delivery was found. The current practice in many centres in the United Kingdom and Scandinavia is to induce delivery no later than 42 weeks, but several studies suggest that the risk of perinatal mortality and morbidity has actually already increased significantly at 41 weeks. 3 4 5 The risk of stillbirth increases gradually from 39 weeks of gestation 13 and increases exponentially as the pregnancy approaches 42 weeks, 3-5 13 whereas the risk of neonatal mortality is not increased until 42 weeks according to most studies. 3-5 13 We therefore found it clinically justified to compare induction of labour at 41 weeks with expectant management and induction at 42 weeks for maternal and perinatal outcomes. At the start of the present trial, only two studies (one was an abstract) out of 30 included in the Cochrane review specifically compared induction of labour at 41 weeks with expectant management until 42 weeks. 14 15 We evaluated if induction of labour at 41 weeks+0-2 days compared with expectant management and induction of labour at 42 weeks+0-1 days was superior in terms of perinatal outcome in healthy women with a low risk pregnancy. Methods Study design SWEPIS (SWEdish Post-term Induction Study) was a multicentre, open label, randomised controlled superiority trial conducted in Sweden from May 2016 to October 2018. The trial was register based, with randomisation and most data collection done by using the Swedish Pregnancy Register. 16 Fourteen hospitals with antenatal clinics linked to the register were involved in the trial. Five of the hospitals were university clinics and nine were county hospitals comprising about 60 000 deliveries per year of the around 115 000 to 120 000 annual deliveries in Sweden. The trial was conducted according to the CONSORT guidelines. The protocol is available online ( ) and as a publication.", "role": "user" }, { "content": "Inducing labour at 41 weeks in low risk pregnancies is associated with a lower risk of newborn death compared with expectant management (a \"wait and see\" approach) until 42 weeks, suggests a trial published by The BMJ. Although the overall risk of death at 42 weeks is low, the researchers say induction of labour should be offered to women no later than 41 full weeks. It is generally accepted that there is an increased risk of problems (\"adverse perinatal outcomes\") for both mother and baby at or beyond 42 weeks of pregnancy. Some studies have suggested that inducing labour from 41 weeks onwards improves these outcomes, but there is no international consensus on how to manage healthy pregnancies lasting more than 41 weeks. Current practice in the UK and Scandinavia is to induce delivery for all women who have not gone into labour by 42 weeks. So researchers in Sweden set out to compare induction of labour at 41 weeks with expectant management until 42 weeks in low risk pregnancies. The trial involved 2,760 women (average age 31 years) with an uncomplicated, single pregnancy recruited from 14 Swedish hospitals between 2016 and 2018. Women were randomly assigned to induction of labour at 41 weeks (1,381) or expectant management (1,379) until induction at 42 weeks if necessary. The main outcome was a combined measure of babies' health, including stillbirth or death in the first few days of life (known as perinatal death), Apgar score less than 7 at five minutes, low oxygen levels, and breathing problems. Other outcomes included admission to an intensive care baby unit, Apgar score less than 4 at five minutes, birth weight, pneumonia, or sepsis. Type of delivery and mothers' health just after giving birth were also assessed. For the main outcome measure, the researchers found no difference between the groups (2.4% of women in the induction group had an adverse perinatal outcome compared with 2.2% in the expectant management group). Other outcomes, such as caesarean sections and mothers' health after giving birth, also did not differ between the groups. However, six babies in the expectant management group died compared with none in the induction group, and the trial was stopped early. The researchers estimate that, for every 230 women induced at 41 weeks, one perinatal death would be prevented. They point to some limitations, such as differences in hospital policies and practices, that could have affected the results. But they say women with low risk pregnancies \"should be informed of the risk profile of induction of labour versus expectant management and offered induction of labour no later than at 41 full weeks. This could be one (of few) interventions that reduces stillbirth,\" they conclude. This view is supported in a linked editorial by Professor Sara Kenyon and colleagues, who say induction at 41 weeks \"looks like the safer option for women and their babies.\" They stress that choice is important within maternity care, and say \"clear information about available options should be accessible to all pregnant women, enabling them to make fully informed and timely decisions.\" ", "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 Objective To evaluate if induction of labour at 41 weeks improves perinatal and maternal outcomes in women with a low risk pregnancy compared with expectant management and induction of labour at 42 weeks. Design Multicentre, open label, randomised controlled superiority trial. Setting 14 hospitals in Sweden, 2016-18. Participants 2760 women with a low risk uncomplicated singleton pregnancy randomised (1:1) by the Swedish Pregnancy Register. 1381 women were assigned to the induction group and 1379 were assigned to the expectant management group. Interventions Induction of labour at 41 weeks and expectant management and induction of labour at 42 weeks. Main outcome measures The primary outcome was a composite perinatal outcome including one or more of stillbirth, neonatal mortality, Apgar score less than 7 at five minutes, pH less than 7.00 or metabolic acidosis (pH <7.05 and base deficit >12 mmol/L) in the umbilical artery, hypoxic ischaemic encephalopathy, intracranial haemorrhage, convulsions, meconium aspiration syndrome, mechanical ventilation within 72 hours, or obstetric brachial plexus injury. Primary analysis was by intention to treat. Results The study was stopped early owing to a significantly higher rate of perinatal mortality in the expectant management group. The composite primary perinatal outcome did not differ between the groups: 2.4% (33/1381) in the induction group and 2.2% (31/1379) in the expectant management group (relative risk 1.06, 95% confidence interval 0.65 to 1.73; P=0.90). No perinatal deaths occurred in the induction group but six (five stillbirths and one early neonatal death) occurred in the expectant management group (P=0.03). The proportion of caesarean delivery, instrumental vaginal delivery, or any major maternal morbidity did not differ between the groups. Conclusions This study comparing induction of labour at 41 weeks with expectant management and induction at 42 weeks does not show any significant difference in the primary composite adverse perinatal outcome. However, a reduction of the secondary outcome perinatal mortality is observed without increasing adverse maternal outcomes. Although these results should be interpreted cautiously, induction of labour ought to be offered to women no later than at 41 weeks and could be one (of few) interventions that reduces the rate of stillbirths. Trial registration Current Controlled Trials ISRCTN26113652 . Introduction Adverse perinatal outcomes gradually increase after 40 gestational weeks and are substantially increased post-term (≥42 weeks (≥294 days)). 1 2 The risk of stillbirth has been shown to increase after term, 1 2 3 4 5 and worldwide as much as 14% of stillbirths are associated with prolonged pregnancy. 2 Furthermore, maternal complications also increase with duration of pregnancy after 40 weeks. 1 To date, no agreement exists on how to manage late term (41 weeks+0 days to 42 weeks+0 days) pregnancies. The World Health Organization recommends induction of labour at 41 weeks, 6 and many countries offer induction of labour between 41 and 42 weeks to avoid prolonged pregnancy. 7 8 Randomised controlled trials have compared induction of labour with expectant management in prolonged pregnancies, most with inconclusive results for perinatal mortality and major morbidity. 9 The results from the latest Cochrane review (2018) showed lower rates of caesarean delivery and perinatal death but a higher rate of operative vaginal delivery in the induction group compared with the expectant management group. 9 After the latest Cochrane review and after the initiation of the present study, 10 two large randomised controlled trials examining low risk pregnancies have been published. A large trial from the United States, ARRIVE (A Randomized Trial of Induction Versus Expectant Management), compared induction of labour in nulliparous women at 39 weeks+0 days to 39 weeks+4 days with expectant management until 41 weeks+0 days. 11 No significant difference was found in perinatal outcome between groups, whereas the frequency of caesarean delivery was significantly lower in the early induction group. Another large recent trial from the Netherlands, INDEX (INDuction of labour at 41 weeks with a policy of EXpectant management until 42 weeks), compared induction of labour at 41 weeks+0 days to 41 weeks+1 day with expectant management until 42 weeks+0 days. 12 The results could not confirm non-inferiority for adverse perinatal outcome of expectant management, instead a significantly higher risk of adverse perinatal outcome was found in the expectant management group. No significant difference in the rate of caesarean delivery was found. The current practice in many centres in the United Kingdom and Scandinavia is to induce delivery no later than 42 weeks, but several studies suggest that the risk of perinatal mortality and morbidity has actually already increased significantly at 41 weeks. 3 4 5 The risk of stillbirth increases gradually from 39 weeks of gestation 13 and increases exponentially as the pregnancy approaches 42 weeks, 3-5 13 whereas the risk of neonatal mortality is not increased until 42 weeks according to most studies. 3-5 13 We therefore found it clinically justified to compare induction of labour at 41 weeks with expectant management and induction at 42 weeks for maternal and perinatal outcomes. At the start of the present trial, only two studies (one was an abstract) out of 30 included in the Cochrane review specifically compared induction of labour at 41 weeks with expectant management until 42 weeks. 14 15 We evaluated if induction of labour at 41 weeks+0-2 days compared with expectant management and induction of labour at 42 weeks+0-1 days was superior in terms of perinatal outcome in healthy women with a low risk pregnancy. Methods Study design SWEPIS (SWEdish Post-term Induction Study) was a multicentre, open label, randomised controlled superiority trial conducted in Sweden from May 2016 to October 2018. The trial was register based, with randomisation and most data collection done by using the Swedish Pregnancy Register. 16 Fourteen hospitals with antenatal clinics linked to the register were involved in the trial. Five of the hospitals were university clinics and nine were county hospitals comprising about 60 000 deliveries per year of the around 115 000 to 120 000 annual deliveries in Sweden. The trial was conducted according to the CONSORT guidelines. The protocol is available online ( ) and as a publication.<|im_end|> <|im_start|>assistant Inducing labour at 41 weeks in low risk pregnancies is associated with a lower risk of newborn death compared with expectant management (a "wait and see" approach) until 42 weeks, suggests a trial published by The BMJ. Although the overall risk of death at 42 weeks is low, the researchers say induction of labour should be offered to women no later than 41 full weeks. It is generally accepted that there is an increased risk of problems ("adverse perinatal outcomes") for both mother and baby at or beyond 42 weeks of pregnancy. Some studies have suggested that inducing labour from 41 weeks onwards improves these outcomes, but there is no international consensus on how to manage healthy pregnancies lasting more than 41 weeks. Current practice in the UK and Scandinavia is to induce delivery for all women who have not gone into labour by 42 weeks. So researchers in Sweden set out to compare induction of labour at 41 weeks with expectant management until 42 weeks in low risk pregnancies. The trial involved 2,760 women (average age 31 years) with an uncomplicated, single pregnancy recruited from 14 Swedish hospitals between 2016 and 2018. Women were randomly assigned to induction of labour at 41 weeks (1,381) or expectant management (1,379) until induction at 42 weeks if necessary. The main outcome was a combined measure of babies' health, including stillbirth or death in the first few days of life (known as perinatal death), Apgar score less than 7 at five minutes, low oxygen levels, and breathing problems. Other outcomes included admission to an intensive care baby unit, Apgar score less than 4 at five minutes, birth weight, pneumonia, or sepsis. Type of delivery and mothers' health just after giving birth were also assessed. For the main outcome measure, the researchers found no difference between the groups (2.4% of women in the induction group had an adverse perinatal outcome compared with 2.2% in the expectant management group). Other outcomes, such as caesarean sections and mothers' health after giving birth, also did not differ between the groups. However, six babies in the expectant management group died compared with none in the induction group, and the trial was stopped early. The researchers estimate that, for every 230 women induced at 41 weeks, one perinatal death would be prevented. They point to some limitations, such as differences in hospital policies and practices, that could have affected the results. But they say women with low risk pregnancies "should be informed of the risk profile of induction of labour versus expectant management and offered induction of labour no later than at 41 full weeks. This could be one (of few) interventions that reduces stillbirth," they conclude. This view is supported in a linked editorial by Professor Sara Kenyon and colleagues, who say induction at 41 weeks "looks like the safer option for women and their babies." They stress that choice is important within maternity care, and say "clear information about available options should be accessible to all pregnant women, enabling them to make fully informed and timely decisions." <|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 Despite considerable progress in schizophrenia genetics, most findings have been for large rare structural variants and common variants in well-imputed regions with few genes implicated from exome sequencing. Whole genome sequencing (WGS) can potentially provide a more complete enumeration of etiological genetic variation apart from the exome and regions of high linkage disequilibrium. We analyze high-coverage WGS data from 1162 Swedish schizophrenia cases and 936 ancestry-matched population controls. Our main objective is to evaluate the contribution to schizophrenia etiology from a variety of genetic variants accessible to WGS but not by previous technologies. Our results suggest that ultra-rare structural variants that affect the boundaries of topologically associated domains (TADs) increase risk for schizophrenia. Alterations in TAD boundaries may lead to dysregulation of gene expression. Future mechanistic studies will be needed to determine the precise functional effects of these variants on biology. Introduction Since the first major study over 70 years ago 1 , twin, family, and adoption studies have strongly and consistently supported the existence of a genetic basis for schizophrenia 2 , 3 , 4 . Its inheritance is complex with both genetic and non-genetic contributions indicated by estimates of pedigree-heritability (60–65%) 3 , 4 and twin-heritability (81%) 2 that are well under 100%. Although these genetic epidemiological results were fairly consistent, their validity was dependent on multiple assumptions and contained specific information about genetic architecture. In the past decade, genome-wide association (GWA) studies that genotyped hundreds of thousands of single-nucleotide polymorphisms (SNPs) in tens of thousands of cases and controls have directly evaluated the common-variant SNP-heritability of schizophrenia 5 , 6 , 7 . In the most recent study of 40,675 schizophrenia cases and 64,643 controls, the SNP-heritability of schizophrenia was 24.4% (SE 0.0091, liability scale), and 145 significant loci were identified 6 . SNP array data can also be used to assess rare copy number variants (CNVs). In the largest study to date of 21,094 cases and 20,227 controls 8 , eight CNVs reached genome-wide significance: CNV deletions at 1q21.1, 2p16.3 ( NRXN 1), 3q29, 15q13.3, and 16p11.2 (distal) and 22q11.2 plus CNV duplications at 7q11.23 and 16p11.2 (proximal). These events were uncommon and any one of these eight CNVs were present in 1.42% of cases and 0.15% of controls. There is evidence that rare coding single-nucleotide variants (SNVs) and insertion–deletions (indels) contribute to risk in a low percentage of cases although few genes have been implicated from exome sequencing 9 , 10 , 11 . Thus, after a decade of increasingly larger studies, the discovered genetic variants that confer risk for schizophrenia are primarily common variants with subtle effects on risk 6 , 7 , 9 , 10 . The interpretation of common variant findings is markedly improved via the addition of functional genomic data from brain 7 , 12 , 13 ; nonetheless, there remains a gap between the pedigree- and twin-heritability estimates for schizophrenia and its SNP-heritability. Some argue that this gap is irrelevant as these different types of heritability are incompatible and as biological insights have always been the core goal of GWA for schizophrenia rather than accounting for twin/pedigree heritability. It is also possible that the heritability gap is informative, that SNP array and WES are missing etiologically important genetic variation. GWA genotyping directly captures 500K-1M SNPs followed by imputation to indirectly assess 7–10 M variants. This process is imprecise as some regions of the genome are not well covered, and some non-SNP types of genetic variation are missed. WES provides data on the protein-coding fraction of the genome (~3%) and will miss many regulatory features. By evaluating high-coverage WGS data on 21,620 individuals in the TOPMed study, Wainschtein et al. 14 reported recovery of nearly all of the pedigree heritability for height and body mass index. The missing heritability was found to reside in rarer genetic variation (minor allele frequency (MAF) 0.0001–0.1) in regions of relatively low linkage disequilibrium (LD) and often outside of protein-coding portions of the genome. The fundamental reason for the missing heritability of height and body mass may merely be technical: the least expensive technologies only partly assess the genome with inexpensive SNP arrays capturing common variants in high LD regions and WES capturing much of the known protein-coding genome. The Wainschtein et al. finding is consistent with prior observations that rarer and evolutionarily younger SNPs have higher SNP-heritability for multiple complex traits 15 . To capture genetic variation as comprehensively as possible, WGS is required. WGS provides nucleotide-level resolution throughout the accessible genome along with detection of most structural variants (SVs). Many types of genetic variation are discoverable by WGS without regard to local LD, and these include SNVs and indels in low LD regions, uncommon or rare regulatory variants, rare SVs missed by SNP arrays and WES due to small size or complexity, and common SVs missed by SNP arrays. The NHLBI TOPMed Program recently published high-coverage (30×) WGS data of 53,831 diverse individuals that included ~381 M SNVs and ~29 M indels 16 . TOPMed WGS identified 16% more variants than low-coverage WGS (6×), with essentially all new variants being rare (MAF < 0.005); and 17% more coding variants than both low-coverage WGS and WES (30×). The distribution of variant sites in TOPMed WGS revealed that the vast majority of human genetic variation is rare and noncoding. There are a few published WGS studies of schizophrenia (Supplementary Table 1 ). Of these studies, many employed family-based designs and the largest case–control WGS study had 321 schizophrenia cases and 148 controls. In this study, we analyze high-coverage WGS from 1162 schizophrenia cases and 936 ancestry-matched population controls. WGS data are generated using identical protocols at the same facility and all WGS data are jointly processed and analyzed. The schizophrenia cases also have SNP array 17 , 18 and exome sequencing data 9 , 10 which is compared to WGS to assess data quality. Our main objective is to evaluate the contribution to schizophrenia etiology from variants that are revealed by WGS but not by", "role": "user" }, { "content": "Most research about the genetics of schizophrenia has sought to understand the role that genes play in the development and heritability of schizophrenia. Many discoveries have been made, but there have been many missing pieces. Now, UNC School of Medicine scientists have conducted the largest-ever whole genome sequencing study of schizophrenia to provide a more complete picture of the role the human genome plays in this disease. Published in Nature Communications, the study co-led by senior author Jin Szatkiewicz, Ph.D., associate professor in the UNC Department of Genetics, suggests that rare structural genetic variants could play a role in schizophrenia. \"Our results suggest that ultra-rare structural variants that affect the boundaries of a specific genome structure increase risk for schizophrenia,\" Szatkiewicz said. \"Alterations in these boundaries may lead to dysregulation of gene expression, and we think future mechanistic studies could determine the precise functional effects these variants have on biology.\" Previous studies on the genetics of schizophrenia have primarily involved using common genetic variations known as SNPs (alterations in common genetic sequences and each affecting a single nucleotide), rare variations in the part of DNA that provide instructions for making proteins, or very large structural variations (alterations affecting a few hundred thousands of nucleotides). These studies give snapshots of the genome, leaving a large portion of the genome a mystery, as it potentially relates to schizophrenia. In the Nature Communications study, Szatkiewicz and colleagues examined the entire genome, using a method called whole genome sequencing (WGS). The primary reason WGS hasn't been more widely used is that it is very expensive. For this study, an international collaboration pooled funding from National Institute of Mental Health grants and matching funds from Sweden's SciLife Labs to conduct deep whole genome sequencing on 1,165 people with schizophrenia and 1,000 controls—the largest known WGS study of schizophrenia ever. As a result, new discoveries were made. Previously undetectable mutations in DNA were found that scientists had never seen before in schizophrenia. In particular, this study highlighted the role that a three-dimensional genome structure known as topologically associated domains (TADs) could play in the development of schizophrenia. TADs are distinct regions of the genome with strict boundaries between them that keep the domains from interacting with genetic material in neighboring TADs. Shifting or breaking these boundaries allows interactions between genes and regulatory elements that normally would not interact. When these interactions occur, gene expression may be changed in undesirable ways that could result in congenital defects, formation of cancers, and developmental disorders. This study found that extremely rare structural variants affecting TAD boundaries in the brain occur significantly more often in people with schizophrenia than in those without it. Structural variants are large mutations that may involve missing or duplicated genetic sequences, or sequences that are not in the typical genome. This finding suggests that misplaced or missing TAD boundaries may also contribute to the development of schizophrenia. This study was the first to discover the connection between anomalies in TADs and the development of schizophrenia. This work has highlighted TADs-affecting structural variants as prime candidates for future mechanistic studies of the biology of schizophrenia. \"A possible future investigation would be to work with patient-derived cells with these TADs-affecting mutations and figure out what exactly happened at the molecular level,\" said Szatkiewicz, an adjunct assistant professor of psychiatry at UNC. \"In the future, we could use this information about the TAD effects to help develop drugs or precision medicine treatments that could repair disrupted TADs or affected gene expressions which may improve patient outcomes.\" This study will be combined with other WGS studies in order to increase the sample size to further confirm these results. This research will also help the scientific community build on the unfolding genetic mysteries of schizophrenia. ", "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 Despite considerable progress in schizophrenia genetics, most findings have been for large rare structural variants and common variants in well-imputed regions with few genes implicated from exome sequencing. Whole genome sequencing (WGS) can potentially provide a more complete enumeration of etiological genetic variation apart from the exome and regions of high linkage disequilibrium. We analyze high-coverage WGS data from 1162 Swedish schizophrenia cases and 936 ancestry-matched population controls. Our main objective is to evaluate the contribution to schizophrenia etiology from a variety of genetic variants accessible to WGS but not by previous technologies. Our results suggest that ultra-rare structural variants that affect the boundaries of topologically associated domains (TADs) increase risk for schizophrenia. Alterations in TAD boundaries may lead to dysregulation of gene expression. Future mechanistic studies will be needed to determine the precise functional effects of these variants on biology. Introduction Since the first major study over 70 years ago 1 , twin, family, and adoption studies have strongly and consistently supported the existence of a genetic basis for schizophrenia 2 , 3 , 4 . Its inheritance is complex with both genetic and non-genetic contributions indicated by estimates of pedigree-heritability (60–65%) 3 , 4 and twin-heritability (81%) 2 that are well under 100%. Although these genetic epidemiological results were fairly consistent, their validity was dependent on multiple assumptions and contained specific information about genetic architecture. In the past decade, genome-wide association (GWA) studies that genotyped hundreds of thousands of single-nucleotide polymorphisms (SNPs) in tens of thousands of cases and controls have directly evaluated the common-variant SNP-heritability of schizophrenia 5 , 6 , 7 . In the most recent study of 40,675 schizophrenia cases and 64,643 controls, the SNP-heritability of schizophrenia was 24.4% (SE 0.0091, liability scale), and 145 significant loci were identified 6 . SNP array data can also be used to assess rare copy number variants (CNVs). In the largest study to date of 21,094 cases and 20,227 controls 8 , eight CNVs reached genome-wide significance: CNV deletions at 1q21.1, 2p16.3 ( NRXN 1), 3q29, 15q13.3, and 16p11.2 (distal) and 22q11.2 plus CNV duplications at 7q11.23 and 16p11.2 (proximal). These events were uncommon and any one of these eight CNVs were present in 1.42% of cases and 0.15% of controls. There is evidence that rare coding single-nucleotide variants (SNVs) and insertion–deletions (indels) contribute to risk in a low percentage of cases although few genes have been implicated from exome sequencing 9 , 10 , 11 . Thus, after a decade of increasingly larger studies, the discovered genetic variants that confer risk for schizophrenia are primarily common variants with subtle effects on risk 6 , 7 , 9 , 10 . The interpretation of common variant findings is markedly improved via the addition of functional genomic data from brain 7 , 12 , 13 ; nonetheless, there remains a gap between the pedigree- and twin-heritability estimates for schizophrenia and its SNP-heritability. Some argue that this gap is irrelevant as these different types of heritability are incompatible and as biological insights have always been the core goal of GWA for schizophrenia rather than accounting for twin/pedigree heritability. It is also possible that the heritability gap is informative, that SNP array and WES are missing etiologically important genetic variation. GWA genotyping directly captures 500K-1M SNPs followed by imputation to indirectly assess 7–10 M variants. This process is imprecise as some regions of the genome are not well covered, and some non-SNP types of genetic variation are missed. WES provides data on the protein-coding fraction of the genome (~3%) and will miss many regulatory features. By evaluating high-coverage WGS data on 21,620 individuals in the TOPMed study, Wainschtein et al. 14 reported recovery of nearly all of the pedigree heritability for height and body mass index. The missing heritability was found to reside in rarer genetic variation (minor allele frequency (MAF) 0.0001–0.1) in regions of relatively low linkage disequilibrium (LD) and often outside of protein-coding portions of the genome. The fundamental reason for the missing heritability of height and body mass may merely be technical: the least expensive technologies only partly assess the genome with inexpensive SNP arrays capturing common variants in high LD regions and WES capturing much of the known protein-coding genome. The Wainschtein et al. finding is consistent with prior observations that rarer and evolutionarily younger SNPs have higher SNP-heritability for multiple complex traits 15 . To capture genetic variation as comprehensively as possible, WGS is required. WGS provides nucleotide-level resolution throughout the accessible genome along with detection of most structural variants (SVs). Many types of genetic variation are discoverable by WGS without regard to local LD, and these include SNVs and indels in low LD regions, uncommon or rare regulatory variants, rare SVs missed by SNP arrays and WES due to small size or complexity, and common SVs missed by SNP arrays. The NHLBI TOPMed Program recently published high-coverage (30×) WGS data of 53,831 diverse individuals that included ~381 M SNVs and ~29 M indels 16 . TOPMed WGS identified 16% more variants than low-coverage WGS (6×), with essentially all new variants being rare (MAF < 0.005); and 17% more coding variants than both low-coverage WGS and WES (30×). The distribution of variant sites in TOPMed WGS revealed that the vast majority of human genetic variation is rare and noncoding. There are a few published WGS studies of schizophrenia (Supplementary Table 1 ). Of these studies, many employed family-based designs and the largest case–control WGS study had 321 schizophrenia cases and 148 controls. In this study, we analyze high-coverage WGS from 1162 schizophrenia cases and 936 ancestry-matched population controls. WGS data are generated using identical protocols at the same facility and all WGS data are jointly processed and analyzed. The schizophrenia cases also have SNP array 17 , 18 and exome sequencing data 9 , 10 which is compared to WGS to assess data quality. Our main objective is to evaluate the contribution to schizophrenia etiology from variants that are revealed by WGS but not by<|im_end|> <|im_start|>assistant Most research about the genetics of schizophrenia has sought to understand the role that genes play in the development and heritability of schizophrenia. Many discoveries have been made, but there have been many missing pieces. Now, UNC School of Medicine scientists have conducted the largest-ever whole genome sequencing study of schizophrenia to provide a more complete picture of the role the human genome plays in this disease. Published in Nature Communications, the study co-led by senior author Jin Szatkiewicz, Ph.D., associate professor in the UNC Department of Genetics, suggests that rare structural genetic variants could play a role in schizophrenia. "Our results suggest that ultra-rare structural variants that affect the boundaries of a specific genome structure increase risk for schizophrenia," Szatkiewicz said. "Alterations in these boundaries may lead to dysregulation of gene expression, and we think future mechanistic studies could determine the precise functional effects these variants have on biology." Previous studies on the genetics of schizophrenia have primarily involved using common genetic variations known as SNPs (alterations in common genetic sequences and each affecting a single nucleotide), rare variations in the part of DNA that provide instructions for making proteins, or very large structural variations (alterations affecting a few hundred thousands of nucleotides). These studies give snapshots of the genome, leaving a large portion of the genome a mystery, as it potentially relates to schizophrenia. In the Nature Communications study, Szatkiewicz and colleagues examined the entire genome, using a method called whole genome sequencing (WGS). The primary reason WGS hasn't been more widely used is that it is very expensive. For this study, an international collaboration pooled funding from National Institute of Mental Health grants and matching funds from Sweden's SciLife Labs to conduct deep whole genome sequencing on 1,165 people with schizophrenia and 1,000 controls—the largest known WGS study of schizophrenia ever. As a result, new discoveries were made. Previously undetectable mutations in DNA were found that scientists had never seen before in schizophrenia. In particular, this study highlighted the role that a three-dimensional genome structure known as topologically associated domains (TADs) could play in the development of schizophrenia. TADs are distinct regions of the genome with strict boundaries between them that keep the domains from interacting with genetic material in neighboring TADs. Shifting or breaking these boundaries allows interactions between genes and regulatory elements that normally would not interact. When these interactions occur, gene expression may be changed in undesirable ways that could result in congenital defects, formation of cancers, and developmental disorders. This study found that extremely rare structural variants affecting TAD boundaries in the brain occur significantly more often in people with schizophrenia than in those without it. Structural variants are large mutations that may involve missing or duplicated genetic sequences, or sequences that are not in the typical genome. This finding suggests that misplaced or missing TAD boundaries may also contribute to the development of schizophrenia. This study was the first to discover the connection between anomalies in TADs and the development of schizophrenia. This work has highlighted TADs-affecting structural variants as prime candidates for future mechanistic studies of the biology of schizophrenia. "A possible future investigation would be to work with patient-derived cells with these TADs-affecting mutations and figure out what exactly happened at the molecular level," said Szatkiewicz, an adjunct assistant professor of psychiatry at UNC. "In the future, we could use this information about the TAD effects to help develop drugs or precision medicine treatments that could repair disrupted TADs or affected gene expressions which may improve patient outcomes." This study will be combined with other WGS studies in order to increase the sample size to further confirm these results. This research will also help the scientific community build on the unfolding genetic mysteries of schizophrenia. <|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 presidential nomination campaigns, individual state primaries and a national competition take place simultaneously. The relationship between divisive state primaries and general election outcomes is substantially different in presidential campaigns than in single-state campaigns. To capture the full impact of divisiveness in presidential campaigns, one must estimate both the impact of national party division (NPD) and the impact of divisive primaries in individual states. To do so, we develop a comprehensive model of state outcomes in presidential campaigns that incorporates both state-level and national-level controls. We also examine and compare several measures of NPD and several measures of divisive state primaries found in previous research. We find that both NPD and divisive state primaries have independent and significant influence on state-level general election outcomes, with the former having a greater and more widespread impact on the national results. The findings are not artifacts of statistical techniques, timeframes or operational definitions. The results are consistent—varying very little across a wide range of methods and specifications. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Introduction The divisive primary hypothesis, first suggested by Key ( 1953 ), posits that when a party’s primary is competitive or the eventual nominee does poorly in the primary, the party suffers in the general election. However, in presidential elections, measuring the impact of divisiveness is complicated by the fact that campaigns are waged both at the state and national level. As a consequence, the relationship between divisive state primaries and general election outcomes is substantially different in presidential campaigns than in subnational campaigns. Substantial research exists on the impact of divisive state primaries, however this research generally ignores the important distinction between national and subnational elections. Presidential elections, unlike state-level elections, directly involve the national parties. In any state, a divided national party could have a negative impact on the performance of its presidential candidate even though that state’s presidential primary was not divisive. Thus we do not know if national-level or state-level divisiveness exerts greater influence on state-level outcomes in presidential elections because existing models do not account for national party division (NPD). In a single-state primary, the winner of the popular vote becomes the party nominee. Presidential primaries are part of a larger, more complex environment. In presidential campaigns, individual state primaries do not determine the identity of the nominee. Rather, they select (or apportion) delegates to the national convention who then select the party nominee. It is common in the literature to use the term “divisive presidential primary” either to describe the divisiveness of an individual state primary or to describe the divisiveness of the national party during the nomination process. There has long been concern that the presidential nomination process undermines party cohesion and encourages intraparty factionalism. When one national party is divided and the other party united, the divided party usually loses the election. The relative divisiveness of the national parties is a critical component of the national campaign, yet it is included neither in models of state primary divisiveness nor in models of aggregate presidential election outcomes. Excluding NPD from models of presidential election outcomes has the potential to bias the estimate of the impact of divisive state primaries or other variables. To measure the full impact of the divisiveness in presidential campaigns, it is necessary to measure both NPD as well as divisive primaries in individual states. NPD is not simply an aggregation of divisive state primaries. NPDs are deeper and larger than state party divisions. A set of divisive state primaries does not necessarily indicate a divided national party in the general election or vice versa. Footnote 1 Absent the influence of NPD, measuring the impact of divisive state primaries might seem relatively straightforward. However, studies of subnational divisive primaries have reached a confusing variety of conclusions (Lengle and Owen 1996 ). Footnote 2 Measuring the impact of divisive state primaries in presidential campaigns is further complicated by the impact of NPD. In this research, we establish and measure the impact of NPD and that of divisive state primaries (DSP). To these ends, we first develop a comprehensive model of state outcomes in presidential campaigns that incorporates both state and national-level controls. As we will explain, there are several ways to define the appropriate timeframe and to specify the model. We test several possible measures of NPD, and several measures of divisive state primaries found in previous research. We show that our findings are not artifacts of statistical techniques, timeframes or operational definitions. The results are consistent; varying only slightly across a wide range of methods and specifications. Divisive State Primaries in Presidential and Subnational Campaigns The causes and consequences of divisive presidential primaries are somewhat different than those of divisive subnational primaries. Footnote 3 The literature on divisive congressional and gubernatorial primaries posits a link between a divisive state primary and the general election outcome in that state. Because presidential nomination campaigns are sequential and national in scope, some of what occurs in individual state primaries spills over to other state contests. Footnote 4 Previous studies (Hacker 1965 ; Kenney and Rice 1987 ; Atkeson 1998 ; Lazarus 2005 ; Southwell 1986 ) have suggested that a divisive subnational primary decreases that party’s vote because (a) supporters of the losing candidate are alienated or discouraged, (b) the primary battle provides rhetorical “ammunition” for the opposing party, or (c) the state party’s resources are depleted. Each of these effects manifests differently in presidential campaigns than in subnational campaigns. In a congressional or gubernatorial campaign, a competitive primary may divide the state party and deplete its resources, hurting its ability to compete in the general election. In a presidential campaign, a few divisive state primaries would neither divide the national party nor deplete its resources. Presidential candidates allocate resources to states based on their strategic importance; if state party resources are depleted in a battleground state, the national campaign will pump money into that state. Footnote 5 In a presidential campaign, because", "role": "user" }, { "content": "Divided political parties rarely win presidential elections, according to a study by political science researchers at the University of Georgia and their co-authors. If the same holds true this year, the Republican Party could be in trouble this presidential general election. The study, which examined national party division in past presidential elections, found that both national party division and divisive state primaries have significant influence on general election outcomes. In this election cycle, the nominee of a divided Republican Party could lose more than 3 percent of the general election vote, compared to what he would have gained if the party were more united. \"History shows that when one party is divided and the other party is united, the divided party almost always loses the presidential election,\" said Paul-Henri Gurian, an associate professor of political science at UGA's School of Public and International Affairs. \"Consider, for example, the elections from 1964 through 1984; in each case the divided party lost.\" The study measures party division during the primaries and indicates how much the more divided party loses in the general election. The study found that divisive state primaries can lead to a 1 to 2 percent decrease in general elections votes in that state. For example, Hillary Clinton received 71 percent of the Democratic vote in the Georgia primary, while Donald Trump received 39 percent of the Republican vote. According to the historical model, a Republican-nominated Trump would lose almost 1 percent of the Georgia vote in the general election because of the divided state primary. National party division has an even greater and more widespread impact on the national results, often leading to decreases of more than 3 percent nationwide. Looking again at the current presidential election cycle, Trump had received 39.5 percent of the total national Republican primary vote as of March 16, while Clinton had received 58.6 percent of the Democratic vote. If these proportions hold for the remainder of the nomination campaign (and if these two candidates win the nominations), then Trump would lose 4.5 percent of the vote in the general election, compared to what he would have received if the national Republican Party was not divided. \"In close elections, such as 2000, 2004 and 2012, 4-5 percent could change the outcome in terms of which party wins the presidency,\" Gurian said. The results of this study provide political analysts with a way to anticipate the impact of each primary and, more importantly, the impact of the total national primary vote on the general election results. Subtracting the percent of the Republican nominee's total popular vote from that of the Democratic nominee and multiplying that by 0.237 indicates how much the Republican nominee is likely to lose in the November election, compared to what would otherwise be expected. The 4.5 percent figure calculated through March 16 can be updated as additional states hold their primaries. (The same can be done for each individual state primary by multiplying by 0.026.) ", "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 presidential nomination campaigns, individual state primaries and a national competition take place simultaneously. The relationship between divisive state primaries and general election outcomes is substantially different in presidential campaigns than in single-state campaigns. To capture the full impact of divisiveness in presidential campaigns, one must estimate both the impact of national party division (NPD) and the impact of divisive primaries in individual states. To do so, we develop a comprehensive model of state outcomes in presidential campaigns that incorporates both state-level and national-level controls. We also examine and compare several measures of NPD and several measures of divisive state primaries found in previous research. We find that both NPD and divisive state primaries have independent and significant influence on state-level general election outcomes, with the former having a greater and more widespread impact on the national results. The findings are not artifacts of statistical techniques, timeframes or operational definitions. The results are consistent—varying very little across a wide range of methods and specifications. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Introduction The divisive primary hypothesis, first suggested by Key ( 1953 ), posits that when a party’s primary is competitive or the eventual nominee does poorly in the primary, the party suffers in the general election. However, in presidential elections, measuring the impact of divisiveness is complicated by the fact that campaigns are waged both at the state and national level. As a consequence, the relationship between divisive state primaries and general election outcomes is substantially different in presidential campaigns than in subnational campaigns. Substantial research exists on the impact of divisive state primaries, however this research generally ignores the important distinction between national and subnational elections. Presidential elections, unlike state-level elections, directly involve the national parties. In any state, a divided national party could have a negative impact on the performance of its presidential candidate even though that state’s presidential primary was not divisive. Thus we do not know if national-level or state-level divisiveness exerts greater influence on state-level outcomes in presidential elections because existing models do not account for national party division (NPD). In a single-state primary, the winner of the popular vote becomes the party nominee. Presidential primaries are part of a larger, more complex environment. In presidential campaigns, individual state primaries do not determine the identity of the nominee. Rather, they select (or apportion) delegates to the national convention who then select the party nominee. It is common in the literature to use the term “divisive presidential primary” either to describe the divisiveness of an individual state primary or to describe the divisiveness of the national party during the nomination process. There has long been concern that the presidential nomination process undermines party cohesion and encourages intraparty factionalism. When one national party is divided and the other party united, the divided party usually loses the election. The relative divisiveness of the national parties is a critical component of the national campaign, yet it is included neither in models of state primary divisiveness nor in models of aggregate presidential election outcomes. Excluding NPD from models of presidential election outcomes has the potential to bias the estimate of the impact of divisive state primaries or other variables. To measure the full impact of the divisiveness in presidential campaigns, it is necessary to measure both NPD as well as divisive primaries in individual states. NPD is not simply an aggregation of divisive state primaries. NPDs are deeper and larger than state party divisions. A set of divisive state primaries does not necessarily indicate a divided national party in the general election or vice versa. Footnote 1 Absent the influence of NPD, measuring the impact of divisive state primaries might seem relatively straightforward. However, studies of subnational divisive primaries have reached a confusing variety of conclusions (Lengle and Owen 1996 ). Footnote 2 Measuring the impact of divisive state primaries in presidential campaigns is further complicated by the impact of NPD. In this research, we establish and measure the impact of NPD and that of divisive state primaries (DSP). To these ends, we first develop a comprehensive model of state outcomes in presidential campaigns that incorporates both state and national-level controls. As we will explain, there are several ways to define the appropriate timeframe and to specify the model. We test several possible measures of NPD, and several measures of divisive state primaries found in previous research. We show that our findings are not artifacts of statistical techniques, timeframes or operational definitions. The results are consistent; varying only slightly across a wide range of methods and specifications. Divisive State Primaries in Presidential and Subnational Campaigns The causes and consequences of divisive presidential primaries are somewhat different than those of divisive subnational primaries. Footnote 3 The literature on divisive congressional and gubernatorial primaries posits a link between a divisive state primary and the general election outcome in that state. Because presidential nomination campaigns are sequential and national in scope, some of what occurs in individual state primaries spills over to other state contests. Footnote 4 Previous studies (Hacker 1965 ; Kenney and Rice 1987 ; Atkeson 1998 ; Lazarus 2005 ; Southwell 1986 ) have suggested that a divisive subnational primary decreases that party’s vote because (a) supporters of the losing candidate are alienated or discouraged, (b) the primary battle provides rhetorical “ammunition” for the opposing party, or (c) the state party’s resources are depleted. Each of these effects manifests differently in presidential campaigns than in subnational campaigns. In a congressional or gubernatorial campaign, a competitive primary may divide the state party and deplete its resources, hurting its ability to compete in the general election. In a presidential campaign, a few divisive state primaries would neither divide the national party nor deplete its resources. Presidential candidates allocate resources to states based on their strategic importance; if state party resources are depleted in a battleground state, the national campaign will pump money into that state. Footnote 5 In a presidential campaign, because<|im_end|> <|im_start|>assistant Divided political parties rarely win presidential elections, according to a study by political science researchers at the University of Georgia and their co-authors. If the same holds true this year, the Republican Party could be in trouble this presidential general election. The study, which examined national party division in past presidential elections, found that both national party division and divisive state primaries have significant influence on general election outcomes. In this election cycle, the nominee of a divided Republican Party could lose more than 3 percent of the general election vote, compared to what he would have gained if the party were more united. "History shows that when one party is divided and the other party is united, the divided party almost always loses the presidential election," said Paul-Henri Gurian, an associate professor of political science at UGA's School of Public and International Affairs. "Consider, for example, the elections from 1964 through 1984; in each case the divided party lost." The study measures party division during the primaries and indicates how much the more divided party loses in the general election. The study found that divisive state primaries can lead to a 1 to 2 percent decrease in general elections votes in that state. For example, Hillary Clinton received 71 percent of the Democratic vote in the Georgia primary, while Donald Trump received 39 percent of the Republican vote. According to the historical model, a Republican-nominated Trump would lose almost 1 percent of the Georgia vote in the general election because of the divided state primary. National party division has an even greater and more widespread impact on the national results, often leading to decreases of more than 3 percent nationwide. Looking again at the current presidential election cycle, Trump had received 39.5 percent of the total national Republican primary vote as of March 16, while Clinton had received 58.6 percent of the Democratic vote. If these proportions hold for the remainder of the nomination campaign (and if these two candidates win the nominations), then Trump would lose 4.5 percent of the vote in the general election, compared to what he would have received if the national Republican Party was not divided. "In close elections, such as 2000, 2004 and 2012, 4-5 percent could change the outcome in terms of which party wins the presidency," Gurian said. The results of this study provide political analysts with a way to anticipate the impact of each primary and, more importantly, the impact of the total national primary vote on the general election results. Subtracting the percent of the Republican nominee's total popular vote from that of the Democratic nominee and multiplying that by 0.237 indicates how much the Republican nominee is likely to lose in the November election, compared to what would otherwise be expected. The 4.5 percent figure calculated through March 16 can be updated as additional states hold their primaries. (The same can be done for each individual state primary by multiplying by 0.026.) <|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 abyssal ocean is broadly characterized by northward flow of the densest waters and southward flow of less-dense waters above them. Understanding what controls the strength and structure of these interhemispheric flows—referred to as the abyssal overturning circulation—is key to quantifying the ocean’s ability to store carbon and heat on timescales exceeding a century. Here we show that, north of 32° S, the depth distribution of the seafloor compels dense southern-origin waters to flow northward below a depth of about 4 kilometres and to return southward predominantly at depths greater than 2.5 kilometres. Unless ventilated from the north, the overlying mid-depths (1 to 2.5 kilometres deep) host comparatively weak mean meridional flow. Backed by analysis of historical radiocarbon measurements, the findings imply that the geometry of the Pacific, Indian and Atlantic basins places a major external constraint on the overturning structure. Main Dense waters originating from the surface at high latitudes make up the overwhelming majority of the ocean volume. Once formed through heat loss and salt gain, they sink to depth and spread across the globe, carrying information about atmosphere–ocean–ice interactions into the slow-paced abyss and contributing to the ocean’s long ‘memory’ of atmospheric conditions 1 . But the memory timescale and climate buffering effect of the deep ocean ultimately depend upon the rate at which these dense waters are removed from deep seas and returned to the surface. Physical controls on the volume and return pathways of dense waters are therefore key to the ocean’s carbon and heat storage capacity and its role in centennial to multi-millennial climate variability 2 , 3 . The cycle of production, modification and consumption of dense water masses is often conceptualized as a meridional overturning circulation composed of two dynamically distinct limbs 4 , 5 ( Fig. 1a ): an abyssal, northward limb that carries the densest Antarctic-sourced waters (Antarctic Bottom Water, AABW) until they upwell into lighter waters of the Indian, Pacific and Atlantic basins; and a shallower, southward limb that carries these lighter deep waters to the Southern Ocean. Because it involves a gradual decrease in the density of AABW, the abyssal branch is considered to be essentially a diabatic circulation. In contrast, the southward flow of overlying deep waters is thought to be predominantly adiabatic, that is, density-preserving 6 , 7 . This dynamical divide is consistent with the two regimes apparent in the deep-ocean density distribution ( Fig. 1a ): north of the Antarctic Circumpolar Current and away from North Atlantic sinking, level density surfaces above depths of about 2.5 km appear to be compatible with an adiabatic arrangement of water masses, whereas the northward descent of abyssal density surfaces signals transformation of AABW as it travels north. The transition between diabatic and adiabatic regimes and the transition from northward to southward mass transport have been linked to the depth profile of basin-averaged mixing rates, and to surface wind forcing over the Southern Ocean 3 , 4 , 5 , 6 , 7 , 8 . Here we show that these two transitions are tied to the depth distribution of the seafloor and are separate from each other. Figure 1: Density surfaces, seafloor areas and the ocean’s overturning. Climatologies 41 , 49 of neutral density ( a ) and zonally summed incrop areas (in units of square metres per degree of latitude and per (kilograms per cubic metre)) ( b ) as a function of latitude and pseudo-depth. The pseudo-depth of density surfaces is found by filling each latitude band from the bottom up with ocean grid cells ordered from dense to light. Density is contoured in black every 0.1 kg m −3 for γ ≥ 27.5 kg m −3 . Grey arrows in a give a simplified view of overturning flows. Flows oriented along (or across) density surfaces correspond to adiabatic (or diabatic) transports. This study focuses on the latitude range 32° S–48° N enclosed in white lines. PowerPoint slide Full size image The deep ocean communicates with the surface in two high-latitude regions ( Fig. 1a ): the North Atlantic, where deep waters are formed and exported southward to ventilate the 27.7–28.14 kg m −3 density range 9 , 10 ; and the Southern Ocean, where rising density surfaces allow deep waters to upwell primarily adiabatically 6 , 7 , 11 , 12 until they are converted into denser AABW or lighter intermediate and mode waters 5 . Note that we use neutral density 13 , denoted γ , as a globally consistent density variable and subtract 1,000 kg m −3 from all density values. Away from these two high-latitude regions, dense waters are isolated from surface exchanges: their density transformation and upwelling rely on deep diabatic processes. We henceforth focus on such processes and restrict the analysis to ocean waters deeper than 1 km between 32° S and 48° N. Geometry At depths of 1–2.5 km, ocean topography is dominated by relatively steep continental slopes and accounts for less than 8% of the total seabed area ( Fig. 2a and b ). Deeper, the emergence of flatter ridges decaying onto abyssal plains markedly increases the seafloor area per unit depth, which quadruples between depths of 2.5 km and 4.3 km. Depth layers therefore have unequal access to the seafloor: the quarter of the water volume which resides below 3.5 km occupies three-quarters of the seabed. This inequality is reinforced when considering the seafloor coverage of density layers—that is, layers defined by a fixed density interval—because the thickness of such layers generally increases with depth in the deep ocean ( Figs 1 and 2c and d ). By analogy with surface outcrop areas, the seafloor area that is intersected (covered) by a given density layer is termed the ‘incrop’ area. The relatively narrow 28–28.25 kg m −3 density range takes up over 80% of the ocean floor between 32° S and 48° N, with the lion’s share going to waters of about 28.11 kg m −3 ( Fig. 2c and d ; see also Extended", "role": "user" }, { "content": "New research from an international team has revealed why the oldest water in the ocean in the North Pacific has remained trapped in a shadow zone around 2km below the sea surface for over 1000 years. To put it in context, the last time this water encountered the atmosphere the Goths had just invaded the Western Roman Empire. The research suggests the time the ancient water spent below the surface is a consequence of the shape of the ocean floor and its impact on vertical circulation. \"Carbon-14 dating had already told us the most ancient water lied in the deep North Pacific. But until now we had struggled to understand why the very oldest waters huddle around the depth of 2km,\" said lead author from the University of New South Wales, Dr Casimir de Lavergne.\"What we have found is that at around 2km below the surface of the Indian and Pacific Oceans there is a 'shadow zone' with barely any vertical movement that suspends ocean water in an area for centuries. The shadow zone is an area of almost stagnant water sitting between the rising currents caused by the rough topography and geothermal heat sources below 2.5km and the shallower wind driven currents closer to the surface. Before this research, models of deep ocean circulation did not accurately account for the constraint of the ocean floor on bottom waters. Once the researchers precisely factored it in they found the bottom water can not rise above 2.5km below the surface, leaving the region directly above isolated. While the researchers have unlocked one part of the puzzle their results also have the potential to tell us much more. \"When this isolated shadow zone traps millennia old ocean water it also traps nutrients and carbon which have a direct impact on the capacity of the ocean to modify climate over centennial time scales,\" said fellow author from Stockholm University, Dr Fabien Roquet. The article Abyssal ocean overturning shaped by seafloor distribution is published in the scientific 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 The abyssal ocean is broadly characterized by northward flow of the densest waters and southward flow of less-dense waters above them. Understanding what controls the strength and structure of these interhemispheric flows—referred to as the abyssal overturning circulation—is key to quantifying the ocean’s ability to store carbon and heat on timescales exceeding a century. Here we show that, north of 32° S, the depth distribution of the seafloor compels dense southern-origin waters to flow northward below a depth of about 4 kilometres and to return southward predominantly at depths greater than 2.5 kilometres. Unless ventilated from the north, the overlying mid-depths (1 to 2.5 kilometres deep) host comparatively weak mean meridional flow. Backed by analysis of historical radiocarbon measurements, the findings imply that the geometry of the Pacific, Indian and Atlantic basins places a major external constraint on the overturning structure. Main Dense waters originating from the surface at high latitudes make up the overwhelming majority of the ocean volume. Once formed through heat loss and salt gain, they sink to depth and spread across the globe, carrying information about atmosphere–ocean–ice interactions into the slow-paced abyss and contributing to the ocean’s long ‘memory’ of atmospheric conditions 1 . But the memory timescale and climate buffering effect of the deep ocean ultimately depend upon the rate at which these dense waters are removed from deep seas and returned to the surface. Physical controls on the volume and return pathways of dense waters are therefore key to the ocean’s carbon and heat storage capacity and its role in centennial to multi-millennial climate variability 2 , 3 . The cycle of production, modification and consumption of dense water masses is often conceptualized as a meridional overturning circulation composed of two dynamically distinct limbs 4 , 5 ( Fig. 1a ): an abyssal, northward limb that carries the densest Antarctic-sourced waters (Antarctic Bottom Water, AABW) until they upwell into lighter waters of the Indian, Pacific and Atlantic basins; and a shallower, southward limb that carries these lighter deep waters to the Southern Ocean. Because it involves a gradual decrease in the density of AABW, the abyssal branch is considered to be essentially a diabatic circulation. In contrast, the southward flow of overlying deep waters is thought to be predominantly adiabatic, that is, density-preserving 6 , 7 . This dynamical divide is consistent with the two regimes apparent in the deep-ocean density distribution ( Fig. 1a ): north of the Antarctic Circumpolar Current and away from North Atlantic sinking, level density surfaces above depths of about 2.5 km appear to be compatible with an adiabatic arrangement of water masses, whereas the northward descent of abyssal density surfaces signals transformation of AABW as it travels north. The transition between diabatic and adiabatic regimes and the transition from northward to southward mass transport have been linked to the depth profile of basin-averaged mixing rates, and to surface wind forcing over the Southern Ocean 3 , 4 , 5 , 6 , 7 , 8 . Here we show that these two transitions are tied to the depth distribution of the seafloor and are separate from each other. Figure 1: Density surfaces, seafloor areas and the ocean’s overturning. Climatologies 41 , 49 of neutral density ( a ) and zonally summed incrop areas (in units of square metres per degree of latitude and per (kilograms per cubic metre)) ( b ) as a function of latitude and pseudo-depth. The pseudo-depth of density surfaces is found by filling each latitude band from the bottom up with ocean grid cells ordered from dense to light. Density is contoured in black every 0.1 kg m −3 for γ ≥ 27.5 kg m −3 . Grey arrows in a give a simplified view of overturning flows. Flows oriented along (or across) density surfaces correspond to adiabatic (or diabatic) transports. This study focuses on the latitude range 32° S–48° N enclosed in white lines. PowerPoint slide Full size image The deep ocean communicates with the surface in two high-latitude regions ( Fig. 1a ): the North Atlantic, where deep waters are formed and exported southward to ventilate the 27.7–28.14 kg m −3 density range 9 , 10 ; and the Southern Ocean, where rising density surfaces allow deep waters to upwell primarily adiabatically 6 , 7 , 11 , 12 until they are converted into denser AABW or lighter intermediate and mode waters 5 . Note that we use neutral density 13 , denoted γ , as a globally consistent density variable and subtract 1,000 kg m −3 from all density values. Away from these two high-latitude regions, dense waters are isolated from surface exchanges: their density transformation and upwelling rely on deep diabatic processes. We henceforth focus on such processes and restrict the analysis to ocean waters deeper than 1 km between 32° S and 48° N. Geometry At depths of 1–2.5 km, ocean topography is dominated by relatively steep continental slopes and accounts for less than 8% of the total seabed area ( Fig. 2a and b ). Deeper, the emergence of flatter ridges decaying onto abyssal plains markedly increases the seafloor area per unit depth, which quadruples between depths of 2.5 km and 4.3 km. Depth layers therefore have unequal access to the seafloor: the quarter of the water volume which resides below 3.5 km occupies three-quarters of the seabed. This inequality is reinforced when considering the seafloor coverage of density layers—that is, layers defined by a fixed density interval—because the thickness of such layers generally increases with depth in the deep ocean ( Figs 1 and 2c and d ). By analogy with surface outcrop areas, the seafloor area that is intersected (covered) by a given density layer is termed the ‘incrop’ area. The relatively narrow 28–28.25 kg m −3 density range takes up over 80% of the ocean floor between 32° S and 48° N, with the lion’s share going to waters of about 28.11 kg m −3 ( Fig. 2c and d ; see also Extended<|im_end|> <|im_start|>assistant New research from an international team has revealed why the oldest water in the ocean in the North Pacific has remained trapped in a shadow zone around 2km below the sea surface for over 1000 years. To put it in context, the last time this water encountered the atmosphere the Goths had just invaded the Western Roman Empire. The research suggests the time the ancient water spent below the surface is a consequence of the shape of the ocean floor and its impact on vertical circulation. "Carbon-14 dating had already told us the most ancient water lied in the deep North Pacific. But until now we had struggled to understand why the very oldest waters huddle around the depth of 2km," said lead author from the University of New South Wales, Dr Casimir de Lavergne."What we have found is that at around 2km below the surface of the Indian and Pacific Oceans there is a 'shadow zone' with barely any vertical movement that suspends ocean water in an area for centuries. The shadow zone is an area of almost stagnant water sitting between the rising currents caused by the rough topography and geothermal heat sources below 2.5km and the shallower wind driven currents closer to the surface. Before this research, models of deep ocean circulation did not accurately account for the constraint of the ocean floor on bottom waters. Once the researchers precisely factored it in they found the bottom water can not rise above 2.5km below the surface, leaving the region directly above isolated. While the researchers have unlocked one part of the puzzle their results also have the potential to tell us much more. "When this isolated shadow zone traps millennia old ocean water it also traps nutrients and carbon which have a direct impact on the capacity of the ocean to modify climate over centennial time scales," said fellow author from Stockholm University, Dr Fabien Roquet. The article Abyssal ocean overturning shaped by seafloor distribution is published in the scientific journal Nature. <|im_end|>
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780, 320, 269, 1891, 370, 780, 8, 69169, 13, 1115, 4007, 24400, 389, 279, 21518, 2134, 220, 843, 11877, 328, 4235, 2166, 11877, 452, 44910, 304, 4251, 5238, 13, 54600, 15332, 8797, 1404, 2217, 578, 5655, 18435, 92606, 449, 279, 7479, 304, 1403, 1579, 2922, 17584, 13918, 320, 23966, 13, 220, 16, 64, 16919, 279, 4892, 23179, 11, 1405, 5655, 21160, 527, 14454, 323, 35990, 10007, 1637, 311, 71702, 349, 279, 220, 1544, 13, 22, 4235, 1591, 13, 975, 21647, 296, 25173, 18, 17915, 2134, 220, 24, 1174, 220, 605, 2652, 323, 279, 16642, 22302, 11, 1405, 16448, 17915, 27529, 2187, 5655, 21160, 311, 709, 9336, 15871, 1008, 72, 370, 7167, 220, 21, 1174, 220, 22, 1174, 220, 806, 1174, 220, 717, 3156, 814, 527, 16489, 1139, 39950, 261, 362, 1905, 54, 477, 30673, 29539, 323, 3941, 21160, 220, 20, 662, 7181, 430, 584, 1005, 21277, 17915, 220, 1032, 1174, 3453, 9437, 63127, 1174, 439, 264, 31550, 13263, 17915, 3977, 323, 33356, 220, 16, 11, 931, 21647, 296, 25173, 18, 505, 682, 17915, 2819, 13, 42581, 505, 1521, 1403, 1579, 2922, 17584, 13918, 11, 29050, 21160, 527, 25181, 505, 7479, 30098, 25, 872, 17915, 18475, 323, 709, 86, 6427, 17631, 389, 5655, 1891, 370, 780, 11618, 13, 1226, 16472, 71627, 5357, 389, 1778, 11618, 323, 9067, 279, 6492, 311, 18435, 21160, 19662, 1109, 220, 16, 13437, 1990, 220, 843, 11877, 328, 323, 220, 2166, 11877, 452, 13, 40018, 2468, 43957, 315, 220, 16, 4235, 17, 13, 20, 13437, 11, 18435, 1948, 5814, 374, 30801, 555, 12309, 32366, 58636, 60108, 323, 9815, 369, 2753, 1109, 220, 23, 4, 315, 279, 2860, 66591, 291, 3158, 320, 23966, 13, 220, 17, 64, 323, 293, 7609, 1611, 10653, 11, 279, 49179, 315, 1344, 1683, 9463, 4282, 1654, 17718, 8800, 88314, 278, 78466, 88101, 12992, 279, 513, 2642, 4081, 3158, 824, 5089, 8149, 11, 902, 30236, 29423, 1990, 43957, 315, 220, 17, 13, 20, 13437, 323, 220, 19, 13, 18, 13437, 13, 45020, 13931, 9093, 617, 78295, 2680, 311, 279, 513, 2642, 4081, 25, 279, 8502, 315, 279, 3090, 8286, 902, 54068, 3770, 220, 18, 13, 20, 13437, 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1,792
[ { "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 Precipitation extremes will increase in a warming climate, but the response of flood magnitudes to heavier precipitation events is less clear. Historically, there is little evidence for systematic increases in flood magnitude despite observed increases in precipitation extremes. Here we investigate how flood magnitudes change in response to warming, using a large initial-condition ensemble of simulations with a single climate model, coupled to a hydrological model. The model chain was applied to historical (1961–2000) and warmer future (2060–2099) climate conditions for 78 watersheds in hydrological Bavaria, a region comprising the headwater catchments of the Inn, Danube and Main River, thus representing an area of expressed hydrological heterogeneity. For the majority of the catchments, we identify a ‘return interval threshold’ in the relationship between precipitation and flood increases: at return intervals above this threshold, further increases in extreme precipitation frequency and magnitude clearly yield increased flood magnitudes; below the threshold, flood magnitude is modulated by land surface processes. We suggest that this threshold behaviour can reconcile climatological and hydrological perspectives on changing flood risk in a warming climate. Introduction There is clear theoretical, model-based, and empirical evidence that global precipitation extremes, i.e. precipitation exceeding a high threshold, will increase in a warming climate 1 , 2 , 3 , 4 . However, there is greatly more uncertainty regarding the hydrologic response regarding flooding and there is not yet clear evidence for widespread increases in flood occurrence either in observations 5 , 6 , 7 , 8 , 9 , 10 or in model simulations 11 , 12 , 13 . While there is still a theoretical expectation that flood events will increase in a warming climate 14 , 15 , 16 , 17 , and while such flood increases have been documented regionally 18 , 19 , the absence of broader observational trends supporting this hypothesis is conspicuous. In the literature on hydrological processes, the lack of such trends is often attributed to changes in non-precipitation-flood drivers, such as temperature-driven decreases in snow accumulation and increases in evaporation that yield decreases in soil moisture 9 , 20 , 21 , 22 , 23 . Because of the compounding nature of different flood drivers, establishing a direct link between increases in extreme precipitation and increases in flooding is challenging 24 , 25 , 26 . Indeed, previous studies suggest that the strength of the relationship between precipitation and discharge may depend on a range of factors including catchment size, event magnitude 25 , 27 , and season 28 though the details of these complex relationships remain largely unknown and are hard to generalize. Further complicating such investigations is the rarity of extreme events with long return intervals and their sparseness in observed precipitation and streamflow records. Several approaches have been proposed to address this data scarcity problem, including: pooling observations across different catchments 29 or seasonal predictive ensemble members 30 , 31 ; tree-ring and historic reconstructions 32 , 33 ; stochastic streamflow generation 34 , 35 ; and ensemble modeling using Single Model Initial-condition Large Ensembles SMILEs 36 . To date, however, few studies have combined atmospheric SMILEs with hydrological models to obtain a SMILE of streamflow time series, i.e. a ‘hydro-SMILE’ 37 , 38 , 39 . The availability of such a hydro-SMILE is crucial in assessing the relationship between future changes in extreme precipitation and flooding – particularly high-end extreme events (i.e., those occurring twice or fewer times per century), which are rare to nonexistent in observed time series. Here, we seek to reconcile the extreme precipitation-flood paradox in a warming climate: is there a precipitation threshold beyond which increasing precipitation extremes directly translate into increasing flood risk? We hypothesize that such a threshold should exist because moderately extreme events may be buffered by decreased soil moisture (due to warming) while very extreme events may quickly lead to soil saturation and subsequently to direct translation of precipitation to runoff. Using a hydro-SMILE approach, we consider precipitation and flood characteristics from historical (1961–2000) and warmer future (2060–2099) climates for 78 catchments in major Bavarian river basins (Main, Danube, and the Inn river with their major tributaries; henceforth Hydrological Bavaria) characterized by a wide variety of hydroclimates, soil types, land uses, and streamflow regimes 39 , 40 . We find that there does indeed exist a catchment-specific extremeness threshold (i.e. return interval threshold) above which precipitation increases clearly yield increased flood magnitudes, and below which flood magnitude is strongly modulated by land surface processes such as soil moisture availability. Ultimately, this finding may help reconcile seemingly conflicting climatological and hydrological perspectives on changing flood risk in a warming climate. Addressing the precipitation-flood paradox is simply not possible using observations alone, as the high-end extreme events of interest are rare to nonexistent in temporally limited observational records. This real-world data limitation effectively precludes statistical analyses of extreme events with return periods exceeding ~50 years. To overcome this problem, we use a hydro-SMILE to obtain a large number of extreme precipitation–streamflow pairs. The hydro-SMILE consists of hydrological simulations obtained by driving a hydrological model with climate simulations from a single model initial-condition large ensemble (SMILE) climate model. The underlying model simulations were originally generated by Willkofer et al. 40 as part of the ClimEx project 41 . The hydro-SMILE simulations consist of daily streamflow (mm d −1 ), snow-water-equivalents (SWE, mm), and soil moisture (%) – all of which were obtained by driving the hydrological model WaSiM-ETH 42 with a 50-member ensemble of high-resolution climate input (spatial: 500 × 500 m 2 , temporal: 3 h) (for further information on the hydro-SMILE see Section “Hydro-SMILE”). While such a large ensemble approach resolves the small or zero size problem for very extreme events, new sources of uncertainty do also arise. We acknowledge that the hydro-SMILE modeling chain is affected by uncertainties introduced through both the underlying climate and hydrological models. Climate model uncertainties include those relating to precipitation process-representation, downscaling, and bias-correction procedures, hydrological model uncertainties comprise model and parameter uncertainties. These latter", "role": "user" }, { "content": "Climate change will lead to more and stronger floods, mainly due to the increase of more intense heavy rainfall. In order to assess how exactly flood risks and the severity of floods will change over time, it is particularly helpful to consider two different types of such extreme precipitation events: weaker and stronger ones. An international group of scientists led by Dr. Manuela Brunner from the Institute of Earth and Environmental Sciences at the University of Freiburg and Prof. Dr. Ralf Ludwig from the Ludwig-Maximilians-Universität München (LMU) have now shed light on this aspect, which has been little researched to date. They found that the weaker and at the same time more frequent extreme precipitation events (on average every 2 to 10 years) are increasing in frequency and quantity, but do not necessarily lead to flooding. In some places, climate change may even reduce the risk of flooding due to drier soils. Similarly, more severe and at the same time less frequent extreme precipitation events (on average less frequent than 50 years and as occurred in the Eifel in July 2021) are increasing in frequency and quantity, but they also generally lead to more frequent flooding. The team published the results of their study in the journal Communications Earth & Environment. In some places, climate change leads to lower flood risk \"During stronger and at the same time rarer extreme precipitation events, such large amounts of rainfall hit the ground that its current condition has little influence on whether flooding will occur,\" explains Manuela Brunner. \"Its capacity to absorb water is exhausted relatively quickly, and from then on the rain runs off over the surface, thus flooding the landscape. It's a different story for the weaker and more frequent extreme precipitation events,\" says Brunner. \"Here, the current soil conditions are crucial. If the soil is dry, it can absorb a lot of water and the risk of flooding is low. However, if there is already high soil moisture, flooding can occur here as well.\" So, as climate change causes many soils to become drier, the flood risk there may decrease for the weaker, more frequent extreme precipitation events—but not for the rare, even more severe ones. Heavy rainfall will generally increase in Bavaria In the specific example of Bavaria, the scientists also predict how the different extreme precipitation events there will become more numerous. Weaker precipitation events, which occurred on average every 50 years from 1961 to 2000, will occur twice as often in the period from 2060 to 2099. Stronger ones, which occurred on average about every 200 years from 1961 to 2000, will occur up to four times more frequently in the future. \"Previous studies have proven that precipitation will increase due to climate change, but the correlation between flood intensities and heavier precipitation events has not yet been sufficiently investigated. That's where we started,\" explains Manuela Brunner. Ralf Ludwig adds, \"With the help of our unique dataset, this study provides an important building block for an urgently needed, better understanding of the very complex relationship between heavy precipitation and runoff extremes.\" This could also help to improve flood forecasts. 78 areas investigated In its analysis, the team identified so-called frequency thresholds in the relationship between future precipitation increase and flood rise for the majority of the 78 headwater catchments studied in the region around the Inn, Danube and Main rivers. These site-specific values describe which extreme precipitation events, classified by their occurring frequency, are also likely to lead to devastating floods, such as the one in July in the Eifel region. For its study, the research team generated a large ensemble of data by coupling hydrological simulations for Bavaria with a large ensemble of simulations with a climate model for the first time. The model chain was applied to historical (1961-2000) and warmer future (2060-2099) climate conditions for 78 river basins. \"The region around the headwater catchments of the Inn, Danube, and Main rivers is an area with pronounced hydrological heterogeneity. As a result, we consider a wide variety of hydroclimates, soil types, land uses and runoff pathways in our study,\" says Brunner. ", "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 Precipitation extremes will increase in a warming climate, but the response of flood magnitudes to heavier precipitation events is less clear. Historically, there is little evidence for systematic increases in flood magnitude despite observed increases in precipitation extremes. Here we investigate how flood magnitudes change in response to warming, using a large initial-condition ensemble of simulations with a single climate model, coupled to a hydrological model. The model chain was applied to historical (1961–2000) and warmer future (2060–2099) climate conditions for 78 watersheds in hydrological Bavaria, a region comprising the headwater catchments of the Inn, Danube and Main River, thus representing an area of expressed hydrological heterogeneity. For the majority of the catchments, we identify a ‘return interval threshold’ in the relationship between precipitation and flood increases: at return intervals above this threshold, further increases in extreme precipitation frequency and magnitude clearly yield increased flood magnitudes; below the threshold, flood magnitude is modulated by land surface processes. We suggest that this threshold behaviour can reconcile climatological and hydrological perspectives on changing flood risk in a warming climate. Introduction There is clear theoretical, model-based, and empirical evidence that global precipitation extremes, i.e. precipitation exceeding a high threshold, will increase in a warming climate 1 , 2 , 3 , 4 . However, there is greatly more uncertainty regarding the hydrologic response regarding flooding and there is not yet clear evidence for widespread increases in flood occurrence either in observations 5 , 6 , 7 , 8 , 9 , 10 or in model simulations 11 , 12 , 13 . While there is still a theoretical expectation that flood events will increase in a warming climate 14 , 15 , 16 , 17 , and while such flood increases have been documented regionally 18 , 19 , the absence of broader observational trends supporting this hypothesis is conspicuous. In the literature on hydrological processes, the lack of such trends is often attributed to changes in non-precipitation-flood drivers, such as temperature-driven decreases in snow accumulation and increases in evaporation that yield decreases in soil moisture 9 , 20 , 21 , 22 , 23 . Because of the compounding nature of different flood drivers, establishing a direct link between increases in extreme precipitation and increases in flooding is challenging 24 , 25 , 26 . Indeed, previous studies suggest that the strength of the relationship between precipitation and discharge may depend on a range of factors including catchment size, event magnitude 25 , 27 , and season 28 though the details of these complex relationships remain largely unknown and are hard to generalize. Further complicating such investigations is the rarity of extreme events with long return intervals and their sparseness in observed precipitation and streamflow records. Several approaches have been proposed to address this data scarcity problem, including: pooling observations across different catchments 29 or seasonal predictive ensemble members 30 , 31 ; tree-ring and historic reconstructions 32 , 33 ; stochastic streamflow generation 34 , 35 ; and ensemble modeling using Single Model Initial-condition Large Ensembles SMILEs 36 . To date, however, few studies have combined atmospheric SMILEs with hydrological models to obtain a SMILE of streamflow time series, i.e. a ‘hydro-SMILE’ 37 , 38 , 39 . The availability of such a hydro-SMILE is crucial in assessing the relationship between future changes in extreme precipitation and flooding – particularly high-end extreme events (i.e., those occurring twice or fewer times per century), which are rare to nonexistent in observed time series. Here, we seek to reconcile the extreme precipitation-flood paradox in a warming climate: is there a precipitation threshold beyond which increasing precipitation extremes directly translate into increasing flood risk? We hypothesize that such a threshold should exist because moderately extreme events may be buffered by decreased soil moisture (due to warming) while very extreme events may quickly lead to soil saturation and subsequently to direct translation of precipitation to runoff. Using a hydro-SMILE approach, we consider precipitation and flood characteristics from historical (1961–2000) and warmer future (2060–2099) climates for 78 catchments in major Bavarian river basins (Main, Danube, and the Inn river with their major tributaries; henceforth Hydrological Bavaria) characterized by a wide variety of hydroclimates, soil types, land uses, and streamflow regimes 39 , 40 . We find that there does indeed exist a catchment-specific extremeness threshold (i.e. return interval threshold) above which precipitation increases clearly yield increased flood magnitudes, and below which flood magnitude is strongly modulated by land surface processes such as soil moisture availability. Ultimately, this finding may help reconcile seemingly conflicting climatological and hydrological perspectives on changing flood risk in a warming climate. Addressing the precipitation-flood paradox is simply not possible using observations alone, as the high-end extreme events of interest are rare to nonexistent in temporally limited observational records. This real-world data limitation effectively precludes statistical analyses of extreme events with return periods exceeding ~50 years. To overcome this problem, we use a hydro-SMILE to obtain a large number of extreme precipitation–streamflow pairs. The hydro-SMILE consists of hydrological simulations obtained by driving a hydrological model with climate simulations from a single model initial-condition large ensemble (SMILE) climate model. The underlying model simulations were originally generated by Willkofer et al. 40 as part of the ClimEx project 41 . The hydro-SMILE simulations consist of daily streamflow (mm d −1 ), snow-water-equivalents (SWE, mm), and soil moisture (%) – all of which were obtained by driving the hydrological model WaSiM-ETH 42 with a 50-member ensemble of high-resolution climate input (spatial: 500 × 500 m 2 , temporal: 3 h) (for further information on the hydro-SMILE see Section “Hydro-SMILE”). While such a large ensemble approach resolves the small or zero size problem for very extreme events, new sources of uncertainty do also arise. We acknowledge that the hydro-SMILE modeling chain is affected by uncertainties introduced through both the underlying climate and hydrological models. Climate model uncertainties include those relating to precipitation process-representation, downscaling, and bias-correction procedures, hydrological model uncertainties comprise model and parameter uncertainties. These latter<|im_end|> <|im_start|>assistant Climate change will lead to more and stronger floods, mainly due to the increase of more intense heavy rainfall. In order to assess how exactly flood risks and the severity of floods will change over time, it is particularly helpful to consider two different types of such extreme precipitation events: weaker and stronger ones. An international group of scientists led by Dr. Manuela Brunner from the Institute of Earth and Environmental Sciences at the University of Freiburg and Prof. Dr. Ralf Ludwig from the Ludwig-Maximilians-Universität München (LMU) have now shed light on this aspect, which has been little researched to date. They found that the weaker and at the same time more frequent extreme precipitation events (on average every 2 to 10 years) are increasing in frequency and quantity, but do not necessarily lead to flooding. In some places, climate change may even reduce the risk of flooding due to drier soils. Similarly, more severe and at the same time less frequent extreme precipitation events (on average less frequent than 50 years and as occurred in the Eifel in July 2021) are increasing in frequency and quantity, but they also generally lead to more frequent flooding. The team published the results of their study in the journal Communications Earth & Environment. In some places, climate change leads to lower flood risk "During stronger and at the same time rarer extreme precipitation events, such large amounts of rainfall hit the ground that its current condition has little influence on whether flooding will occur," explains Manuela Brunner. "Its capacity to absorb water is exhausted relatively quickly, and from then on the rain runs off over the surface, thus flooding the landscape. It's a different story for the weaker and more frequent extreme precipitation events," says Brunner. "Here, the current soil conditions are crucial. If the soil is dry, it can absorb a lot of water and the risk of flooding is low. However, if there is already high soil moisture, flooding can occur here as well." So, as climate change causes many soils to become drier, the flood risk there may decrease for the weaker, more frequent extreme precipitation events—but not for the rare, even more severe ones. Heavy rainfall will generally increase in Bavaria In the specific example of Bavaria, the scientists also predict how the different extreme precipitation events there will become more numerous. Weaker precipitation events, which occurred on average every 50 years from 1961 to 2000, will occur twice as often in the period from 2060 to 2099. Stronger ones, which occurred on average about every 200 years from 1961 to 2000, will occur up to four times more frequently in the future. "Previous studies have proven that precipitation will increase due to climate change, but the correlation between flood intensities and heavier precipitation events has not yet been sufficiently investigated. That's where we started," explains Manuela Brunner. Ralf Ludwig adds, "With the help of our unique dataset, this study provides an important building block for an urgently needed, better understanding of the very complex relationship between heavy precipitation and runoff extremes." This could also help to improve flood forecasts. 78 areas investigated In its analysis, the team identified so-called frequency thresholds in the relationship between future precipitation increase and flood rise for the majority of the 78 headwater catchments studied in the region around the Inn, Danube and Main rivers. These site-specific values describe which extreme precipitation events, classified by their occurring frequency, are also likely to lead to devastating floods, such as the one in July in the Eifel region. For its study, the research team generated a large ensemble of data by coupling hydrological simulations for Bavaria with a large ensemble of simulations with a climate model for the first time. The model chain was applied to historical (1961-2000) and warmer future (2060-2099) climate conditions for 78 river basins. "The region around the headwater catchments of the Inn, Danube, and Main rivers is an area with pronounced hydrological heterogeneity. As a result, we consider a wide variety of hydroclimates, soil types, land uses and runoff pathways in our study," says Brunner. <|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 Physical exercise stimulates adult neurogenesis, yet the underlying mechanisms remain poorly understood. A fundamental component of the innate neuroregenerative capacity of zebrafish is the proliferative and neurogenic ability of the neural stem/progenitor cells. Here, we show that in the intact spinal cord, this plasticity response can be activated by physical exercise by demonstrating that the cholinergic neurotransmission from spinal locomotor neurons activates spinal neural stem/progenitor cells, leading to neurogenesis in the adult zebrafish. We also show that GABA acts in a non-synaptic fashion to maintain neural stem/progenitor cell quiescence in the spinal cord and that training-induced activation of neurogenesis requires a reduction of GABA A receptors. Furthermore, both pharmacological stimulation of cholinergic receptors, as well as interference with GABAergic signaling, promote functional recovery after spinal cord injury. Our findings provide a model for locomotor networks’ activity-dependent neurogenesis during homeostasis and regeneration in the adult zebrafish spinal cord. Introduction Neurotransmitter signaling is traditionally associated with communication between neurons. However, several reports suggest that neurotransmitters also influence critical aspects of neurogenesis, including proliferation, migration, and differentiation, under both physiological and pathological conditions 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 . The association between neurotransmitter signaling and neurogenesis appears to be primarily dependent on transmitter receptors that are not confined to neurons. Such receptors are now known to be expressed on diverse cell types in the central nervous system, including stem and progenitor cells 4 , 13 . Therefore, neuronal network activity can directly affect neurogenesis 8 , 14 . Previous studies highlighted a link between neurogenesis and neurotransmission, showing the direct effects of the cholinergic and GABAergic signaling in the modulation of the stem/progenitor cells in the mammalian hippocampus and spinal cord 3 , 8 , 13 , 15 , 16 , 17 , yet it remains unclear how neuronal activity is linked to neurogenic activity in the adult spinal cord. Hence, we hypothesized that prolonged spinal network activity, after training, could stimulate the animal growth rate by engaging the spinal proliferative and neurogenic programs. In the early development of the vertebrate spinal cord, all neurons follow a specific genetic program that defines their identities and assigns them a specific neurotransmitter phenotype 18 . Spinal neurons are organized into distinct networks that integrate and process sensory and motor-related information important for various movements 19 , 20 , 21 . Among the spinal networks, the central pattern generators (CPGs) function as local “control and command” centers that are essential for generating the rhythmicity and coordination required for muscle activity during locomotion 19 , 20 , 21 . At the level of spinal locomotor circuits, several classes of premotor interneurons use specific neurotransmitters, including glutamate, γ-aminobutyric acid (GABA), glycine, and acetylcholine (ACh), to mediate their functions 22 . However, it is unknown whether these neurotransmitters released during locomotion can directly affect the neural stem/progenitor cells (NSPCs) within the spinal cord. If so, by identifying neurotransmitters with neurogenic potential could expose the neurons that control these processes. Therefore, neurotransmitter signaling may play an essential activity-dependent role in regulating and fine-tuning the adult spinal cord neurogenesis. To determine whether physical activity can induce spinal cord neurogenesis, we applied an array of anatomical, pharmacological, electrophysiological, and behavioral approaches in adult zebrafish. Our data demonstrate that cholinergic (synaptic) and GABAergic (non-synaptic) neurotransmission regulates the activity of the NSPCs in opposite manners. We show that among spinal interneurons, it is the locomotor V2a interneurons that mediate the essential cholinergic input to NSPCs. The results demonstrate that spinal network activity plays a crucial role in modulating non-motor and non-neuronal functions in the nervous system besides generating motor behaviors. Results Physical activity induces animal growth and proliferation in the spinal cord Several studies have documented the impact of physical activity on neurogenesis in the mammalian hippocampus 11 , 23 , 24 , 25 , 26 . Unlike mammals, zebrafish retain a remarkable adult neurogenic capacity in many central nervous system areas, including the spinal cord 27 , 28 , 29 , 30 . We first tested whether physical activity leads to proliferative and neurogenic events and assayed global consequences on animal growth by using our recently developed forced swim protocol 31 . We observed that prolonged physical activity (>2 weeks) significantly increased animal growth (Supplementary Fig. 1 ). Combining our exercise protocol with the thymidine analog 5-bromo-2ʹ-deoxyuridine (BrdU), a marker of DNA synthesis, we observed a 3-fold increase in the number of BrdU + cells in the spinal cord after 2 weeks of training (short-term survival; Fig. 1a–c ). After a BrdU pulse, we could also trace the migrated cells out of the proliferative central canal niche (Fig. 1a, b ). After 2 weeks rest from the exercise, the proliferation rate dropped to the level of untrained control animals (Fig. 1a, c ), demonstrating the dynamic and reversible nature of exercise-induced proliferation. Fig. 1: Exercise-induced transient activation of the NSPCs and neurogenesis in the adult spinal cord. a Inverted confocal images from whole-mount adult zebrafish spinal cord hemisegments showing cycling (BrdU + ) cells in control animals (untrained), following 2 weeks of training and 2 weeks rest after training. b Similar distribution pattern of BrdU + cells in the spinal cord comparing untrained, trained, and resting zebrafish. c Quantification of BrdU + cells per hemisegment in different conditions show that the enhanced proliferation after training is reversible ( P = 4.418E-10). d Expression pattern of her4.1 : GFP (NSPCs; green) in close apposition of the adult zebrafish spinal cord’s central canal. e The vast majority (~97.5%) of the her4.1 + cells (green) express the stem cell marker Sox2 (magenta). Arrowheads indicate double-labeled cells. f Cycling her4.1 + radial glia cells (BrdU + , magenta; GFP, green). Training increased the number of BrdU + / her4.1 + cells per hemisegment. g Quantification of the average BrdU + cells per spinal cord section co-expressing neuronal markers (mef-2, HuC/D, or NeuN) in untrained (control) and trained animals.", "role": "user" }, { "content": "Researchers at Karolinska Institutet, the German Center for Neurodegenerative Diseases (DZNE) and Columbia University Irving Medical Center have found an unexpected link between spinal locomotor network activity and adult neurogenesis in the adult zebrafish spinal cord. The study has recently been published in Nature Communications. Since the first demonstration of spinal central pattern generators (CPGs) in the early '70s, the activity of neurons involved in the central pattern generator networks has been considered only in terms of their contribution to locomotion. \"We can now reveal an unforeseen yet central non-motor function of spinal locomotor neurons and demonstrate how they dynamically regulate neurogenesis and regeneration following spinal cord injury,\" says Konstantinos Ampatzis, researcher at the Department of Neuroscience and corresponding author. What does your study show? \"In this study, we identify the direct contribution of the spinal locomotor neurons in activating the spinal cord stem cell population, glial cells that can generate new neurons in the adult zebrafish. Therefore, during prolonged locomotion, as we see after training, the stem cells receive excessive synaptic input that allows them to exit their quiescent state and proliferate.\" The researchers revealed that acetylcholine and GABA are the two neurotransmitters that can directly affect the stem cells in the adult zebrafish spinal cord; however, they act antagonistically to each other. \"To identify the neurons that provide the cholinergic input to activate the stem cells was among the most unexpected findings. We found that a particular type of spinal locomotor interneurons, named V2a's, is among the neurons that link locomotion and stem cell activation,\" Konstantinos Ampatzis continues. How might your findings be put to use? \"The overall outcome is a comprehensive understanding of the plasticity and adaptations (mechanisms, structural changes) that develop in response to physical activity and how these adaptive phenomena underlie pathogenicity after injury and/or regeneration of spinal networks. The results are expected to have a substantial impact because they lay the groundwork for developing new, more effective targeted treatments for restoration of the spinal cord after injury,\" Konstantinos Ampatzis explains. The study involved a set of different methodologies in neuroscience, such as anatomy, electrophysiology, pharmacology, and behavior in the adult zebrafish. In their experiments, the researchers took advantage of the experimental amenability of the adult zebrafish. \"This model animal is ideal for these studies. It has an anatomically simple nervous system yet possesses all vertebrate features. It offers unprecedented access to neuronal circuits in behaving animals, and it has a rare ability to regenerate after injury.\" What is your next step? \"Our next step is to identify the type of neurons that are born under homeostasis, training and spinal cord injury. We need to identify if the new neurons replace the existing ones or if they act as add-ons on the spinal cord networks,\" says Konstantinos Ampatzis. ", "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 Physical exercise stimulates adult neurogenesis, yet the underlying mechanisms remain poorly understood. A fundamental component of the innate neuroregenerative capacity of zebrafish is the proliferative and neurogenic ability of the neural stem/progenitor cells. Here, we show that in the intact spinal cord, this plasticity response can be activated by physical exercise by demonstrating that the cholinergic neurotransmission from spinal locomotor neurons activates spinal neural stem/progenitor cells, leading to neurogenesis in the adult zebrafish. We also show that GABA acts in a non-synaptic fashion to maintain neural stem/progenitor cell quiescence in the spinal cord and that training-induced activation of neurogenesis requires a reduction of GABA A receptors. Furthermore, both pharmacological stimulation of cholinergic receptors, as well as interference with GABAergic signaling, promote functional recovery after spinal cord injury. Our findings provide a model for locomotor networks’ activity-dependent neurogenesis during homeostasis and regeneration in the adult zebrafish spinal cord. Introduction Neurotransmitter signaling is traditionally associated with communication between neurons. However, several reports suggest that neurotransmitters also influence critical aspects of neurogenesis, including proliferation, migration, and differentiation, under both physiological and pathological conditions 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 . The association between neurotransmitter signaling and neurogenesis appears to be primarily dependent on transmitter receptors that are not confined to neurons. Such receptors are now known to be expressed on diverse cell types in the central nervous system, including stem and progenitor cells 4 , 13 . Therefore, neuronal network activity can directly affect neurogenesis 8 , 14 . Previous studies highlighted a link between neurogenesis and neurotransmission, showing the direct effects of the cholinergic and GABAergic signaling in the modulation of the stem/progenitor cells in the mammalian hippocampus and spinal cord 3 , 8 , 13 , 15 , 16 , 17 , yet it remains unclear how neuronal activity is linked to neurogenic activity in the adult spinal cord. Hence, we hypothesized that prolonged spinal network activity, after training, could stimulate the animal growth rate by engaging the spinal proliferative and neurogenic programs. In the early development of the vertebrate spinal cord, all neurons follow a specific genetic program that defines their identities and assigns them a specific neurotransmitter phenotype 18 . Spinal neurons are organized into distinct networks that integrate and process sensory and motor-related information important for various movements 19 , 20 , 21 . Among the spinal networks, the central pattern generators (CPGs) function as local “control and command” centers that are essential for generating the rhythmicity and coordination required for muscle activity during locomotion 19 , 20 , 21 . At the level of spinal locomotor circuits, several classes of premotor interneurons use specific neurotransmitters, including glutamate, γ-aminobutyric acid (GABA), glycine, and acetylcholine (ACh), to mediate their functions 22 . However, it is unknown whether these neurotransmitters released during locomotion can directly affect the neural stem/progenitor cells (NSPCs) within the spinal cord. If so, by identifying neurotransmitters with neurogenic potential could expose the neurons that control these processes. Therefore, neurotransmitter signaling may play an essential activity-dependent role in regulating and fine-tuning the adult spinal cord neurogenesis. To determine whether physical activity can induce spinal cord neurogenesis, we applied an array of anatomical, pharmacological, electrophysiological, and behavioral approaches in adult zebrafish. Our data demonstrate that cholinergic (synaptic) and GABAergic (non-synaptic) neurotransmission regulates the activity of the NSPCs in opposite manners. We show that among spinal interneurons, it is the locomotor V2a interneurons that mediate the essential cholinergic input to NSPCs. The results demonstrate that spinal network activity plays a crucial role in modulating non-motor and non-neuronal functions in the nervous system besides generating motor behaviors. Results Physical activity induces animal growth and proliferation in the spinal cord Several studies have documented the impact of physical activity on neurogenesis in the mammalian hippocampus 11 , 23 , 24 , 25 , 26 . Unlike mammals, zebrafish retain a remarkable adult neurogenic capacity in many central nervous system areas, including the spinal cord 27 , 28 , 29 , 30 . We first tested whether physical activity leads to proliferative and neurogenic events and assayed global consequences on animal growth by using our recently developed forced swim protocol 31 . We observed that prolonged physical activity (>2 weeks) significantly increased animal growth (Supplementary Fig. 1 ). Combining our exercise protocol with the thymidine analog 5-bromo-2ʹ-deoxyuridine (BrdU), a marker of DNA synthesis, we observed a 3-fold increase in the number of BrdU + cells in the spinal cord after 2 weeks of training (short-term survival; Fig. 1a–c ). After a BrdU pulse, we could also trace the migrated cells out of the proliferative central canal niche (Fig. 1a, b ). After 2 weeks rest from the exercise, the proliferation rate dropped to the level of untrained control animals (Fig. 1a, c ), demonstrating the dynamic and reversible nature of exercise-induced proliferation. Fig. 1: Exercise-induced transient activation of the NSPCs and neurogenesis in the adult spinal cord. a Inverted confocal images from whole-mount adult zebrafish spinal cord hemisegments showing cycling (BrdU + ) cells in control animals (untrained), following 2 weeks of training and 2 weeks rest after training. b Similar distribution pattern of BrdU + cells in the spinal cord comparing untrained, trained, and resting zebrafish. c Quantification of BrdU + cells per hemisegment in different conditions show that the enhanced proliferation after training is reversible ( P = 4.418E-10). d Expression pattern of her4.1 : GFP (NSPCs; green) in close apposition of the adult zebrafish spinal cord’s central canal. e The vast majority (~97.5%) of the her4.1 + cells (green) express the stem cell marker Sox2 (magenta). Arrowheads indicate double-labeled cells. f Cycling her4.1 + radial glia cells (BrdU + , magenta; GFP, green). Training increased the number of BrdU + / her4.1 + cells per hemisegment. g Quantification of the average BrdU + cells per spinal cord section co-expressing neuronal markers (mef-2, HuC/D, or NeuN) in untrained (control) and trained animals.<|im_end|> <|im_start|>assistant Researchers at Karolinska Institutet, the German Center for Neurodegenerative Diseases (DZNE) and Columbia University Irving Medical Center have found an unexpected link between spinal locomotor network activity and adult neurogenesis in the adult zebrafish spinal cord. The study has recently been published in Nature Communications. Since the first demonstration of spinal central pattern generators (CPGs) in the early '70s, the activity of neurons involved in the central pattern generator networks has been considered only in terms of their contribution to locomotion. "We can now reveal an unforeseen yet central non-motor function of spinal locomotor neurons and demonstrate how they dynamically regulate neurogenesis and regeneration following spinal cord injury," says Konstantinos Ampatzis, researcher at the Department of Neuroscience and corresponding author. What does your study show? "In this study, we identify the direct contribution of the spinal locomotor neurons in activating the spinal cord stem cell population, glial cells that can generate new neurons in the adult zebrafish. Therefore, during prolonged locomotion, as we see after training, the stem cells receive excessive synaptic input that allows them to exit their quiescent state and proliferate." The researchers revealed that acetylcholine and GABA are the two neurotransmitters that can directly affect the stem cells in the adult zebrafish spinal cord; however, they act antagonistically to each other. "To identify the neurons that provide the cholinergic input to activate the stem cells was among the most unexpected findings. We found that a particular type of spinal locomotor interneurons, named V2a's, is among the neurons that link locomotion and stem cell activation," Konstantinos Ampatzis continues. How might your findings be put to use? "The overall outcome is a comprehensive understanding of the plasticity and adaptations (mechanisms, structural changes) that develop in response to physical activity and how these adaptive phenomena underlie pathogenicity after injury and/or regeneration of spinal networks. The results are expected to have a substantial impact because they lay the groundwork for developing new, more effective targeted treatments for restoration of the spinal cord after injury," Konstantinos Ampatzis explains. The study involved a set of different methodologies in neuroscience, such as anatomy, electrophysiology, pharmacology, and behavior in the adult zebrafish. In their experiments, the researchers took advantage of the experimental amenability of the adult zebrafish. "This model animal is ideal for these studies. It has an anatomically simple nervous system yet possesses all vertebrate features. It offers unprecedented access to neuronal circuits in behaving animals, and it has a rare ability to regenerate after injury." What is your next step? "Our next step is to identify the type of neurons that are born under homeostasis, training and spinal cord injury. We need to identify if the new neurons replace the existing ones or if they act as add-ons on the spinal cord networks," says Konstantinos Ampatzis. <|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 Group 3 innate lymphoid cells (ILC3s) are major regulators of inflammation, infection, microbiota composition and metabolism 1 . ILC3s and neuronal cells have been shown to interact at discrete mucosal locations to steer mucosal defence 2 , 3 . Nevertheless, it is unclear whether neuroimmune circuits operate at an organismal level, integrating extrinsic environmental signals to orchestrate ILC3 responses. Here we show that light-entrained and brain-tuned circadian circuits regulate enteric ILC3s, intestinal homeostasis, gut defence and host lipid metabolism in mice. We found that enteric ILC3s display circadian expression of clock genes and ILC3-related transcription factors. ILC3-autonomous ablation of the circadian regulator Arntl led to disrupted gut ILC3 homeostasis, impaired epithelial reactivity, a deregulated microbiome, increased susceptibility to bowel infection and disrupted lipid metabolism. Loss of ILC3-intrinsic Arntl shaped the gut ‘postcode receptors’ of ILC3s. Strikingly, light–dark cycles, feeding rhythms and microbial cues differentially regulated ILC3 clocks, with light signals being the major entraining cues of ILC3s. Accordingly, surgically or genetically induced deregulation of brain rhythmicity led to disrupted circadian ILC3 oscillations, a deregulated microbiome and altered lipid metabolism. Our work reveals a circadian circuitry that translates environmental light cues into enteric ILC3s, shaping intestinal health, metabolism and organismal homeostasis. Main ILC3s have been shown to be part of discrete mucosal neuroimmune cell units 2 , 3 , 4 , 5 , raising the hypothesis that ILC3s may also integrate systemic neuroimmune circuits to regulate tissue integrity and organismic homeostasis. Circadian rhythms rely on local and systemic cues to coordinate mammalian physiology and are genetically encoded by molecular clocks that allow organisms to anticipate and adapt to extrinsic environmental changes 6 , 7 . The circadian clock machinery consists of an autoregulatory network of feedback loops primarily driven by the activators ARNTL and CLOCK and the repressors PER1–PER3, CRY1 and CRY2, amongst others 6 , 7 . Analysis of subsets of intestinal ILCs and their bone marrow progenitors revealed that mature ILC3s express high levels of circadian clock genes (Fig. 1a–c , Extended Data Fig. 1a–d ). Notably, ILC3s displayed a circadian pattern of Per1 Venus expression (Fig. 1b ) and transcriptional analysis of ILC3 revealed circadian expression of master clock regulators and ILC3-related transcription factors (Fig. 1c ). To test whether ILC3s are regulated in a circadian manner, we investigated whether intestinal ILC3s require intrinsic clock signals. Thus, we interfered with the expression of the master circadian activator Arntl . Arntl fl mice were bred to Vav1 Cre mice, allowing conditional deletion of Arntl in all haematopoietic cells ( Arntl ΔVav1 mice). Although Arntl ΔVav1 mice displayed normal numbers of intestinal natural killer (NK) cells and enteric group 1 and 2 ILCs, gut ILC3s were severely and selectively reduced in these mice when compared to their wild-type littermate controls (Fig. 1d, e , Extended Data Fig. 2a, b ). To more precisely define ILC3-intrinsic effects, we generated mixed bone marrow chimaeras by transferring Arntl -competent ( Arntl fl ) or Arntl -deficient ( Arntl ΔVav1 ) bone marrow against a third-party wild-type competitor into alymphoid hosts (Fig. 1f ). Analysis of such chimaeras confirmed cell-autonomous circadian regulation of ILC3s, while their innate and adaptive counterparts were unperturbed (Fig. 1g , Extended Data Fig. 2c ). Fig. 1: Intestinal ILC3s are controlled in a circadian manner. a , Gene expression in CLPs, ILCPs and intestinal ILC3s. CLP and ILCP n = 4; ILC3 n = 6. b , PER1–VENUS mean fluorescence intensity (MFI). CLP and ILCP n = 6; ILC3 n = 4. c , Circadian gene expression in enteric ILC3s; n = 5. d , Intestinal ILC subsets in Arntl fl and Arntl ΔVav1 mice; n = 4. e , Cell numbers of intestinal ILC3s and IL-17- and IL-22-producing ILC3 subsets in Arntl fl and Arntl ΔVav1 mice; n = 4. f , Generation of mixed bone marrow chimaeras. g , Percentage of donor cells and cell numbers of ILC3s, IL-17 and IL-22-producing ILC3 subsets in the gut from mixed bone marrow chimaeras. Arntl fl n = 5, Arntl ΔVav1 n = 7. b , c , White and grey represent light and dark periods, respectively. Data are representative of three independent experiments. n represents biologically independent samples ( a , c ) or animals ( b , d – g ). Data shown as mean ± s.e.m. a , Two-way ANOVA and Tukey’s test; b , c , cosinor analysis; d , e , g , Two-tailed Mann–Whitney U test. * P < 0.05; ** P < 0.01; *** P < 0.001; NS, not significant. Source Data . Full size image To investigate the functional effect of ILC3-intrinsic circadian signals, we deleted Arntl in RORγt-expressing cells by breeding Rorgt Cre mice (also known as Rorc Cre ) to Arntl fl mice ( Arntl ΔRorgt mice). When compared to their wild-type littermate controls, Arntl ΔRorgt mice showed a selective reduction of ILC3 subsets and IL-17- and IL-22-producing ILC3s (Fig. 2a, b , Extended Data Fig. 3a–j ). Notably, independent deletion of Nr1d1 also perturbed subsets of enteric ILC3s, further supporting a role of the clock machinery in ILC3s (Extended Data Fig. 4a–e ). ILC3s have been shown to regulate the expression of genes related to epithelial reactivity and microbial composition 1 . Analysis of Arntl fl and Arntl ΔRorgt mice revealed a profound reduction in the expression of reactivity genes in the Arntl ΔRorgt intestinal epithelium; notably, Reg3b , Reg3g , Muc3 and Muc13 were consistently reduced in Arntl -deficient mice (Fig. 2c ). Furthermore, Arntl ΔRorgt mice displayed altered diurnal patterns of Proteobacteria and Bacteroidetes (Fig. 2d , Extended Data Fig. 3j ). To investigate whether disruption of ILC3-intrinsic ARNTL affected enteric defence, we tested how Arntl ΔRorgt mice responded to intestinal infection. To this end, we bred Arntl ΔRorgt mice to Rag1 −/− mice to exclude putative T cell effects (Extended Data Fig. 3g–i ). Rag1 −/− Arntl ΔRorgt mice were infected with the attaching and effacing bacteria Citrobacter rodentium 2 . When compared to their", "role": "user" }, { "content": "It is well known that individuals who work night shifts or travel often across different time zones have a higher tendency to become overweight and suffer from gut inflammation. The underlying cause for this robust phenomenon has been the subject of many studies that tried to relate physiological processes with the activity of the brain's circadian clock, which is generated in response to the daylight cycle. Now, the group of Henrique Veiga-Fernandes, at the Champalimaud Centre for the Unknown in Lisbon, Portugal, discovered that the function of a group of immune cells, which are known to be strong contributors to gut health, is directly controlled by the brain's circadian clock. Their findings were published today in the scientific journal Nature. \"Sleep deprivation, or altered sleep habits, can have dramatic health consequences, resulting in a range of diseases that frequently have an immune component, such as bowel inflammatory conditions,\" says Veiga-Fernandes, the principal investigator. \"To understand why this happens, we started by asking whether immune cells in the gut are influenced by the circadian clock.\" The big clock and the little clock Almost all cells in the body have an internal genetic machinery that follows the circadian rhythm through the expression of what are commonly known as \"clock genes.\" The clock genes work like little clocks that inform cells of the time of day and thereby help the organs and systems that the cells make up together, anticipate what is going to happen, for instance if it's time to eat or sleep. Even though these cell clocks are autonomous, they still need to be synchronized in order to make sure that \"everyone is on the same page.\" \"The cells inside the body don't have direct information about external light, which means that individual cell clocks can be off,\" Veiga-Fernandes explains. \"The job of the brain's clock, which receives direct information about daylight, is to synchronize all of these little clocks inside the body so that all systems are in synch, which is absolutely crucial for our wellbeing.\" Among the variety of immune cells that are present in the intestine, the team discovered that Type 3 Innate Lymphoid Cells (ILC3s) were particularly susceptible to perturbations of their clock genes. \"These cells fulfill important functions in the gut: they fight infection, control the integrity of the gut epithelium and instruct lipid absorption,\" explains Veiga-Fernandes. \"When we disrupted their clocks, we found that the number of ILC3s in the gut was significantly reduced. This resulted in severe inflammation, breaching of the gut barrier, and increased fat accumulation.\" These robust results drove the team to investigate why is the number of ILC3s in the gut affected so strongly by the brain's circadian clock. The answer to this question ended up being the missing link they were searching for. It's all about being in the right place at the right time When the team analyzed how disrupting the brain's circadian clock influenced the expression of different genes in ILC3s, they found that it resulted in a very specific problem: the molecular zip-code was missing! It so happens that in order to localize to the intestine, ILC3s need to express a protein on their membrane that works as a molecular zip-code. This 'tag' instructs ILC3s, which are transient residents in the gut, where to migrate. In the absence of the brain's circadian inputs, ILC3s failed to express this tag, which meant they were unable to reach their destination. According to Veiga-Fernandes, these results are very exciting, because they clarify why gut health becomes compromised in individuals who are routinely active during the night. \"This mechanism is a beautiful example of evolutionary adaptation,\" says Veiga-Fernandes. \"During the day's active period, which is when you feed, the brain's circadian clock reduces the activity of ILC3s in order to promote healthy lipid metabolism. But then, the gut could be damaged during feeding. So after the feeding period is over, the brain's circadian clock instructs ILC3s to come back into the gut, where they are now needed to fight against invaders and promote regeneration of the epithelium.\" \"It comes as no surprise then,\" he continues, \"that people who work at night can suffer from inflammatory intestinal disorders. It has all to do with the fact that this specific neuro-immune axis is so well-regulated by the brain's clock that any changes in our habits have an immediate impact on these important, ancient immune cells.\" This study joins a series of groundbreaking discoveries produced by Veiga-Fernandes and his team, all drawing new links between the immune and nervous systems. \"The concept that the nervous system can coordinate the function of the immune system is entirely novel. It has been a very inspiring journey; the more we learn about this link, the more we understand how important it is for our wellbeing and we are looking forward to seeing what we will find next,\" he concludes. ", "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 Group 3 innate lymphoid cells (ILC3s) are major regulators of inflammation, infection, microbiota composition and metabolism 1 . ILC3s and neuronal cells have been shown to interact at discrete mucosal locations to steer mucosal defence 2 , 3 . Nevertheless, it is unclear whether neuroimmune circuits operate at an organismal level, integrating extrinsic environmental signals to orchestrate ILC3 responses. Here we show that light-entrained and brain-tuned circadian circuits regulate enteric ILC3s, intestinal homeostasis, gut defence and host lipid metabolism in mice. We found that enteric ILC3s display circadian expression of clock genes and ILC3-related transcription factors. ILC3-autonomous ablation of the circadian regulator Arntl led to disrupted gut ILC3 homeostasis, impaired epithelial reactivity, a deregulated microbiome, increased susceptibility to bowel infection and disrupted lipid metabolism. Loss of ILC3-intrinsic Arntl shaped the gut ‘postcode receptors’ of ILC3s. Strikingly, light–dark cycles, feeding rhythms and microbial cues differentially regulated ILC3 clocks, with light signals being the major entraining cues of ILC3s. Accordingly, surgically or genetically induced deregulation of brain rhythmicity led to disrupted circadian ILC3 oscillations, a deregulated microbiome and altered lipid metabolism. Our work reveals a circadian circuitry that translates environmental light cues into enteric ILC3s, shaping intestinal health, metabolism and organismal homeostasis. Main ILC3s have been shown to be part of discrete mucosal neuroimmune cell units 2 , 3 , 4 , 5 , raising the hypothesis that ILC3s may also integrate systemic neuroimmune circuits to regulate tissue integrity and organismic homeostasis. Circadian rhythms rely on local and systemic cues to coordinate mammalian physiology and are genetically encoded by molecular clocks that allow organisms to anticipate and adapt to extrinsic environmental changes 6 , 7 . The circadian clock machinery consists of an autoregulatory network of feedback loops primarily driven by the activators ARNTL and CLOCK and the repressors PER1–PER3, CRY1 and CRY2, amongst others 6 , 7 . Analysis of subsets of intestinal ILCs and their bone marrow progenitors revealed that mature ILC3s express high levels of circadian clock genes (Fig. 1a–c , Extended Data Fig. 1a–d ). Notably, ILC3s displayed a circadian pattern of Per1 Venus expression (Fig. 1b ) and transcriptional analysis of ILC3 revealed circadian expression of master clock regulators and ILC3-related transcription factors (Fig. 1c ). To test whether ILC3s are regulated in a circadian manner, we investigated whether intestinal ILC3s require intrinsic clock signals. Thus, we interfered with the expression of the master circadian activator Arntl . Arntl fl mice were bred to Vav1 Cre mice, allowing conditional deletion of Arntl in all haematopoietic cells ( Arntl ΔVav1 mice). Although Arntl ΔVav1 mice displayed normal numbers of intestinal natural killer (NK) cells and enteric group 1 and 2 ILCs, gut ILC3s were severely and selectively reduced in these mice when compared to their wild-type littermate controls (Fig. 1d, e , Extended Data Fig. 2a, b ). To more precisely define ILC3-intrinsic effects, we generated mixed bone marrow chimaeras by transferring Arntl -competent ( Arntl fl ) or Arntl -deficient ( Arntl ΔVav1 ) bone marrow against a third-party wild-type competitor into alymphoid hosts (Fig. 1f ). Analysis of such chimaeras confirmed cell-autonomous circadian regulation of ILC3s, while their innate and adaptive counterparts were unperturbed (Fig. 1g , Extended Data Fig. 2c ). Fig. 1: Intestinal ILC3s are controlled in a circadian manner. a , Gene expression in CLPs, ILCPs and intestinal ILC3s. CLP and ILCP n = 4; ILC3 n = 6. b , PER1–VENUS mean fluorescence intensity (MFI). CLP and ILCP n = 6; ILC3 n = 4. c , Circadian gene expression in enteric ILC3s; n = 5. d , Intestinal ILC subsets in Arntl fl and Arntl ΔVav1 mice; n = 4. e , Cell numbers of intestinal ILC3s and IL-17- and IL-22-producing ILC3 subsets in Arntl fl and Arntl ΔVav1 mice; n = 4. f , Generation of mixed bone marrow chimaeras. g , Percentage of donor cells and cell numbers of ILC3s, IL-17 and IL-22-producing ILC3 subsets in the gut from mixed bone marrow chimaeras. Arntl fl n = 5, Arntl ΔVav1 n = 7. b , c , White and grey represent light and dark periods, respectively. Data are representative of three independent experiments. n represents biologically independent samples ( a , c ) or animals ( b , d – g ). Data shown as mean ± s.e.m. a , Two-way ANOVA and Tukey’s test; b , c , cosinor analysis; d , e , g , Two-tailed Mann–Whitney U test. * P < 0.05; ** P < 0.01; *** P < 0.001; NS, not significant. Source Data . Full size image To investigate the functional effect of ILC3-intrinsic circadian signals, we deleted Arntl in RORγt-expressing cells by breeding Rorgt Cre mice (also known as Rorc Cre ) to Arntl fl mice ( Arntl ΔRorgt mice). When compared to their wild-type littermate controls, Arntl ΔRorgt mice showed a selective reduction of ILC3 subsets and IL-17- and IL-22-producing ILC3s (Fig. 2a, b , Extended Data Fig. 3a–j ). Notably, independent deletion of Nr1d1 also perturbed subsets of enteric ILC3s, further supporting a role of the clock machinery in ILC3s (Extended Data Fig. 4a–e ). ILC3s have been shown to regulate the expression of genes related to epithelial reactivity and microbial composition 1 . Analysis of Arntl fl and Arntl ΔRorgt mice revealed a profound reduction in the expression of reactivity genes in the Arntl ΔRorgt intestinal epithelium; notably, Reg3b , Reg3g , Muc3 and Muc13 were consistently reduced in Arntl -deficient mice (Fig. 2c ). Furthermore, Arntl ΔRorgt mice displayed altered diurnal patterns of Proteobacteria and Bacteroidetes (Fig. 2d , Extended Data Fig. 3j ). To investigate whether disruption of ILC3-intrinsic ARNTL affected enteric defence, we tested how Arntl ΔRorgt mice responded to intestinal infection. To this end, we bred Arntl ΔRorgt mice to Rag1 −/− mice to exclude putative T cell effects (Extended Data Fig. 3g–i ). Rag1 −/− Arntl ΔRorgt mice were infected with the attaching and effacing bacteria Citrobacter rodentium 2 . When compared to their<|im_end|> <|im_start|>assistant It is well known that individuals who work night shifts or travel often across different time zones have a higher tendency to become overweight and suffer from gut inflammation. The underlying cause for this robust phenomenon has been the subject of many studies that tried to relate physiological processes with the activity of the brain's circadian clock, which is generated in response to the daylight cycle. Now, the group of Henrique Veiga-Fernandes, at the Champalimaud Centre for the Unknown in Lisbon, Portugal, discovered that the function of a group of immune cells, which are known to be strong contributors to gut health, is directly controlled by the brain's circadian clock. Their findings were published today in the scientific journal Nature. "Sleep deprivation, or altered sleep habits, can have dramatic health consequences, resulting in a range of diseases that frequently have an immune component, such as bowel inflammatory conditions," says Veiga-Fernandes, the principal investigator. "To understand why this happens, we started by asking whether immune cells in the gut are influenced by the circadian clock." The big clock and the little clock Almost all cells in the body have an internal genetic machinery that follows the circadian rhythm through the expression of what are commonly known as "clock genes." The clock genes work like little clocks that inform cells of the time of day and thereby help the organs and systems that the cells make up together, anticipate what is going to happen, for instance if it's time to eat or sleep. Even though these cell clocks are autonomous, they still need to be synchronized in order to make sure that "everyone is on the same page." "The cells inside the body don't have direct information about external light, which means that individual cell clocks can be off," Veiga-Fernandes explains. "The job of the brain's clock, which receives direct information about daylight, is to synchronize all of these little clocks inside the body so that all systems are in synch, which is absolutely crucial for our wellbeing." Among the variety of immune cells that are present in the intestine, the team discovered that Type 3 Innate Lymphoid Cells (ILC3s) were particularly susceptible to perturbations of their clock genes. "These cells fulfill important functions in the gut: they fight infection, control the integrity of the gut epithelium and instruct lipid absorption," explains Veiga-Fernandes. "When we disrupted their clocks, we found that the number of ILC3s in the gut was significantly reduced. This resulted in severe inflammation, breaching of the gut barrier, and increased fat accumulation." These robust results drove the team to investigate why is the number of ILC3s in the gut affected so strongly by the brain's circadian clock. The answer to this question ended up being the missing link they were searching for. It's all about being in the right place at the right time When the team analyzed how disrupting the brain's circadian clock influenced the expression of different genes in ILC3s, they found that it resulted in a very specific problem: the molecular zip-code was missing! It so happens that in order to localize to the intestine, ILC3s need to express a protein on their membrane that works as a molecular zip-code. This 'tag' instructs ILC3s, which are transient residents in the gut, where to migrate. In the absence of the brain's circadian inputs, ILC3s failed to express this tag, which meant they were unable to reach their destination. According to Veiga-Fernandes, these results are very exciting, because they clarify why gut health becomes compromised in individuals who are routinely active during the night. "This mechanism is a beautiful example of evolutionary adaptation," says Veiga-Fernandes. "During the day's active period, which is when you feed, the brain's circadian clock reduces the activity of ILC3s in order to promote healthy lipid metabolism. But then, the gut could be damaged during feeding. So after the feeding period is over, the brain's circadian clock instructs ILC3s to come back into the gut, where they are now needed to fight against invaders and promote regeneration of the epithelium." "It comes as no surprise then," he continues, "that people who work at night can suffer from inflammatory intestinal disorders. It has all to do with the fact that this specific neuro-immune axis is so well-regulated by the brain's clock that any changes in our habits have an immediate impact on these important, ancient immune cells." This study joins a series of groundbreaking discoveries produced by Veiga-Fernandes and his team, all drawing new links between the immune and nervous systems. "The concept that the nervous system can coordinate the function of the immune system is entirely novel. It has been a very inspiring journey; the more we learn about this link, the more we understand how important it is for our wellbeing and we are looking forward to seeing what we will find next," he concludes. <|im_end|>
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2,652
[ { "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 A small, male cockroach (7 mm in length) in Dominican amber is described as Supella dominicana sp. n. (Blattida: Ectobiidae = Blattellidae). The dark tegmina, which are equal to the length of the abdomen, have a yellow cross bar and a central stripe giving the illusion that the body is divided into two halves. The pronotum is partially triangular in outline, with rounded edges and unusually flat surface. The fore femora contain two short apical terminal spines and a series of short wide-spaced marginal spines. The fore tarsus has the first article surpassing the others combined. The 7-segmented cerci are longer than wide. The arolia are well developed and the tarsal claws are symmetrical, of equal length, each with a blunt tooth. The two styles are small, equal in shape and with a branched seta. Developing spermatids are present at the tip of the abdomen. This fossil, which is the first ectobiid cockroach described from Dominican amber, provides some new features of the genus Supella Shelford, 1911. Access provided by MPDL Services gGmbH c/o Max Planck Digital Library Working on a manuscript? Avoid the common mistakes Introduction Dominican amber contains a wealth of information on the biodiversity, ecology, biogeography, speciation and extinction of plants and animals in the mid-Cenozoic (Poinar 1999 , 2010 ). It contains valuable information on the parasites and pathogens of past organisms, including malaria-carrying mosquitoes and nematomorph-infected cockroaches. Regarding cockroaches, we remember those maintained in laboratory cultures at schools and universities for various physiological and behavioral experiments. Yet, these represented only a small fraction with the majority of species occurring throughout tropical and subtropical regions around the world (Hinkelman 2021a , b , 2022 ; Wappler and Vršanský 2021 ). Habits of cockroaches vary considerably and not all live around human habitations. Some live in caves while others prefer stumps or under bark and some genera are soil-burrowing (see Sendi 2021 ; Vršanský et al. 2019a ; Song et al. 2021 ). Some are active during the day while others come out at night. Body size can also vary greatly, ranging from 2 mm long in myrmecophilic cockroaches (Bohn et al. 2021 ) to 66 mm for the Neotropical species Megaloblatta blaberoides (Walker, 1871) (Bell et al. 2007 ). This species can have an overall length of over 120 mm. Cockroaches are considered medically important insects since they are carriers of human pathogens, including bacteria that cause gastroenteritis infections such as salmonella, staphylococcus and streptococcus, resulting in diarrhea, fever, and vomiting. They can also carry viruses (Vršanský et al. 2019b ). Among those closely associated with human habitations around the world are the German cockroach ( Blatella germanica Linnaeus, 1767), the oriental cockroach ( Blatta orientalis Linnaeus, 1758), the brown-banded cockroach ( Supella longipalpa (Fabricius, 1798)) and the American cockroach ( Periplaneta americana Linnaeus, 1758). Aside from these insects spreading pathogens and causing allergic reactions, just their presence and inability to eliminate them from homes can result in psychological stress and low morale (Bowles et al. 2018 ). Currently, the genus Supella contains three subgenera (Rehn 1947 ) and ten species. Nine of them occur in the Ethiopian zoogeographical region (Princis 1969 ; Roth 1985 , 1991 ) and one species in the Saharo - Sindian regional zone (specifically the Arabian Peninsula – Grandcolas 1994 ). The present paper describes a cockroach of the genus Supella Shelford, 1911 from Dominican amber, thus revealing another insect taxon which has no native species remaining in Hispaniola (see also Lewis et al. 1990 ) or even in the entire Nearctic and Neotropics. Materials and methods The fossil originated from La Toca amber mine in the northern mountain range (Cordillera Septentrional) of the Dominican Republic between Puerto Plata and Santiago (Poinar 1991 ; Donnelly 1988 ). Amber from mines in this region was produced by Hymenaea protera Poinar, 1991 (Poinar 1991 ) (Fabaceae). Dating of Dominican amber is controversial, with the youngest proposed age of 20–15 Mya based on Foraminifera (Iturralde-Vinent and MacPhee 1996 ) and the oldest of 45–30 Mya based on coccoliths (Cepek in Schlee 1990). These dates are based on microfossils in the strata containing the amber that is secondarily deposited in turbiditic sandstones of the Upper Eocene to Lower Miocene Mamey Group (Draper et al. 1994 ). Dilcher et al. ( 1992 ) stated that “…the amber clasts, from all physical characteristics, were already matured amber at the time of re-deposition into marine basins. Therefore, the age of the amber is greater than Miocene and quite likely is as early as late Eocene”. The issue is further complicated by the discovery of Early Oligocene amber in Puerto Rico and Maastrichtian-Paleocene amber in Jamaica (Iturralde-Vinent, 2001 ) showing that amber from a range of deposits occurs in the Greater Antilles. Observations and photographs were made with a Nikon SMZ-10 R stereoscopic microscope and Nikon Optiphot compound microscope with magnifications up to 600 X. Helicon Focus Pro X64 was used to stack photos for better clarity and depth of field. Systematic paleontology Order: Blattida Latreille, 1810 (typified Blattariae Latreille, 1810) Family: Ectobiidae Brunner von Wattenwyl, 1865 = Blatellidae Karny, 1908 Subfamily: Pseudophyllodromiinae Hebard, 1929 Genus Supella Shelford, 1911 Supella dominicana sp. n. Zoobank code: E64B2B5E-CC3C-423 A-9813-00B4D238724A. Diagnosis (based on a complete adult male holotype) Small body (7 mm long); tegmina dark, with yellow cross bar and central stripe giving the illusion that the body is divided into two halves, external border of tegmina pale; pronotum triangular to trapezoidal in outline, with rounded edges and flat dorsum; tegmina short, not surpassing abdomen; twice as long as wide, apicies rounded; marginal field of tegmina extends to 43% of wing length; forewing costo-radial field with veins numerous (16), oblique. Fore femora with two apical spines and a series of short marginal spines. Foretarsus with first article surpassing the other articles combined; pulvillus only on fourth tarsomere, arolia well developed, tarsal claws symmetrical, blunt toothed; styles small, equal in shape, with branched setae. Description ( Figs. 1 , 2 , 3", "role": "user" }, { "content": "The cockroach, reviled around the world for its sickness-causing potential and general creepiness, now occupies an important position in the study of amber fossils thanks to research by an Oregon State University scientist. George Poinar Jr., professor emeritus in the OSU College of Science, has identified a new cockroach species. The male specimen, which Poinar named Supella dominicana, is encased in Dominican amber and is the first fossil cockroach to be found with sperm cells. \"It is well preserved with a yellow cross bar across the wings and a central, vertical, yellow stripe that appears to divide the body into two parts,\" he said. \"It has long spines, used for defense, on its legs, especially the hind legs. Also of interest is the sperm bundle containing spermatozoa with dark acrosomes, structures covering the head of the sperm, since fossil sperm are rare.\" The specimen, about 30 million years old, is also the only cockroach of its variety, ectobiid, to be discovered in amber from the Dominican Republic, though it has no living descendants in the Dominican or anywhere in the West Indies. As is the case with another Supella cockroach described earlier from Mexican amber, S. dominicana's closest living relatives are in Africa and Asia. Credit: Oregon State University \"So what caused these cockroaches to become extinct when it is so difficult to get rid of them today?\" wondered Poinar, an international expert in using plant and animal life forms preserved in amber to learn about the biology and ecology of the distant past. There are more than 4,000 species of cockroaches crawling around multiple habitats all over the Earth, but only about 30 types of roaches share habitat with humans, and just a handful of those are regarded as pests. But they are highly regarded as such, Poinar notes. Ancient, primitive and extraordinarily resilient, cockroaches can survive in temperatures well below freezing and can withstand pressures of up to 900 times their body weight, he said—which means if you try to kill one by stepping on it, you probably won't succeed. Cockroaches are so tough that they can live for a week after being decapitated, he added, and they can scuttle at a lightning pace—their speed to body length ratio is equivalent to a human running at about 200 mph. Since it doesn't bother cockroaches to walk through sewage or decaying matter, they'll potentially contaminate whatever surface they touch in your home as they search for food in the form of grease, crumbs, pantry items, even book bindings and cardboard. Credit: Oregon State University \"They are considered medically important insects since they are carriers of human pathogens, including bacteria that cause salmonella, staphylococcus and streptococcus,\" Poinar said. \"They also harbor viruses. And in addition to spreading pathogens and causing allergic reactions, just their presence is very unsettling.\" Prodigiously reproductive, able to squeeze into tiny hiding places and equipped with enzymes that protect them from toxic substances, cockroaches are not easily evicted once they show up somewhere, he said. There's also growing evidence that they're developing resistance to many insecticides. \"The difficulty in eliminating them from homes once they've taken up residence can cause a lot of stress,\" Poinar said. \"Many might say that the best place for a cockroach is entombed in amber.\" Poinar's identification of the new species was published in the journal Biologia. ", "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 A small, male cockroach (7 mm in length) in Dominican amber is described as Supella dominicana sp. n. (Blattida: Ectobiidae = Blattellidae). The dark tegmina, which are equal to the length of the abdomen, have a yellow cross bar and a central stripe giving the illusion that the body is divided into two halves. The pronotum is partially triangular in outline, with rounded edges and unusually flat surface. The fore femora contain two short apical terminal spines and a series of short wide-spaced marginal spines. The fore tarsus has the first article surpassing the others combined. The 7-segmented cerci are longer than wide. The arolia are well developed and the tarsal claws are symmetrical, of equal length, each with a blunt tooth. The two styles are small, equal in shape and with a branched seta. Developing spermatids are present at the tip of the abdomen. This fossil, which is the first ectobiid cockroach described from Dominican amber, provides some new features of the genus Supella Shelford, 1911. Access provided by MPDL Services gGmbH c/o Max Planck Digital Library Working on a manuscript? Avoid the common mistakes Introduction Dominican amber contains a wealth of information on the biodiversity, ecology, biogeography, speciation and extinction of plants and animals in the mid-Cenozoic (Poinar 1999 , 2010 ). It contains valuable information on the parasites and pathogens of past organisms, including malaria-carrying mosquitoes and nematomorph-infected cockroaches. Regarding cockroaches, we remember those maintained in laboratory cultures at schools and universities for various physiological and behavioral experiments. Yet, these represented only a small fraction with the majority of species occurring throughout tropical and subtropical regions around the world (Hinkelman 2021a , b , 2022 ; Wappler and Vršanský 2021 ). Habits of cockroaches vary considerably and not all live around human habitations. Some live in caves while others prefer stumps or under bark and some genera are soil-burrowing (see Sendi 2021 ; Vršanský et al. 2019a ; Song et al. 2021 ). Some are active during the day while others come out at night. Body size can also vary greatly, ranging from 2 mm long in myrmecophilic cockroaches (Bohn et al. 2021 ) to 66 mm for the Neotropical species Megaloblatta blaberoides (Walker, 1871) (Bell et al. 2007 ). This species can have an overall length of over 120 mm. Cockroaches are considered medically important insects since they are carriers of human pathogens, including bacteria that cause gastroenteritis infections such as salmonella, staphylococcus and streptococcus, resulting in diarrhea, fever, and vomiting. They can also carry viruses (Vršanský et al. 2019b ). Among those closely associated with human habitations around the world are the German cockroach ( Blatella germanica Linnaeus, 1767), the oriental cockroach ( Blatta orientalis Linnaeus, 1758), the brown-banded cockroach ( Supella longipalpa (Fabricius, 1798)) and the American cockroach ( Periplaneta americana Linnaeus, 1758). Aside from these insects spreading pathogens and causing allergic reactions, just their presence and inability to eliminate them from homes can result in psychological stress and low morale (Bowles et al. 2018 ). Currently, the genus Supella contains three subgenera (Rehn 1947 ) and ten species. Nine of them occur in the Ethiopian zoogeographical region (Princis 1969 ; Roth 1985 , 1991 ) and one species in the Saharo - Sindian regional zone (specifically the Arabian Peninsula – Grandcolas 1994 ). The present paper describes a cockroach of the genus Supella Shelford, 1911 from Dominican amber, thus revealing another insect taxon which has no native species remaining in Hispaniola (see also Lewis et al. 1990 ) or even in the entire Nearctic and Neotropics. Materials and methods The fossil originated from La Toca amber mine in the northern mountain range (Cordillera Septentrional) of the Dominican Republic between Puerto Plata and Santiago (Poinar 1991 ; Donnelly 1988 ). Amber from mines in this region was produced by Hymenaea protera Poinar, 1991 (Poinar 1991 ) (Fabaceae). Dating of Dominican amber is controversial, with the youngest proposed age of 20–15 Mya based on Foraminifera (Iturralde-Vinent and MacPhee 1996 ) and the oldest of 45–30 Mya based on coccoliths (Cepek in Schlee 1990). These dates are based on microfossils in the strata containing the amber that is secondarily deposited in turbiditic sandstones of the Upper Eocene to Lower Miocene Mamey Group (Draper et al. 1994 ). Dilcher et al. ( 1992 ) stated that “…the amber clasts, from all physical characteristics, were already matured amber at the time of re-deposition into marine basins. Therefore, the age of the amber is greater than Miocene and quite likely is as early as late Eocene”. The issue is further complicated by the discovery of Early Oligocene amber in Puerto Rico and Maastrichtian-Paleocene amber in Jamaica (Iturralde-Vinent, 2001 ) showing that amber from a range of deposits occurs in the Greater Antilles. Observations and photographs were made with a Nikon SMZ-10 R stereoscopic microscope and Nikon Optiphot compound microscope with magnifications up to 600 X. Helicon Focus Pro X64 was used to stack photos for better clarity and depth of field. Systematic paleontology Order: Blattida Latreille, 1810 (typified Blattariae Latreille, 1810) Family: Ectobiidae Brunner von Wattenwyl, 1865 = Blatellidae Karny, 1908 Subfamily: Pseudophyllodromiinae Hebard, 1929 Genus Supella Shelford, 1911 Supella dominicana sp. n. Zoobank code: E64B2B5E-CC3C-423 A-9813-00B4D238724A. Diagnosis (based on a complete adult male holotype) Small body (7 mm long); tegmina dark, with yellow cross bar and central stripe giving the illusion that the body is divided into two halves, external border of tegmina pale; pronotum triangular to trapezoidal in outline, with rounded edges and flat dorsum; tegmina short, not surpassing abdomen; twice as long as wide, apicies rounded; marginal field of tegmina extends to 43% of wing length; forewing costo-radial field with veins numerous (16), oblique. Fore femora with two apical spines and a series of short marginal spines. Foretarsus with first article surpassing the other articles combined; pulvillus only on fourth tarsomere, arolia well developed, tarsal claws symmetrical, blunt toothed; styles small, equal in shape, with branched setae. Description ( Figs. 1 , 2 , 3<|im_end|> <|im_start|>assistant The cockroach, reviled around the world for its sickness-causing potential and general creepiness, now occupies an important position in the study of amber fossils thanks to research by an Oregon State University scientist. George Poinar Jr., professor emeritus in the OSU College of Science, has identified a new cockroach species. The male specimen, which Poinar named Supella dominicana, is encased in Dominican amber and is the first fossil cockroach to be found with sperm cells. "It is well preserved with a yellow cross bar across the wings and a central, vertical, yellow stripe that appears to divide the body into two parts," he said. "It has long spines, used for defense, on its legs, especially the hind legs. Also of interest is the sperm bundle containing spermatozoa with dark acrosomes, structures covering the head of the sperm, since fossil sperm are rare." The specimen, about 30 million years old, is also the only cockroach of its variety, ectobiid, to be discovered in amber from the Dominican Republic, though it has no living descendants in the Dominican or anywhere in the West Indies. As is the case with another Supella cockroach described earlier from Mexican amber, S. dominicana's closest living relatives are in Africa and Asia. Credit: Oregon State University "So what caused these cockroaches to become extinct when it is so difficult to get rid of them today?" wondered Poinar, an international expert in using plant and animal life forms preserved in amber to learn about the biology and ecology of the distant past. There are more than 4,000 species of cockroaches crawling around multiple habitats all over the Earth, but only about 30 types of roaches share habitat with humans, and just a handful of those are regarded as pests. But they are highly regarded as such, Poinar notes. Ancient, primitive and extraordinarily resilient, cockroaches can survive in temperatures well below freezing and can withstand pressures of up to 900 times their body weight, he said—which means if you try to kill one by stepping on it, you probably won't succeed. Cockroaches are so tough that they can live for a week after being decapitated, he added, and they can scuttle at a lightning pace—their speed to body length ratio is equivalent to a human running at about 200 mph. Since it doesn't bother cockroaches to walk through sewage or decaying matter, they'll potentially contaminate whatever surface they touch in your home as they search for food in the form of grease, crumbs, pantry items, even book bindings and cardboard. Credit: Oregon State University "They are considered medically important insects since they are carriers of human pathogens, including bacteria that cause salmonella, staphylococcus and streptococcus," Poinar said. "They also harbor viruses. And in addition to spreading pathogens and causing allergic reactions, just their presence is very unsettling." Prodigiously reproductive, able to squeeze into tiny hiding places and equipped with enzymes that protect them from toxic substances, cockroaches are not easily evicted once they show up somewhere, he said. There's also growing evidence that they're developing resistance to many insecticides. "The difficulty in eliminating them from homes once they've taken up residence can cause a lot of stress," Poinar said. "Many might say that the best place for a cockroach is entombed in amber." Poinar's identification of the new species was published in the journal Biologia. <|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 A deeper understanding of early disease mechanisms occurring in Parkinson’s disease (PD) is needed to reveal restorative targets. Here we report that human induced pluripotent stem cell (iPSC)-derived dopaminergic neurons (DAn) obtained from healthy individuals or patients harboring LRRK2 PD-causing mutation can create highly complex networks with evident signs of functional maturation over time. Compared to control neuronal networks, LRRK2 PD patients’ networks displayed an elevated bursting behavior, in the absence of neurodegeneration. By combining functional calcium imaging, biophysical modeling, and DAn-lineage tracing, we found a decrease in DAn neurite density that triggered overall functional alterations in PD neuronal networks. Our data implicate early dysfunction as a prime focus that may contribute to the initiation of downstream degenerative pathways preceding DAn loss in PD, highlighting a potential window of opportunity for pre-symptomatic assessment of chronic degenerative diseases. Introduction Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, with an estimated prevalence in industrialized countries of 0.3% in the general population, which increases to 1.0% in people older than 60 years and to 3.0% in people older than 80 years 1 . Clinically, PD is characterized by classical motor syndrome linked to a progressive loss of dopamine-containing neurons (DAn) in the substantia nigra pars compacta, and disabling non-motor symptoms related to extranigral lesions. Current therapies for PD are symptomatic and do not limit the progression of disability with time. It has been proposed that early intervention might slow down or even stop disease progression, by preserving neurons from the undergoing irreversible neurodegeneration 1 , 2 . However, early treatment relies on early diagnosis, which unfortunately is especially complicated in the case of PD. Current diagnostic modalities in PD are based on the presence of motor symptoms, a stage at which up to 70% of DAn have been lost 3 . Even though pre-motor symptoms are known to precede clinical diagnosis of PD by as much as a decade, they are rather unspecific and unsuitable as stand-alone biomarkers of the disease 4 . Therefore, the identification of early diagnostic or progression markers of PD represents an urgent medical need. Although the majority of PD cases are of unknown cause, so-called idiopathic PD, around 5% have been shown to have a genetic basis, with mutations in the LRRK2 gene accounting for the largest number of patients of familial PD 5 . Interestingly, LRRK2 polymorphisms are also considered a relevant genetic determinant for sporadic PD 6 , and LRRK2 function appears dysregulated in sporadic cases of PD 7 , even in the absence of LRRK2 mutations/polymorphisms. These findings, together with the fact that PD associated with mutations in LRRK2 (L2-PD) is clinically indistinguishable from sporadic PD, position LRRK2 as an essential player for understanding both genetic and idiopathic PD 8 . LRRK2 is a highly complex protein with multiple enzymatic domains, involved in a variety of intracellular signaling pathways and cellular processes such as cytoskeleton dynamics, vesicle trafficking and endocytosis, autophagy, reactive oxygen species, mitochondrial metabolism, and function of immune cells. However, the exact physiological role of LRRK2 and its implication for PD pathogenesis remains unknown 8 . Of especial relevance for the investigation of early disease markers, transgenic mouse models of L2-PD display, before any events of neurodegeneration, an abnormally elevated excitatory activity and altered spine morphology in dorsal striatal spiny projection neurons 9 . Moreover, experimental models for other neurodegenerative conditions such as Alzheimer’s disease 10 , 11 and amyotrophic lateral sclerosis 12 , have been shown to exhibit neuron hyperexcitability before the disease onset. It has also been demonstrated that the combination of PD with dementia often correlates with a disruption of both functional and effective connectivity in the cortex 13 . In contrast, the association of PD with depression correlates with disrupted functional connectivity between the median cingulate cortex and the prefrontal cortex and cerebellum 14 , 15 . The development of induced pluripotent stem cell (iPSC) technologies enables the generation of patient-specific, disease-relevant, cell-based experimental models of human diseases. Importantly, iPSC-based models can recapitulate some of the earliest signs of disease, even at pre-symptomatic stages 12 , 16 . In this study, we used an experimental platform based on DAn-enriched neuronal cultures derived from L2-PD patients, their gene-edited isogenic counterparts, or from healthy individuals. Such cultures formed active neuronal networks, the functionality of which was analyzed by calcium imaging. After multiple iterations of experimental characterization and biophysical modeling of neuronal network behavior, we could identify early alterations in PD neuronal function that were not present in control networks, and that predated the onset of neuron degeneration. Results Generation and characterization of iPSC-derived DA neurons A total of seven iPSC lines representing L2-PD patients and healthy aged-matched controls, along with gene-edited counterparts and fluorescent TH reporters, were used for the current studies (see Table 1 and “Methods” for further details). Some of these iPSC lines have been previously generated and fully characterized in our laboratories 17 , 18 , 19 , whereas two additional TH reporter lines were generated for this study (Supplementary Fig. 1 ). Table 1 Summary of the healthy controls and patients used in this study. Full size table iPSC differentiation toward DAn fate was performed using a modified version of the previously established midbrain floor-plate protocol 20 , which enabled the maintenance of differentiated cells for up to 10 weeks 21 . Briefly, we first cultured iPSCs on Matrigel with mTeSR medium until they reached 80% confluence, then we induced specification toward the ventral midbrain (VM) fate using a combination of knockout serum medium and neural induction medium (Fig. 1a ). At day 12 post-plating (D12) the cells exhibited a homogeneous morphology and marker profile of VM floor-plate progenitors, expressing FOXA2+/LMX1A+ and the VM NPC markers such as OTX2 and EN1 paired with the neuroectodermal stem cell marker Nestin (Fig. 1b ). These progenitors were then cultured in neuronal differentiation medium supplemented with growth factors including BDNF, GNDF, TGF-β, and DAPT, with the aim to foster neuronal differentiation and survival (Fig. 1a ). At", "role": "user" }, { "content": "Researchers from IDIBELL and the University of Barcelona (UB) report that neurons derived from Parkinson's patients show impairments in their transmission before neurodegeneration. The study used dopaminergic neurons differentiated from patient stem cells as a model. Parkinson's is a neurodegenerative disease characterized by the death of dopaminergic neurons. This neuronal death leads to a series of motor manifestations characteristic of the disease, such as tremors, rigidity, slowness of movement, or postural instability. In most cases, the cause of the disease is unknown; however, mutations in the LRRK2 gene are responsible for 5% of cases. Current therapies against Parkinson's focus on alleviating symptoms, but do not stop its progression. It is thought that early interventions before the appearance of the first symptoms that prevent neuronal death could slow down or even stop the evolution of the disease. However, currently, the diagnosis is based on the appearance of symptoms, when 70% of the neurons have already been lost. A group of researchers from IDIBELL and the University of Barcelona (UB) has identified early functional deficiencies, before death, in neurons derived from patients with genetic Parkinson's. Dr.Antonella Consiglio says, \"These discoveries open the door to early diagnosis, which would allow us to carry out a premature intervention that would slow down neuronal death, and therefore, would stop the evolution of the disease.\" In this work, dopaminergic neurons, the most vulnerable in Parkinson's, differentiated from stem cells (iPSC) of healthy individuals and patients with genetic Parkinson's, have been used as a model. Researchers have observed that these dopaminergic neurons are capable of maturing and forming functional neural networks in culture, in both control and Parkinson's disease conditions. However, this work published in npj Parkinson's Disease shows that neurons from individuals with Parkinson's are more spontaneously active and present more explosion episodes in which, for example, the entire network is activated at the same time. All this occurs before the neurodegeneration. The researchers believe that this early neuronal dysfunction could be contributing to initiating the cascade of events responsible for the death of dopaminergic neurons, and consequently, Parkinson's disease. Furthermore, this work highlights the extraordinary window of opportunity provided by experimental models based on iPSC in the understanding and presymptomatic evaluation of neurodegenerative diseases. ", "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 A deeper understanding of early disease mechanisms occurring in Parkinson’s disease (PD) is needed to reveal restorative targets. Here we report that human induced pluripotent stem cell (iPSC)-derived dopaminergic neurons (DAn) obtained from healthy individuals or patients harboring LRRK2 PD-causing mutation can create highly complex networks with evident signs of functional maturation over time. Compared to control neuronal networks, LRRK2 PD patients’ networks displayed an elevated bursting behavior, in the absence of neurodegeneration. By combining functional calcium imaging, biophysical modeling, and DAn-lineage tracing, we found a decrease in DAn neurite density that triggered overall functional alterations in PD neuronal networks. Our data implicate early dysfunction as a prime focus that may contribute to the initiation of downstream degenerative pathways preceding DAn loss in PD, highlighting a potential window of opportunity for pre-symptomatic assessment of chronic degenerative diseases. Introduction Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, with an estimated prevalence in industrialized countries of 0.3% in the general population, which increases to 1.0% in people older than 60 years and to 3.0% in people older than 80 years 1 . Clinically, PD is characterized by classical motor syndrome linked to a progressive loss of dopamine-containing neurons (DAn) in the substantia nigra pars compacta, and disabling non-motor symptoms related to extranigral lesions. Current therapies for PD are symptomatic and do not limit the progression of disability with time. It has been proposed that early intervention might slow down or even stop disease progression, by preserving neurons from the undergoing irreversible neurodegeneration 1 , 2 . However, early treatment relies on early diagnosis, which unfortunately is especially complicated in the case of PD. Current diagnostic modalities in PD are based on the presence of motor symptoms, a stage at which up to 70% of DAn have been lost 3 . Even though pre-motor symptoms are known to precede clinical diagnosis of PD by as much as a decade, they are rather unspecific and unsuitable as stand-alone biomarkers of the disease 4 . Therefore, the identification of early diagnostic or progression markers of PD represents an urgent medical need. Although the majority of PD cases are of unknown cause, so-called idiopathic PD, around 5% have been shown to have a genetic basis, with mutations in the LRRK2 gene accounting for the largest number of patients of familial PD 5 . Interestingly, LRRK2 polymorphisms are also considered a relevant genetic determinant for sporadic PD 6 , and LRRK2 function appears dysregulated in sporadic cases of PD 7 , even in the absence of LRRK2 mutations/polymorphisms. These findings, together with the fact that PD associated with mutations in LRRK2 (L2-PD) is clinically indistinguishable from sporadic PD, position LRRK2 as an essential player for understanding both genetic and idiopathic PD 8 . LRRK2 is a highly complex protein with multiple enzymatic domains, involved in a variety of intracellular signaling pathways and cellular processes such as cytoskeleton dynamics, vesicle trafficking and endocytosis, autophagy, reactive oxygen species, mitochondrial metabolism, and function of immune cells. However, the exact physiological role of LRRK2 and its implication for PD pathogenesis remains unknown 8 . Of especial relevance for the investigation of early disease markers, transgenic mouse models of L2-PD display, before any events of neurodegeneration, an abnormally elevated excitatory activity and altered spine morphology in dorsal striatal spiny projection neurons 9 . Moreover, experimental models for other neurodegenerative conditions such as Alzheimer’s disease 10 , 11 and amyotrophic lateral sclerosis 12 , have been shown to exhibit neuron hyperexcitability before the disease onset. It has also been demonstrated that the combination of PD with dementia often correlates with a disruption of both functional and effective connectivity in the cortex 13 . In contrast, the association of PD with depression correlates with disrupted functional connectivity between the median cingulate cortex and the prefrontal cortex and cerebellum 14 , 15 . The development of induced pluripotent stem cell (iPSC) technologies enables the generation of patient-specific, disease-relevant, cell-based experimental models of human diseases. Importantly, iPSC-based models can recapitulate some of the earliest signs of disease, even at pre-symptomatic stages 12 , 16 . In this study, we used an experimental platform based on DAn-enriched neuronal cultures derived from L2-PD patients, their gene-edited isogenic counterparts, or from healthy individuals. Such cultures formed active neuronal networks, the functionality of which was analyzed by calcium imaging. After multiple iterations of experimental characterization and biophysical modeling of neuronal network behavior, we could identify early alterations in PD neuronal function that were not present in control networks, and that predated the onset of neuron degeneration. Results Generation and characterization of iPSC-derived DA neurons A total of seven iPSC lines representing L2-PD patients and healthy aged-matched controls, along with gene-edited counterparts and fluorescent TH reporters, were used for the current studies (see Table 1 and “Methods” for further details). Some of these iPSC lines have been previously generated and fully characterized in our laboratories 17 , 18 , 19 , whereas two additional TH reporter lines were generated for this study (Supplementary Fig. 1 ). Table 1 Summary of the healthy controls and patients used in this study. Full size table iPSC differentiation toward DAn fate was performed using a modified version of the previously established midbrain floor-plate protocol 20 , which enabled the maintenance of differentiated cells for up to 10 weeks 21 . Briefly, we first cultured iPSCs on Matrigel with mTeSR medium until they reached 80% confluence, then we induced specification toward the ventral midbrain (VM) fate using a combination of knockout serum medium and neural induction medium (Fig. 1a ). At day 12 post-plating (D12) the cells exhibited a homogeneous morphology and marker profile of VM floor-plate progenitors, expressing FOXA2+/LMX1A+ and the VM NPC markers such as OTX2 and EN1 paired with the neuroectodermal stem cell marker Nestin (Fig. 1b ). These progenitors were then cultured in neuronal differentiation medium supplemented with growth factors including BDNF, GNDF, TGF-β, and DAPT, with the aim to foster neuronal differentiation and survival (Fig. 1a ). At<|im_end|> <|im_start|>assistant Researchers from IDIBELL and the University of Barcelona (UB) report that neurons derived from Parkinson's patients show impairments in their transmission before neurodegeneration. The study used dopaminergic neurons differentiated from patient stem cells as a model. Parkinson's is a neurodegenerative disease characterized by the death of dopaminergic neurons. This neuronal death leads to a series of motor manifestations characteristic of the disease, such as tremors, rigidity, slowness of movement, or postural instability. In most cases, the cause of the disease is unknown; however, mutations in the LRRK2 gene are responsible for 5% of cases. Current therapies against Parkinson's focus on alleviating symptoms, but do not stop its progression. It is thought that early interventions before the appearance of the first symptoms that prevent neuronal death could slow down or even stop the evolution of the disease. However, currently, the diagnosis is based on the appearance of symptoms, when 70% of the neurons have already been lost. A group of researchers from IDIBELL and the University of Barcelona (UB) has identified early functional deficiencies, before death, in neurons derived from patients with genetic Parkinson's. Dr.Antonella Consiglio says, "These discoveries open the door to early diagnosis, which would allow us to carry out a premature intervention that would slow down neuronal death, and therefore, would stop the evolution of the disease." In this work, dopaminergic neurons, the most vulnerable in Parkinson's, differentiated from stem cells (iPSC) of healthy individuals and patients with genetic Parkinson's, have been used as a model. Researchers have observed that these dopaminergic neurons are capable of maturing and forming functional neural networks in culture, in both control and Parkinson's disease conditions. However, this work published in npj Parkinson's Disease shows that neurons from individuals with Parkinson's are more spontaneously active and present more explosion episodes in which, for example, the entire network is activated at the same time. All this occurs before the neurodegeneration. The researchers believe that this early neuronal dysfunction could be contributing to initiating the cascade of events responsible for the death of dopaminergic neurons, and consequently, Parkinson's disease. Furthermore, this work highlights the extraordinary window of opportunity provided by experimental models based on iPSC in the understanding and presymptomatic evaluation of neurodegenerative diseases. <|im_end|>
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1,906
[ { "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 degree to which species can rapidly adapt is key to survival in the face of climatic and other anthropogenic changes. For little brown bats ( Myotis lucifugus ), whose populations have experienced declines of over 90% because of the introduced fungal pathogen that causes white-nose syndrome (WNS), survival of the species may ultimately depend upon its capacity for adaptive change. Here, we present evidence of selectively driven change (adaptation), despite dramatic nonadaptive genomic shifts (genetic drift) associated with population declines. We compared the genetic makeups of wild survivors versus non-survivors of WNS, and found significant shifts in allele frequencies of genes associated with regulating arousal from hibernation (GABARB1), breakdown of fats (cGMP-PK1), and vocalizations (FOXP2). Changes at these genes are suggestive of evolutionary adaptation, given that WNS causes bats to arouse with unusual frequency from hibernation, contributing to premature depletion of fat reserves. However, whether these putatively adaptive shifts in allele frequencies translate into sufficient increases in survival for the species to rebound in the face of WNS is unknown. Introduction Events that kill large portions of populations, including naturally and anthropogenically induced disasters, increasingly threaten biodiversity 1 , 2 . Invasive species are a major trigger of these declines 3 , including invasive pathogens, against which native species can experience high mortality due to a lack of co-evolutionary defenses 4 , 5 , 6 . Introduced fungal pathogens can be particularly dangerous—they can frequently survive in the environment for extended periods, affect a relatively broad range of hosts, and can be highly virulent 7 , thereby driving mass-mortalities of native species (e.g. amphibian chytrid 8 , snake fungal disease 9 , sea fan aspergillosis 10 , and others 11 , 12 , 13 ) as well as threatening agricultural crops 14 , 15 (e.g. rice blast disease 16 and Fusarium wilt in bananas 17 ). Although host mortalities may have little impact on fungal pathogens, the pathogens can exert incredibly strong selective pressures on their host populations 18 . A pressing conservation question is whether host populations can evolve resistance or tolerance during such epidemics—a necessary first step towards preventing extinction. Strong selective pressures might theoretically lead to an evolutionary rescue effect if host populations adapt 19 . However, acute events that kill off most members of a species also reduce the genetic diversity upon which natural selection can act, thereby limiting the capacity for adaptive change 20 . White-nose syndrome (WNS) is a disease affecting bats, which is caused by the invasive fungus Pseudogymnoascus destructans 21 . This highly destructive pathogen has decimated populations of bats, with 12 North American species currently affected 22 , and some populations experiencing losses of 90–100% 23 . The fungus was first inadvertently introduced to North America by humans in 2006 (in the northeastern U.S.) 24 , and is spreading across the continent, largely via infected bats 25 . The exact mechanism of death is not known, but bats apparently die from secondary physiological complications (e.g. depleted fat reserves) associated with too frequent arousals from hibernation 26 . Here, we conduct a genome scan to test for evidence of evolutionary changes in little brown bats ( Myotis lucifugus ) in response to WNS. The recent expansion of the fungus into our study area in 2014 combined with the staggering impact of WNS on the local population (roughly 78%) 27 provides an opportunity to study the initial evolutionary effects of this pathogen, which continues to spread throughout the continent. Eurasian bats within the genus Myotis —in the native range of the pathogen—tolerate fungal growths with no noticeable mortality 28 , 29 . In contrast, little brown bats were the most common bats in eastern North America prior to WNS, but due to population losses, the species has now been listed as endangered by the IUCN 30 and the federal government of Canada 31 , with a similar decision by the U.S. government pending 32 . Despite large observed declines, some individuals may have greater genetic-based tolerance or resistance to the disease, raising the potential for adaptive change in little brown bats via selective forces acting on standing genetic variation. However, dramatic population losses may confound the effectiveness of selection or purge potential adaptive variants via genetic drift. Information about these evolutionary processes can help inform the tempo and pace of management efforts for this species, by indicating which, if any, populations are adapting to the pathogen and what traits may be important for survival. Results In our tests for evolutionary changes in little brown bats, we compared the genetic makeup of “survivors” and “non-survivors” of the disease (see Fig. 1 ) in a genome-wide survey of 19,797 single nucleotide polymorphisms (SNPs) among 14,345 loci (140 bp segments) generated from a reduced representation library (ddRadSeq 33 ). We detected the effects of stochastic, non-adaptive genomic changes in otherwise neutral portions of the genome (genetic drift) reflective of the large numbers that have died from WNS in this species. Nevertheless, we also identified genetic changes (based on F ST -outlier analyses) that may have contributed to survival (as opposed to changes simply due to strong genetic drift), where the signature of selection can be detected by levels of genetic differentiation at a gene that exceeds background levels across the genome 34 , 35 . See methods for more details. Figure 1 Sampling locations of little brown bats. ( A ) Sequenced survivors ( n = 9, marked by stars) and non-survivors ( n = 29, crosses), jittered around similar collection sites (black dots); the size of the symbol indicates relative differences in the number of samples per site (see Table S1 for details). Survivors undertake short-distance migrations away from hibernacula in spring, which is reflected in their scattered collection locations. Non-survivors are closely associated with underground hibernation sites, with most ( B ) collected within hibernacula (~26 carcasses marked by circles on the floor of a mine), although some ( C ) leave these sites prematurely, like these dead bats on the outer", "role": "user" }, { "content": "A new study from University of Michigan biologists presents the first genetic evidence of resistance in some bats to white-nose syndrome, a deadly fungal disease that has decimated some North American bat populations. The study involved northern Michigan populations of the little brown bat, one of the most common bats in eastern North America prior to the arrival of white-nose syndrome in 2006. Since then, some populations of the small, insect-eating bat have experienced declines of more than 90%. U-M researchers collected tissue samples from wild little brown bats that survived the disease, as well as individuals killed by the fungal pathogen. They compared the genetic makeup of the two groups and found differences in genes associated with regulating arousal from hibernation, the breakdown of fats and echolocation. \"Because we found differences in genes associated with regulating hibernation and breakdown of fats, it could be that bats that are genetically predisposed to be a little bit fatter or to sleep more deeply are less susceptible to the disease,\" said U-M's Giorgia Auteri, first author of a paper scheduled for publication Feb. 20 in the journal Scientific Reports. \"Changes at these genes are suggestive of evolutionary adaptation, given that white-nose syndrome causes bats to arouse with unusual frequency from winter hibernation, contributing to premature depletion of fat reserves,\" said Auteri, a doctoral student in the Department of Ecology and Evolutionary Biology who conducted the study for her dissertation. The other author of the Scientific Reports paper is U-M biologist Lacey Knowles, Auteri's faculty adviser. While the study was small—involving tissue samples from 25 little brown bats killed by white-nose syndrome and nine bats that survived the disease—the authors say their sample size is large enough to detect genetic changes driven by natural selection. A larger follow-up study is underway, expanding both the number of bats and the areas affected by the disease, to develop a fuller picture of adaptive change that may be key to the species' survival. The fungal pathogen that causes white-nose syndrome was inadvertently introduced in the northeastern United States in 2006 and is currently spreading across the continent. Thirteen species of North American bats are currently affected, with some populations experiencing losses of 90-100%. The disease is named for a distinctive fungal growth around the muzzles and on the wings of hibernating bats. The U-M team's study area is Michigan's northern Lower Peninsula and Upper Peninsula. White-nose syndrome fungus was first detected there in 2014, and its arrival allowed the researchers to study the pathogen's initial evolutionary impact. For the study, the U-M researchers collected tissue samples from dead little brown bats found in or near hibernation sites during the winter. The hibernation sites were concentrated in the western Upper Peninsula and primarily consisted of abandoned iron and copper mines. During the summer, they also collected small tissue samples from survivors that emerged successfully from hibernation despite exposure to the disease. Surviving bats had healing wing lesions or scars from the fungus. In the laboratory, DNA was extracted from the tissues and sequenced, and the sequences were mapped to a previously generated reference genome for the species. A genome scan was conducted to test for evidence of evolutionary changes in response to white-nose syndrome. The researchers found significant differences in three genes associated with arousal from hibernation (GABARB1), breakdown of fats (cGMP-PK1) and echolocation (FOXP2), as well as a fourth gene (PLA2G7) that regulates the release of histamines from mast cells. \"The function of one gene we identified hints that summer activities such as hunting via echolocation may be an important determinant of which individuals survive the winter infection period,\" Auteri said. \"This suggests that conservation of summer foraging habitat—not just winter hibernation sites—may promote population recovery in bats affected by white-nose syndrome.\" The observed genetic differences are suggestive of very rapid—though not unprecedented—evolutionary adaptation driven by natural selection, according to Auteri and Knowles. \"This apparent adaptation occurred very quickly, involves genes with a variety of functions which likely act across seasons in order to contribute to survivorship, and has taken place despite an observable reduction in genetic diversity associated with population declines,\" said Knowles, a professor in the Department of Ecology and Evolutionary Biology and a curator at the U-M Museum of Zoology. Auteri and Knowles said it's too soon to say how the evolutionary changes they uncovered are likely to affect the little brown bat's prospects. After all, these bats have suffered dramatic population declines, and low population sizes inherently make a species more vulnerable to further perturbations. \"But we're finding the hint that there could be these genetic changes that are occurring that might provide some type of survival in the future,\" Knowles said. \"So as these variants increase, there's some hope that these bats are not all going to die from the disease itself.\" Because little brown bats only have one pup per year, recovery of the species would likely take a long time, according to Auteri and Knowles. Due to population losses, little brown bats have been listed as endangered by the International Union for Conservation of Nature and by the federal government of Canada, with a similar decision by the U.S. government pending. ", "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 degree to which species can rapidly adapt is key to survival in the face of climatic and other anthropogenic changes. For little brown bats ( Myotis lucifugus ), whose populations have experienced declines of over 90% because of the introduced fungal pathogen that causes white-nose syndrome (WNS), survival of the species may ultimately depend upon its capacity for adaptive change. Here, we present evidence of selectively driven change (adaptation), despite dramatic nonadaptive genomic shifts (genetic drift) associated with population declines. We compared the genetic makeups of wild survivors versus non-survivors of WNS, and found significant shifts in allele frequencies of genes associated with regulating arousal from hibernation (GABARB1), breakdown of fats (cGMP-PK1), and vocalizations (FOXP2). Changes at these genes are suggestive of evolutionary adaptation, given that WNS causes bats to arouse with unusual frequency from hibernation, contributing to premature depletion of fat reserves. However, whether these putatively adaptive shifts in allele frequencies translate into sufficient increases in survival for the species to rebound in the face of WNS is unknown. Introduction Events that kill large portions of populations, including naturally and anthropogenically induced disasters, increasingly threaten biodiversity 1 , 2 . Invasive species are a major trigger of these declines 3 , including invasive pathogens, against which native species can experience high mortality due to a lack of co-evolutionary defenses 4 , 5 , 6 . Introduced fungal pathogens can be particularly dangerous—they can frequently survive in the environment for extended periods, affect a relatively broad range of hosts, and can be highly virulent 7 , thereby driving mass-mortalities of native species (e.g. amphibian chytrid 8 , snake fungal disease 9 , sea fan aspergillosis 10 , and others 11 , 12 , 13 ) as well as threatening agricultural crops 14 , 15 (e.g. rice blast disease 16 and Fusarium wilt in bananas 17 ). Although host mortalities may have little impact on fungal pathogens, the pathogens can exert incredibly strong selective pressures on their host populations 18 . A pressing conservation question is whether host populations can evolve resistance or tolerance during such epidemics—a necessary first step towards preventing extinction. Strong selective pressures might theoretically lead to an evolutionary rescue effect if host populations adapt 19 . However, acute events that kill off most members of a species also reduce the genetic diversity upon which natural selection can act, thereby limiting the capacity for adaptive change 20 . White-nose syndrome (WNS) is a disease affecting bats, which is caused by the invasive fungus Pseudogymnoascus destructans 21 . This highly destructive pathogen has decimated populations of bats, with 12 North American species currently affected 22 , and some populations experiencing losses of 90–100% 23 . The fungus was first inadvertently introduced to North America by humans in 2006 (in the northeastern U.S.) 24 , and is spreading across the continent, largely via infected bats 25 . The exact mechanism of death is not known, but bats apparently die from secondary physiological complications (e.g. depleted fat reserves) associated with too frequent arousals from hibernation 26 . Here, we conduct a genome scan to test for evidence of evolutionary changes in little brown bats ( Myotis lucifugus ) in response to WNS. The recent expansion of the fungus into our study area in 2014 combined with the staggering impact of WNS on the local population (roughly 78%) 27 provides an opportunity to study the initial evolutionary effects of this pathogen, which continues to spread throughout the continent. Eurasian bats within the genus Myotis —in the native range of the pathogen—tolerate fungal growths with no noticeable mortality 28 , 29 . In contrast, little brown bats were the most common bats in eastern North America prior to WNS, but due to population losses, the species has now been listed as endangered by the IUCN 30 and the federal government of Canada 31 , with a similar decision by the U.S. government pending 32 . Despite large observed declines, some individuals may have greater genetic-based tolerance or resistance to the disease, raising the potential for adaptive change in little brown bats via selective forces acting on standing genetic variation. However, dramatic population losses may confound the effectiveness of selection or purge potential adaptive variants via genetic drift. Information about these evolutionary processes can help inform the tempo and pace of management efforts for this species, by indicating which, if any, populations are adapting to the pathogen and what traits may be important for survival. Results In our tests for evolutionary changes in little brown bats, we compared the genetic makeup of “survivors” and “non-survivors” of the disease (see Fig. 1 ) in a genome-wide survey of 19,797 single nucleotide polymorphisms (SNPs) among 14,345 loci (140 bp segments) generated from a reduced representation library (ddRadSeq 33 ). We detected the effects of stochastic, non-adaptive genomic changes in otherwise neutral portions of the genome (genetic drift) reflective of the large numbers that have died from WNS in this species. Nevertheless, we also identified genetic changes (based on F ST -outlier analyses) that may have contributed to survival (as opposed to changes simply due to strong genetic drift), where the signature of selection can be detected by levels of genetic differentiation at a gene that exceeds background levels across the genome 34 , 35 . See methods for more details. Figure 1 Sampling locations of little brown bats. ( A ) Sequenced survivors ( n = 9, marked by stars) and non-survivors ( n = 29, crosses), jittered around similar collection sites (black dots); the size of the symbol indicates relative differences in the number of samples per site (see Table S1 for details). Survivors undertake short-distance migrations away from hibernacula in spring, which is reflected in their scattered collection locations. Non-survivors are closely associated with underground hibernation sites, with most ( B ) collected within hibernacula (~26 carcasses marked by circles on the floor of a mine), although some ( C ) leave these sites prematurely, like these dead bats on the outer<|im_end|> <|im_start|>assistant A new study from University of Michigan biologists presents the first genetic evidence of resistance in some bats to white-nose syndrome, a deadly fungal disease that has decimated some North American bat populations. The study involved northern Michigan populations of the little brown bat, one of the most common bats in eastern North America prior to the arrival of white-nose syndrome in 2006. Since then, some populations of the small, insect-eating bat have experienced declines of more than 90%. U-M researchers collected tissue samples from wild little brown bats that survived the disease, as well as individuals killed by the fungal pathogen. They compared the genetic makeup of the two groups and found differences in genes associated with regulating arousal from hibernation, the breakdown of fats and echolocation. "Because we found differences in genes associated with regulating hibernation and breakdown of fats, it could be that bats that are genetically predisposed to be a little bit fatter or to sleep more deeply are less susceptible to the disease," said U-M's Giorgia Auteri, first author of a paper scheduled for publication Feb. 20 in the journal Scientific Reports. "Changes at these genes are suggestive of evolutionary adaptation, given that white-nose syndrome causes bats to arouse with unusual frequency from winter hibernation, contributing to premature depletion of fat reserves," said Auteri, a doctoral student in the Department of Ecology and Evolutionary Biology who conducted the study for her dissertation. The other author of the Scientific Reports paper is U-M biologist Lacey Knowles, Auteri's faculty adviser. While the study was small—involving tissue samples from 25 little brown bats killed by white-nose syndrome and nine bats that survived the disease—the authors say their sample size is large enough to detect genetic changes driven by natural selection. A larger follow-up study is underway, expanding both the number of bats and the areas affected by the disease, to develop a fuller picture of adaptive change that may be key to the species' survival. The fungal pathogen that causes white-nose syndrome was inadvertently introduced in the northeastern United States in 2006 and is currently spreading across the continent. Thirteen species of North American bats are currently affected, with some populations experiencing losses of 90-100%. The disease is named for a distinctive fungal growth around the muzzles and on the wings of hibernating bats. The U-M team's study area is Michigan's northern Lower Peninsula and Upper Peninsula. White-nose syndrome fungus was first detected there in 2014, and its arrival allowed the researchers to study the pathogen's initial evolutionary impact. For the study, the U-M researchers collected tissue samples from dead little brown bats found in or near hibernation sites during the winter. The hibernation sites were concentrated in the western Upper Peninsula and primarily consisted of abandoned iron and copper mines. During the summer, they also collected small tissue samples from survivors that emerged successfully from hibernation despite exposure to the disease. Surviving bats had healing wing lesions or scars from the fungus. In the laboratory, DNA was extracted from the tissues and sequenced, and the sequences were mapped to a previously generated reference genome for the species. A genome scan was conducted to test for evidence of evolutionary changes in response to white-nose syndrome. The researchers found significant differences in three genes associated with arousal from hibernation (GABARB1), breakdown of fats (cGMP-PK1) and echolocation (FOXP2), as well as a fourth gene (PLA2G7) that regulates the release of histamines from mast cells. "The function of one gene we identified hints that summer activities such as hunting via echolocation may be an important determinant of which individuals survive the winter infection period," Auteri said. "This suggests that conservation of summer foraging habitat—not just winter hibernation sites—may promote population recovery in bats affected by white-nose syndrome." The observed genetic differences are suggestive of very rapid—though not unprecedented—evolutionary adaptation driven by natural selection, according to Auteri and Knowles. "This apparent adaptation occurred very quickly, involves genes with a variety of functions which likely act across seasons in order to contribute to survivorship, and has taken place despite an observable reduction in genetic diversity associated with population declines," said Knowles, a professor in the Department of Ecology and Evolutionary Biology and a curator at the U-M Museum of Zoology. Auteri and Knowles said it's too soon to say how the evolutionary changes they uncovered are likely to affect the little brown bat's prospects. After all, these bats have suffered dramatic population declines, and low population sizes inherently make a species more vulnerable to further perturbations. "But we're finding the hint that there could be these genetic changes that are occurring that might provide some type of survival in the future," Knowles said. "So as these variants increase, there's some hope that these bats are not all going to die from the disease itself." Because little brown bats only have one pup per year, recovery of the species would likely take a long time, according to Auteri and Knowles. Due to population losses, little brown bats have been listed as endangered by the International Union for Conservation of Nature and by the federal government of Canada, with a similar decision by the U.S. government pending. <|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 model of particle physics is remarkably successful because it is consistent with (almost) all experimental results. However, it fails to explain dark matter, dark energy and the imbalance between matter and antimatter in the Universe. Because discrepancies between standard-model predictions and experimental observations may provide evidence of new physics, an accurate evaluation of these predictions requires highly precise values of the fundamental physical constants. Among them, the fine-structure constant α is of particular importance because it sets the strength of the electromagnetic interaction between light and charged elementary particles, such as the electron and the muon. Here we use matter-wave interferometry to measure the recoil velocity of a rubidium atom that absorbs a photon, and determine the fine-structure constant α −1 = 137.035999206(11) with a relative accuracy of 81 parts per trillion. The accuracy of eleven digits in α leads to an electron g factor 1 , 2 —the most precise prediction of the standard model—that has a greatly reduced uncertainty. Our value of the fine-structure constant differs by more than 5 standard deviations from the best available result from caesium recoil measurements 3 . Our result modifies the constraints on possible candidate dark-matter particles proposed to explain the anomalous decays of excited states of 8 Be nuclei 4 and paves the way for testing the discrepancy observed in the magnetic moment anomaly of the muon 5 in the electron sector 6 . Main The fine-structure constant α is the pillar of our system of fundamental constants. As the measure of the strength of the electromagnetic interaction in the low-energy limit, it has been measured using diverse physical phenomena: the quantum Hall effect, the Josephson effect, the atomic fine structure, atomic recoils and the electron magnetic moment anomaly 7 . Comparison of results across sub-fields of physics is a powerful test of the consistency between theory and experiment. In particular, the fine-structure constant is a crucial parameter for testing quantum electrodynamics (QED) and the standard model. This test relies on the comparison between the measured value of the electron gyromagnetic anomaly a e = ( g e − 2)/2 (where g e is the electron g factor) and its theoretical value. The standard-model prediction a e , SM is dominated by the QED term given by a perturbation series of α /π, and contains additional contributions from hadronic and weak interactions. Numerical and analytical evaluations of the coefficients of the QED series are firmly established up to the eighth order, and the accuracy of the tenth order has been improved over the past years 1 , 2 , 8 . Assuming that the prediction of the standard model is correct, comparison of the theory with the most accurate measurement of the electron magnetic moment 9 leads to a value of the fine-structure constant with a relative accuracy of 2.4 × 10 −10 dominated by experimental precision 9 (see Fig. 1 ). Fig. 1: Precision measurements of the fine-structure constant. Comparison of most precise determinations of the fine-structure constant so far. The red points are from g e − 2 measurements and QED calculations, and the green and blue points are obtained from measurements of caesium and rubidium atomic recoils, respectively. Errors bars correspond to ±1 σ uncertainty. Previous data are from ref. 34 (Washington 1987), ref. 10 (Stanford 2002), ref. 18 (LKB 2011), ref. 9 (Harvard 2008), ref. 2 (RIKEN 2019) and ref. 3 (Berkeley 2018). Inset, magnification of the most accurate values of the fine-structure constant. Full size image From a different point of view, to test the prediction of the standard model, we need independent measurements of α with a similar precision to evaluate a e , SM . The most successful independent approach is based on the measurement of the recoil velocity ( v r = ħk / m ) of an atom of mass m that absorbs a photon of momentum ħk (refs. 10 , 11 ). Here ħ is the reduced Planck constant ( ħ = h /(2π)) and k = 2π/ λ is the photon wave vector, where λ is the laser wavelength. Such a measurement yields the ratio h / m and then α via the relation $${\\alpha }^{2}=\\frac{2{R}_{\\infty }}{c}\\times \\frac{m}{{m}_{{\\rm{e}}}}\\times \\frac{h}{m}.$$ (1) The Rydberg constant R ∞ is determined from hydrogen spectroscopy with an accuracy of 1.9 parts per trillion (ppt; ). The atom-to-electron mass ratio m / m e is obtained from the ratio of the relative atomic mass of the atom A r ( m ) (known at 69 ppt for rubidium 12 , 13 ) and the relative atomic mass of the electron A r ( m e ) (known at 30 ppt) 14 . The speed of light in vacuum, c , has a fixed value. Here, we present a measurement of the recoil velocity on rubidium atoms. We measured h / m ( 87 Rb) = 4.59135925890(65) × 10 −9 m 2 s −1 . In the international system of units adopted in 2019, in which h has a fixed value, we obtain m ( 87 Rb) = 1.44316089776(21) × 10 −25 kg. This is the most accurate atomic mass measurement so far, to our knowledge. This results leads to a fine-structure constant α of $${\\alpha }^{-1}=137.035999206(11).$$ The uncertainty contribution from the ratio h / m ( 87 Rb) is 2.4 × 10 −11 (statistical) and 6.8 × 10 −11 (systematic). Our result improves the accuracy on α by a factor of 2.5 over the previous caesium recoil measurement 3 but, most notably, it reveals a 5.4 σ difference from this latest measurement. We built a dedicated experimental setup and implemented robust methods to control systematic effects. By accelerating atoms up to 6 m s −1 in 6 ms and using typical two-photon Raman transitions as beam splitters for the matter waves, we obtained a relative sensitivity on the recoil velocity of 0.6 ppb in 1 h of integration (0.3 ppb on α ). This sensitivity is more than three times better than that", "role": "user" }, { "content": "The validation and application of theories in physics require the measurement of universal values known as fundamental constants. A team of French researchers has just conducted the most accurate measurement to date of the fine-structure constant, which characterizes the strength of interaction between light and charged elementary particles, such as electrons. This value has just been determined with an accuracy of 11 significant digits; improving the precision of the previous measurement by a factor of 3. The scientists achieved such precision by enhancing their experimental set-up, in an effort to reduce inaccuracies and to control effects that can create perturbations of the measurement. The experiment involves cold rubidium atoms with a temperature approaching absolute zero. When they absorb photons, these atoms recoil at a velocity that depends on their mass. The highly precise measurement of this phenomenon helps to improve the knowledge of the fine-structure constant. These results, which will appear in Nature on 3 December, open new prospects for testing the Standard Model's theoretical predictions. The use of more accurate constants can help to answer fundamental questions, such as the origin of dark matter in the universe. ", "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 model of particle physics is remarkably successful because it is consistent with (almost) all experimental results. However, it fails to explain dark matter, dark energy and the imbalance between matter and antimatter in the Universe. Because discrepancies between standard-model predictions and experimental observations may provide evidence of new physics, an accurate evaluation of these predictions requires highly precise values of the fundamental physical constants. Among them, the fine-structure constant α is of particular importance because it sets the strength of the electromagnetic interaction between light and charged elementary particles, such as the electron and the muon. Here we use matter-wave interferometry to measure the recoil velocity of a rubidium atom that absorbs a photon, and determine the fine-structure constant α −1 = 137.035999206(11) with a relative accuracy of 81 parts per trillion. The accuracy of eleven digits in α leads to an electron g factor 1 , 2 —the most precise prediction of the standard model—that has a greatly reduced uncertainty. Our value of the fine-structure constant differs by more than 5 standard deviations from the best available result from caesium recoil measurements 3 . Our result modifies the constraints on possible candidate dark-matter particles proposed to explain the anomalous decays of excited states of 8 Be nuclei 4 and paves the way for testing the discrepancy observed in the magnetic moment anomaly of the muon 5 in the electron sector 6 . Main The fine-structure constant α is the pillar of our system of fundamental constants. As the measure of the strength of the electromagnetic interaction in the low-energy limit, it has been measured using diverse physical phenomena: the quantum Hall effect, the Josephson effect, the atomic fine structure, atomic recoils and the electron magnetic moment anomaly 7 . Comparison of results across sub-fields of physics is a powerful test of the consistency between theory and experiment. In particular, the fine-structure constant is a crucial parameter for testing quantum electrodynamics (QED) and the standard model. This test relies on the comparison between the measured value of the electron gyromagnetic anomaly a e = ( g e − 2)/2 (where g e is the electron g factor) and its theoretical value. The standard-model prediction a e , SM is dominated by the QED term given by a perturbation series of α /π, and contains additional contributions from hadronic and weak interactions. Numerical and analytical evaluations of the coefficients of the QED series are firmly established up to the eighth order, and the accuracy of the tenth order has been improved over the past years 1 , 2 , 8 . Assuming that the prediction of the standard model is correct, comparison of the theory with the most accurate measurement of the electron magnetic moment 9 leads to a value of the fine-structure constant with a relative accuracy of 2.4 × 10 −10 dominated by experimental precision 9 (see Fig. 1 ). Fig. 1: Precision measurements of the fine-structure constant. Comparison of most precise determinations of the fine-structure constant so far. The red points are from g e − 2 measurements and QED calculations, and the green and blue points are obtained from measurements of caesium and rubidium atomic recoils, respectively. Errors bars correspond to ±1 σ uncertainty. Previous data are from ref. 34 (Washington 1987), ref. 10 (Stanford 2002), ref. 18 (LKB 2011), ref. 9 (Harvard 2008), ref. 2 (RIKEN 2019) and ref. 3 (Berkeley 2018). Inset, magnification of the most accurate values of the fine-structure constant. Full size image From a different point of view, to test the prediction of the standard model, we need independent measurements of α with a similar precision to evaluate a e , SM . The most successful independent approach is based on the measurement of the recoil velocity ( v r = ħk / m ) of an atom of mass m that absorbs a photon of momentum ħk (refs. 10 , 11 ). Here ħ is the reduced Planck constant ( ħ = h /(2π)) and k = 2π/ λ is the photon wave vector, where λ is the laser wavelength. Such a measurement yields the ratio h / m and then α via the relation $${\alpha }^{2}=\frac{2{R}_{\infty }}{c}\times \frac{m}{{m}_{{\rm{e}}}}\times \frac{h}{m}.$$ (1) The Rydberg constant R ∞ is determined from hydrogen spectroscopy with an accuracy of 1.9 parts per trillion (ppt; ). The atom-to-electron mass ratio m / m e is obtained from the ratio of the relative atomic mass of the atom A r ( m ) (known at 69 ppt for rubidium 12 , 13 ) and the relative atomic mass of the electron A r ( m e ) (known at 30 ppt) 14 . The speed of light in vacuum, c , has a fixed value. Here, we present a measurement of the recoil velocity on rubidium atoms. We measured h / m ( 87 Rb) = 4.59135925890(65) × 10 −9 m 2 s −1 . In the international system of units adopted in 2019, in which h has a fixed value, we obtain m ( 87 Rb) = 1.44316089776(21) × 10 −25 kg. This is the most accurate atomic mass measurement so far, to our knowledge. This results leads to a fine-structure constant α of $${\alpha }^{-1}=137.035999206(11).$$ The uncertainty contribution from the ratio h / m ( 87 Rb) is 2.4 × 10 −11 (statistical) and 6.8 × 10 −11 (systematic). Our result improves the accuracy on α by a factor of 2.5 over the previous caesium recoil measurement 3 but, most notably, it reveals a 5.4 σ difference from this latest measurement. We built a dedicated experimental setup and implemented robust methods to control systematic effects. By accelerating atoms up to 6 m s −1 in 6 ms and using typical two-photon Raman transitions as beam splitters for the matter waves, we obtained a relative sensitivity on the recoil velocity of 0.6 ppb in 1 h of integration (0.3 ppb on α ). This sensitivity is more than three times better than that<|im_end|> <|im_start|>assistant The validation and application of theories in physics require the measurement of universal values known as fundamental constants. A team of French researchers has just conducted the most accurate measurement to date of the fine-structure constant, which characterizes the strength of interaction between light and charged elementary particles, such as electrons. This value has just been determined with an accuracy of 11 significant digits; improving the precision of the previous measurement by a factor of 3. The scientists achieved such precision by enhancing their experimental set-up, in an effort to reduce inaccuracies and to control effects that can create perturbations of the measurement. The experiment involves cold rubidium atoms with a temperature approaching absolute zero. When they absorb photons, these atoms recoil at a velocity that depends on their mass. The highly precise measurement of this phenomenon helps to improve the knowledge of the fine-structure constant. These results, which will appear in Nature on 3 December, open new prospects for testing the Standard Model's theoretical predictions. The use of more accurate constants can help to answer fundamental questions, such as the origin of dark matter in the universe. <|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 Use of immune checkpoint inhibitors that target programmed cell death-1 (PD-1) can lead to various autoimmune-related adverse events (irAEs) including psoriasis-like dermatitis. Our observations on human samples indicated enhanced epidermal infiltration of CD8 T cells, and the pathogenesis of which appears to be dependent on IL-6 in the PD-1 signal blockade-induced psoriasis-like dermatitis. By using a murine model of imiquimod-induced psoriasis-like dermatitis, we further demonstrated that PD-1 deficiency accelerates skin inflammation with activated cytotoxic CD8 T cells into the epidermis, which engage in pathogenic cross-talk with keratinocytes resulting in production of IL-6. Moreover, genetically modified mice lacking PD-1 expression only on CD8 T cells developed accelerated dermatitis, moreover, blockade of IL-6 signaling by anti-IL-6 receptor antibody could ameliorate the dermatitis. Collectively, PD-1 signal blockade-induced psoriasis-like dermatitis is mediated by PD-1 signaling on CD8 T cells, and furthermore, IL-6 is likely to be a therapeutic target for the dermatitis. Introduction For cancer immune therapies that regulate T cells to enhance immune responses, T cells must successfully recognize tumor antigens through their T-cell receptors (TCRs) and become activated in order to expel tumors 1 , 2 . In addition, a number of stimulatory and inhibitory receptor and ligand pairs expressed on T cells, antigen-presenting cells (APCs) or tumor cells, termed immune checkpoints, also play crucial roles for both T cell activation and inhibition 3 . Programmed cell death-1 (PD-1) is one of these immune checkpoint molecules, which was initially detected in activated murine T cells upon TCR engagement 4 and subsequently in exhausted T cells 5 . Its ligands, programmed cell death-ligand 1 (PD-L1) and PD-L2, are expressed on various cell types, including hematopoietic cells infiltrating tumors, including APCs, and on non-hematopoietic cells such as cancer cells 6 , 7 . The interaction between PD-1 and its ligands reduces T cell function by inducing exhaustion, apoptosis, anergy, and downregulation of cytokine production by T cells, leading to suppression of the antitumor immune response 8 , 9 . In melanoma, PD-1 expression is detected on tumor-infiltrating lymphocytes including tumor antigen–specific T cells, which are functionally impaired. Moreover, the biological activity of these cells can be partially recovered by inhibiting the PD-1 pathway 10 , 11 , 12 . Indeed, anti-PD-1 blocking antibodies such as nivolumab and pembrolizumab function as immune checkpoint inhibitors, and have proven effective for the treatment of melanoma 13 , 14 . However, as the PD-1 pathway also maintains peripheral T cell tolerance and regulates inflammation 15 , inhibition of this pathway may lead to autoimmune manifestations referred to as immune-related adverse events (irAEs) 16 , 17 . Early clinical trials and reviews have reported that anti-PD-1 antibody-related irAEs occur in more than 70% of patients, and cutaneous irAEs are the most frequently observed (approximately 40%). Further, most cutaneous irAEs are mild (low-grade) and manageable with topical steroids 16 , 18 , 19 , 20 , 21 . On the other hand, it has also been recently reported that two-thirds of patients with cutaneous irAEs reportedly required systemic corticosteroids for the treatment of eruptions, and 19% of patients discontinued cancer-immunotherapy due to irAEs, even though 75% experienced antitumor responses with the therapy 22 . High-dose and/or long-term use of systemic immunosuppressive therapies are required to control such irAEs 23 , potentially resulting in prolonged interruption of cancer treatment. Moreover, these immunosuppressive therapies may also abrogate the antitumor response by counteracting lymphocyte activation 20 , 24 . Therefore, more efficacious, systemic therapies that resolve the symptoms of irAEs while also enabling shorter interruptions of cancer treatments and do not interfere with their antitumor effects would be ideal. In addition, a recent American Society of Clinical Oncology guideline suggests that cutaneous irAEs are increasingly recognized as a contributing factor to treatment noncompliance, discontinuation, or dose modification 24 . Plausibly, such skin manifestations cause changes in appearance along with discomfort, which reduces patient quality of life and results in loss of treatment motivation. We previously reported a case of nivolumab-induced psoriasis-like dermatitis 25 , which has been reported to develop in patients treated with anti-PD-1/PD-L1 antibody 25 , 26 . The latest post-marketing surveillance of nivolumab in Japan reports that 2,391 cases of cutaneous irAE occurred, of which 103 cases (4.3 %) were labeled as psoriasis. Notably, more than 18% (19 /103) of those cases were reportedly severe 27 . Importantly, the mechanism by which psoriasis-like dermatitis occurs following PD-1/PD-L1 inhibition remains unknown, and strategies to mitigate the occurrence of especially severe cases are yet to be identified. With the recent increase in use of anti-PD-1 antibody for patients with various types of cancers, clarification of the underlying mechanisms and development of more efficacious treatment for PD-1 signal blockade-induced psoriasis-like dermatitis is needed. Application of imiquimod (IMQ), a toll-like receptor 7/8 agonist, is known to induce psoriasis-like dermatitis in both humans 28 and mice 29 . Furthermore, it has already been reported that both PD-1 genetic deficiency and blockade of PD-1 with a specific monoclonal antibody exacerbate IMQ-induced psoriasis-like dermatitis in mice 30 . Therefore, it is likely that the pathophysiological mechanism of PD-1 signal blockade-induced psoriasis-like dermatitis could be elucidated using this murine model. The present study aimed to elucidate the characteristics and mechanisms underlying psoriasis-like dermatitis induced by blocking PD-1 signaling, and to identify suitable treatments. The observations from human samples and further experiments using a preclinical murine model of IMQ-induced psoriasis-like dermatitis demonstrated that the dermatitis was accelerated by an increase of skin-infiltrating activated, cytotoxic CD8 T cells allowing pathogenic crosstalk with keratinocytes and subsequent production of IL-6. Moreover, blockade of interleukin (IL)-6 signaling by anti-IL-6 receptor blocking antibody (MR16-1) restrained the PD-1 signal blockade provoked by severe dermatitis by inhibiting both Th17 cell differentiation and cytotoxic CD8 T cell activation. Thus, this highlights the significance of IL-6 blockade therapy specifically for the regulation of PD-1 signal blockade-induced dermatitis. Results Increased CD8/CD4 ratio of epidermal-infiltrating lymphocytes in cases of anti-PD-1 antibody-induced psoriasis-like dermatitis compared to cases of idiopathic psoriasis Immunohistochemical (IHC) evaluation of skin biopsy samples, as demonstrated in", "role": "user" }, { "content": "Using the body's immune system to fight cancer has great potential, but can also bring serious side effects, including itchy and painful skin reactions. But now, researchers from Japan have found how these skin reactions happen, potentially leading to a way to prevent them. In a study published this month in Communications Biology, researchers from the University of Tsukuba have determined that one unpleasant side effect of immunotherapy with PD-1 inhibitors, called \"anti-PD-1 antibody-induced psoriasis-like dermatitis,\" is caused by inflammation resulting from high levels of a specific protein. Cancer immunotherapies work through a process that allows the body's T cells to recognize and attack cancers. But because these same processes regulate inflammation, things can get out of balance. Therapies targeting PD-1 often lead to side effects called immune-related adverse events (irAEs), which happen in more than 70% of patients who take them. The most common of these is a skin reaction, and while some of these are mild and can be easily treated with steroid creams, other patients have itchy, painful, or scaly rashes requiring more intensive treatment. Nearly a fifth of patients receiving immunotherapy stop taking the treatment because of irAEs—even though the treatment may be working well against their cancer. \"Inhibition of the PD-1 pathway is becoming front-line treatment for more and more cancers,\" says senior author Professor Naoko Okiyama. \"But it can't work if patients experience adverse events and discontinue treatment because of them. We hoped that by finding out exactly how PD-1 inhibitors cause dermatitis, we could also find a way to stop it.\" The new study builds on earlier research from the same team, who examined blood samples from cancer patients with this side effect, finding high levels of a cell signaling protein called IL-6. Testing this theoretical connection in mice, they found that PD-1 deficiency increased numbers of a specific type of white blood cells (called CD8 T cells) infiltrating the epidermis. CD8 T cells help the immune system kill viruses and bacteria as well as cancer cells. But when activated in large numbers, they can cause an excessive immune response leading to irAEs. The experiments in mice showed that PD-1 expressed on CD8 T cells regulates skin inflammation. The mice with PD-1 deficiency had high levels of IL-6 expression and subsequently developed dermatitis. As a final step, the researchers used an antibody to block IL-6 signaling in some of these mice—and those mice developed significantly less dermatitis than the control group. \"Altogether, the results clearly show the efficacy of targeting IL-6 in mice,\" explains Professor Okiyama. \"With further study in humans, we may have a potential approach to resolving PD-1-related dermatitis.\" On the basis of these results, the researchers also propose that blockade of both IL-6 and PD-1 together could have an even better combined anti-cancer effect, though this has not yet been systematically studied. It's also unknown whether the approach will work as well in people as it does in mice. \"Our most striking finding is the importance of PD-1 expression on CD8 T cells in the development of dermatitis, showing real potential of IL-6 as a target for therapeutic intervention,\" says Professor Okiyama. \"But the hope is that we can implement this combined strategy without compromising the anti-tumor effects of the anti-PD-1 therapy.\" Immunotherapies for cancer treatment are still relatively new; therefore, limited information is available on their long-term side effects in comparison with older chemotherapy treatments. As increasing numbers of cancer patients are treated with anti-PD-1 immunotherapy, it will be ever more important to identify strategies to prevent or lessen these adverse events. ", "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 Use of immune checkpoint inhibitors that target programmed cell death-1 (PD-1) can lead to various autoimmune-related adverse events (irAEs) including psoriasis-like dermatitis. Our observations on human samples indicated enhanced epidermal infiltration of CD8 T cells, and the pathogenesis of which appears to be dependent on IL-6 in the PD-1 signal blockade-induced psoriasis-like dermatitis. By using a murine model of imiquimod-induced psoriasis-like dermatitis, we further demonstrated that PD-1 deficiency accelerates skin inflammation with activated cytotoxic CD8 T cells into the epidermis, which engage in pathogenic cross-talk with keratinocytes resulting in production of IL-6. Moreover, genetically modified mice lacking PD-1 expression only on CD8 T cells developed accelerated dermatitis, moreover, blockade of IL-6 signaling by anti-IL-6 receptor antibody could ameliorate the dermatitis. Collectively, PD-1 signal blockade-induced psoriasis-like dermatitis is mediated by PD-1 signaling on CD8 T cells, and furthermore, IL-6 is likely to be a therapeutic target for the dermatitis. Introduction For cancer immune therapies that regulate T cells to enhance immune responses, T cells must successfully recognize tumor antigens through their T-cell receptors (TCRs) and become activated in order to expel tumors 1 , 2 . In addition, a number of stimulatory and inhibitory receptor and ligand pairs expressed on T cells, antigen-presenting cells (APCs) or tumor cells, termed immune checkpoints, also play crucial roles for both T cell activation and inhibition 3 . Programmed cell death-1 (PD-1) is one of these immune checkpoint molecules, which was initially detected in activated murine T cells upon TCR engagement 4 and subsequently in exhausted T cells 5 . Its ligands, programmed cell death-ligand 1 (PD-L1) and PD-L2, are expressed on various cell types, including hematopoietic cells infiltrating tumors, including APCs, and on non-hematopoietic cells such as cancer cells 6 , 7 . The interaction between PD-1 and its ligands reduces T cell function by inducing exhaustion, apoptosis, anergy, and downregulation of cytokine production by T cells, leading to suppression of the antitumor immune response 8 , 9 . In melanoma, PD-1 expression is detected on tumor-infiltrating lymphocytes including tumor antigen–specific T cells, which are functionally impaired. Moreover, the biological activity of these cells can be partially recovered by inhibiting the PD-1 pathway 10 , 11 , 12 . Indeed, anti-PD-1 blocking antibodies such as nivolumab and pembrolizumab function as immune checkpoint inhibitors, and have proven effective for the treatment of melanoma 13 , 14 . However, as the PD-1 pathway also maintains peripheral T cell tolerance and regulates inflammation 15 , inhibition of this pathway may lead to autoimmune manifestations referred to as immune-related adverse events (irAEs) 16 , 17 . Early clinical trials and reviews have reported that anti-PD-1 antibody-related irAEs occur in more than 70% of patients, and cutaneous irAEs are the most frequently observed (approximately 40%). Further, most cutaneous irAEs are mild (low-grade) and manageable with topical steroids 16 , 18 , 19 , 20 , 21 . On the other hand, it has also been recently reported that two-thirds of patients with cutaneous irAEs reportedly required systemic corticosteroids for the treatment of eruptions, and 19% of patients discontinued cancer-immunotherapy due to irAEs, even though 75% experienced antitumor responses with the therapy 22 . High-dose and/or long-term use of systemic immunosuppressive therapies are required to control such irAEs 23 , potentially resulting in prolonged interruption of cancer treatment. Moreover, these immunosuppressive therapies may also abrogate the antitumor response by counteracting lymphocyte activation 20 , 24 . Therefore, more efficacious, systemic therapies that resolve the symptoms of irAEs while also enabling shorter interruptions of cancer treatments and do not interfere with their antitumor effects would be ideal. In addition, a recent American Society of Clinical Oncology guideline suggests that cutaneous irAEs are increasingly recognized as a contributing factor to treatment noncompliance, discontinuation, or dose modification 24 . Plausibly, such skin manifestations cause changes in appearance along with discomfort, which reduces patient quality of life and results in loss of treatment motivation. We previously reported a case of nivolumab-induced psoriasis-like dermatitis 25 , which has been reported to develop in patients treated with anti-PD-1/PD-L1 antibody 25 , 26 . The latest post-marketing surveillance of nivolumab in Japan reports that 2,391 cases of cutaneous irAE occurred, of which 103 cases (4.3 %) were labeled as psoriasis. Notably, more than 18% (19 /103) of those cases were reportedly severe 27 . Importantly, the mechanism by which psoriasis-like dermatitis occurs following PD-1/PD-L1 inhibition remains unknown, and strategies to mitigate the occurrence of especially severe cases are yet to be identified. With the recent increase in use of anti-PD-1 antibody for patients with various types of cancers, clarification of the underlying mechanisms and development of more efficacious treatment for PD-1 signal blockade-induced psoriasis-like dermatitis is needed. Application of imiquimod (IMQ), a toll-like receptor 7/8 agonist, is known to induce psoriasis-like dermatitis in both humans 28 and mice 29 . Furthermore, it has already been reported that both PD-1 genetic deficiency and blockade of PD-1 with a specific monoclonal antibody exacerbate IMQ-induced psoriasis-like dermatitis in mice 30 . Therefore, it is likely that the pathophysiological mechanism of PD-1 signal blockade-induced psoriasis-like dermatitis could be elucidated using this murine model. The present study aimed to elucidate the characteristics and mechanisms underlying psoriasis-like dermatitis induced by blocking PD-1 signaling, and to identify suitable treatments. The observations from human samples and further experiments using a preclinical murine model of IMQ-induced psoriasis-like dermatitis demonstrated that the dermatitis was accelerated by an increase of skin-infiltrating activated, cytotoxic CD8 T cells allowing pathogenic crosstalk with keratinocytes and subsequent production of IL-6. Moreover, blockade of interleukin (IL)-6 signaling by anti-IL-6 receptor blocking antibody (MR16-1) restrained the PD-1 signal blockade provoked by severe dermatitis by inhibiting both Th17 cell differentiation and cytotoxic CD8 T cell activation. Thus, this highlights the significance of IL-6 blockade therapy specifically for the regulation of PD-1 signal blockade-induced dermatitis. Results Increased CD8/CD4 ratio of epidermal-infiltrating lymphocytes in cases of anti-PD-1 antibody-induced psoriasis-like dermatitis compared to cases of idiopathic psoriasis Immunohistochemical (IHC) evaluation of skin biopsy samples, as demonstrated in<|im_end|> <|im_start|>assistant Using the body's immune system to fight cancer has great potential, but can also bring serious side effects, including itchy and painful skin reactions. But now, researchers from Japan have found how these skin reactions happen, potentially leading to a way to prevent them. In a study published this month in Communications Biology, researchers from the University of Tsukuba have determined that one unpleasant side effect of immunotherapy with PD-1 inhibitors, called "anti-PD-1 antibody-induced psoriasis-like dermatitis," is caused by inflammation resulting from high levels of a specific protein. Cancer immunotherapies work through a process that allows the body's T cells to recognize and attack cancers. But because these same processes regulate inflammation, things can get out of balance. Therapies targeting PD-1 often lead to side effects called immune-related adverse events (irAEs), which happen in more than 70% of patients who take them. The most common of these is a skin reaction, and while some of these are mild and can be easily treated with steroid creams, other patients have itchy, painful, or scaly rashes requiring more intensive treatment. Nearly a fifth of patients receiving immunotherapy stop taking the treatment because of irAEs—even though the treatment may be working well against their cancer. "Inhibition of the PD-1 pathway is becoming front-line treatment for more and more cancers," says senior author Professor Naoko Okiyama. "But it can't work if patients experience adverse events and discontinue treatment because of them. We hoped that by finding out exactly how PD-1 inhibitors cause dermatitis, we could also find a way to stop it." The new study builds on earlier research from the same team, who examined blood samples from cancer patients with this side effect, finding high levels of a cell signaling protein called IL-6. Testing this theoretical connection in mice, they found that PD-1 deficiency increased numbers of a specific type of white blood cells (called CD8 T cells) infiltrating the epidermis. CD8 T cells help the immune system kill viruses and bacteria as well as cancer cells. But when activated in large numbers, they can cause an excessive immune response leading to irAEs. The experiments in mice showed that PD-1 expressed on CD8 T cells regulates skin inflammation. The mice with PD-1 deficiency had high levels of IL-6 expression and subsequently developed dermatitis. As a final step, the researchers used an antibody to block IL-6 signaling in some of these mice—and those mice developed significantly less dermatitis than the control group. "Altogether, the results clearly show the efficacy of targeting IL-6 in mice," explains Professor Okiyama. "With further study in humans, we may have a potential approach to resolving PD-1-related dermatitis." On the basis of these results, the researchers also propose that blockade of both IL-6 and PD-1 together could have an even better combined anti-cancer effect, though this has not yet been systematically studied. It's also unknown whether the approach will work as well in people as it does in mice. "Our most striking finding is the importance of PD-1 expression on CD8 T cells in the development of dermatitis, showing real potential of IL-6 as a target for therapeutic intervention," says Professor Okiyama. "But the hope is that we can implement this combined strategy without compromising the anti-tumor effects of the anti-PD-1 therapy." Immunotherapies for cancer treatment are still relatively new; therefore, limited information is available on their long-term side effects in comparison with older chemotherapy treatments. As increasing numbers of cancer patients are treated with anti-PD-1 immunotherapy, it will be ever more important to identify strategies to prevent or lessen these adverse events. <|im_end|>
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2,322
[ { "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 Biochemical circuits made of rationally designed DNA molecules are proofs of concept for embedding control within complex molecular environments. They hold promise for transforming the current technologies in chemistry, biology, medicine and material science by introducing programmable and responsive behaviour to diverse molecular systems. As the transformative power of a technology depends on its accessibility, two main challenges are an automated design process and simple experimental procedures. Here we demonstrate the use of circuit design software, combined with the use of unpurified strands and simplified experimental procedures, for creating a complex DNA strand displacement circuit that consists of 78 distinct species. We develop a systematic procedure for overcoming the challenges involved in using unpurified DNA strands. We also develop a model that takes synthesis errors into consideration and semi-quantitatively reproduces the experimental data. Our methods now enable even novice researchers to successfully design and construct complex DNA strand displacement circuits. Introduction The success of computer engineering has inspired attempts to use hierarchical and systematic approaches for developing molecular devices with increasing complexity. To enable the design and construction of a wide range of functional molecular systems, we need software tools such as a compiler that can automatically translate high-level functions to low-level molecular implementations and provide models and simulations for predicting and debugging the behaviours of designed molecular systems. The mechanism of DNA strand displacement has been used to create a variety of synthetic molecular systems including circuits, motors and triggered assembly of structures 1 . Software tools have been developed for designing and analysing DNA strand displacement systems, capable of generating nucleic acid sequences from well-defined structures and molecular interactions 2 , 3 , calculating the thermodynamic 2 , 4 , 5 and kinetic 6 properties of designed molecules, and evaluating if the behaviours of the molecular systems agree with the higher-level designs 3 , 7 , 8 , 9 , 10 , 11 . There also exist a few molecular compilers that can translate abstract functions such as a logic function to DNA strand displacement implementations without requiring an understanding of the molecular level details 12 , 13 . However, there has been little independent experimental validation of these compilers, most of which were developed in parallel with or after experimental findings 12 , 14 . In addition to software tools that facilitate automated design and analysis of DNA strand displacement circuits, we also need to simplify the experimental procedures for creating these circuits in vitro , so that it is possible for researchers with diverse backgrounds to build their own circuits and explore potential applications. A great inspiration is DNA origami 15 , a technique that folds DNA into sophisticated structures. In just 10 years since its birth, DNA origami has become one of the most significant successes in the field of DNA nanotechnology. Over 170 research groups have contributed to advancing this technique or developing it for applications in a variety of research areas 16 , 17 , 18 , 19 . A fundamental reason why DNA origami was able to quickly spread around the world is that the experimental procedure is extremely simple and makes use of cheap, unpurified nucleic-acid strands. In contrast, other than a few very simple circuits with just one or two double-stranded components 20 , most DNA strand displacement circuits were constructed using strands that were purchased either purified or unpurified, but all followed by in-house polyacrylamide gel electrophoresis (PAGE) purification to reduce undesired products due to synthesis errors and stoichiometry errors 12 , 14 , 21 . Purified strands are approximately ten times more expensive than unpurified strands, which significantly increases the cost for building large-scale DNA circuits. In-house PAGE purification is both time consuming and labour intensive. In this work, we show that one can successfully build a complex DNA strand displacement circuit, using DNA sequences automatically generated from a molecular compiler. We also show that one can even do so using cheap, unpurified DNA strands, following simple and systematic experimental procedures. Results Circuit design A simple DNA strand displacement motif called the seesaw gate was developed to scale up the complexity of DNA circuits 22 and was used to demonstrate digital logic computation 12 and neural network computation 23 . The Seesaw Compiler 12 , 24 was developed to automatically translate an arbitrary feed forward digital logic circuit into its equivalent seesaw DNA circuit ( Fig. 1 ). The compiler takes an input file that describes a logic circuit with a list of input and output terminals, and a list of AND, OR, NOT, NAND and NOR gates with the connectivity of their terminals specified. First, a technique called dual-rail logic is applied to translate the original logic circuit into an equivalent circuit that contains AND and OR gates only 25 . This is because the NOT gate cannot be directly implemented in multi-layer use-once DNA circuits, if the OFF and ON state of a signal is represented by low and high concentration of a single DNA strand, respectively. If a NOT gate were implemented this way, then output molecules of the gate could be immediately produced in the absence of input. However, once this reaction reaches equilibrium it cannot be reversed, even if input molecules are added at a later point. With dual-rail logic, each terminal in the original circuit is replaced by two terminals, representing the OFF and ON states of a signal separately (for example, each input signal x i is replaced by and ). Thus, no reaction will take place until signal molecules on one of the two wires have arrived. With this representation, the NOT gate can be implemented by exchanging the two wires of an input and output signal. Each AND, OR, NAND and NOR gate in the original circuit is replaced by a pair of AND and OR gates. Figure 1: Automated circuit design steps using the Seesaw Compiler. A feedforward digital logic circuit is first translated into an equivalent dual-rail logic circuit and then translated into an equivalent seesaw", "role": "user" }, { "content": "Electronic circuits are found in almost everything from smartphones to spacecraft and are useful in a variety of computational problems from simple addition to determining the trajectories of interplanetary satellites. At Caltech, a group of researchers led by Assistant Professor of Bioengineering Lulu Qian is working to create circuits using not the usual silicon transistors but strands of DNA. The Qian group has made the technology of DNA circuits accessible to even novice researchers—including undergraduate students—using a software tool they developed called the Seesaw Compiler. Now, they have experimentally demonstrated that the tool can be used to quickly design DNA circuits that can then be built out of cheap \"unpurified\" DNA strands, following a systematic wet-lab procedure devised by Qian and colleagues. A paper describing the work appears in the February 23 issue of Nature Communications. Although DNA is best known as the molecule that encodes the genetic information of living things, they are also useful chemical building blocks. This is because the smaller molecules that make up a strand of DNA, called nucleotides, bind together only with very specific rules—an A nucleotide binds to a T, and a C nucleotide binds to a G. A strand of DNA is a sequence of nucleotides and can become a double strand if it binds with a sequence of complementary nucleotides. DNA circuits are good at collecting information within a biochemical environment, processing the information locally and controlling the behavior of individual molecules. Circuits built out of DNA strands instead of silicon transistors can be used in completely different ways than electronic circuits. \"A DNA circuit could add 'smarts' to chemicals, medicines, or materials by making their functions responsive to the changes in their environments,\" Qian says. \"Importantly, these adaptive functions can be programmed by humans.\" To build a DNA circuit that can, for example, compute the square root of a number between 0 and 16, researchers first have to carefully design a mixture of single and partially double-stranded DNA that can chemically recognize a set of DNA strands whose concentrations represent the value of the original number. Mixing these together triggers a cascade of zipping and unzipping reactions, each reaction releasing a specific DNA strand upon binding. Once the reactions are complete, the identities of the resulting DNA strands reveal the answer to the problem. With the Seesaw Compiler, a researcher could tell a computer the desired function to be calculated and the computer would design the DNA sequences and mixtures needed. However, it was not clear how well these automatically designed DNA sequences and mixtures would work for building DNA circuits with new functions; for example, computing the rules that govern how a cell evolves by sensing neighboring cells. \"Constructing a circuit made of DNA has thus far been difficult for those who are not in this research area, because every circuit with a new function requires DNA strands with new sequences and there are no off-the-shelf DNA circuit components that can be purchased,\" says Chris Thachuk, senior postdoctoral scholar in computing and mathematical sciences and second author on the paper. \"Our circuit-design software is a step toward enabling researchers to just type in what they want to do or compute and having the software figure out all the DNA strands needed to perform the computation, together with simulations to predict the DNA circuit's behavior in a test tube. Even though these DNA strands are still not off-the-shelf products, we have now shown that they do work well for new circuits with user-designed functions.\" \"In the 1950s, only a few research labs that understood the physics of transistors could build early versions of electronic circuits and control their functions,\" says Qian. \"But today many software tools are available that use simple and human-friendly languages to design complex electronic circuits embedded in smart machines. Our software is kind of like that: it translates simple and human-friendly descriptions of computation to the design of complex DNA circuits.\" The Seesaw Compiler was put to the test in 2015 in a unique course at Caltech, taught by Qian and called \"Design and Construction of Programmable Molecular Systems\" (BE/CS 196 ab). \"How do you evaluate the accessibility of a new technology? You give the technology to someone who is intellectually capable but has minimal prior background,\" Qian says. \"The students in this class were undergrads and first-year graduate students majoring in computer science and bioengineering,\" says Anupama Thubagere, a graduate student in biology and bioengineering and first author on the paper. \"I started working with them as a head teaching assistant and together we soon discovered that using the Seesaw Compiler to design a DNA circuit was easy for everyone.\" However, building the designed circuit in the wet lab was not so simple. Thus, with continued efforts after the class, the group set out to develop a systematic wet-lab procedure that could guide researchers—even novices like undergraduate students—through the process of building DNA circuits. \"Fortunately, we found a general solution to every challenge that we encountered, now making it easy for everyone to build their own DNA circuits,\" Thubagere says. The group showed that it was possible to use cheap, \"unpurified\" DNA strands in these circuits using the new process. This was only possible because steps in the systematic wet-lab procedure were designed to compensate for the lower synthesis quality of the DNA strands. \"We hope that this work will convince more computer scientists and researchers from other fields to join our community in developing increasingly powerful molecular machines and to explore a much wider range of applications that will eventually lead to the transformation of technology that has been promised by the invention of molecular computers,\" Qian says. The paper is titled, \"Compiler-aided systematic construction of large-scale DNA strand displacement circuits using unpurified components.\" ", "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 Biochemical circuits made of rationally designed DNA molecules are proofs of concept for embedding control within complex molecular environments. They hold promise for transforming the current technologies in chemistry, biology, medicine and material science by introducing programmable and responsive behaviour to diverse molecular systems. As the transformative power of a technology depends on its accessibility, two main challenges are an automated design process and simple experimental procedures. Here we demonstrate the use of circuit design software, combined with the use of unpurified strands and simplified experimental procedures, for creating a complex DNA strand displacement circuit that consists of 78 distinct species. We develop a systematic procedure for overcoming the challenges involved in using unpurified DNA strands. We also develop a model that takes synthesis errors into consideration and semi-quantitatively reproduces the experimental data. Our methods now enable even novice researchers to successfully design and construct complex DNA strand displacement circuits. Introduction The success of computer engineering has inspired attempts to use hierarchical and systematic approaches for developing molecular devices with increasing complexity. To enable the design and construction of a wide range of functional molecular systems, we need software tools such as a compiler that can automatically translate high-level functions to low-level molecular implementations and provide models and simulations for predicting and debugging the behaviours of designed molecular systems. The mechanism of DNA strand displacement has been used to create a variety of synthetic molecular systems including circuits, motors and triggered assembly of structures 1 . Software tools have been developed for designing and analysing DNA strand displacement systems, capable of generating nucleic acid sequences from well-defined structures and molecular interactions 2 , 3 , calculating the thermodynamic 2 , 4 , 5 and kinetic 6 properties of designed molecules, and evaluating if the behaviours of the molecular systems agree with the higher-level designs 3 , 7 , 8 , 9 , 10 , 11 . There also exist a few molecular compilers that can translate abstract functions such as a logic function to DNA strand displacement implementations without requiring an understanding of the molecular level details 12 , 13 . However, there has been little independent experimental validation of these compilers, most of which were developed in parallel with or after experimental findings 12 , 14 . In addition to software tools that facilitate automated design and analysis of DNA strand displacement circuits, we also need to simplify the experimental procedures for creating these circuits in vitro , so that it is possible for researchers with diverse backgrounds to build their own circuits and explore potential applications. A great inspiration is DNA origami 15 , a technique that folds DNA into sophisticated structures. In just 10 years since its birth, DNA origami has become one of the most significant successes in the field of DNA nanotechnology. Over 170 research groups have contributed to advancing this technique or developing it for applications in a variety of research areas 16 , 17 , 18 , 19 . A fundamental reason why DNA origami was able to quickly spread around the world is that the experimental procedure is extremely simple and makes use of cheap, unpurified nucleic-acid strands. In contrast, other than a few very simple circuits with just one or two double-stranded components 20 , most DNA strand displacement circuits were constructed using strands that were purchased either purified or unpurified, but all followed by in-house polyacrylamide gel electrophoresis (PAGE) purification to reduce undesired products due to synthesis errors and stoichiometry errors 12 , 14 , 21 . Purified strands are approximately ten times more expensive than unpurified strands, which significantly increases the cost for building large-scale DNA circuits. In-house PAGE purification is both time consuming and labour intensive. In this work, we show that one can successfully build a complex DNA strand displacement circuit, using DNA sequences automatically generated from a molecular compiler. We also show that one can even do so using cheap, unpurified DNA strands, following simple and systematic experimental procedures. Results Circuit design A simple DNA strand displacement motif called the seesaw gate was developed to scale up the complexity of DNA circuits 22 and was used to demonstrate digital logic computation 12 and neural network computation 23 . The Seesaw Compiler 12 , 24 was developed to automatically translate an arbitrary feed forward digital logic circuit into its equivalent seesaw DNA circuit ( Fig. 1 ). The compiler takes an input file that describes a logic circuit with a list of input and output terminals, and a list of AND, OR, NOT, NAND and NOR gates with the connectivity of their terminals specified. First, a technique called dual-rail logic is applied to translate the original logic circuit into an equivalent circuit that contains AND and OR gates only 25 . This is because the NOT gate cannot be directly implemented in multi-layer use-once DNA circuits, if the OFF and ON state of a signal is represented by low and high concentration of a single DNA strand, respectively. If a NOT gate were implemented this way, then output molecules of the gate could be immediately produced in the absence of input. However, once this reaction reaches equilibrium it cannot be reversed, even if input molecules are added at a later point. With dual-rail logic, each terminal in the original circuit is replaced by two terminals, representing the OFF and ON states of a signal separately (for example, each input signal x i is replaced by and ). Thus, no reaction will take place until signal molecules on one of the two wires have arrived. With this representation, the NOT gate can be implemented by exchanging the two wires of an input and output signal. Each AND, OR, NAND and NOR gate in the original circuit is replaced by a pair of AND and OR gates. Figure 1: Automated circuit design steps using the Seesaw Compiler. A feedforward digital logic circuit is first translated into an equivalent dual-rail logic circuit and then translated into an equivalent seesaw<|im_end|> <|im_start|>assistant Electronic circuits are found in almost everything from smartphones to spacecraft and are useful in a variety of computational problems from simple addition to determining the trajectories of interplanetary satellites. At Caltech, a group of researchers led by Assistant Professor of Bioengineering Lulu Qian is working to create circuits using not the usual silicon transistors but strands of DNA. The Qian group has made the technology of DNA circuits accessible to even novice researchers—including undergraduate students—using a software tool they developed called the Seesaw Compiler. Now, they have experimentally demonstrated that the tool can be used to quickly design DNA circuits that can then be built out of cheap "unpurified" DNA strands, following a systematic wet-lab procedure devised by Qian and colleagues. A paper describing the work appears in the February 23 issue of Nature Communications. Although DNA is best known as the molecule that encodes the genetic information of living things, they are also useful chemical building blocks. This is because the smaller molecules that make up a strand of DNA, called nucleotides, bind together only with very specific rules—an A nucleotide binds to a T, and a C nucleotide binds to a G. A strand of DNA is a sequence of nucleotides and can become a double strand if it binds with a sequence of complementary nucleotides. DNA circuits are good at collecting information within a biochemical environment, processing the information locally and controlling the behavior of individual molecules. Circuits built out of DNA strands instead of silicon transistors can be used in completely different ways than electronic circuits. "A DNA circuit could add 'smarts' to chemicals, medicines, or materials by making their functions responsive to the changes in their environments," Qian says. "Importantly, these adaptive functions can be programmed by humans." To build a DNA circuit that can, for example, compute the square root of a number between 0 and 16, researchers first have to carefully design a mixture of single and partially double-stranded DNA that can chemically recognize a set of DNA strands whose concentrations represent the value of the original number. Mixing these together triggers a cascade of zipping and unzipping reactions, each reaction releasing a specific DNA strand upon binding. Once the reactions are complete, the identities of the resulting DNA strands reveal the answer to the problem. With the Seesaw Compiler, a researcher could tell a computer the desired function to be calculated and the computer would design the DNA sequences and mixtures needed. However, it was not clear how well these automatically designed DNA sequences and mixtures would work for building DNA circuits with new functions; for example, computing the rules that govern how a cell evolves by sensing neighboring cells. "Constructing a circuit made of DNA has thus far been difficult for those who are not in this research area, because every circuit with a new function requires DNA strands with new sequences and there are no off-the-shelf DNA circuit components that can be purchased," says Chris Thachuk, senior postdoctoral scholar in computing and mathematical sciences and second author on the paper. "Our circuit-design software is a step toward enabling researchers to just type in what they want to do or compute and having the software figure out all the DNA strands needed to perform the computation, together with simulations to predict the DNA circuit's behavior in a test tube. Even though these DNA strands are still not off-the-shelf products, we have now shown that they do work well for new circuits with user-designed functions." "In the 1950s, only a few research labs that understood the physics of transistors could build early versions of electronic circuits and control their functions," says Qian. "But today many software tools are available that use simple and human-friendly languages to design complex electronic circuits embedded in smart machines. Our software is kind of like that: it translates simple and human-friendly descriptions of computation to the design of complex DNA circuits." The Seesaw Compiler was put to the test in 2015 in a unique course at Caltech, taught by Qian and called "Design and Construction of Programmable Molecular Systems" (BE/CS 196 ab). "How do you evaluate the accessibility of a new technology? You give the technology to someone who is intellectually capable but has minimal prior background," Qian says. "The students in this class were undergrads and first-year graduate students majoring in computer science and bioengineering," says Anupama Thubagere, a graduate student in biology and bioengineering and first author on the paper. "I started working with them as a head teaching assistant and together we soon discovered that using the Seesaw Compiler to design a DNA circuit was easy for everyone." However, building the designed circuit in the wet lab was not so simple. Thus, with continued efforts after the class, the group set out to develop a systematic wet-lab procedure that could guide researchers—even novices like undergraduate students—through the process of building DNA circuits. "Fortunately, we found a general solution to every challenge that we encountered, now making it easy for everyone to build their own DNA circuits," Thubagere says. The group showed that it was possible to use cheap, "unpurified" DNA strands in these circuits using the new process. This was only possible because steps in the systematic wet-lab procedure were designed to compensate for the lower synthesis quality of the DNA strands. "We hope that this work will convince more computer scientists and researchers from other fields to join our community in developing increasingly powerful molecular machines and to explore a much wider range of applications that will eventually lead to the transformation of technology that has been promised by the invention of molecular computers," Qian says. The paper is titled, "Compiler-aided systematic construction of large-scale DNA strand displacement circuits using unpurified components." <|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 Nutrient subsidies across ecotone boundaries can enhance productivity in the recipient ecosystem, especially if the nutrients are transferred from a nutrient rich to an oligotrophic ecosystem. This study demonstrates that seabird nutrients from islands are assimilated by endosymbionts in corals on fringing reefs and enhance growth of a dominant reef-building species, Acropora formosa . Nitrogen stable isotope ratios (δ 15 N) of zooxanthellae were enriched in corals near seabird colonies and decreased linearly with distance from land, suggesting that ornithogenic nutrients were assimilated in corals. In a one-year reciprocal transplant experiment, A. formosa fragments grew up to four times faster near the seabird site than conspecifics grown without the influence of seabird nutrients. The corals influenced by elevated ornithogenic nutrients were located within a marine protected area with abundant herbivorous fish populations, which kept nuisance macroalgae to negligible levels despite high nutrient concentrations. In this pristine setting, seabird nutrients provide a beneficial nutrient subsidy that increases growth of the ecologically important branching corals. The findings highlight the importance of catchment–to–reef management, not only for ameliorating negative impacts from land but also to maintain beneficial nutrient subsidies, in this case seabird guano. Introduction Nutrient subsidies can transcend ecosystem boundaries where they can enhance productivity 1 and functional diversity 2 , alter food webs 3 , and increase stability 4 and persistence of recipient marine communities 5 . Allochthonous nutrients can transcend ecotones either passively, such as macroalgal detritus that washes up on coastlines 3 , 6 , 7 , or via active vectors including seabirds 1 , 8 . The ecological effects of these nutrient subsidies are particularly pronounced when the receiving ecosystem has low production 5 , 9 . A case in point is the Gulf of California islands where seabirds forage in highly productive marine waters and deposit guano around their roosting sites that enhance local productivity 1 and influence community structure in terrestrial desert ecosystems 4 , 10 . Nutrient enrichment from seabird colonies can also increase marine production via sea–land–sea transfer. For example, ornithogenic nutrients increased macroalgal production 11 and altered benthic community structure of a temperate intertidal rocky reef community 12 . In tropical ecosystems, seabird nutrients can enrich nitrogen inputs to soil on islands 8 , 13 and increase nutrient availability in adjacent pelagic 14 and benthic food webs 15 . Seabird-derived nutrients have been traced into coral holobionts 16 , however the ecological effects of these nutrients on reef-building (scleractinian) corals have not been demonstrated previously. This study assessed the influence of seabird nutrient subsidies on coral growth rates using a spatial gradient sampling scheme and a reciprocal transplant experiment. Coral reefs are among the most productive ecosystems yet occur in oligotrophic waters 17 . This paradigm is due largely to the tight coupling in nutrient cycling between the coral host and endosymbionts (commonly referred to as zooxanthellae), whereby inorganic nutrients excreted by the coral animal are assimilated by the symbiotic dinoflagellates of the family Symbiodiniaceae 18 to support photosynthesis 19 . In turn, the zooxanthellae translocate organic compounds to the coral animal to support metabolic demands 19 . Within the coral holobiont, endosymbionts can acquire inorganic nutrients from their host’s waste metabolites or from surrounding seawater 20 . At a community level, the mutualistic association between the branching coral Sylophora pistillata and the coral obligate damselfish Dascyllus marginatus results in significantly higher growth rates of corals with resident damselfish due to nutrient subsidies from the fish waste 21 . Thus, external nutrients that elevate local nitrogen conditions in waters surrounding corals can increase zooxanthellae density, enhancing photosynthesis and coral growth rates 22 , 23 . However, there are environmental constraints and energetic costs associated with the maintenance of the mutualistic association between corals and endosymbionts with some studies showing that excessive nutrients can act like a stressor and cause a breakdown in the coral-algal symbiosis 24 . Elevated nutrient concentrations to coral reefs today are typically associated with anthropogenic sources including human sewage 25 , 26 , 27 , 28 and agricultural fertilizer 29 , 30 , where their effects are often considered detrimental to the coral reef ecosystem 31 . By contrast, nutrient subsidies from natural nutrient sources such as bird guano are principally excreted in an organic form of nitrogen 32 that undergoes speciation into various forms of nitrogen 33 and it remains to be shown whether it acts as a natural analogue to anthropogenic nutrient inputs. Nutrients generally increase cell densities of endosymbionts 22 , however the biochemical effect of this on corals is conflicting. Some studies show an increase in photosynthetic performance 34 and calcification 35 , 36 with increased nutritional supply. Conversely, other studies show a decrease in autotrophy caused by a chemical imbalance in the zooxanthellae 37 and a build-up of reactive oxygen species 38 , 39 which affects the stress tolerance of corals 40 . The relationship between nutrient availability and coral growth and photobiology is context-dependent, with exogenous factors like nutrient source likely a key determinant of the direction of the response at an individual coral level 41 . At the community level, excess nutrients can alter coral reproduction 42 and lead to loss of coral diversity and percent cover 43 . It can stimulate macroalgal growth and give algae a competitive advantage over slower-growing reef-building corals that once established, can create changes in chemical conditions on the reef 44 , 45 that maintain the reef in a macroalgal dominated state 46 . However, most studies on nutrient impacts on corals have been conducted on reefs that are already in a degraded state 47 or subject to multiple stressors in addition to excess nutrient availability 48 , including habitat transformation 49 and overfishing 50 . The reduction in numbers of herbivorous fishes, even at low levels of subsistence fishing 51 , together with increased nutrient delivery has been shown to erode resilience of coral reefs and cause transitions from healthy coral-dominated reefs to degraded algal-dominated systems 52 . By contrast, there are few studies", "role": "user" }, { "content": "A University of Otago study has shown the positive impact bird poo, or guano, has on coral growth in tropical seas. Published online in the respected scientific journal Scientific Reports, the study Seabird nutrients are assimilated by corals and enhance coral growth rates demonstrates that seabird nutrients can significantly boost coral growth rates, offering a positive news story in a decade that has documented dramatic declines in reef health and percentage cover. \"The findings have important implications for catchment-to-reef connectivity and demonstrate that coral conservation should also consider catchment management in addition to marine protection,\" says author Dr. Candida Savage, of Otago's Department of Marine Science. The research was conducted in two Fiji marine protected areas; one remote island (Namena) with an intact coastal forest with breeding seabirds, the other (Cousteau) is away from any seabirds and their associated guano. Natural chemical tracers in coral tissues showed that corals growing near the roosting seabirds took up seabird nutrients. A one-year growth experiment demonstrated that corals grew up to four times faster at the Namena reef compared to the Cousteau reef due to the presence of seabirds. \"Bird guano is known for its qualities as a fertiliser, however the impact it had on coral growth has been unknown until now. I was astounded at how much of a difference the presence of guano had in promoting coral growth,\" Dr. Savage says. The research shows that natural sources of nutrients like seabird guano may benefit coral reefs, in contrast to man-made nutrients from land that tend to degrade coral reefs. Comparison of staghorn corals grown for one year without the influence of seabird guano (three corals on left) with corals grown near a seabird colony (three corals on right). Credit: Dr Candida Savage Coral reefs face multiple global and local threats including excess nutrient runoff from land. Over the last decade, the percent of threatened reefs has increased by 30 per cent, with nearly 75 per cent of the world's reefs threatened today. Coral reefs are crucially important for biodiversity and people. Despite covering less than one per cent of the earth's surface, coral reefs are home to one-quarter of all marine fish species and countless invertebrates. Data obtained on the reefresilience website illustrates the importance of coral reefs for humans. At least five hundred million people rely on coral reefs for food, coastal protection, and livelihoods. In developing countries, coral reefs contribute about one-quarter of the total fish catch, providing food to an estimated one billion people in Asia alone. They form natural barriers that protect nearby shorelines from the eroding forces of the sea, thereby protecting coastal dwellings, agricultural land and beaches. Corals growing underwater at a site with roosting seabirds grew up to four times faster than corals grown distant from seabirds. Credit: Dr Candida Savage \"Given that nearly one-third of seabird species are at risk of extinction globally and now that we know how beneficial seabird subsidies are for coral growth, we should consider catchment-to-reef management to protect our marine ecosystems. This could be in the form of protection of established seabird nesting grounds or promoting new seabird habitats by enhancing natural vegetation on land alongside protecting marine areas. If the birds are there, the benefits of their droppings will be too,\" Dr. Savage 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 Nutrient subsidies across ecotone boundaries can enhance productivity in the recipient ecosystem, especially if the nutrients are transferred from a nutrient rich to an oligotrophic ecosystem. This study demonstrates that seabird nutrients from islands are assimilated by endosymbionts in corals on fringing reefs and enhance growth of a dominant reef-building species, Acropora formosa . Nitrogen stable isotope ratios (δ 15 N) of zooxanthellae were enriched in corals near seabird colonies and decreased linearly with distance from land, suggesting that ornithogenic nutrients were assimilated in corals. In a one-year reciprocal transplant experiment, A. formosa fragments grew up to four times faster near the seabird site than conspecifics grown without the influence of seabird nutrients. The corals influenced by elevated ornithogenic nutrients were located within a marine protected area with abundant herbivorous fish populations, which kept nuisance macroalgae to negligible levels despite high nutrient concentrations. In this pristine setting, seabird nutrients provide a beneficial nutrient subsidy that increases growth of the ecologically important branching corals. The findings highlight the importance of catchment–to–reef management, not only for ameliorating negative impacts from land but also to maintain beneficial nutrient subsidies, in this case seabird guano. Introduction Nutrient subsidies can transcend ecosystem boundaries where they can enhance productivity 1 and functional diversity 2 , alter food webs 3 , and increase stability 4 and persistence of recipient marine communities 5 . Allochthonous nutrients can transcend ecotones either passively, such as macroalgal detritus that washes up on coastlines 3 , 6 , 7 , or via active vectors including seabirds 1 , 8 . The ecological effects of these nutrient subsidies are particularly pronounced when the receiving ecosystem has low production 5 , 9 . A case in point is the Gulf of California islands where seabirds forage in highly productive marine waters and deposit guano around their roosting sites that enhance local productivity 1 and influence community structure in terrestrial desert ecosystems 4 , 10 . Nutrient enrichment from seabird colonies can also increase marine production via sea–land–sea transfer. For example, ornithogenic nutrients increased macroalgal production 11 and altered benthic community structure of a temperate intertidal rocky reef community 12 . In tropical ecosystems, seabird nutrients can enrich nitrogen inputs to soil on islands 8 , 13 and increase nutrient availability in adjacent pelagic 14 and benthic food webs 15 . Seabird-derived nutrients have been traced into coral holobionts 16 , however the ecological effects of these nutrients on reef-building (scleractinian) corals have not been demonstrated previously. This study assessed the influence of seabird nutrient subsidies on coral growth rates using a spatial gradient sampling scheme and a reciprocal transplant experiment. Coral reefs are among the most productive ecosystems yet occur in oligotrophic waters 17 . This paradigm is due largely to the tight coupling in nutrient cycling between the coral host and endosymbionts (commonly referred to as zooxanthellae), whereby inorganic nutrients excreted by the coral animal are assimilated by the symbiotic dinoflagellates of the family Symbiodiniaceae 18 to support photosynthesis 19 . In turn, the zooxanthellae translocate organic compounds to the coral animal to support metabolic demands 19 . Within the coral holobiont, endosymbionts can acquire inorganic nutrients from their host’s waste metabolites or from surrounding seawater 20 . At a community level, the mutualistic association between the branching coral Sylophora pistillata and the coral obligate damselfish Dascyllus marginatus results in significantly higher growth rates of corals with resident damselfish due to nutrient subsidies from the fish waste 21 . Thus, external nutrients that elevate local nitrogen conditions in waters surrounding corals can increase zooxanthellae density, enhancing photosynthesis and coral growth rates 22 , 23 . However, there are environmental constraints and energetic costs associated with the maintenance of the mutualistic association between corals and endosymbionts with some studies showing that excessive nutrients can act like a stressor and cause a breakdown in the coral-algal symbiosis 24 . Elevated nutrient concentrations to coral reefs today are typically associated with anthropogenic sources including human sewage 25 , 26 , 27 , 28 and agricultural fertilizer 29 , 30 , where their effects are often considered detrimental to the coral reef ecosystem 31 . By contrast, nutrient subsidies from natural nutrient sources such as bird guano are principally excreted in an organic form of nitrogen 32 that undergoes speciation into various forms of nitrogen 33 and it remains to be shown whether it acts as a natural analogue to anthropogenic nutrient inputs. Nutrients generally increase cell densities of endosymbionts 22 , however the biochemical effect of this on corals is conflicting. Some studies show an increase in photosynthetic performance 34 and calcification 35 , 36 with increased nutritional supply. Conversely, other studies show a decrease in autotrophy caused by a chemical imbalance in the zooxanthellae 37 and a build-up of reactive oxygen species 38 , 39 which affects the stress tolerance of corals 40 . The relationship between nutrient availability and coral growth and photobiology is context-dependent, with exogenous factors like nutrient source likely a key determinant of the direction of the response at an individual coral level 41 . At the community level, excess nutrients can alter coral reproduction 42 and lead to loss of coral diversity and percent cover 43 . It can stimulate macroalgal growth and give algae a competitive advantage over slower-growing reef-building corals that once established, can create changes in chemical conditions on the reef 44 , 45 that maintain the reef in a macroalgal dominated state 46 . However, most studies on nutrient impacts on corals have been conducted on reefs that are already in a degraded state 47 or subject to multiple stressors in addition to excess nutrient availability 48 , including habitat transformation 49 and overfishing 50 . The reduction in numbers of herbivorous fishes, even at low levels of subsistence fishing 51 , together with increased nutrient delivery has been shown to erode resilience of coral reefs and cause transitions from healthy coral-dominated reefs to degraded algal-dominated systems 52 . By contrast, there are few studies<|im_end|> <|im_start|>assistant A University of Otago study has shown the positive impact bird poo, or guano, has on coral growth in tropical seas. Published online in the respected scientific journal Scientific Reports, the study Seabird nutrients are assimilated by corals and enhance coral growth rates demonstrates that seabird nutrients can significantly boost coral growth rates, offering a positive news story in a decade that has documented dramatic declines in reef health and percentage cover. "The findings have important implications for catchment-to-reef connectivity and demonstrate that coral conservation should also consider catchment management in addition to marine protection," says author Dr. Candida Savage, of Otago's Department of Marine Science. The research was conducted in two Fiji marine protected areas; one remote island (Namena) with an intact coastal forest with breeding seabirds, the other (Cousteau) is away from any seabirds and their associated guano. Natural chemical tracers in coral tissues showed that corals growing near the roosting seabirds took up seabird nutrients. A one-year growth experiment demonstrated that corals grew up to four times faster at the Namena reef compared to the Cousteau reef due to the presence of seabirds. "Bird guano is known for its qualities as a fertiliser, however the impact it had on coral growth has been unknown until now. I was astounded at how much of a difference the presence of guano had in promoting coral growth," Dr. Savage says. The research shows that natural sources of nutrients like seabird guano may benefit coral reefs, in contrast to man-made nutrients from land that tend to degrade coral reefs. Comparison of staghorn corals grown for one year without the influence of seabird guano (three corals on left) with corals grown near a seabird colony (three corals on right). Credit: Dr Candida Savage Coral reefs face multiple global and local threats including excess nutrient runoff from land. Over the last decade, the percent of threatened reefs has increased by 30 per cent, with nearly 75 per cent of the world's reefs threatened today. Coral reefs are crucially important for biodiversity and people. Despite covering less than one per cent of the earth's surface, coral reefs are home to one-quarter of all marine fish species and countless invertebrates. Data obtained on the reefresilience website illustrates the importance of coral reefs for humans. At least five hundred million people rely on coral reefs for food, coastal protection, and livelihoods. In developing countries, coral reefs contribute about one-quarter of the total fish catch, providing food to an estimated one billion people in Asia alone. They form natural barriers that protect nearby shorelines from the eroding forces of the sea, thereby protecting coastal dwellings, agricultural land and beaches. Corals growing underwater at a site with roosting seabirds grew up to four times faster than corals grown distant from seabirds. Credit: Dr Candida Savage "Given that nearly one-third of seabird species are at risk of extinction globally and now that we know how beneficial seabird subsidies are for coral growth, we should consider catchment-to-reef management to protect our marine ecosystems. This could be in the form of protection of established seabird nesting grounds or promoting new seabird habitats by enhancing natural vegetation on land alongside protecting marine areas. If the birds are there, the benefits of their droppings will be too," Dr. Savage says. <|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 Intramolecular motions in proteins are one of the important factors that determine their biological activity and interactions with molecules of biological importance. Magnetic relaxation of 15 N amide nuclei allows one to monitor motions of protein backbone over a wide range of time scales. 15 N{ 1 H} nuclear Overhauser effect is essential for the identification of fast backbone motions in proteins. Therefore, exact measurements of NOE values and their accuracies are critical for determining the picosecond time scale of protein backbone. Measurement of dynamic NOE allows for the determination of NOE values and their probable errors defined by any sound criterion of nonlinear regression methods. The dynamic NOE measurements can be readily applied for non-deuterated or deuterated proteins in both HSQC and TROSY-type experiments. Comparison of the dynamic NOE method with commonly implied steady-state NOE is presented in measurements performed at three magnetic field strengths. It is also shown that improperly set NOE measurement cannot be restored with correction factors reported in the literature. Working on a manuscript? Avoid the common mistakes Introduction Since its first use of magnetic relaxation measurements of 15 N nuclei applied to the protein, the staphylococcal nuclease (Kay et al. 1989 ), this method has become indispensable in the determination of molecular motions in biopolymers (Jarymowycz and Stone 2006 ; Kempf and Loria 2003 ; Palmer, III 2004 ; Reddy and Rayney 2010 ; Stetz et al. 2019 ). The canonical triad of relaxation parameters—longitudinal ( R 1 ) and transverse ( R 2 ) relaxation rates accompanied by the 15 N{ 1 H} nuclear Overhauser effect (NOE)—have been most often used in studies investigating the mobility of backbone in proteins. It is a common opinion that 15 N{ 1 H} NOE is unique among the mentioned three relaxation parameters because it is regarded as essential for the accurate estimation of the spectral density function at high frequencies (ω H ± ω N ), and it is crucial for the identification of fast backbone motions. (Idiyatullin et al. 2001 ; Gong and Ishima 2007 ; Ferrage et al. 2009 ). The most common method for the determination of X{ 1 H} NOE is a steady-state approach. It requires measurements of the longitudinal polarization at the thermal equilibrium of spin X system, S 0 , and the steady-state longitudinal X polarization under 1 H irradiation, S sat (Noggle and Schirmer 1971 ). Note that the nuclear Overhauser effect , defined as \\(\\varepsilon = {{S_{sat} } \\mathord{\\left/ {\\vphantom {{S_{sat} } {S_{0} }}} \\right. \\kern-\\nulldelimiterspace} {S_{0} }}\\) , should not be mistaken with nuclear Overhauser enhancement , \\(\\eta = {{\\left( {S_{sat} - S_{0} } \\right)} \\mathord{\\left/ {\\vphantom {{\\left( {S_{sat} - S_{0} } \\right)} {S_{0} = \\varepsilon - 1}}} \\right. \\kern-\\nulldelimiterspace} {S_{0} = \\varepsilon - 1}}\\) (Harris et al. 1997 ). It has to be pointed out that NOE measurements appear to be very demanding and artifact prone observations. One of severe obstacles in these experiments is their ca . tenfold lower sensitivity in comparison to R 1 N and R 2 N which is due to the fact that the NOE experiments with 1 H detection start with the equilibrium 15 N magnetization rather than 1 H. The steady-state 15 N{ 1 H} NOEs (ssNOE) are normally determined as a ratio of cross-peak intensities in two experiments—with and without saturation of H N resonances. Such arrangement creates problems with computing statistically validated assessment of experimental errors. 15 N{ 1 H} NOE pulse sequence requires a very careful design as well. Properly chosen recycle delays between subsequent scans and saturation time of H N protons have to take into account the time needed to reach the equilibrium or stationary values of 15 N and H N magnetizations (Harris and Newman 1976 ; Canet 1976 ; Renner et al. 2002 ). Exchange of H N protons with the bulk water combined with the long longitudinal relaxation time of water protons leads to prolonged recycle delay in the spectrum acquired without saturation of H N resonances. Unintentional irradiation of the water resonance suppresses H N and other exchangeable signals owing to the saturation transfer and many non-exchangeable 1 H resonances via direct or indirect NOE with water (Grzesiek and Bax 1993 ) while interference of DD/CSA relaxation mechanisms of 15 N amide nuclei disturbs the steady-state 15 N polarization during 1 H irradiation (Ferrage et al. 2009 ). All aforementioned processes depend directly or indirectly on the longitudinal relaxation rates of amide 1 H and 15 N nuclei R 1 H and R 1 N as well as the longitudinal relaxation rate of water protons, R 1 W , and the exchange rate between water and amide protons, k . In this study, the dynamic NMR experiment (DNOE), a forgotten method of the NOE determination in proteins, was experimentally tested, and the results were compared with independently performed steady-state NOE measurements at several magnetic fields for widely studied, small, globular protein ubiquitin. Additionally, several difficulties inherent in 15 N{ 1 H} NOEs and methods for overcoming or minimizing these difficulties are cautiously discussed. Experimental The uniformly labeled U-[ 15 N] human ubiquitin was obtained from Cambridge Isotope Laboratories, Inc in lyophilized powder form and dissolved to 0.8 mM protein concentration in buffer containing 10 mM sodium phosphate at pH 6.6 and 0.01% ( m / v ) NaN 3 . DSS- d 6 of 0.1% ( m / v ) in 99.9% D 2 O was placed in a sealed capillary inserted into the 5 mm NMR tube. Amide resonance assignments of ubiquitin were taken from BioMagResBank (BMRB) using the accession code 6457 (Cornilescu et al. 1998 ). NMR experiments were performed on three Bruker Avance NEO spectrometers operating at 1 H frequencies of 700, 800 and 950 MHz equipped with cryogenic TCI probes. The temperature was controlled before and after each measurement with an ethylene glycol reference sample (Rainford et al. 1979 ) and was set to 25 °C. The temperature was stable with maximum detected deviation of", "role": "user" }, { "content": "A fresh new look at an old technique in protein biochemistry has shown that it should be reintroduced to the spectroscopy toolkit. For decades, scientists have used nuclear magnetic resonance (NMR) spectroscopy to probe the molecular motions of proteins on various timescales. This technique has revealed aspects of enzyme reactions, protein folding and other biological processes, all on an atomic scale. Typically, spectroscopists will gage the rotation of NMR-active atoms in the protein backbone with and without proton irradiation to calculate a ratio known as a steady-state nuclear Overhauser effect (NOE); however, it was not always done this way. Before steady-state NOE experiments became the norm in biological investigations, scientists would often take a greater number of measurements over the course of an irradiation experiment. This method, termed \"dynamic\" NOE, might seem more complicated, but according to Ph.D. student Vladlena Kharchenko, it is no more time consuming than steady-state NOE, while dynamic NOE provides additional information about protein flexibility and is far more accurate to minute biological motions in proteins. \"It works for proteins and makes studying their dynamics even more accurate,\" says Kharchenko, a member of Łukasz Jaremko's lab at KAUST. \"Our message to biological NMR spectroscopists is simple: 'Don't be afraid of dynamic NOE.'\" To prove the technique's worth, Kharchenko, Jaremko and their team performed a series of NMR experiments on ubiquitin, a globular protein that regulates a range of processes inside the cell. Working with Mariusz Jaremko, also from KAUST, and collaborators in Poland, the researchers collected both steady-state and dynamic NOE measurements and demonstrated that the dynamic approach is always preferable—except under a few specific conditions, such as when instrument access is limited or when proteins degrade very rapidly. Notably, the steady-state approach proved especially prone to errors in regions of the ubiquitin protein that were flexible and disposed to moving around. The dynamic technique, in comparison, offered no such misleading results. In light of their findings, the KAUST team hopes that other scientists with an interest in atomic-level protein mechanics will now begin to adopt, or at least reconsider, dynamic NMR methods. Kharchenko says that sometimes, \"it's worth dusting off forgotten methods and checking if they fit to new emerging questions and systems of research interest.\" ", "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 Intramolecular motions in proteins are one of the important factors that determine their biological activity and interactions with molecules of biological importance. Magnetic relaxation of 15 N amide nuclei allows one to monitor motions of protein backbone over a wide range of time scales. 15 N{ 1 H} nuclear Overhauser effect is essential for the identification of fast backbone motions in proteins. Therefore, exact measurements of NOE values and their accuracies are critical for determining the picosecond time scale of protein backbone. Measurement of dynamic NOE allows for the determination of NOE values and their probable errors defined by any sound criterion of nonlinear regression methods. The dynamic NOE measurements can be readily applied for non-deuterated or deuterated proteins in both HSQC and TROSY-type experiments. Comparison of the dynamic NOE method with commonly implied steady-state NOE is presented in measurements performed at three magnetic field strengths. It is also shown that improperly set NOE measurement cannot be restored with correction factors reported in the literature. Working on a manuscript? Avoid the common mistakes Introduction Since its first use of magnetic relaxation measurements of 15 N nuclei applied to the protein, the staphylococcal nuclease (Kay et al. 1989 ), this method has become indispensable in the determination of molecular motions in biopolymers (Jarymowycz and Stone 2006 ; Kempf and Loria 2003 ; Palmer, III 2004 ; Reddy and Rayney 2010 ; Stetz et al. 2019 ). The canonical triad of relaxation parameters—longitudinal ( R 1 ) and transverse ( R 2 ) relaxation rates accompanied by the 15 N{ 1 H} nuclear Overhauser effect (NOE)—have been most often used in studies investigating the mobility of backbone in proteins. It is a common opinion that 15 N{ 1 H} NOE is unique among the mentioned three relaxation parameters because it is regarded as essential for the accurate estimation of the spectral density function at high frequencies (ω H ± ω N ), and it is crucial for the identification of fast backbone motions. (Idiyatullin et al. 2001 ; Gong and Ishima 2007 ; Ferrage et al. 2009 ). The most common method for the determination of X{ 1 H} NOE is a steady-state approach. It requires measurements of the longitudinal polarization at the thermal equilibrium of spin X system, S 0 , and the steady-state longitudinal X polarization under 1 H irradiation, S sat (Noggle and Schirmer 1971 ). Note that the nuclear Overhauser effect , defined as \(\varepsilon = {{S_{sat} } \mathord{\left/ {\vphantom {{S_{sat} } {S_{0} }}} \right. \kern-\nulldelimiterspace} {S_{0} }}\) , should not be mistaken with nuclear Overhauser enhancement , \(\eta = {{\left( {S_{sat} - S_{0} } \right)} \mathord{\left/ {\vphantom {{\left( {S_{sat} - S_{0} } \right)} {S_{0} = \varepsilon - 1}}} \right. \kern-\nulldelimiterspace} {S_{0} = \varepsilon - 1}}\) (Harris et al. 1997 ). It has to be pointed out that NOE measurements appear to be very demanding and artifact prone observations. One of severe obstacles in these experiments is their ca . tenfold lower sensitivity in comparison to R 1 N and R 2 N which is due to the fact that the NOE experiments with 1 H detection start with the equilibrium 15 N magnetization rather than 1 H. The steady-state 15 N{ 1 H} NOEs (ssNOE) are normally determined as a ratio of cross-peak intensities in two experiments—with and without saturation of H N resonances. Such arrangement creates problems with computing statistically validated assessment of experimental errors. 15 N{ 1 H} NOE pulse sequence requires a very careful design as well. Properly chosen recycle delays between subsequent scans and saturation time of H N protons have to take into account the time needed to reach the equilibrium or stationary values of 15 N and H N magnetizations (Harris and Newman 1976 ; Canet 1976 ; Renner et al. 2002 ). Exchange of H N protons with the bulk water combined with the long longitudinal relaxation time of water protons leads to prolonged recycle delay in the spectrum acquired without saturation of H N resonances. Unintentional irradiation of the water resonance suppresses H N and other exchangeable signals owing to the saturation transfer and many non-exchangeable 1 H resonances via direct or indirect NOE with water (Grzesiek and Bax 1993 ) while interference of DD/CSA relaxation mechanisms of 15 N amide nuclei disturbs the steady-state 15 N polarization during 1 H irradiation (Ferrage et al. 2009 ). All aforementioned processes depend directly or indirectly on the longitudinal relaxation rates of amide 1 H and 15 N nuclei R 1 H and R 1 N as well as the longitudinal relaxation rate of water protons, R 1 W , and the exchange rate between water and amide protons, k . In this study, the dynamic NMR experiment (DNOE), a forgotten method of the NOE determination in proteins, was experimentally tested, and the results were compared with independently performed steady-state NOE measurements at several magnetic fields for widely studied, small, globular protein ubiquitin. Additionally, several difficulties inherent in 15 N{ 1 H} NOEs and methods for overcoming or minimizing these difficulties are cautiously discussed. Experimental The uniformly labeled U-[ 15 N] human ubiquitin was obtained from Cambridge Isotope Laboratories, Inc in lyophilized powder form and dissolved to 0.8 mM protein concentration in buffer containing 10 mM sodium phosphate at pH 6.6 and 0.01% ( m / v ) NaN 3 . DSS- d 6 of 0.1% ( m / v ) in 99.9% D 2 O was placed in a sealed capillary inserted into the 5 mm NMR tube. Amide resonance assignments of ubiquitin were taken from BioMagResBank (BMRB) using the accession code 6457 (Cornilescu et al. 1998 ). NMR experiments were performed on three Bruker Avance NEO spectrometers operating at 1 H frequencies of 700, 800 and 950 MHz equipped with cryogenic TCI probes. The temperature was controlled before and after each measurement with an ethylene glycol reference sample (Rainford et al. 1979 ) and was set to 25 °C. The temperature was stable with maximum detected deviation of<|im_end|> <|im_start|>assistant A fresh new look at an old technique in protein biochemistry has shown that it should be reintroduced to the spectroscopy toolkit. For decades, scientists have used nuclear magnetic resonance (NMR) spectroscopy to probe the molecular motions of proteins on various timescales. This technique has revealed aspects of enzyme reactions, protein folding and other biological processes, all on an atomic scale. Typically, spectroscopists will gage the rotation of NMR-active atoms in the protein backbone with and without proton irradiation to calculate a ratio known as a steady-state nuclear Overhauser effect (NOE); however, it was not always done this way. Before steady-state NOE experiments became the norm in biological investigations, scientists would often take a greater number of measurements over the course of an irradiation experiment. This method, termed "dynamic" NOE, might seem more complicated, but according to Ph.D. student Vladlena Kharchenko, it is no more time consuming than steady-state NOE, while dynamic NOE provides additional information about protein flexibility and is far more accurate to minute biological motions in proteins. "It works for proteins and makes studying their dynamics even more accurate," says Kharchenko, a member of Łukasz Jaremko's lab at KAUST. "Our message to biological NMR spectroscopists is simple: 'Don't be afraid of dynamic NOE.'" To prove the technique's worth, Kharchenko, Jaremko and their team performed a series of NMR experiments on ubiquitin, a globular protein that regulates a range of processes inside the cell. Working with Mariusz Jaremko, also from KAUST, and collaborators in Poland, the researchers collected both steady-state and dynamic NOE measurements and demonstrated that the dynamic approach is always preferable—except under a few specific conditions, such as when instrument access is limited or when proteins degrade very rapidly. Notably, the steady-state approach proved especially prone to errors in regions of the ubiquitin protein that were flexible and disposed to moving around. The dynamic technique, in comparison, offered no such misleading results. In light of their findings, the KAUST team hopes that other scientists with an interest in atomic-level protein mechanics will now begin to adopt, or at least reconsider, dynamic NMR methods. Kharchenko says that sometimes, "it's worth dusting off forgotten methods and checking if they fit to new emerging questions and systems of research interest." <|im_end|>
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579, 97192, 26412, 1302, 279, 24981, 21395, 220, 868, 452, 83245, 2391, 220, 16, 473, 76327, 367, 320, 37, 618, 425, 1880, 453, 13, 220, 1049, 24, 7609, 2052, 46752, 11618, 6904, 6089, 477, 46345, 389, 279, 68102, 43685, 7969, 315, 1097, 579, 220, 16, 473, 323, 220, 868, 452, 97192, 432, 220, 16, 473, 323, 432, 220, 16, 452, 439, 1664, 439, 279, 68102, 43685, 4478, 315, 3090, 463, 35511, 11, 432, 220, 16, 468, 1174, 323, 279, 9473, 4478, 1990, 3090, 323, 1097, 579, 463, 35511, 11, 597, 662, 763, 420, 4007, 11, 279, 8915, 452, 18953, 9526, 320, 35, 9173, 36, 705, 264, 25565, 1749, 315, 279, 5782, 36, 26314, 304, 28896, 11, 574, 9526, 750, 12793, 11, 323, 279, 3135, 1051, 7863, 449, 29235, 10887, 24981, 21395, 5782, 36, 22323, 520, 3892, 24924, 5151, 369, 13882, 20041, 11, 2678, 11, 13509, 1299, 13128, 53336, 85986, 13, 23212, 11, 3892, 27129, 38088, 304, 220, 868, 452, 90, 220, 16, 473, 92, 5782, 17812, 323, 5528, 369, 74017, 477, 77391, 1521, 27129, 527, 92485, 14407, 13, 57708, 578, 78909, 30929, 549, 42095, 220, 868, 452, 60, 3823, 53336, 85986, 574, 12457, 505, 24562, 2209, 51782, 78717, 11, 4953, 304, 14869, 98635, 1534, 17138, 1376, 323, 56767, 311, 220, 15, 13, 23, 84317, 13128, 20545, 304, 4240, 8649, 220, 605, 84317, 39695, 79106, 520, 37143, 220, 21, 13, 21, 323, 220, 15, 13, 1721, 4, 320, 296, 611, 348, 883, 33278, 220, 18, 662, 423, 1242, 12, 294, 220, 21, 315, 220, 15, 13, 16, 4, 320, 296, 611, 348, 883, 304, 220, 1484, 13, 24, 4, 423, 220, 17, 507, 574, 9277, 304, 264, 19584, 2107, 35605, 22306, 1139, 279, 220, 20, 9653, 452, 18953, 14019, 13, 3383, 579, 58081, 32272, 315, 53336, 85986, 1051, 4529, 505, 24432, 34015, 1079, 26913, 320, 33, 18953, 33, 8, 1701, 279, 85045, 2082, 220, 22926, 22, 320, 91641, 458, 2445, 84, 1880, 453, 13, 220, 2550, 23, 7609, 452, 18953, 21896, 1051, 10887, 389, 2380, 19215, 7197, 7671, 685, 87683, 9618, 442, 2481, 10565, 520, 220, 16, 473, 34873, 315, 220, 7007, 11, 220, 4728, 323, 220, 15862, 37594, 19167, 449, 16106, 29569, 350, 11487, 63610, 13, 578, 9499, 574, 14400, 1603, 323, 1306, 1855, 19179, 449, 459, 8537, 64651, 37807, 2119, 5905, 6205, 320, 60139, 8350, 1880, 453, 13, 220, 4468, 24, 883, 323, 574, 743, 311, 220, 914, 37386, 34, 13, 578, 9499, 574, 15528, 449, 7340, 16914, 38664, 315, 128257, 198, 128256, 78191, 198, 32, 7878, 502, 1427, 520, 459, 2362, 15105, 304, 13128, 17332, 52755, 706, 6982, 430, 433, 1288, 387, 76267, 30317, 311, 279, 66425, 51856, 66994, 13, 1789, 11026, 11, 14248, 617, 1511, 11499, 24924, 58081, 320, 45, 18953, 8, 66425, 51856, 311, 22477, 279, 31206, 54245, 315, 28896, 389, 5370, 3115, 31296, 13, 1115, 15105, 706, 10675, 13878, 315, 49242, 25481, 11, 13128, 45842, 323, 1023, 24156, 11618, 11, 682, 389, 459, 25524, 5569, 13, 46402, 11, 66425, 2445, 454, 1705, 690, 342, 425, 279, 12984, 315, 452, 18953, 32344, 33299, 304, 279, 13128, 56527, 449, 323, 2085, 82586, 76327, 367, 311, 11294, 264, 11595, 3967, 439, 264, 24981, 21395, 11499, 6193, 4317, 882, 2515, 320, 9173, 36, 1237, 4869, 11, 433, 574, 539, 2744, 2884, 420, 1648, 13, 13538, 24981, 21395, 5782, 36, 21896, 6244, 279, 7617, 304, 24156, 26969, 11, 14248, 1053, 3629, 1935, 264, 7191, 1396, 315, 22323, 927, 279, 3388, 315, 459, 76327, 367, 9526, 13, 1115, 1749, 11, 61937, 330, 22269, 1, 5782, 36, 11, 2643, 2873, 810, 17395, 11, 719, 4184, 311, 2405, 920, 13, 5575, 30734, 49121, 20774, 1132, 56155, 11, 433, 374, 912, 810, 892, 35208, 1109, 24981, 21395, 5782, 36, 11, 1418, 8915, 5782, 36, 5825, 5217, 2038, 922, 13128, 25152, 323, 374, 3117, 810, 13687, 311, 9568, 24156, 54245, 304, 28896, 13, 330, 2181, 4375, 369, 28896, 323, 3727, 21630, 872, 30295, 1524, 810, 13687, 1359, 2795, 20774, 1132, 56155, 11, 264, 4562, 315, 27006, 223, 3178, 53440, 622, 69468, 9509, 596, 10278, 520, 90078, 8721, 13, 330, 8140, 1984, 311, 24156, 452, 18953, 66425, 2445, 454, 1705, 374, 4382, 25, 364, 8161, 956, 387, 16984, 315, 8915, 5782, 36, 30251, 2057, 12391, 279, 15105, 596, 5922, 11, 20774, 1132, 56155, 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1,982
[ { "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 Seahorses have a circum-global distribution in tropical to temperate coastal waters. Yet, seahorses show many adaptations for a sedentary, cryptic lifestyle: they require specific habitats, such as seagrass, kelp or coral reefs, lack pelvic and caudal fins, and give birth to directly developed offspring without pronounced pelagic larval stage, rendering long-range dispersal by conventional means inefficient. Here we investigate seahorses’ worldwide dispersal and biogeographic patterns based on a de novo genome assembly of Hippocampus erectus as well as 358 re-sequenced genomes from 21 species. Seahorses evolved in the late Oligocene and subsequent circum-global colonization routes are identified and linked to changing dynamics in ocean currents and paleo-temporal seaway openings. Furthermore, the genetic basis of the recurring “bony spines” adaptive phenotype is linked to independent substitutions in a key developmental gene. Analyses thus suggest that rafting via ocean currents compensates for poor dispersal and rapid adaptation facilitates colonizing new habitats. Introduction Explaining mechanisms of marine biodiversification is challenging, owing to persistent paucity of information on patterns of speciation and phylogeography in marine ecosystems 1 , 2 , 3 . Major geological vicariance events, such as the closure of the Panama seaway 4 or the Tethys seaway 5 , 6 , have been suggested to impact patterns of marine biodiversification, particularly for organisms whose dispersal strategies rely on ocean currents transporting pelagic larvae or rafting individuals across large distances 7 . In such lineages, ecomorphological divergence and local adaptation after a colonization event can be slow even in the presence of strong divergent selective pressures 8 . Thus, comprehensive studies addressing spatio-temporal diversification patterns that include dynamics of geophysical processes, as well as knowledge of the genetic bases and developmental mechanisms of key adaptive traits, are required to understand the mechanisms that drive the evolution of marine biodiversity. The radiation of seahorses (Family Syngnathidae ) is a particularly iconic and suitable model system to investigate the effects that tectonic activity and ocean current dynamics can have on the dispersal and diversification of marine taxa due to the seahorses’ dispersal by rafting 7 , 9 , as well as to study the rapid evolution of adaptive phenotypes in new environments. Seahorse genomes evolve under some of the highest mutation rates among teleosts 10 and have the greatest diversification rates within their family (Supplementary Fig. 1 , Figshare: Dataset 1 ). All seahorses are sedentary but exhibit specialized morphological and life-history traits 11 , 12 , 13 , such as a prehensile tail (and the lack of a caudal fin), an elongated snout, lack of pelvic fins, an armor of bony plates instead of scales, and a unique mode of male pregnancy whereby males give birth to developed juveniles 14 , 15 . Species of seahorses differ widely in body size, color patterns and other adaptive traits to their respective environments 11 , such as the presence or absence of bony spines, which are likely an adaption against predators 16 . Previous research revealed that the evolutionary origin of seahorses likely lies in the Late Oligocene’s Indo-Pacific 17 , 18 , 19 from where different lineages dispersed around the globe despite the seahorses’ poor endurance swimming abilities and their reliance on rafting as primary long-distance dispersal strategy 9 , 20 . Nonetheless, a comprehensive understanding of the seahorses’ colonization routes is still missing as phylogenetic reconstructions were typically either derived only from relatively few species and/or few genetic markers 18 , 21 , 22 , 23 . Here, we study the diversification patterns of these unique fishes based on the analysis of multiple sequenced seahorse genomes. By conducting comprehensive phylogenetic analyses, we infer their demographic history and clarify the role of seaway closures during their diversification as part of tracing the colonization routes from the origin of their common ancestor to their current distribution. Additionally, we address the adaptive phenotypic evolution of seahorses by studying the development of one of the most eye-catching traits within the genus: the presence or absence of bony spines. Results and discussion Global diversity of seahorses Using PacBio long-read sequencing (~115-fold coverage), Illumina short-read sequencing (~243-fold coverage), and Hi-C technology (~184-fold coverage) we de novo assembled the genome of a male Hippocampus erectus . With a contig N50 of 15.5 Mb, our chromosome-level assembly (total size 420.66 Mb; comprising 22 superscaffolds corresponding to the expected chromosome number) (Supplementary Figs. 2 – 4 , Supplementary Tables 1– 4 , and Supplementary Data 1 ) improved in sequence contiguity over previously available assemblies generated from Illumina short reads alone (contig N50: 14.57 kb) 10 , 24 . We re-sequenced the genomes (~16-fold coverage) of 358 seahorse specimens comprising 21 species reflecting Hippocampus ’ global distribution, with representatives of major seahorse lineages (Fig. 1a , Supplementary Fig. 5a , Supplementary Data 2 ). Fig. 1: Genetic diversity and phylogenetic relationships of 358 seahorse specimens. a Geographic sampling locations for sampled seahorses with patterns of nucleotide diversity ( π ) of the 21 seahorse species across 22 chromosomes. Maps from Wessel et al. (2013) under GNU GPL license 91 . b Neighbor-joining tree constructed with genome-wide SNPs of 358 seahorses. Location pin symbols in ( a ) and branch background in ( b ) correspond to each other. Seahorses illustrations by Geng Qin. Source data are provided as a Source Data file. Full size image Our analysis identified each seahorse species as a monophyletic group in a neighbor-joining tree inferred from 41 million genome-wide single nucleotide polymorphisms (SNPs) (Fig. 1b , Supplementary Tables 5 – 8 ), and they formed distinct clusters in a principal component analysis (Supplementary Fig. 5b ). Genetic diversity ( θπ and θω ) varied substantially among species and chromosomes, as it was, for example, generally higher for seahorses in the North Atlantic Ocean biome than in the South Atlantic Ocean biome (Fig. 1a , Supplementary Figs. 6 , 7 , Figshare: Dataset 2 ). The time-calibrated tree estimated that the common ancestor of all extant seahorses lived ~20–25 Ma (million years ago) (Fig. 2a , Supplementary Figs.", "role": "user" }, { "content": "Seahorses are extremely poor swimmers. Surprisingly, however, they can be found in all of the world's oceans. On the basis of almost 360 different seahorse genomes, a group of researchers studied how these special fish were able to spread so suc-cessfully worldwide. Based on an evolutionary tree of 21 species it was possible to reconstruct the dispersal routes of seahorses worldwide and to explain where and when new species emerged. The international research collaboration involving the research team led by evolutionary biologist Professor Axel Meyer at the University of Konstanz and researchers from China and Singapore was able to identify factors that led to the success of the seahorse from a developmental biology perspective: its quickness to adapt by, for example, repeatedly evolving spines in the skin and its fast genetic rates of evolution. The results will be published on 17 February 2021 in Nature Communications. Seahorses of the genus Hippocampus emerged about 25 million years ago in the Indo-Pacific region from pipefish, their closest relatives. And while the latter usually swim fairly well, seahorses lack their pelvic and tail fins and evolved a prehensile tail instead that can be used, for example, to hold on to seaweed or corals. Early on, they split into two main groups. \"One group stayed mainly in the same place, while the other spread all over the world,\" says Dr. Ralf Schneider, who is now a postdoc-toral researcher at the GEOMAR Helmholtz Centre for Ocean Research Kiel, and participated in the study while working as a doctoral researcher in Axel Meyer's re-search team. In their original home waters of the Indo-Pacific, the remaining species diversified in a unique island environment, while the other group made its way into the Pacific Ocean via Africa, Europe and the Americas. Traveling the world by raft The particularly large amount of data collected for the study enabled the research team to create an especially reliable seahorse tree showing the relationships be-tween species and the global dispersal routes of the seahorse. Evolutionary biologist, Dr. Schneider, says: \"If you compare the relationships between the species to the ocean currents, you notice that seahorses were transported across the oceans.\" If, for example, they were carried out to sea during storms, they used their grasping tail to hold on to anything they could find, like a piece of algae or a tree trunk. These are places where the animals could survive for a long time. The currents often swept these \"rafts\" hundreds of kilometers across the ocean before they landed someplace where the seahorses could hop off and find a new home. Since seahorses have been around for more than 25 million years, it was important to factor in that ocean currents have changed over time as tectonic plates have shift-ed. For example, about 15 million years ago, the Tethys Ocean was almost as large as today's Mediterranean Sea. On the west side, where the Strait of Gibraltar is lo-cated today, it connected to the Atlantic Ocean. On the east side, where the Arabian Peninsula is today, it led to the Indian Ocean. Tectonic shifts change ocean currents The researchers were able to underscore, for example, that the seahorses were able to colonize the Tethys Ocean via the Arabian Sea just before the tectonic plates shifted and sealed off the eastern connection. The resulting current flowing westward towards the Atlantic Ocean brought seahorses to North America. A few million years later, this western connection also closed and the entire Tethys Ocean dried out. Ralf Schneider: \"Until now it was unclear whether seahorses in the Atlantic all traced their lineage to species from the Arabian Sea that had traveled south along the east coast of Africa, around the Cape of Good Hope and across the southern Atlantic Ocean to reach South America. We found out that a second lineage of seahorses had done just that, albeit later.\" Since the research team gathered 20 animal samples from each habitat, it was also possible to measure the genetic variation between individuals. And this generally revealed: The greater the variation, the larger the population. \"We can reconstruct the age of a variation based on its type. This makes it possible to calculate the size of the population at different points in time,\" the evolutionary biologist explains. This calculation reveals that the population that crossed the Atlantic Ocean to North America was very small, supporting the hypothesis that it have come from just a few animals brought there by the ocean's currents while holding on to a raft. The same data also showed that, even today, seahorses from Africa cross the southern Atlantic Ocean and introduce their genetic material into the South American population. Fast and flexible adaptation Seahorses not only spread around the world by traveling with the ocean currents, but they were also surprisingly good at settling in new habitats. Seahorses have greatly modified genomes and, throughout their evolution, they have lost many genes, emerged with new ones or gained duplicates. This means: Seahorses change very quickly in comparison to other fish. This is probably why different types of \"bony spines\" evolved quickly and independently of each other that protect seahorses from predation in some habitats. Some of the genes have been identified that exhibit particular modifications for cer-tain species, but they are not the same for all species. Multiple fast and independent selections led to the development of spines, and although the same genes play a role in this development, different mutations were responsible. This shows that the slower, sessile seahorses were particularly able to adapt quickly to their environments. This is one of the main reasons the research team gives for seahorses being so successful in colonizing new habitats. ", "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 Seahorses have a circum-global distribution in tropical to temperate coastal waters. Yet, seahorses show many adaptations for a sedentary, cryptic lifestyle: they require specific habitats, such as seagrass, kelp or coral reefs, lack pelvic and caudal fins, and give birth to directly developed offspring without pronounced pelagic larval stage, rendering long-range dispersal by conventional means inefficient. Here we investigate seahorses’ worldwide dispersal and biogeographic patterns based on a de novo genome assembly of Hippocampus erectus as well as 358 re-sequenced genomes from 21 species. Seahorses evolved in the late Oligocene and subsequent circum-global colonization routes are identified and linked to changing dynamics in ocean currents and paleo-temporal seaway openings. Furthermore, the genetic basis of the recurring “bony spines” adaptive phenotype is linked to independent substitutions in a key developmental gene. Analyses thus suggest that rafting via ocean currents compensates for poor dispersal and rapid adaptation facilitates colonizing new habitats. Introduction Explaining mechanisms of marine biodiversification is challenging, owing to persistent paucity of information on patterns of speciation and phylogeography in marine ecosystems 1 , 2 , 3 . Major geological vicariance events, such as the closure of the Panama seaway 4 or the Tethys seaway 5 , 6 , have been suggested to impact patterns of marine biodiversification, particularly for organisms whose dispersal strategies rely on ocean currents transporting pelagic larvae or rafting individuals across large distances 7 . In such lineages, ecomorphological divergence and local adaptation after a colonization event can be slow even in the presence of strong divergent selective pressures 8 . Thus, comprehensive studies addressing spatio-temporal diversification patterns that include dynamics of geophysical processes, as well as knowledge of the genetic bases and developmental mechanisms of key adaptive traits, are required to understand the mechanisms that drive the evolution of marine biodiversity. The radiation of seahorses (Family Syngnathidae ) is a particularly iconic and suitable model system to investigate the effects that tectonic activity and ocean current dynamics can have on the dispersal and diversification of marine taxa due to the seahorses’ dispersal by rafting 7 , 9 , as well as to study the rapid evolution of adaptive phenotypes in new environments. Seahorse genomes evolve under some of the highest mutation rates among teleosts 10 and have the greatest diversification rates within their family (Supplementary Fig. 1 , Figshare: Dataset 1 ). All seahorses are sedentary but exhibit specialized morphological and life-history traits 11 , 12 , 13 , such as a prehensile tail (and the lack of a caudal fin), an elongated snout, lack of pelvic fins, an armor of bony plates instead of scales, and a unique mode of male pregnancy whereby males give birth to developed juveniles 14 , 15 . Species of seahorses differ widely in body size, color patterns and other adaptive traits to their respective environments 11 , such as the presence or absence of bony spines, which are likely an adaption against predators 16 . Previous research revealed that the evolutionary origin of seahorses likely lies in the Late Oligocene’s Indo-Pacific 17 , 18 , 19 from where different lineages dispersed around the globe despite the seahorses’ poor endurance swimming abilities and their reliance on rafting as primary long-distance dispersal strategy 9 , 20 . Nonetheless, a comprehensive understanding of the seahorses’ colonization routes is still missing as phylogenetic reconstructions were typically either derived only from relatively few species and/or few genetic markers 18 , 21 , 22 , 23 . Here, we study the diversification patterns of these unique fishes based on the analysis of multiple sequenced seahorse genomes. By conducting comprehensive phylogenetic analyses, we infer their demographic history and clarify the role of seaway closures during their diversification as part of tracing the colonization routes from the origin of their common ancestor to their current distribution. Additionally, we address the adaptive phenotypic evolution of seahorses by studying the development of one of the most eye-catching traits within the genus: the presence or absence of bony spines. Results and discussion Global diversity of seahorses Using PacBio long-read sequencing (~115-fold coverage), Illumina short-read sequencing (~243-fold coverage), and Hi-C technology (~184-fold coverage) we de novo assembled the genome of a male Hippocampus erectus . With a contig N50 of 15.5 Mb, our chromosome-level assembly (total size 420.66 Mb; comprising 22 superscaffolds corresponding to the expected chromosome number) (Supplementary Figs. 2 – 4 , Supplementary Tables 1– 4 , and Supplementary Data 1 ) improved in sequence contiguity over previously available assemblies generated from Illumina short reads alone (contig N50: 14.57 kb) 10 , 24 . We re-sequenced the genomes (~16-fold coverage) of 358 seahorse specimens comprising 21 species reflecting Hippocampus ’ global distribution, with representatives of major seahorse lineages (Fig. 1a , Supplementary Fig. 5a , Supplementary Data 2 ). Fig. 1: Genetic diversity and phylogenetic relationships of 358 seahorse specimens. a Geographic sampling locations for sampled seahorses with patterns of nucleotide diversity ( π ) of the 21 seahorse species across 22 chromosomes. Maps from Wessel et al. (2013) under GNU GPL license 91 . b Neighbor-joining tree constructed with genome-wide SNPs of 358 seahorses. Location pin symbols in ( a ) and branch background in ( b ) correspond to each other. Seahorses illustrations by Geng Qin. Source data are provided as a Source Data file. Full size image Our analysis identified each seahorse species as a monophyletic group in a neighbor-joining tree inferred from 41 million genome-wide single nucleotide polymorphisms (SNPs) (Fig. 1b , Supplementary Tables 5 – 8 ), and they formed distinct clusters in a principal component analysis (Supplementary Fig. 5b ). Genetic diversity ( θπ and θω ) varied substantially among species and chromosomes, as it was, for example, generally higher for seahorses in the North Atlantic Ocean biome than in the South Atlantic Ocean biome (Fig. 1a , Supplementary Figs. 6 , 7 , Figshare: Dataset 2 ). The time-calibrated tree estimated that the common ancestor of all extant seahorses lived ~20–25 Ma (million years ago) (Fig. 2a , Supplementary Figs.<|im_end|> <|im_start|>assistant Seahorses are extremely poor swimmers. Surprisingly, however, they can be found in all of the world's oceans. On the basis of almost 360 different seahorse genomes, a group of researchers studied how these special fish were able to spread so suc-cessfully worldwide. Based on an evolutionary tree of 21 species it was possible to reconstruct the dispersal routes of seahorses worldwide and to explain where and when new species emerged. The international research collaboration involving the research team led by evolutionary biologist Professor Axel Meyer at the University of Konstanz and researchers from China and Singapore was able to identify factors that led to the success of the seahorse from a developmental biology perspective: its quickness to adapt by, for example, repeatedly evolving spines in the skin and its fast genetic rates of evolution. The results will be published on 17 February 2021 in Nature Communications. Seahorses of the genus Hippocampus emerged about 25 million years ago in the Indo-Pacific region from pipefish, their closest relatives. And while the latter usually swim fairly well, seahorses lack their pelvic and tail fins and evolved a prehensile tail instead that can be used, for example, to hold on to seaweed or corals. Early on, they split into two main groups. "One group stayed mainly in the same place, while the other spread all over the world," says Dr. Ralf Schneider, who is now a postdoc-toral researcher at the GEOMAR Helmholtz Centre for Ocean Research Kiel, and participated in the study while working as a doctoral researcher in Axel Meyer's re-search team. In their original home waters of the Indo-Pacific, the remaining species diversified in a unique island environment, while the other group made its way into the Pacific Ocean via Africa, Europe and the Americas. Traveling the world by raft The particularly large amount of data collected for the study enabled the research team to create an especially reliable seahorse tree showing the relationships be-tween species and the global dispersal routes of the seahorse. Evolutionary biologist, Dr. Schneider, says: "If you compare the relationships between the species to the ocean currents, you notice that seahorses were transported across the oceans." If, for example, they were carried out to sea during storms, they used their grasping tail to hold on to anything they could find, like a piece of algae or a tree trunk. These are places where the animals could survive for a long time. The currents often swept these "rafts" hundreds of kilometers across the ocean before they landed someplace where the seahorses could hop off and find a new home. Since seahorses have been around for more than 25 million years, it was important to factor in that ocean currents have changed over time as tectonic plates have shift-ed. For example, about 15 million years ago, the Tethys Ocean was almost as large as today's Mediterranean Sea. On the west side, where the Strait of Gibraltar is lo-cated today, it connected to the Atlantic Ocean. On the east side, where the Arabian Peninsula is today, it led to the Indian Ocean. Tectonic shifts change ocean currents The researchers were able to underscore, for example, that the seahorses were able to colonize the Tethys Ocean via the Arabian Sea just before the tectonic plates shifted and sealed off the eastern connection. The resulting current flowing westward towards the Atlantic Ocean brought seahorses to North America. A few million years later, this western connection also closed and the entire Tethys Ocean dried out. Ralf Schneider: "Until now it was unclear whether seahorses in the Atlantic all traced their lineage to species from the Arabian Sea that had traveled south along the east coast of Africa, around the Cape of Good Hope and across the southern Atlantic Ocean to reach South America. We found out that a second lineage of seahorses had done just that, albeit later." Since the research team gathered 20 animal samples from each habitat, it was also possible to measure the genetic variation between individuals. And this generally revealed: The greater the variation, the larger the population. "We can reconstruct the age of a variation based on its type. This makes it possible to calculate the size of the population at different points in time," the evolutionary biologist explains. This calculation reveals that the population that crossed the Atlantic Ocean to North America was very small, supporting the hypothesis that it have come from just a few animals brought there by the ocean's currents while holding on to a raft. The same data also showed that, even today, seahorses from Africa cross the southern Atlantic Ocean and introduce their genetic material into the South American population. Fast and flexible adaptation Seahorses not only spread around the world by traveling with the ocean currents, but they were also surprisingly good at settling in new habitats. Seahorses have greatly modified genomes and, throughout their evolution, they have lost many genes, emerged with new ones or gained duplicates. This means: Seahorses change very quickly in comparison to other fish. This is probably why different types of "bony spines" evolved quickly and independently of each other that protect seahorses from predation in some habitats. Some of the genes have been identified that exhibit particular modifications for cer-tain species, but they are not the same for all species. Multiple fast and independent selections led to the development of spines, and although the same genes play a role in this development, different mutations were responsible. This shows that the slower, sessile seahorses were particularly able to adapt quickly to their environments. This is one of the main reasons the research team gives for seahorses being so successful in colonizing new habitats. <|im_end|>
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2,613
[ { "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 Topological insulators are a new class of quantum materials that are characterized by robust topological surface states (TSSs) inside the bulk insulating gap 1 , 2 , which hold great potential for applications in quantum information and spintronics as well as thermoelectrics. One major obstacle is the relatively small size of the bulk bandgap, which is typically around 0.3 eV for the known topological insulator materials (ref. 3 and references therein). Here we demonstrate through ab initio calculations that a known superconductor BaBiO 3 (BBO) with a T c of nearly 30 K (refs 4 , 5 ) emerges as a topological insulator in the electron-doped region. BBO exhibits a large topological energy gap of 0.7 eV, inside which a Dirac type of TSSs exists. As the first oxide topological insulator, BBO is naturally stable against surface oxidization and degradation, distinct from chalcogenide topological insulators 6 , 7 , 8 . An extra advantage of BBO lies in its ability to serve as an interface between TSSs and superconductors to realize Majorana fermions for future applications in quantum computation 9 . Main Mixed-valent perovskite oxides based on BBO (refs 4 , 5 ) are, like cuprates, well-known superconductors. The parent compound BBO crystallizes in a mononclinic lattice 10 that is distorted from the perovskite structure, and this distortion is attributed to the coexistence of two valence states, Bi 3+ (6 s 2 ) and Bi 5+ (6 s 0 ), due to charge disproportion of the formal Bi 4+ . Octahedral BiO 6 breathes out and in for Bi 3+ and Bi 5+ , respectively 10 . Under hole-doping conditions, such as in Ba 1− x K x BiO 3 ( x ∼ 0.4; ref. 5 ) and BaBi 1− x Pb x O 3 ( x ∼ 0.3; refs 4 , 11 ), the breathing distortion is suppressed, resulting in a simple perovskite lattice 12 in which superconductivity emerges. Recent ab initio calculations 13 have assigned the higher T c superconductivity to a correlation-enhanced electron–phonon coupling mechanism, stimulating the prediction and synthesis of new superconductor candidates among mixed-valent thallium perovskites 14 , 15 , 16 . The existing superconductivity has meant that research has mainly focused on hole-doped compounds, leaving electron-doped compounds relatively unexplored. In addition, the spin–orbit coupling (SOC) effect was not taken into account in previous theoretical study (ref. 13 and references therein), because the electronic states in the superconducting (hole-doped) region mainly result from Bi- 6 s and O- 2 p orbitals whose SOC effect is usually negligible. By including the SOC effect in density-functional theory (DFT) calculations of the BBO band structure, we discovered a band inversion between the first (Bi- 6 s state) and second (Bi- 6 p state) conduction bands, which is stable against lattice distortions. This inversion indicates that BBO is a three-dimensional topological insulator with a large indirect energy gap of 0.7 eV when doped by electrons instead of holes. The band structure of ideal cubic BBO reveals that the conduction bands are modified markedly when SOC is included owing to the presence of the Bi- 6 p states, as illustrated in Fig. 1a . The first conduction band crossing the Fermi energy ( E F ) has a considerable Bi- 6 s contribution over the whole Brillouin zone, except at the R momentum point where the Bi- 6 p contribution is dominant with the Bi- 6 s lying above it. Although one can see an inversion between Bi- 6 p and 6 s states here, there is a zero energy gap at R without SOC because of the degeneracy of the p states. In previous literature that did not employ SOC, actually, this feature was already revealed. When SOC is included, we found that the | p , j = 3/2〉 and | p , j = 1/2〉 states split, which results in the large indirect energy gap of 0.7 eV in the vicinity of the R point. We point out that the band inversion strength is as large as nearly 2 eV, which is the energy difference between Bi- 6 s and | p , j = 1/2〉 states at the R point, as shown in Fig. 1b . Unlike bulk HgTe (ref. 17 ), a well-known topological insulator, this inversion occurs between the | s , j = 1/2〉 state and the | p , j = 1/2〉 state, rather than the | p , j = 3/2〉 state. As the Bi atom is the inversion centre of the perovskite lattice, the Bi- 6 s and Bi- 6 p states have + and − parities, respectively. Thus, a topological insulator state can be obtained if E F is shifted up into this energy gap. The parities of all the valence bands below this gap were also calculated at all time-reversal invariant momenta, Γ, X, M and R, which yielded Z 2 topological invariants (1;111), confirming the topological non-trivial feature according to the parity criteria 18 . This is also consistent with a previous study of a topological insulator phase with Z 2 (1;111) in the perovskite lattice based on the model Hamiltonian 19 . At a doping rate of one electron per formula unit, E F shifts inside the s – p inversion gap, and all the Bi ions become Bi 3+ . Consequently, a cubic phase appears when the BiO 6 breathing distortion is suppressed, similar to the hole-doping case 12 . When the lone-pair Bi- 6 s state is fully occupied, we found that the new cubic lattice expands slightly in comparison with the undoped lattice. Although the s band becomes narrower in this case, the band inversion remains owing to the large s – p inversion strength (see Supplementary Fig. S1 ). Figure 1: Crystal structures and band structures of BBO. a , Ideal cubic perovskite lattice with the cubic Brillouin zone, and the band inversion process. The Bi atom is represented by the purple ball, O atoms by red balls and Ba atoms", "role": "user" }, { "content": "Most materials show one function, for example, a material can be a metal, a semiconductor, or an insulator. Metals such as copper are used as conducting wires with only low resistance and energy loss. Superconductors are metals which can conduct current even without any resistance, although only far below room temperature. Semiconductors, the foundation of current computer technology, show only low conduction of current, while insulators show no conductivity at all. Physicists have recently been excited about a new exotic type of materials, so-called topological insulators. A topological insulator is insulating inside the bulk like a normal insulator, while on the surface it shows conductivity like a metal. When a topological insulator is interfaced with a superconductor, a mysterious particle called Majorana fermion emerges, which can be used to fabricate a quantum computer that can run much more quickly than any current computer. Searching for Majorana fermions based on a topological insulator–superconductor interface has thus become a hot race just very recently. Computer-based materials design has demonstrated its power in scientific research, saving resources and also accelerating the search for new materials for specific purposes. By employing state-of-art materials design methods, Dr. Binghai Yan and his collaborators from the Max Planck Institute for Chemical Physics of Solids and Johannes Gutenberg University Mainz (JGU) have recently predicted that the oxide compound BaBiO3 combines two required properties, i.e., topological insulator and superconductivity. This material has been known for about thirty years as a high-temperature superconductor of Tc of nearly 30 Kelvin with p-type doping. Now it has been discovered to be also a topological insulator with n-type doping. A p-n junction type of simple device assisted by gating or electrolyte gating is proposed to realize Majorana fermions for quantum computation, which does not require a complex interface between two materials. In addition to their options for use in quantum computers, topological insulators hold great potential applications in the emerging technology of spintronics and thermoelectrics for energy harvesting. One major obstacle for widespread application is the relatively small size of the bulk band gap, which is typically around 0.3 electron-volts (eV) for previously known topological insulator materials. Currently identified material exhibits a much larger energy-gap of 0.7 eV. Inside the energy-gap, metallic topological surface states exist with a Dirac-cone type of band structures. The research leading to the recent publication in Nature Physics was performed by a team of researchers from Dresden and Mainz around the theoretical physicist Dr. Binghai Yan and the experimental chemists Professor Martin Jansen and Professor Claudia Felser. \"Now we are trying to synthesize n-type doped BaBiO3,\" said Jansen. \"And we hope to be soon able to realize our idea.\" ", "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 Topological insulators are a new class of quantum materials that are characterized by robust topological surface states (TSSs) inside the bulk insulating gap 1 , 2 , which hold great potential for applications in quantum information and spintronics as well as thermoelectrics. One major obstacle is the relatively small size of the bulk bandgap, which is typically around 0.3 eV for the known topological insulator materials (ref. 3 and references therein). Here we demonstrate through ab initio calculations that a known superconductor BaBiO 3 (BBO) with a T c of nearly 30 K (refs 4 , 5 ) emerges as a topological insulator in the electron-doped region. BBO exhibits a large topological energy gap of 0.7 eV, inside which a Dirac type of TSSs exists. As the first oxide topological insulator, BBO is naturally stable against surface oxidization and degradation, distinct from chalcogenide topological insulators 6 , 7 , 8 . An extra advantage of BBO lies in its ability to serve as an interface between TSSs and superconductors to realize Majorana fermions for future applications in quantum computation 9 . Main Mixed-valent perovskite oxides based on BBO (refs 4 , 5 ) are, like cuprates, well-known superconductors. The parent compound BBO crystallizes in a mononclinic lattice 10 that is distorted from the perovskite structure, and this distortion is attributed to the coexistence of two valence states, Bi 3+ (6 s 2 ) and Bi 5+ (6 s 0 ), due to charge disproportion of the formal Bi 4+ . Octahedral BiO 6 breathes out and in for Bi 3+ and Bi 5+ , respectively 10 . Under hole-doping conditions, such as in Ba 1− x K x BiO 3 ( x ∼ 0.4; ref. 5 ) and BaBi 1− x Pb x O 3 ( x ∼ 0.3; refs 4 , 11 ), the breathing distortion is suppressed, resulting in a simple perovskite lattice 12 in which superconductivity emerges. Recent ab initio calculations 13 have assigned the higher T c superconductivity to a correlation-enhanced electron–phonon coupling mechanism, stimulating the prediction and synthesis of new superconductor candidates among mixed-valent thallium perovskites 14 , 15 , 16 . The existing superconductivity has meant that research has mainly focused on hole-doped compounds, leaving electron-doped compounds relatively unexplored. In addition, the spin–orbit coupling (SOC) effect was not taken into account in previous theoretical study (ref. 13 and references therein), because the electronic states in the superconducting (hole-doped) region mainly result from Bi- 6 s and O- 2 p orbitals whose SOC effect is usually negligible. By including the SOC effect in density-functional theory (DFT) calculations of the BBO band structure, we discovered a band inversion between the first (Bi- 6 s state) and second (Bi- 6 p state) conduction bands, which is stable against lattice distortions. This inversion indicates that BBO is a three-dimensional topological insulator with a large indirect energy gap of 0.7 eV when doped by electrons instead of holes. The band structure of ideal cubic BBO reveals that the conduction bands are modified markedly when SOC is included owing to the presence of the Bi- 6 p states, as illustrated in Fig. 1a . The first conduction band crossing the Fermi energy ( E F ) has a considerable Bi- 6 s contribution over the whole Brillouin zone, except at the R momentum point where the Bi- 6 p contribution is dominant with the Bi- 6 s lying above it. Although one can see an inversion between Bi- 6 p and 6 s states here, there is a zero energy gap at R without SOC because of the degeneracy of the p states. In previous literature that did not employ SOC, actually, this feature was already revealed. When SOC is included, we found that the | p , j = 3/2〉 and | p , j = 1/2〉 states split, which results in the large indirect energy gap of 0.7 eV in the vicinity of the R point. We point out that the band inversion strength is as large as nearly 2 eV, which is the energy difference between Bi- 6 s and | p , j = 1/2〉 states at the R point, as shown in Fig. 1b . Unlike bulk HgTe (ref. 17 ), a well-known topological insulator, this inversion occurs between the | s , j = 1/2〉 state and the | p , j = 1/2〉 state, rather than the | p , j = 3/2〉 state. As the Bi atom is the inversion centre of the perovskite lattice, the Bi- 6 s and Bi- 6 p states have + and − parities, respectively. Thus, a topological insulator state can be obtained if E F is shifted up into this energy gap. The parities of all the valence bands below this gap were also calculated at all time-reversal invariant momenta, Γ, X, M and R, which yielded Z 2 topological invariants (1;111), confirming the topological non-trivial feature according to the parity criteria 18 . This is also consistent with a previous study of a topological insulator phase with Z 2 (1;111) in the perovskite lattice based on the model Hamiltonian 19 . At a doping rate of one electron per formula unit, E F shifts inside the s – p inversion gap, and all the Bi ions become Bi 3+ . Consequently, a cubic phase appears when the BiO 6 breathing distortion is suppressed, similar to the hole-doping case 12 . When the lone-pair Bi- 6 s state is fully occupied, we found that the new cubic lattice expands slightly in comparison with the undoped lattice. Although the s band becomes narrower in this case, the band inversion remains owing to the large s – p inversion strength (see Supplementary Fig. S1 ). Figure 1: Crystal structures and band structures of BBO. a , Ideal cubic perovskite lattice with the cubic Brillouin zone, and the band inversion process. The Bi atom is represented by the purple ball, O atoms by red balls and Ba atoms<|im_end|> <|im_start|>assistant Most materials show one function, for example, a material can be a metal, a semiconductor, or an insulator. Metals such as copper are used as conducting wires with only low resistance and energy loss. Superconductors are metals which can conduct current even without any resistance, although only far below room temperature. Semiconductors, the foundation of current computer technology, show only low conduction of current, while insulators show no conductivity at all. Physicists have recently been excited about a new exotic type of materials, so-called topological insulators. A topological insulator is insulating inside the bulk like a normal insulator, while on the surface it shows conductivity like a metal. When a topological insulator is interfaced with a superconductor, a mysterious particle called Majorana fermion emerges, which can be used to fabricate a quantum computer that can run much more quickly than any current computer. Searching for Majorana fermions based on a topological insulator–superconductor interface has thus become a hot race just very recently. Computer-based materials design has demonstrated its power in scientific research, saving resources and also accelerating the search for new materials for specific purposes. By employing state-of-art materials design methods, Dr. Binghai Yan and his collaborators from the Max Planck Institute for Chemical Physics of Solids and Johannes Gutenberg University Mainz (JGU) have recently predicted that the oxide compound BaBiO3 combines two required properties, i.e., topological insulator and superconductivity. This material has been known for about thirty years as a high-temperature superconductor of Tc of nearly 30 Kelvin with p-type doping. Now it has been discovered to be also a topological insulator with n-type doping. A p-n junction type of simple device assisted by gating or electrolyte gating is proposed to realize Majorana fermions for quantum computation, which does not require a complex interface between two materials. In addition to their options for use in quantum computers, topological insulators hold great potential applications in the emerging technology of spintronics and thermoelectrics for energy harvesting. One major obstacle for widespread application is the relatively small size of the bulk band gap, which is typically around 0.3 electron-volts (eV) for previously known topological insulator materials. Currently identified material exhibits a much larger energy-gap of 0.7 eV. Inside the energy-gap, metallic topological surface states exist with a Dirac-cone type of band structures. The research leading to the recent publication in Nature Physics was performed by a team of researchers from Dresden and Mainz around the theoretical physicist Dr. Binghai Yan and the experimental chemists Professor Martin Jansen and Professor Claudia Felser. "Now we are trying to synthesize n-type doped BaBiO3," said Jansen. "And we hope to be soon able to realize our idea." <|im_end|>
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1629, 1790, 810, 6288, 1109, 904, 1510, 6500, 13, 80993, 369, 17559, 3444, 81682, 919, 3196, 389, 264, 1948, 5848, 1672, 10733, 4235, 9712, 444, 36869, 3834, 706, 8617, 3719, 264, 4106, 7102, 1120, 1633, 6051, 13, 17863, 6108, 7384, 2955, 706, 21091, 1202, 2410, 304, 12624, 3495, 11, 14324, 5070, 323, 1101, 69741, 279, 2778, 369, 502, 7384, 369, 3230, 10096, 13, 3296, 51297, 1614, 8838, 38921, 7384, 2955, 5528, 11, 2999, 13, 54587, 26279, 25191, 323, 813, 79119, 505, 279, 7639, 9878, 377, 10181, 369, 36424, 28415, 315, 11730, 3447, 323, 55205, 52686, 3907, 4802, 89, 320, 41, 55795, 8, 617, 6051, 19698, 430, 279, 51180, 24549, 14659, 37196, 46, 18, 33511, 1403, 2631, 6012, 11, 602, 1770, 2637, 1948, 5848, 1672, 10733, 323, 2307, 77752, 1968, 13, 1115, 3769, 706, 1027, 3967, 369, 922, 27219, 1667, 439, 264, 1579, 12, 35658, 2307, 444, 36869, 315, 350, 66, 315, 7154, 220, 966, 92073, 449, 281, 10827, 97928, 13, 4800, 433, 706, 1027, 11352, 311, 387, 1101, 264, 1948, 5848, 1672, 10733, 449, 308, 10827, 97928, 13, 362, 281, 5392, 49341, 955, 315, 4382, 3756, 39061, 555, 74499, 477, 73396, 668, 74499, 374, 11223, 311, 13383, 17559, 3444, 81682, 919, 369, 31228, 35547, 11, 902, 1587, 539, 1397, 264, 6485, 3834, 1990, 1403, 7384, 13, 763, 5369, 311, 872, 2671, 369, 1005, 304, 31228, 19002, 11, 1948, 5848, 1672, 42391, 3412, 2294, 4754, 8522, 304, 279, 24084, 5557, 315, 12903, 35785, 1233, 323, 30945, 4748, 772, 6329, 369, 4907, 66747, 13, 3861, 3682, 33287, 369, 24716, 3851, 374, 279, 12309, 2678, 1404, 315, 279, 20155, 7200, 13225, 11, 902, 374, 11383, 2212, 220, 15, 13, 18, 17130, 8437, 337, 2641, 320, 68, 53, 8, 369, 8767, 3967, 1948, 5848, 1672, 10733, 7384, 13, 25122, 11054, 3769, 50829, 264, 1790, 8294, 4907, 89657, 315, 220, 15, 13, 22, 384, 53, 13, 28468, 279, 4907, 89657, 11, 46258, 1948, 5848, 7479, 5415, 3073, 449, 264, 31194, 582, 15204, 68, 955, 315, 7200, 14726, 13, 578, 3495, 6522, 311, 279, 3293, 17009, 304, 22037, 28415, 574, 10887, 555, 264, 2128, 315, 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2,037
[ { "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 explored human induced pluripotent stem cells (hiPSCs) derived from different tissues to gain insights into genomic integrity at single-nucleotide resolution. We used genome sequencing data from two large hiPSC repositories involving 696 hiPSCs and daughter subclones. We find ultraviolet light (UV)-related damage in ~72% of skin fibroblast-derived hiPSCs (F-hiPSCs), occasionally resulting in substantial mutagenesis (up to 15 mutations per megabase). We demonstrate remarkable genomic heterogeneity between independent F-hiPSC clones derived during the same round of reprogramming due to oligoclonal fibroblast populations. In contrast, blood-derived hiPSCs (B-hiPSCs) had fewer mutations and no UV damage but a high prevalence of acquired BCOR mutations (26.9% of lines). We reveal strong selection pressure for BCOR mutations in F-hiPSCs and B-hiPSCs and provide evidence that they arise in vitro. Directed differentiation of hiPSCs and RNA sequencing showed that BCOR mutations have functional consequences. Our work strongly suggests that detailed nucleotide-resolution characterization is essential before using hiPSCs. Main In regenerative medicine, human induced pluripotent stem cells (hiPSCs) and latterly organoids have become attractive model systems because they can be propagated and differentiated into many cell types. Specifically, hiPSCs have been adopted as a cellular model of choice for in vitro disease modeling as well as being considered for cell-based therapies 1 , 2 , 3 . The genomic integrity and tumorigenic potential of human pluripotent stem cells have been explored previously, but systematic large-scale, whole-genome assessments of mutagenesis at single-nucleotide resolution have been limited 4 , 5 , 6 , 7 , 8 . Human embryonic stem cells (hESCs) cultured in vitro have been reported to harbor TP53 mutations and recurrent chromosomal-scale genomic abnormalities ascribed to selection pressure 9 , 10 , 11 , 12 , 13 , 14 . However, in contrast, a recent study showed a low mutation burden in clinical-grade hESCs, and no cancer driver mutations were detected 15 . The mutational burden in any given hiPSC comprises mutations that were preexisting in the parental somatic cells from which it was derived and mutations that have accumulated over the course of reprogramming, cell culture and passaging 7 , 16 , 17 , 18 , 19 , 20 , 21 , 22 . Several small-scale genomic studies have shown that in some cell lines, preexisting somatic mutations make up a substantial proportion of the total burden 22 , 23 , 24 , 25 , 26 , 27 , 28 . With the advent of clinical trials using hiPSCs (e.g., NCT04339764 ) comes the need to gain in-depth understanding of the mutational landscape and potential risks of using these cells 29 , 30 . Here we contrast skin-derived (F-hiPSCs) and blood-derived (B-hiPSCs) from one individual. We then comprehensively assess hiPSCs from one of the world’s largest stem cell banks, HipSci, and an alternative cohort called Insignia. All lines had been karyotypically prescreened and deemed as chromosomally stable. We utilized combinations of whole-genome sequencing (WGS) and whole-exome sequencing (WES) of 555 hiPSC samples and 141 B-hiPSC-derived subclones (Supplementary Table 1 ) to understand the extent and origin of genomic damage and the possible implications. Results Genomic variations in skin and blood derived hiPSCs To first understand the extent to which the source of somatic cells used to make hiPSCs impacted on mutational load, we compared genomic variation in two independent F-hiPSCs and two independent B-hiPSCs from a 22-year-old healthy adult male (S2) (Fig. 1a ). F-hiPSCs were derived from skin fibroblasts, and B-hiPSCs were derived from peripheral blood endothelial progenitor cells (EPCs). Additionally, we derived F-hiPSCs and B-hiPSCs from six healthy males (S7, oaqd, paab, yemz, qorq and quls) and four healthy females (iudw, laey, eipl and fawm) (Fig. 1a ). Fig. 1: Comparison of mutation burden in EPC-derived and F-hiPSCs. a , Source of hiPSCs. Multiple hiPSC lines created from patient S2 contrasted to fibroblast- and EPC-derived hiPSCs created from ten other individuals. b , Mutation burden of substitutions, double substitutions (first row), substitution types (second row), skin-derived signatures (third row), indel types (fourth row) and rearrangements (lowest row). Supplementary Table 2 provides source information. UV-specific features, such as elevated CC>TT double substitutions and UV mutational signatures, were enriched in F-hiPSCs. Full size image WGS analysis revealed a greater number of mutations in F-hiPSCs as compared to B-hiPSCs in the individual S2 (~4.4 increase), and in lines derived from the other ten donors (Fig. 1b and Supplementary Table 2 ). There were very few structural variants (SVs) observed; thus, chromosomal-scale aberrations were not distinguishing between F-hiPSCs and B-hiPSCs (Supplementary Table 2 ). We noted considerable heterogeneity in the total numbers of mutations between sister hiPSCs from the same donor, S2; one F-hiPSC line (S2_SF3_P2) had 8,171 single substitutions, 1,879 double substitutions and 226 indels, whereas the other F-hiPSC line (S2_SF2_P2) had 1,873 single substitutions, 17 double substitutions and 71 indels (Fig. 1b ). Mutational signature analysis demonstrated striking predominance of UV-associated substitutions (Reference Signature/COSMIC) Signature 7 (ref. 31 ) in the F-hiPSCs, characterized by C>T transitions at T C A, T C C and T C T (Fig. 1b and Extended Data Fig. 1 ). This finding is consistent with previously published work that attributed UV signatures in hiPSCs to preexisting damage in parental skin fibroblasts 8 , 32 . In contrast, EPC-derived B-hiPSCs did not show any evidence of UV damage but showed patterns consistent with possible oxidative damage (signature 18, characterized by C>A mutations at T C T, G C A and A C A; Fig. 1 and Extended Data Fig. 1 ). Consistent with in vitro studies 33 , 34 , double substitutions were enriched in UV-damaged F-hiPSCs (Fig. 1b ). In all, we concluded that F-hiPSCs carry UV-related genomic damage as a result of sunlight exposure in vivo that does not manifest in EPC-derived B-hiPSCs. Importantly, screening for copy-number aberrations underestimated the substantial substitution/indel-based variation that exists in hiPSCs. High prevalence of UV-associated DNA damage in F-hiPSCs We asked whether these findings were applicable across F-hiPSC lines generally. Therefore, we interrogated all lines in the HipSci stem cell bank,", "role": "user" }, { "content": "DNA damage caused by factors such as ultraviolet radiation affect nearly three-quarters of all stem cell lines derived from human skin cells, say Cambridge researchers, who argue that whole genome sequencing is essential for confirming if cell lines are usable. Stem cells are a special type of cell that can be programmed to become almost any type of cell within the body. They are currently used for studies on the development of organs and even the early stages of the embryo. Increasingly, researchers are turning to stem cells as ways of developing new treatments, known as cell-based therapies. Other potential applications include programming stem cells to grow into nerve cells to replace those lost to neurodegeneration in diseases such as Parkinson's. Originally, stem cells were derived from embryos, but it is now possible to derive stem cells from adult skin cells. These so-called induced pluripotent stem cells (iPSCs) have now been generated from a range of tissues, including blood, which is increasing in popularity due to its ease of derivation. However, researchers at the University of Cambridge and Wellcome Sanger Institute have discovered a problem with stem cell lines derived from both skin cells and blood. When they examined the genomes of the stem cell lines in detail, they found that nearly three quarters carried substantial damage to their DNA that could compromise their use both in research and, crucially, in cell-based therapies. Their findings represent the largest genetic study to date of iPSCs and are published today in Nature Genetics. DNA is made up of three billions pairs of nucleotides, molecules represented by the letters A, C, G and T. Over time, damage to our DNA, for example from ultraviolet radiation, can lead to mutations—a letter C might change to a letter T, for example. \"Fingerprints\" left on our DNA can reveal what is responsible for this damage. As these mutations accumulate, they can have a profound effect on the function of cells and in some cases lead to tumors. Dr. Foad Rouhani, who carried out the work while at the University of Cambridge and the Wellcome Sanger Institute, said: \"We noticed that some of the iPS cells that we were generating looked really different from each other, even when they were derived from the same patient and derived in the same experiment. The most striking thing was that pairs of iPS cells would have a vastly different genetic landscape—one line would have minimal damage and the other would have a level of mutations more commonly seen in tumors. One possible reason for this could be that a cell on the surface of the skin is likely to have greater exposure to sunlight than a cell below the surface and therefore eventually may lead to iPS cells with greater levels of genomic damage.\" The researchers used a common technique known as whole genome sequencing to inspect the entire DNA of stem cell lines in different cohorts, including the HipSci cohort at the Wellcome Sanger Institute and discovered that as many as 72% of the lines showed signs of major UV damage. Professor Serena Nik-Zainal from the Department of Medical Genetics at the University of Cambridge said: \"Almost three-quarters of the cell lines had UV damage. Some samples had an enormous amount of mutations—sometimes more than we find in tumors. We were all hugely surprised to learn this, given that most of these lines were derived from skin biopsies of healthy people.\" They decided to turn their attention to cell lines not derived from skin and focused on blood derived iPSCs as these are becoming increasingly popular due to the ease of obtaining blood samples. They found that while these blood-derived iPSCs, too, carried mutations, they had lower levels of mutations than skin-derived iPS cells and no UV damage. However, around a quarter carried mutations in a gene called BCOR, an important gene in blood cancers. To investigate whether these BCOR mutations had any functional impact, they differentiated the iPSCs and turned them into neurons, tracking their progress along the way. Dr. Rouhani said: \"What we saw was that there were problems in generating neurons from iPSCs that have BCOR mutations—they had a tendency to favor other cell types instead. This is a significant finding, particularly if one is intending to use those lines for neurological research.\" When they examined the blood samples, they discovered that the BCOR mutations were not present within the patient: instead, the process of culturing cells appears to increase the frequency of these mutations, which may have implications for other researchers working with cells in culture. Scientists typically screen their cell lines for problems at the chromosomal level—for example by checking to see that the requisite 23 pairs of chromosomes are present. However, this would not be sufficiently detailed to pick up the potentially major problems that this new study has identified. Importantly, without looking in detail at the genomes of these stem cells, researchers and clinicians would be unaware of the underlying damage that is present with the cell lines they are working with. \"The DNA damage that we saw was at a nucleotide level,\" says Professor Nik-Zainal. \"If you think of the human genome as like a book, most researchers would check the number of chapters and be satisfied that there were none missing. But what we saw was that even with the correct number of chapters in place, lots of the words were garbled.\" Fortunately, says Professor Nik-Zainal, there is a way round the problem: using whole genome sequencing to look in detail for the errors at the outset. \"The cost of whole genome sequencing has dropped dramatically in recent years to around £500 per sample, though it's the analysis and interpretation that's the hardest bit. If a research question involves cell lines and cellular models, and particularly if we're going to introduce these lines back into patients, we may have to consider sequencing the genomes of these lines to understand what we are dealing with and get a sense of whether they are suitable for use.\" Dr. Rouhani adds: \"In recent years we have been finding out more and more about how even our healthy cells carry many mutations and therefore it is not a realistic aim to produce stem cell lines with zero mutations. The goal should be to know as much as possible about the nature and extent of the DNA damage to make informed choices about the ultimate use of these stem cell lines. \"If a line is to be used for cell based therapies in patients for example, then we need to understand more about the implications of these mutations so that both clinicians and patients are better informed of the risks involved in the 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 We explored human induced pluripotent stem cells (hiPSCs) derived from different tissues to gain insights into genomic integrity at single-nucleotide resolution. We used genome sequencing data from two large hiPSC repositories involving 696 hiPSCs and daughter subclones. We find ultraviolet light (UV)-related damage in ~72% of skin fibroblast-derived hiPSCs (F-hiPSCs), occasionally resulting in substantial mutagenesis (up to 15 mutations per megabase). We demonstrate remarkable genomic heterogeneity between independent F-hiPSC clones derived during the same round of reprogramming due to oligoclonal fibroblast populations. In contrast, blood-derived hiPSCs (B-hiPSCs) had fewer mutations and no UV damage but a high prevalence of acquired BCOR mutations (26.9% of lines). We reveal strong selection pressure for BCOR mutations in F-hiPSCs and B-hiPSCs and provide evidence that they arise in vitro. Directed differentiation of hiPSCs and RNA sequencing showed that BCOR mutations have functional consequences. Our work strongly suggests that detailed nucleotide-resolution characterization is essential before using hiPSCs. Main In regenerative medicine, human induced pluripotent stem cells (hiPSCs) and latterly organoids have become attractive model systems because they can be propagated and differentiated into many cell types. Specifically, hiPSCs have been adopted as a cellular model of choice for in vitro disease modeling as well as being considered for cell-based therapies 1 , 2 , 3 . The genomic integrity and tumorigenic potential of human pluripotent stem cells have been explored previously, but systematic large-scale, whole-genome assessments of mutagenesis at single-nucleotide resolution have been limited 4 , 5 , 6 , 7 , 8 . Human embryonic stem cells (hESCs) cultured in vitro have been reported to harbor TP53 mutations and recurrent chromosomal-scale genomic abnormalities ascribed to selection pressure 9 , 10 , 11 , 12 , 13 , 14 . However, in contrast, a recent study showed a low mutation burden in clinical-grade hESCs, and no cancer driver mutations were detected 15 . The mutational burden in any given hiPSC comprises mutations that were preexisting in the parental somatic cells from which it was derived and mutations that have accumulated over the course of reprogramming, cell culture and passaging 7 , 16 , 17 , 18 , 19 , 20 , 21 , 22 . Several small-scale genomic studies have shown that in some cell lines, preexisting somatic mutations make up a substantial proportion of the total burden 22 , 23 , 24 , 25 , 26 , 27 , 28 . With the advent of clinical trials using hiPSCs (e.g., NCT04339764 ) comes the need to gain in-depth understanding of the mutational landscape and potential risks of using these cells 29 , 30 . Here we contrast skin-derived (F-hiPSCs) and blood-derived (B-hiPSCs) from one individual. We then comprehensively assess hiPSCs from one of the world’s largest stem cell banks, HipSci, and an alternative cohort called Insignia. All lines had been karyotypically prescreened and deemed as chromosomally stable. We utilized combinations of whole-genome sequencing (WGS) and whole-exome sequencing (WES) of 555 hiPSC samples and 141 B-hiPSC-derived subclones (Supplementary Table 1 ) to understand the extent and origin of genomic damage and the possible implications. Results Genomic variations in skin and blood derived hiPSCs To first understand the extent to which the source of somatic cells used to make hiPSCs impacted on mutational load, we compared genomic variation in two independent F-hiPSCs and two independent B-hiPSCs from a 22-year-old healthy adult male (S2) (Fig. 1a ). F-hiPSCs were derived from skin fibroblasts, and B-hiPSCs were derived from peripheral blood endothelial progenitor cells (EPCs). Additionally, we derived F-hiPSCs and B-hiPSCs from six healthy males (S7, oaqd, paab, yemz, qorq and quls) and four healthy females (iudw, laey, eipl and fawm) (Fig. 1a ). Fig. 1: Comparison of mutation burden in EPC-derived and F-hiPSCs. a , Source of hiPSCs. Multiple hiPSC lines created from patient S2 contrasted to fibroblast- and EPC-derived hiPSCs created from ten other individuals. b , Mutation burden of substitutions, double substitutions (first row), substitution types (second row), skin-derived signatures (third row), indel types (fourth row) and rearrangements (lowest row). Supplementary Table 2 provides source information. UV-specific features, such as elevated CC>TT double substitutions and UV mutational signatures, were enriched in F-hiPSCs. Full size image WGS analysis revealed a greater number of mutations in F-hiPSCs as compared to B-hiPSCs in the individual S2 (~4.4 increase), and in lines derived from the other ten donors (Fig. 1b and Supplementary Table 2 ). There were very few structural variants (SVs) observed; thus, chromosomal-scale aberrations were not distinguishing between F-hiPSCs and B-hiPSCs (Supplementary Table 2 ). We noted considerable heterogeneity in the total numbers of mutations between sister hiPSCs from the same donor, S2; one F-hiPSC line (S2_SF3_P2) had 8,171 single substitutions, 1,879 double substitutions and 226 indels, whereas the other F-hiPSC line (S2_SF2_P2) had 1,873 single substitutions, 17 double substitutions and 71 indels (Fig. 1b ). Mutational signature analysis demonstrated striking predominance of UV-associated substitutions (Reference Signature/COSMIC) Signature 7 (ref. 31 ) in the F-hiPSCs, characterized by C>T transitions at T C A, T C C and T C T (Fig. 1b and Extended Data Fig. 1 ). This finding is consistent with previously published work that attributed UV signatures in hiPSCs to preexisting damage in parental skin fibroblasts 8 , 32 . In contrast, EPC-derived B-hiPSCs did not show any evidence of UV damage but showed patterns consistent with possible oxidative damage (signature 18, characterized by C>A mutations at T C T, G C A and A C A; Fig. 1 and Extended Data Fig. 1 ). Consistent with in vitro studies 33 , 34 , double substitutions were enriched in UV-damaged F-hiPSCs (Fig. 1b ). In all, we concluded that F-hiPSCs carry UV-related genomic damage as a result of sunlight exposure in vivo that does not manifest in EPC-derived B-hiPSCs. Importantly, screening for copy-number aberrations underestimated the substantial substitution/indel-based variation that exists in hiPSCs. High prevalence of UV-associated DNA damage in F-hiPSCs We asked whether these findings were applicable across F-hiPSC lines generally. Therefore, we interrogated all lines in the HipSci stem cell bank,<|im_end|> <|im_start|>assistant DNA damage caused by factors such as ultraviolet radiation affect nearly three-quarters of all stem cell lines derived from human skin cells, say Cambridge researchers, who argue that whole genome sequencing is essential for confirming if cell lines are usable. Stem cells are a special type of cell that can be programmed to become almost any type of cell within the body. They are currently used for studies on the development of organs and even the early stages of the embryo. Increasingly, researchers are turning to stem cells as ways of developing new treatments, known as cell-based therapies. Other potential applications include programming stem cells to grow into nerve cells to replace those lost to neurodegeneration in diseases such as Parkinson's. Originally, stem cells were derived from embryos, but it is now possible to derive stem cells from adult skin cells. These so-called induced pluripotent stem cells (iPSCs) have now been generated from a range of tissues, including blood, which is increasing in popularity due to its ease of derivation. However, researchers at the University of Cambridge and Wellcome Sanger Institute have discovered a problem with stem cell lines derived from both skin cells and blood. When they examined the genomes of the stem cell lines in detail, they found that nearly three quarters carried substantial damage to their DNA that could compromise their use both in research and, crucially, in cell-based therapies. Their findings represent the largest genetic study to date of iPSCs and are published today in Nature Genetics. DNA is made up of three billions pairs of nucleotides, molecules represented by the letters A, C, G and T. Over time, damage to our DNA, for example from ultraviolet radiation, can lead to mutations—a letter C might change to a letter T, for example. "Fingerprints" left on our DNA can reveal what is responsible for this damage. As these mutations accumulate, they can have a profound effect on the function of cells and in some cases lead to tumors. Dr. Foad Rouhani, who carried out the work while at the University of Cambridge and the Wellcome Sanger Institute, said: "We noticed that some of the iPS cells that we were generating looked really different from each other, even when they were derived from the same patient and derived in the same experiment. The most striking thing was that pairs of iPS cells would have a vastly different genetic landscape—one line would have minimal damage and the other would have a level of mutations more commonly seen in tumors. One possible reason for this could be that a cell on the surface of the skin is likely to have greater exposure to sunlight than a cell below the surface and therefore eventually may lead to iPS cells with greater levels of genomic damage." The researchers used a common technique known as whole genome sequencing to inspect the entire DNA of stem cell lines in different cohorts, including the HipSci cohort at the Wellcome Sanger Institute and discovered that as many as 72% of the lines showed signs of major UV damage. Professor Serena Nik-Zainal from the Department of Medical Genetics at the University of Cambridge said: "Almost three-quarters of the cell lines had UV damage. Some samples had an enormous amount of mutations—sometimes more than we find in tumors. We were all hugely surprised to learn this, given that most of these lines were derived from skin biopsies of healthy people." They decided to turn their attention to cell lines not derived from skin and focused on blood derived iPSCs as these are becoming increasingly popular due to the ease of obtaining blood samples. They found that while these blood-derived iPSCs, too, carried mutations, they had lower levels of mutations than skin-derived iPS cells and no UV damage. However, around a quarter carried mutations in a gene called BCOR, an important gene in blood cancers. To investigate whether these BCOR mutations had any functional impact, they differentiated the iPSCs and turned them into neurons, tracking their progress along the way. Dr. Rouhani said: "What we saw was that there were problems in generating neurons from iPSCs that have BCOR mutations—they had a tendency to favor other cell types instead. This is a significant finding, particularly if one is intending to use those lines for neurological research." When they examined the blood samples, they discovered that the BCOR mutations were not present within the patient: instead, the process of culturing cells appears to increase the frequency of these mutations, which may have implications for other researchers working with cells in culture. Scientists typically screen their cell lines for problems at the chromosomal level—for example by checking to see that the requisite 23 pairs of chromosomes are present. However, this would not be sufficiently detailed to pick up the potentially major problems that this new study has identified. Importantly, without looking in detail at the genomes of these stem cells, researchers and clinicians would be unaware of the underlying damage that is present with the cell lines they are working with. "The DNA damage that we saw was at a nucleotide level," says Professor Nik-Zainal. "If you think of the human genome as like a book, most researchers would check the number of chapters and be satisfied that there were none missing. But what we saw was that even with the correct number of chapters in place, lots of the words were garbled." Fortunately, says Professor Nik-Zainal, there is a way round the problem: using whole genome sequencing to look in detail for the errors at the outset. "The cost of whole genome sequencing has dropped dramatically in recent years to around £500 per sample, though it's the analysis and interpretation that's the hardest bit. If a research question involves cell lines and cellular models, and particularly if we're going to introduce these lines back into patients, we may have to consider sequencing the genomes of these lines to understand what we are dealing with and get a sense of whether they are suitable for use." Dr. Rouhani adds: "In recent years we have been finding out more and more about how even our healthy cells carry many mutations and therefore it is not a realistic aim to produce stem cell lines with zero mutations. The goal should be to know as much as possible about the nature and extent of the DNA damage to make informed choices about the ultimate use of these stem cell lines. "If a line is to be used for cell based therapies in patients for example, then we need to understand more about the implications of these mutations so that both clinicians and patients are better informed of the risks involved in the 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 Atomic beams are a longstanding technology for atom-based sensors and clocks with widespread use in commercial frequency standards. Here, we report the demonstration of a chip-scale microwave atomic beam clock using coherent population trapping (CPT) interrogation in a passively pumped atomic beam device. The beam device consists of a hermetically sealed vacuum cell fabricated from an anodically bonded stack of glass and Si wafers in which lithographically defined capillaries produce Rb atomic beams and passive pumps maintain the vacuum environment. A prototype chip-scale clock is realized using Ramsey CPT spectroscopy of the atomic beam over a 10 mm distance and demonstrates a fractional frequency stability of ≈1.2 × 10 −9 / \\(\\sqrt{\\tau }\\) for integration times, τ, from 1 s to 250 s, limited by detection noise. Optimized atomic beam clocks based on this approach may exceed the long-term stability of existing chip-scale clocks, and leading long-term systematics are predicted to limit the ultimate fractional frequency stability below 10 −12 . Introduction The development of low-power, chip-scale atomic devices including clocks and magnetometers has been enabled by advances in the optical interrogation of atoms confined in microfabricated vapor cells 1 . These miniaturized devices commonly use coherent population trapping (CPT) resonances in alkali atoms, which generate a coherent dark state between hyperfine atomic ground states using two optical fields in a Λ-scheme 2 . Optical probing of the microwave transition avoids the need for bulky microwave cavities, providing a compact and low-power method for probing the atoms and enabling battery-powered operation 3 , 4 . Buffer gases are commonly used to reduce the decoherence rate from wall collisions and narrow the atomic line. As a result, devices such as the chip-scale atomic clock (CSAC) can realize ≈10 −11 fractional frequency stability at 1000 s of averaging while consuming only 120 mW of power 5 . Thermal drifts and aging of the buffer gas environment, along with light shifts and other systematics, contribute to the long-term instability of buffer gas systems and degrades clock performance in existing CSACs beyond 1000 s of averaging with a drift rate of ~10 −9 per month. Clocks based on atomic beams and laser-cooled gases operate in ultra-high vacuum (UHV) environments and avoid shifts from buffer gases, allowing for higher frequency stability and continuous averaging over periods of days or weeks. Laser-cooling technology underpins the most advanced atomic clocks 6 , and while recent efforts in photonic integration 7 , 8 and vacuum technology 9 , 10 , 11 have advanced the state of the art, significant hurdles to miniaturization and low-power operation remain 12 . Atomic beams have played a significant role throughout the history of frequency metrology, serving as commercial frequency standards since the 1960s and as national frequency standards for realization of the SI second 13 , 14 . Miniaturized atomic beams 15 , 16 , 17 , 18 , 19 offer a path for exceeding the long-term stability of existing chip-scale devices while circumventing the complexity and power needs of more advanced laser-cooled schemes. In this work, we demonstrate a chip-scale atomic beam clock built using a passively pumped Rb atomic beam device as shown in Fig. 1 . The beam device contains a Rb reservoir that feeds a microcapillary array and generates Rb atomic beams in an internal, evacuated cavity. Fabrication of the device is realized using a stack of lithographically defined planar structures which are anodically bonded to form a hermetic package. Spectroscopic measurements of the atomic flux and beam collimation are presented to demonstrate the successful realization of the atomic beam device. The atom beam device presents a pathway for realizing low-power, low-drift atomic sensors using microfabricated components and supports further integration with advanced thermal and photonic packaging to realize highly manufacturable quantum sensors. Fig. 1: Overview of chip-scale atomic beam device. a Image of atomic beam device with labeled components (peanut for scale). Rb vapor in the source cavity feeds a buried microcapillary array and forms an atomic beam (indicated by a red-to-blue arrow) in the drift cavity. Non-evaporable getters (NEGs) and graphite maintain the vacuum environment in the device. b Expanded view of the beam device showing component layers as well as Rb pill dispensers, graphite rods, and NEG pumps. c Schematic of the microcapillary array etched in a Si wafer. Each capillary has a 100 µm × 100 µm square cross-section. The array collimates the atomic beam and provides differential pumping between the source and drift regions. d The final anodic bond which hermetically seals the device occurs in an ultra-high vacuum (UHV) chamber. Full size image The microwave atomic beam clock is demonstrated using Ramsey CPT interrogation in the atomic beam device. Ramsey spectroscopy of the 87 Rb ground-state hyperfine transitions is measured across a 10 mm distance and demonstrates quantum coherence across the device. The magnetically insensitive m F = 0 hyperfine transition is used to realize the atomic beam clock signal, and a clock short-term fractional frequency stability of ≈1.2 × 10 −9 is achieved at 1 s of integration in this prototype device. The performance of this beam clock is limited by technical noise, and an optimized cm-scale device is expected to achieve stability better than 10 −10 at 1 s of integration with a stability floor below 10 −12 , supported by a detailed analysis of the sources of drift in atomic beam clocks. Results The passively pumped atom beam device is fabricated from a multi-layer stack of Si and glass wafers as shown in Fig. 1 . The layers are anodically bonded to form a hermetically sealed vacuum cell with dimensions of 25 mm × 23 mm × 5 mm and ≈0.4 cm 3 of internal volume. Internal components include Rb molybdate Zr/Al pill-type dispensers for generating Rb vapor in an internal source cavity 20 as well as graphite and Zr/V/Fe non-evaporable getters (NEGs) in a separate drift cavity which maintain the vacuum environment. A series of microcapillaries connect the two internal cavities and produce atomic beams which freely", "role": "user" }, { "content": "A new type of miniature atomic clock could provide better timing over the span of weeks and months compared with current systems. Researchers at the National Institute of Standards and Technology (NIST), in collaboration with researchers from Georgia Tech, have made the first-of-its-kind chip-scale beam clock. Their work has been published in Nature Communications. Atomic clocks take many forms, but the oldest and one of the most prominent designs is built using atomic beams. These clocks send a beam of atoms through a vacuum chamber. At one end of the chamber, the atoms are set in a specific quantum state, and they start \"ticking.\" At the other end their ticking rate is measured or \"read out.\" Using the atoms' precise ticking rate, other clocks can be compared to atomic beam clocks, and adjusted to match their timing. NIST has been using atomic beams for timekeeping since the 1950s. For decades, beam clocks were used to keep the primary standard for the second, and they are still part of NIST's national timekeeping ensemble. Beam clocks are precise, stable and accurate, but they're currently not the most portable. The vacuum chambers where the atoms travel are key to the success of these clocks, but they're bulky in part due to the size of the microwave cavity used to probe the atomic \"ticking.\" The vacuum chamber for NIST-7, the last beam clock used for the primary frequency standard in the U.S., was more than 2.5 meters or 8 feet long. Smaller commercial clocks about the size of a briefcase are common, but they still require a significant amount of power (about 50 watts) to run. For comparison, smartphones require about a third of a watt for typical operation. Chip-scale atomic clocks (CSACs) were developed by NIST in 2001. Advances in microfabrication techniques let NIST make vapor cells, tiny chambers where the clock's atoms are held and measured, the size of a grain of rice; the entire clock is about the size of a piece of sushi. These clocks consume very little power and can run on batteries to provide timing in critical situations where GPS can't reach. CSACs have found numerous applications in underwater oil and gas exploration, military navigation, and even telecommunications. However, the clocks' timekeeping tends to drift when temperatures shift and the gas surrounding the atoms degrades. \"The CSAC is low-power and has high performance given its size. It's a wonderful device, but it does drift after running for a few thousand seconds,\" said William McGehee, a physicist at NIST. \"Beam clocks have been around since the 1950s and are stable, but still need a lot of power. What if we could combine the best aspects of these two systems?\" Using microfabrication techniques learned from the CSAC, the group fabricated a chip-scale atomic beam device using a stack of etched silicon and glass layers. This device is a highly miniaturized version of the chambers that have been used in atomic beam clocks like NIST-7 and is about the size of a postage stamp. Atomic vapor cell construction techniques developed at NIST and etched microcapillary arrays developed at Georgia Tech were key to shrinking the vacuum chambers of larger beam clocks. In the device, one chamber contains a small pill of rubidium. That chamber heats up, releasing a stream of rubidium atoms through microcapillaries, channels only 100 micrometers wide. Those tiny channels connect to another chamber with materials that can absorb—or collect—individual gas molecules, called non-evaporable getters, or NEGs, which pull the rubidium atoms along and collect them, keeping the vacuum in the microcapillaries clean. Tiny rods of graphite also help collect stray atoms through the process. Right now, this chip-scale beam device is a prototype for a miniature atomic beam clock. Initial tests of the chip-scale beam clock showed performance at a level slightly worse than existing CSACs, but the team sees a path toward improved stability. The researchers hope to push their precision by another factor of 10, and to exceed the stability of existing CSACs by 100 times over week time scales. ", "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 Atomic beams are a longstanding technology for atom-based sensors and clocks with widespread use in commercial frequency standards. Here, we report the demonstration of a chip-scale microwave atomic beam clock using coherent population trapping (CPT) interrogation in a passively pumped atomic beam device. The beam device consists of a hermetically sealed vacuum cell fabricated from an anodically bonded stack of glass and Si wafers in which lithographically defined capillaries produce Rb atomic beams and passive pumps maintain the vacuum environment. A prototype chip-scale clock is realized using Ramsey CPT spectroscopy of the atomic beam over a 10 mm distance and demonstrates a fractional frequency stability of ≈1.2 × 10 −9 / \(\sqrt{\tau }\) for integration times, τ, from 1 s to 250 s, limited by detection noise. Optimized atomic beam clocks based on this approach may exceed the long-term stability of existing chip-scale clocks, and leading long-term systematics are predicted to limit the ultimate fractional frequency stability below 10 −12 . Introduction The development of low-power, chip-scale atomic devices including clocks and magnetometers has been enabled by advances in the optical interrogation of atoms confined in microfabricated vapor cells 1 . These miniaturized devices commonly use coherent population trapping (CPT) resonances in alkali atoms, which generate a coherent dark state between hyperfine atomic ground states using two optical fields in a Λ-scheme 2 . Optical probing of the microwave transition avoids the need for bulky microwave cavities, providing a compact and low-power method for probing the atoms and enabling battery-powered operation 3 , 4 . Buffer gases are commonly used to reduce the decoherence rate from wall collisions and narrow the atomic line. As a result, devices such as the chip-scale atomic clock (CSAC) can realize ≈10 −11 fractional frequency stability at 1000 s of averaging while consuming only 120 mW of power 5 . Thermal drifts and aging of the buffer gas environment, along with light shifts and other systematics, contribute to the long-term instability of buffer gas systems and degrades clock performance in existing CSACs beyond 1000 s of averaging with a drift rate of ~10 −9 per month. Clocks based on atomic beams and laser-cooled gases operate in ultra-high vacuum (UHV) environments and avoid shifts from buffer gases, allowing for higher frequency stability and continuous averaging over periods of days or weeks. Laser-cooling technology underpins the most advanced atomic clocks 6 , and while recent efforts in photonic integration 7 , 8 and vacuum technology 9 , 10 , 11 have advanced the state of the art, significant hurdles to miniaturization and low-power operation remain 12 . Atomic beams have played a significant role throughout the history of frequency metrology, serving as commercial frequency standards since the 1960s and as national frequency standards for realization of the SI second 13 , 14 . Miniaturized atomic beams 15 , 16 , 17 , 18 , 19 offer a path for exceeding the long-term stability of existing chip-scale devices while circumventing the complexity and power needs of more advanced laser-cooled schemes. In this work, we demonstrate a chip-scale atomic beam clock built using a passively pumped Rb atomic beam device as shown in Fig. 1 . The beam device contains a Rb reservoir that feeds a microcapillary array and generates Rb atomic beams in an internal, evacuated cavity. Fabrication of the device is realized using a stack of lithographically defined planar structures which are anodically bonded to form a hermetic package. Spectroscopic measurements of the atomic flux and beam collimation are presented to demonstrate the successful realization of the atomic beam device. The atom beam device presents a pathway for realizing low-power, low-drift atomic sensors using microfabricated components and supports further integration with advanced thermal and photonic packaging to realize highly manufacturable quantum sensors. Fig. 1: Overview of chip-scale atomic beam device. a Image of atomic beam device with labeled components (peanut for scale). Rb vapor in the source cavity feeds a buried microcapillary array and forms an atomic beam (indicated by a red-to-blue arrow) in the drift cavity. Non-evaporable getters (NEGs) and graphite maintain the vacuum environment in the device. b Expanded view of the beam device showing component layers as well as Rb pill dispensers, graphite rods, and NEG pumps. c Schematic of the microcapillary array etched in a Si wafer. Each capillary has a 100 µm × 100 µm square cross-section. The array collimates the atomic beam and provides differential pumping between the source and drift regions. d The final anodic bond which hermetically seals the device occurs in an ultra-high vacuum (UHV) chamber. Full size image The microwave atomic beam clock is demonstrated using Ramsey CPT interrogation in the atomic beam device. Ramsey spectroscopy of the 87 Rb ground-state hyperfine transitions is measured across a 10 mm distance and demonstrates quantum coherence across the device. The magnetically insensitive m F = 0 hyperfine transition is used to realize the atomic beam clock signal, and a clock short-term fractional frequency stability of ≈1.2 × 10 −9 is achieved at 1 s of integration in this prototype device. The performance of this beam clock is limited by technical noise, and an optimized cm-scale device is expected to achieve stability better than 10 −10 at 1 s of integration with a stability floor below 10 −12 , supported by a detailed analysis of the sources of drift in atomic beam clocks. Results The passively pumped atom beam device is fabricated from a multi-layer stack of Si and glass wafers as shown in Fig. 1 . The layers are anodically bonded to form a hermetically sealed vacuum cell with dimensions of 25 mm × 23 mm × 5 mm and ≈0.4 cm 3 of internal volume. Internal components include Rb molybdate Zr/Al pill-type dispensers for generating Rb vapor in an internal source cavity 20 as well as graphite and Zr/V/Fe non-evaporable getters (NEGs) in a separate drift cavity which maintain the vacuum environment. A series of microcapillaries connect the two internal cavities and produce atomic beams which freely<|im_end|> <|im_start|>assistant A new type of miniature atomic clock could provide better timing over the span of weeks and months compared with current systems. Researchers at the National Institute of Standards and Technology (NIST), in collaboration with researchers from Georgia Tech, have made the first-of-its-kind chip-scale beam clock. Their work has been published in Nature Communications. Atomic clocks take many forms, but the oldest and one of the most prominent designs is built using atomic beams. These clocks send a beam of atoms through a vacuum chamber. At one end of the chamber, the atoms are set in a specific quantum state, and they start "ticking." At the other end their ticking rate is measured or "read out." Using the atoms' precise ticking rate, other clocks can be compared to atomic beam clocks, and adjusted to match their timing. NIST has been using atomic beams for timekeeping since the 1950s. For decades, beam clocks were used to keep the primary standard for the second, and they are still part of NIST's national timekeeping ensemble. Beam clocks are precise, stable and accurate, but they're currently not the most portable. The vacuum chambers where the atoms travel are key to the success of these clocks, but they're bulky in part due to the size of the microwave cavity used to probe the atomic "ticking." The vacuum chamber for NIST-7, the last beam clock used for the primary frequency standard in the U.S., was more than 2.5 meters or 8 feet long. Smaller commercial clocks about the size of a briefcase are common, but they still require a significant amount of power (about 50 watts) to run. For comparison, smartphones require about a third of a watt for typical operation. Chip-scale atomic clocks (CSACs) were developed by NIST in 2001. Advances in microfabrication techniques let NIST make vapor cells, tiny chambers where the clock's atoms are held and measured, the size of a grain of rice; the entire clock is about the size of a piece of sushi. These clocks consume very little power and can run on batteries to provide timing in critical situations where GPS can't reach. CSACs have found numerous applications in underwater oil and gas exploration, military navigation, and even telecommunications. However, the clocks' timekeeping tends to drift when temperatures shift and the gas surrounding the atoms degrades. "The CSAC is low-power and has high performance given its size. It's a wonderful device, but it does drift after running for a few thousand seconds," said William McGehee, a physicist at NIST. "Beam clocks have been around since the 1950s and are stable, but still need a lot of power. What if we could combine the best aspects of these two systems?" Using microfabrication techniques learned from the CSAC, the group fabricated a chip-scale atomic beam device using a stack of etched silicon and glass layers. This device is a highly miniaturized version of the chambers that have been used in atomic beam clocks like NIST-7 and is about the size of a postage stamp. Atomic vapor cell construction techniques developed at NIST and etched microcapillary arrays developed at Georgia Tech were key to shrinking the vacuum chambers of larger beam clocks. In the device, one chamber contains a small pill of rubidium. That chamber heats up, releasing a stream of rubidium atoms through microcapillaries, channels only 100 micrometers wide. Those tiny channels connect to another chamber with materials that can absorb—or collect—individual gas molecules, called non-evaporable getters, or NEGs, which pull the rubidium atoms along and collect them, keeping the vacuum in the microcapillaries clean. Tiny rods of graphite also help collect stray atoms through the process. Right now, this chip-scale beam device is a prototype for a miniature atomic beam clock. Initial tests of the chip-scale beam clock showed performance at a level slightly worse than existing CSACs, but the team sees a path toward improved stability. The researchers hope to push their precision by another factor of 10, and to exceed the stability of existing CSACs by 100 times over week time scales. <|im_end|>
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2,196
[ { "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 polycystic kidney disease (PKD), fluid-filled cysts arise from tubules in kidneys and other organs. Human kidney organoids can reconstitute PKD cystogenesis in a genetically specific way, but the mechanisms underlying cystogenesis remain elusive. Here we show that subjecting organoids to fluid shear stress in a PKD-on-a-chip microphysiological system promotes cyst expansion via an absorptive rather than a secretory pathway. A diffusive static condition partially substitutes for fluid flow, implicating volume and solute concentration as key mediators of this effect. Surprisingly, cyst-lining epithelia in organoids polarize outwards towards the media, arguing against a secretory mechanism. Rather, cyst formation is driven by glucose transport into lumens of outwards-facing epithelia, which can be blocked pharmacologically. In PKD mice, glucose is imported through cysts into the renal interstitium, which detaches from tubules to license expansion. Thus, absorption can mediate PKD cyst growth in human organoids, with implications for disease mechanism and potential for therapy development. Introduction Autosomal dominant polycystic kidney disease (PKD) is commonly inherited as a heterozygous, loss-of-function mutation in either PKD1 or PKD2 , which encode the proteins polycystin-1 (PC1) or polycystin-2 (PC2), respectively 1 , 2 . PKD is characterized by the growth of large, fluid-filled cysts from ductal structures in kidneys and other organs, and is among the most common life-threatening monogenic diseases and kidney disorders 3 . Tolvaptan (Jynarque), a vasopressin receptor antagonist that decreases water absorption into the collecting ducts, was recently approved for treatment of PKD in the United States, but only modestly delays cyst growth and has side effects that limit its use 4 , 5 . At the molecular level, PC1 and PC2 form a receptor-channel complex at the primary cilium that is poorly understood but possibly acts as a flow-sensitive mechanosensor 6 , 7 , 8 , 9 , 10 , 11 . Loss of this complex results in the gradual expansion and dedifferentiation of the tubular epithelium, including increased proliferation and altered transporter expression and localization 12 , 13 , 14 . As mechanisms of PKD are difficult to decipher in vivo, and murine models do not fully phenocopy or genocopy the human disease, we have developed a human model of PKD in vitro 15 , 16 , 17 . We, together with other groups around the world, have invented methods to derive kidney organoids from human pluripotent stem cells (hPSC), which contain podocyte, proximal tubule, and distal tubule segments in contiguous, nephron-like arrangements 17 , 18 , 19 , 20 . Differentiation of these organoids is highly sensitive to the physical properties of the extracellular microenvironment 21 . Organoids derived from gene-edited hPSC with biallelic, truncating mutations in PKD1 or PKD2 develop cysts from kidney tubules, reconstituting the pathognomonic hallmark of the disease 15 , 16 , 17 . Interestingly, culture of organoids under suspension conditions dramatically increases the expressivity of the PKD phenotype, revealing a critical role for microenvironment in cystogenesis 16 . Fluid flow is a major feature of the nephron microenvironment, which is believed to play an important role in PKD 4 , 5 , 7 , 8 , 22 . However, physiological rates of flow have not yet been achieved in kidney organoid cultures or PKD models. ‘Kidney on a chip’ microphysiological systems provide fit-for-purpose platforms integrating flow with kidney cells to model physiology and disease in a setting that more closely simulates the in vivo condition than monolayer cultures 23 , 24 , 25 , 26 , 27 . There is currently intense interest in integrating organ on chip systems with organoids, which can be derived from hPSC as a renewable and gene-editable cell source 28 , 29 , 30 , 31 , 32 . We therefore investigated the effect of flow on PKD in a human organoid on a chip microphysiological system. Results Flow induces cyst swelling in PKD organoids Prior to introducing flow, we first confirmed the specificity and timing of the PKD phenotype in static cultures. PKD1 −/− or PKD2 −/− hPSC were differentiated side-by-side with isogenic controls under static, adherent culture conditions to form kidney organoids. On day 18 of differentiation, prior to cyst formation, organoids were carefully detached from the underlying substratum and transferred to suspension cultures in low-attachment plates. Under these conditions, the majority of PKD1 −/− or PKD2 −/− organoids formed cysts within 1–2 weeks, whereas isogenic control organoids rarely formed cysts (Fig. 1a ). In repeated trials, the difference between PKD organoids and isogenic controls was quantifiable and highly significant (Fig. 1a ). Thus, PKD organoid formed cysts in a genotype-specific manner, strongly suggesting that this phenotype was specific to the disease state. This differs from other types of three-dimensional cultures of epithelial cells, in which hollow ‘cysts’ (spheroids) arise irrespective of PKD genotype and represent a default configuration of the epithelium rather than a disease-specific phenotype 17 , 33 , 34 , 35 . Fig. 1: Organoid PKD cysts expand under flow. a Representative images of organoids on days following transfer to suspension culture (upper), with quantification (lower) of cyst incidence as a fraction of the total number of organoids (mean ± s.e.m. from n ≥ 4 independent experiments per condition; **** p < 0.0001). b Schematic of workflow for fluidic condition. c Time-lapse phase contrast images of PKD organoids under flow (0.2 dynes/cm 2 ), representative of four independent experiments. d Average growth rates of control organoids (Ctrl org.), non-cystic compartments of PKD organoids (PKD org.), and cystic compartments of PKD organoids (PKD cysts) under flow (0.2 dynes/cm 2 ). Each experiment was performed for 6 h. Cyst growth rate was calculated on an individual basis as the maximal size of the cyst during the time course, divided by the time point at which the cyst reached this size (mean ± s.e.m. from n ≥ four independent experiments; each dot represents the average growth rate of organoids in a single experiment. **** p < 0.0001). Full size image To understand how flow affects PKD in organoids, we designed a microfluidic system that allows for live", "role": "user" }, { "content": "A study of kidney organoids in a novel lab environment might have downstream implications for the treatment of polycystic kidney disease (PKD), an incurable condition that affects more than 12 million people worldwide. One key discovery of the study: Sugar appears to play a role in the formation of fluid-filled cysts that are PKD's hallmark. In people, these cysts grow big enough to impair kidney function and ultimately cause the organs to fail, necessitating dialysis therapy or transplant. The findings were published in Nature Communications. The co-lead authors are Sienna Li and Ramila Gulieva, research scientists in the lab of Benjamin Freedman, a nephrology investigator at the University of Washington School of Medicine. \"Sugar uptake is something that kidneys do all the time,\" said Freedman, a co-senior author. \"We found that increasing the levels of sugar in the dish cultures caused cysts to swell. And when we employed drugs known to block sugar absorption in the kidneys, it blocked this swelling. But I think it relates less to blood sugar level and more to how kidney cells take in sugar—which in this process seemed to go rogue and give rise to cysts.\" For years Freedman has studied PKD in organoids grown from pluripotent stem cells. Organoids resemble miniature kidneys: They contain filtering cells connected to tubes and can respond to infection and therapeutics in ways that parallel the responses of kidneys in people. Mini-kidney tube structures have sugar receptors (red, upper left) and form outward-facing PKD cysts (center), which swell by taking in sugar (green, lower right). Credit: Benjamin Freedman Lab / University of Washington School of Medicine Although his team can grow organoids that give rise to PKD cysts, the mechanisms of those cysts' formation are not yet understood. In this investigation, the researchers focused on how the flow of fluid within the kidney contributes to PKD. To do so, they invented a new tool that merged a kidney organoid with a microfluidic chip. This allowed a combination of water, sugar, amino acids and other nutrients to flow over organoids that had been gene-edited to mimic PKD. \"We were expecting the PKD cysts in the organoids to get worse under flow because the disease is associated with the physiological flow rates that we were exploring,\" Freedman explained. \"The surprising part was that the process of cyst-swelling involved absorption: the intake of fluid inward through cells from outside the cyst. That's the opposite of what is commonly thought, which is that cysts form by pushing fluid outward through cells. It's a whole new way of thinking about cyst formation.\" In the chips, the researchers observed that the cells lining the walls of the PKD cysts faced outward as they stretched and swelled, such that the tops of the cells were on the outside of the cysts. This inverted arrangement—these cells would be facing inward in living kidneys—suggests that cysts grow by pulling in sugar-rich fluid, not by secreting the liquid. The observation gives researchers more information about how cysts form in organoids, a finding that will have to be tested further in vivo. As well, the fact that sugar levels drive cyst development points to new potential therapeutic options. \"The results of the experiment are significant because there is a whole class of molecules that block sugar uptake in the kidneys and are attractive therapeutics for a number of conditions,\" Freedman said. \"They haven't been tested yet, but we view this as a proof-of-concept that these drugs could potentially help PKD 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 In polycystic kidney disease (PKD), fluid-filled cysts arise from tubules in kidneys and other organs. Human kidney organoids can reconstitute PKD cystogenesis in a genetically specific way, but the mechanisms underlying cystogenesis remain elusive. Here we show that subjecting organoids to fluid shear stress in a PKD-on-a-chip microphysiological system promotes cyst expansion via an absorptive rather than a secretory pathway. A diffusive static condition partially substitutes for fluid flow, implicating volume and solute concentration as key mediators of this effect. Surprisingly, cyst-lining epithelia in organoids polarize outwards towards the media, arguing against a secretory mechanism. Rather, cyst formation is driven by glucose transport into lumens of outwards-facing epithelia, which can be blocked pharmacologically. In PKD mice, glucose is imported through cysts into the renal interstitium, which detaches from tubules to license expansion. Thus, absorption can mediate PKD cyst growth in human organoids, with implications for disease mechanism and potential for therapy development. Introduction Autosomal dominant polycystic kidney disease (PKD) is commonly inherited as a heterozygous, loss-of-function mutation in either PKD1 or PKD2 , which encode the proteins polycystin-1 (PC1) or polycystin-2 (PC2), respectively 1 , 2 . PKD is characterized by the growth of large, fluid-filled cysts from ductal structures in kidneys and other organs, and is among the most common life-threatening monogenic diseases and kidney disorders 3 . Tolvaptan (Jynarque), a vasopressin receptor antagonist that decreases water absorption into the collecting ducts, was recently approved for treatment of PKD in the United States, but only modestly delays cyst growth and has side effects that limit its use 4 , 5 . At the molecular level, PC1 and PC2 form a receptor-channel complex at the primary cilium that is poorly understood but possibly acts as a flow-sensitive mechanosensor 6 , 7 , 8 , 9 , 10 , 11 . Loss of this complex results in the gradual expansion and dedifferentiation of the tubular epithelium, including increased proliferation and altered transporter expression and localization 12 , 13 , 14 . As mechanisms of PKD are difficult to decipher in vivo, and murine models do not fully phenocopy or genocopy the human disease, we have developed a human model of PKD in vitro 15 , 16 , 17 . We, together with other groups around the world, have invented methods to derive kidney organoids from human pluripotent stem cells (hPSC), which contain podocyte, proximal tubule, and distal tubule segments in contiguous, nephron-like arrangements 17 , 18 , 19 , 20 . Differentiation of these organoids is highly sensitive to the physical properties of the extracellular microenvironment 21 . Organoids derived from gene-edited hPSC with biallelic, truncating mutations in PKD1 or PKD2 develop cysts from kidney tubules, reconstituting the pathognomonic hallmark of the disease 15 , 16 , 17 . Interestingly, culture of organoids under suspension conditions dramatically increases the expressivity of the PKD phenotype, revealing a critical role for microenvironment in cystogenesis 16 . Fluid flow is a major feature of the nephron microenvironment, which is believed to play an important role in PKD 4 , 5 , 7 , 8 , 22 . However, physiological rates of flow have not yet been achieved in kidney organoid cultures or PKD models. ‘Kidney on a chip’ microphysiological systems provide fit-for-purpose platforms integrating flow with kidney cells to model physiology and disease in a setting that more closely simulates the in vivo condition than monolayer cultures 23 , 24 , 25 , 26 , 27 . There is currently intense interest in integrating organ on chip systems with organoids, which can be derived from hPSC as a renewable and gene-editable cell source 28 , 29 , 30 , 31 , 32 . We therefore investigated the effect of flow on PKD in a human organoid on a chip microphysiological system. Results Flow induces cyst swelling in PKD organoids Prior to introducing flow, we first confirmed the specificity and timing of the PKD phenotype in static cultures. PKD1 −/− or PKD2 −/− hPSC were differentiated side-by-side with isogenic controls under static, adherent culture conditions to form kidney organoids. On day 18 of differentiation, prior to cyst formation, organoids were carefully detached from the underlying substratum and transferred to suspension cultures in low-attachment plates. Under these conditions, the majority of PKD1 −/− or PKD2 −/− organoids formed cysts within 1–2 weeks, whereas isogenic control organoids rarely formed cysts (Fig. 1a ). In repeated trials, the difference between PKD organoids and isogenic controls was quantifiable and highly significant (Fig. 1a ). Thus, PKD organoid formed cysts in a genotype-specific manner, strongly suggesting that this phenotype was specific to the disease state. This differs from other types of three-dimensional cultures of epithelial cells, in which hollow ‘cysts’ (spheroids) arise irrespective of PKD genotype and represent a default configuration of the epithelium rather than a disease-specific phenotype 17 , 33 , 34 , 35 . Fig. 1: Organoid PKD cysts expand under flow. a Representative images of organoids on days following transfer to suspension culture (upper), with quantification (lower) of cyst incidence as a fraction of the total number of organoids (mean ± s.e.m. from n ≥ 4 independent experiments per condition; **** p < 0.0001). b Schematic of workflow for fluidic condition. c Time-lapse phase contrast images of PKD organoids under flow (0.2 dynes/cm 2 ), representative of four independent experiments. d Average growth rates of control organoids (Ctrl org.), non-cystic compartments of PKD organoids (PKD org.), and cystic compartments of PKD organoids (PKD cysts) under flow (0.2 dynes/cm 2 ). Each experiment was performed for 6 h. Cyst growth rate was calculated on an individual basis as the maximal size of the cyst during the time course, divided by the time point at which the cyst reached this size (mean ± s.e.m. from n ≥ four independent experiments; each dot represents the average growth rate of organoids in a single experiment. **** p < 0.0001). Full size image To understand how flow affects PKD in organoids, we designed a microfluidic system that allows for live<|im_end|> <|im_start|>assistant A study of kidney organoids in a novel lab environment might have downstream implications for the treatment of polycystic kidney disease (PKD), an incurable condition that affects more than 12 million people worldwide. One key discovery of the study: Sugar appears to play a role in the formation of fluid-filled cysts that are PKD's hallmark. In people, these cysts grow big enough to impair kidney function and ultimately cause the organs to fail, necessitating dialysis therapy or transplant. The findings were published in Nature Communications. The co-lead authors are Sienna Li and Ramila Gulieva, research scientists in the lab of Benjamin Freedman, a nephrology investigator at the University of Washington School of Medicine. "Sugar uptake is something that kidneys do all the time," said Freedman, a co-senior author. "We found that increasing the levels of sugar in the dish cultures caused cysts to swell. And when we employed drugs known to block sugar absorption in the kidneys, it blocked this swelling. But I think it relates less to blood sugar level and more to how kidney cells take in sugar—which in this process seemed to go rogue and give rise to cysts." For years Freedman has studied PKD in organoids grown from pluripotent stem cells. Organoids resemble miniature kidneys: They contain filtering cells connected to tubes and can respond to infection and therapeutics in ways that parallel the responses of kidneys in people. Mini-kidney tube structures have sugar receptors (red, upper left) and form outward-facing PKD cysts (center), which swell by taking in sugar (green, lower right). Credit: Benjamin Freedman Lab / University of Washington School of Medicine Although his team can grow organoids that give rise to PKD cysts, the mechanisms of those cysts' formation are not yet understood. In this investigation, the researchers focused on how the flow of fluid within the kidney contributes to PKD. To do so, they invented a new tool that merged a kidney organoid with a microfluidic chip. This allowed a combination of water, sugar, amino acids and other nutrients to flow over organoids that had been gene-edited to mimic PKD. "We were expecting the PKD cysts in the organoids to get worse under flow because the disease is associated with the physiological flow rates that we were exploring," Freedman explained. "The surprising part was that the process of cyst-swelling involved absorption: the intake of fluid inward through cells from outside the cyst. That's the opposite of what is commonly thought, which is that cysts form by pushing fluid outward through cells. It's a whole new way of thinking about cyst formation." In the chips, the researchers observed that the cells lining the walls of the PKD cysts faced outward as they stretched and swelled, such that the tops of the cells were on the outside of the cysts. This inverted arrangement—these cells would be facing inward in living kidneys—suggests that cysts grow by pulling in sugar-rich fluid, not by secreting the liquid. The observation gives researchers more information about how cysts form in organoids, a finding that will have to be tested further in vivo. As well, the fact that sugar levels drive cyst development points to new potential therapeutic options. "The results of the experiment are significant because there is a whole class of molecules that block sugar uptake in the kidneys and are attractive therapeutics for a number of conditions," Freedman said. "They haven't been tested yet, but we view this as a proof-of-concept that these drugs could potentially help PKD 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 Groundwater discharge generates streamflow and influences stream thermal regimes. However, the water quality and thermal buffering capacity of groundwater depends on the aquifer source-depth. Here, we pair multi-year air and stream temperature signals to categorize 1729 sites across the continental United States as having major dam influence, shallow or deep groundwater signatures, or lack of pronounced groundwater (atmospheric) signatures. Approximately 40% of non-dam stream sites have substantial groundwater contributions as indicated by characteristic paired air and stream temperature signal metrics. Streams with shallow groundwater signatures account for half of all groundwater signature sites and show reduced baseflow and a higher proportion of warming trends compared to sites with deep groundwater signatures. These findings align with theory that shallow groundwater is more vulnerable to temperature increase and depletion. Streams with atmospheric signatures tend to drain watersheds with low slope and greater human disturbance, indicating reduced stream-groundwater connectivity in populated valley settings. Introduction Groundwater discharge zones establish active stream–groundwater hydrologic connectivity through the advective exchange of water. As a critical contributor to streamflow generation, groundwater discharge influences water quantity and quality throughout stream networks, especially during seasonal low flows and dry conditions 1 . Many streams host ecologically important ‘groundwater-dependent ecosystems’ 2 , yet these habitats face growing threats from climate change and groundwater contamination 1 , 3 , 4 . Aquatic organisms are particularly susceptible to shifts in thermal regimes because they have life cycles that rely on annual thermal cues 5 and metabolic rates influenced by stream temperature 6 . The relatively stable thermal regimes of some groundwater discharge zones can buffer stream temperatures against long-term air temperature trends and short-term hot and cold extremes 2 ; therefore, groundwater discharges can provide important stream channel thermal refuges and refugia for sensitive aquatic organisms such as salmonid fishes 7 , 8 . However, in response to climate change and land development, streams and rivers have recently shown widespread warming 9 , 10 . Observed stream warming trends are spatially heterogeneous due in part to spatially variable groundwater contributions to streamflow 11 . Thus, effective watershed management will require a process-based characterization of groundwater contribution to streamflow 12 at ecologically relevant scales to predict future stream thermal regimes. The magnitude, spatial distribution, and source-flow path characteristics of groundwater discharge can control the physical characteristics of individual streams 8 , 13 , 14 and whole stream networks 15 . Characterizing the depth of contributing groundwater is particularly important for understanding broad-scale responses of stream ecosystems to land development and climate change 16 for three main reasons: first, groundwater depth is associated with annual thermal stability as natural surface temperature fluctuations are prominent within the shallow aquifer but quickly attenuate with depth 13 . Deeper groundwater (defined here as greater than approximately 6 m from the land surface) shows little annual thermal variability relative to shallow groundwater 17 that flows through the near-surface portion of the ‘critical zone’ 18 .Therefore, groundwater discharge can either impart stability (deep groundwater) or variability (shallow groundwater) on atmospheric-driven stream thermal regimes. Hydrogeologic climate simulations support this definition, as water tables below 5 m have shown decoupling from surface energy balances 19 . Second, shallow groundwater is inherently more sensitive to land-use changes 20 and surface contamination 21 , 22 , 23 . Thus, effective watershed management may have a different urgency depending on the depth of contributing groundwater. Also, naturally, deep and shallow groundwater tend to have different chemical profiles 24 , 25 , 26 , which has important implications for surface water quality and stream ecosystem function including delivery of legacy contaminants 15 . Third, shallow groundwater can be directly depleted via transpiration 27 , irrigation withdrawals 28 , and is more vulnerable to seasonal water table drawdown during dry periods while discharge from deeper groundwater sources is more seasonably stable 29 . This depth-dependent effect can affect stream water transit times and catchment water balance, emphasizing the importance of parsing shallow versus deep contributing groundwater flow paths 24 . Though understanding the implications of climate change and land development for stream ecosystems requires quantifying the magnitude and source-depth of groundwater discharge, we lack efficient and broadly applicable methods to characterize source groundwater depth. Most hydrologic techniques for evaluating the physical properties of groundwater discharge are labor-intensive and not spatially and temporally scalable 30 . More efficient methods, such as stream water temperature sensitivity linear regression analyses 31 or physically based hydrograph separation techniques 32 do not directly differentiate groundwater source-depth. Inference of groundwater source-depth is possible using water chemistry end-member mixing 33 or water isotopic data 34 , but these analyses cannot inherently specify shallow groundwater flow paths without additional hydrologic characterization, and are time and resource-intensive. In the absence of groundwater discharge, annual stream water temperature signals are often well coupled to seasonal variation of local air temperature 35 . A departure from this coupling in terms of seasonal magnitude and timing is characteristic of influence from varied depth groundwater discharge 8 or dam operation 36 . Discharge of shallow groundwater to streams has physical properties closely tied to seasonally dynamic air temperature and precipitation, quickly responding to short-term perturbations such as hot, dry summers 37 . Discharge from deep groundwater sources does not tend to respond to anomalous weather years but is sensitive to long-term climate trends at extended time scales ranging from decadal to centennial 16 , 38 , 39 . In this work, we used a newly refined methodology to classify 1729 stream sites across the continental United States as having shallow or deep groundwater signatures, lacking a pronounced groundwater signature, or having major dam influence, based on publicly available multi-year air and stream water temperature records and metadata. Our analysis harnesses the relatively high annual variability in shallow groundwater temperatures and the stability of deep groundwater temperatures to identify characteristic paired air and stream water annual temperature signal relations. We used our classification to (1) compare our annual temperature signal-based categorization to baseflow indices, (2) explore continental spatial patterns and", "role": "user" }, { "content": "A UConn Ph.D. candidate and a faculty member have developed a novel way of gathering data about streams fed by groundwater that provide important insights about the possible effects of climate change. Water is constantly on the move: through the air, through waterways, and underground. Life depends on a consistent supply of water and details about its journey are necessary for understanding and managing this dynamic resource. However, those details are often difficult to measure. UConn Ph.D. candidate Danielle Hare, in the lab of associate professor of Natural Resources and the Environment Ashley Helton, has expanded on a novel method to easily access vital details about groundwater, and in doing so, they have discovered that many streams are more vulnerable to stressors like climate change than previously thought. The team has published their findings in the latest issue of Nature Communications. Precipitation enters streams and rivers by flowing over land surfaces, or it percolates through soil into the groundwater. Groundwater then flows back into waterways, but understanding the details, such as the depth of groundwater entering streams, is more challenging. \"Normally, you'd have to go to a site and spend a lot of time and money just to figure out the source of groundwater discharging to the stream,\" she says. These details are important for watershed managers, who take into account numerous variables to keep water clean and safe, both for drinking water and for wildlife habitats. Details like depth are crucial because, for example, shallower groundwater reserves are more prone to disturbances than deeper sources. Hare says one of the threats to the streams supplied by shallower groundwater is climate change, as shallow groundwater is more susceptible to warming and has grave impacts on water resources down the line. Helton explains some of the roles groundwater plays for streams and groundwater-dependent ecosystems. \"You can think about the three services that groundwater provides to streams as it discharges back to the streams at the surface,\" she says. \"First is flow; groundwater provides water and deeper groundwater provides more consistent flow. Second, groundwater provides a temperature buffer and what is called thermal refuge for organisms, and deeper groundwater provides more stable temperatures. Third, groundwater provides nutrients and carbon for ecosystems and deeper groundwater often has a different chemical profile.\" In the case of streams with significant groundwater inputs, Helton says management often defaults to assuming that groundwater-dependent streams are managed similarly. Hare, with a strong interest in stream temperatures and groundwater dynamics, sought to explore if this was truly the case as part of a class project. \"This project was open-ended and it was a great opportunity to combine my interests. We were not sure if it would work, but even if it didn't, I knew I would learn along the way,\" says Hare. Hare used data that is frequently gathered and often publicly accessible: stream and air temperature measurement. These data are paired at over 1,700 streams nationwide, and the researchers were able to deduce which streams had substantial groundwater inputs and, of those, which were deep or shallow groundwater-fed. The findings were eye-opening. \"Something that surprised me was just how prominent shallow groundwater sites are across the US. We saw about 40% of the sites had substantial groundwater component, and how many of those were shallow were about 50%. I would not have guessed that; I would have guessed that there were more deep groundwater,\" says Hare. The researchers were excited that what started as a course project for Hare has turned into such a powerful tool. \"This method is straightforward and accessible to watershed managers and stakeholders. There is a lot of power to that. There is no need to spend a lot money to define different geology, we can simply use a temperature logger or thermometer to monitor the temperatures. They are widely available and straightforward,\" says Hare. Hare and Helton are hopeful this information will be considered in making watershed management decisions going forward. \"The sites that are dominated by groundwater are really wide spread and about half were shallow,\" says Helton. However, this could be problematic when sites are managed as if they are deep groundwater-fed sites. Hare cautions that managers could be missing out on important conservation opportunities in the face of challenges that can impact groundwater replenishment. \"The streams that are shallow are not going to be buffered as well as we previously thought,\" says Hare. \"Especially when considering the groundwater dependent ecosystems, when we're thinking about fishes that we really do need to consider or else we may have a missed opportunity as far as mitigating, supporting, observing that important ecosystem resource.\" For those tasked with managing these important watersheds, this new method ensures vital information is no longer out of reach, says Hare. \"Where the power is in this study and what makes it distinct is we separate the shallow versus deep components of groundwater. Not only are we able to find streams that are more groundwater-dominated, we can parse that information into whether it is groundwater shallow or deep. The shallow are going to be more susceptible to both climate warming and development changes.\" ", "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 Groundwater discharge generates streamflow and influences stream thermal regimes. However, the water quality and thermal buffering capacity of groundwater depends on the aquifer source-depth. Here, we pair multi-year air and stream temperature signals to categorize 1729 sites across the continental United States as having major dam influence, shallow or deep groundwater signatures, or lack of pronounced groundwater (atmospheric) signatures. Approximately 40% of non-dam stream sites have substantial groundwater contributions as indicated by characteristic paired air and stream temperature signal metrics. Streams with shallow groundwater signatures account for half of all groundwater signature sites and show reduced baseflow and a higher proportion of warming trends compared to sites with deep groundwater signatures. These findings align with theory that shallow groundwater is more vulnerable to temperature increase and depletion. Streams with atmospheric signatures tend to drain watersheds with low slope and greater human disturbance, indicating reduced stream-groundwater connectivity in populated valley settings. Introduction Groundwater discharge zones establish active stream–groundwater hydrologic connectivity through the advective exchange of water. As a critical contributor to streamflow generation, groundwater discharge influences water quantity and quality throughout stream networks, especially during seasonal low flows and dry conditions 1 . Many streams host ecologically important ‘groundwater-dependent ecosystems’ 2 , yet these habitats face growing threats from climate change and groundwater contamination 1 , 3 , 4 . Aquatic organisms are particularly susceptible to shifts in thermal regimes because they have life cycles that rely on annual thermal cues 5 and metabolic rates influenced by stream temperature 6 . The relatively stable thermal regimes of some groundwater discharge zones can buffer stream temperatures against long-term air temperature trends and short-term hot and cold extremes 2 ; therefore, groundwater discharges can provide important stream channel thermal refuges and refugia for sensitive aquatic organisms such as salmonid fishes 7 , 8 . However, in response to climate change and land development, streams and rivers have recently shown widespread warming 9 , 10 . Observed stream warming trends are spatially heterogeneous due in part to spatially variable groundwater contributions to streamflow 11 . Thus, effective watershed management will require a process-based characterization of groundwater contribution to streamflow 12 at ecologically relevant scales to predict future stream thermal regimes. The magnitude, spatial distribution, and source-flow path characteristics of groundwater discharge can control the physical characteristics of individual streams 8 , 13 , 14 and whole stream networks 15 . Characterizing the depth of contributing groundwater is particularly important for understanding broad-scale responses of stream ecosystems to land development and climate change 16 for three main reasons: first, groundwater depth is associated with annual thermal stability as natural surface temperature fluctuations are prominent within the shallow aquifer but quickly attenuate with depth 13 . Deeper groundwater (defined here as greater than approximately 6 m from the land surface) shows little annual thermal variability relative to shallow groundwater 17 that flows through the near-surface portion of the ‘critical zone’ 18 .Therefore, groundwater discharge can either impart stability (deep groundwater) or variability (shallow groundwater) on atmospheric-driven stream thermal regimes. Hydrogeologic climate simulations support this definition, as water tables below 5 m have shown decoupling from surface energy balances 19 . Second, shallow groundwater is inherently more sensitive to land-use changes 20 and surface contamination 21 , 22 , 23 . Thus, effective watershed management may have a different urgency depending on the depth of contributing groundwater. Also, naturally, deep and shallow groundwater tend to have different chemical profiles 24 , 25 , 26 , which has important implications for surface water quality and stream ecosystem function including delivery of legacy contaminants 15 . Third, shallow groundwater can be directly depleted via transpiration 27 , irrigation withdrawals 28 , and is more vulnerable to seasonal water table drawdown during dry periods while discharge from deeper groundwater sources is more seasonably stable 29 . This depth-dependent effect can affect stream water transit times and catchment water balance, emphasizing the importance of parsing shallow versus deep contributing groundwater flow paths 24 . Though understanding the implications of climate change and land development for stream ecosystems requires quantifying the magnitude and source-depth of groundwater discharge, we lack efficient and broadly applicable methods to characterize source groundwater depth. Most hydrologic techniques for evaluating the physical properties of groundwater discharge are labor-intensive and not spatially and temporally scalable 30 . More efficient methods, such as stream water temperature sensitivity linear regression analyses 31 or physically based hydrograph separation techniques 32 do not directly differentiate groundwater source-depth. Inference of groundwater source-depth is possible using water chemistry end-member mixing 33 or water isotopic data 34 , but these analyses cannot inherently specify shallow groundwater flow paths without additional hydrologic characterization, and are time and resource-intensive. In the absence of groundwater discharge, annual stream water temperature signals are often well coupled to seasonal variation of local air temperature 35 . A departure from this coupling in terms of seasonal magnitude and timing is characteristic of influence from varied depth groundwater discharge 8 or dam operation 36 . Discharge of shallow groundwater to streams has physical properties closely tied to seasonally dynamic air temperature and precipitation, quickly responding to short-term perturbations such as hot, dry summers 37 . Discharge from deep groundwater sources does not tend to respond to anomalous weather years but is sensitive to long-term climate trends at extended time scales ranging from decadal to centennial 16 , 38 , 39 . In this work, we used a newly refined methodology to classify 1729 stream sites across the continental United States as having shallow or deep groundwater signatures, lacking a pronounced groundwater signature, or having major dam influence, based on publicly available multi-year air and stream water temperature records and metadata. Our analysis harnesses the relatively high annual variability in shallow groundwater temperatures and the stability of deep groundwater temperatures to identify characteristic paired air and stream water annual temperature signal relations. We used our classification to (1) compare our annual temperature signal-based categorization to baseflow indices, (2) explore continental spatial patterns and<|im_end|> <|im_start|>assistant A UConn Ph.D. candidate and a faculty member have developed a novel way of gathering data about streams fed by groundwater that provide important insights about the possible effects of climate change. Water is constantly on the move: through the air, through waterways, and underground. Life depends on a consistent supply of water and details about its journey are necessary for understanding and managing this dynamic resource. However, those details are often difficult to measure. UConn Ph.D. candidate Danielle Hare, in the lab of associate professor of Natural Resources and the Environment Ashley Helton, has expanded on a novel method to easily access vital details about groundwater, and in doing so, they have discovered that many streams are more vulnerable to stressors like climate change than previously thought. The team has published their findings in the latest issue of Nature Communications. Precipitation enters streams and rivers by flowing over land surfaces, or it percolates through soil into the groundwater. Groundwater then flows back into waterways, but understanding the details, such as the depth of groundwater entering streams, is more challenging. "Normally, you'd have to go to a site and spend a lot of time and money just to figure out the source of groundwater discharging to the stream," she says. These details are important for watershed managers, who take into account numerous variables to keep water clean and safe, both for drinking water and for wildlife habitats. Details like depth are crucial because, for example, shallower groundwater reserves are more prone to disturbances than deeper sources. Hare says one of the threats to the streams supplied by shallower groundwater is climate change, as shallow groundwater is more susceptible to warming and has grave impacts on water resources down the line. Helton explains some of the roles groundwater plays for streams and groundwater-dependent ecosystems. "You can think about the three services that groundwater provides to streams as it discharges back to the streams at the surface," she says. "First is flow; groundwater provides water and deeper groundwater provides more consistent flow. Second, groundwater provides a temperature buffer and what is called thermal refuge for organisms, and deeper groundwater provides more stable temperatures. Third, groundwater provides nutrients and carbon for ecosystems and deeper groundwater often has a different chemical profile." In the case of streams with significant groundwater inputs, Helton says management often defaults to assuming that groundwater-dependent streams are managed similarly. Hare, with a strong interest in stream temperatures and groundwater dynamics, sought to explore if this was truly the case as part of a class project. "This project was open-ended and it was a great opportunity to combine my interests. We were not sure if it would work, but even if it didn't, I knew I would learn along the way," says Hare. Hare used data that is frequently gathered and often publicly accessible: stream and air temperature measurement. These data are paired at over 1,700 streams nationwide, and the researchers were able to deduce which streams had substantial groundwater inputs and, of those, which were deep or shallow groundwater-fed. The findings were eye-opening. "Something that surprised me was just how prominent shallow groundwater sites are across the US. We saw about 40% of the sites had substantial groundwater component, and how many of those were shallow were about 50%. I would not have guessed that; I would have guessed that there were more deep groundwater," says Hare. The researchers were excited that what started as a course project for Hare has turned into such a powerful tool. "This method is straightforward and accessible to watershed managers and stakeholders. There is a lot of power to that. There is no need to spend a lot money to define different geology, we can simply use a temperature logger or thermometer to monitor the temperatures. They are widely available and straightforward," says Hare. Hare and Helton are hopeful this information will be considered in making watershed management decisions going forward. "The sites that are dominated by groundwater are really wide spread and about half were shallow," says Helton. However, this could be problematic when sites are managed as if they are deep groundwater-fed sites. Hare cautions that managers could be missing out on important conservation opportunities in the face of challenges that can impact groundwater replenishment. "The streams that are shallow are not going to be buffered as well as we previously thought," says Hare. "Especially when considering the groundwater dependent ecosystems, when we're thinking about fishes that we really do need to consider or else we may have a missed opportunity as far as mitigating, supporting, observing that important ecosystem resource." For those tasked with managing these important watersheds, this new method ensures vital information is no longer out of reach, says Hare. "Where the power is in this study and what makes it distinct is we separate the shallow versus deep components of groundwater. Not only are we able to find streams that are more groundwater-dominated, we can parse that information into whether it is groundwater shallow or deep. The shallow are going to be more susceptible to both climate warming and development changes." <|im_end|>
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2,265
[ { "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 Achieving national targets for net-zero carbon emissions will require atmospheric carbon dioxide removal strategies compatible with rising agricultural production. One possible method for delivering on these goals is enhanced rock weathering, which involves modifying soils with crushed silicate rocks, such as basalt. Here we use dynamic carbon budget modelling to assess the carbon dioxide removal potential and agricultural benefits of implementing enhanced rock weathering strategies across UK arable croplands. We find that enhanced rock weathering could deliver net carbon dioxide removal of 6–30 MtCO 2 yr − 1 for the United Kingdom by 2050, representing up to 45% of the atmospheric carbon removal required nationally to meet net-zero emissions. This suggests that enhanced rock weathering could play a crucial role in national climate mitigation strategies if it were to gain acceptance across national political, local community and farm scales. We show that it is feasible to eliminate the energy-demanding requirement for milling rocks to fine particle sizes. Co-benefits of enhanced rock weathering include substantial mitigation of nitrous oxide, the third most important greenhouse gas, widespread reversal of soil acidification and considerable cost savings from reduced fertilizer usage. Our analyses provide a guide for other nations to pursue their carbon dioxide removal ambitions and decarbonize agriculture—a key source of greenhouse gases. Main Governments worldwide are increasingly translating the Paris Agreement under the United Nations Framework Convention on Climate Change into national strategies for achieving net-zero carbon emissions by 2050. More than 120 nations have set full decarbonization goals that account for 51% of global CO 2 emissions, with the United Kingdom among several of these nations legislating for net-zero emissions 1 . The United Kingdom, where the industrial revolution driven by burning fossil fuels originated, is responsible for ~5% of the cumulative CO 2 emissions over the period 1751–2018 that drive climate change 2 . Carbon emissions in the United Kingdom have declined by 43% between 1990 and 2018 owing to the rise of renewables, and the transition from coal to natural gas, while growing the economy by 75% (ref. 3 ). Continued phase-out of emissions is, however, required to meet the United Kingdom’s net-zero commitment, together with the capture and storage of residual emissions using carbon dioxide removal (CDR) technologies and a strengthening of nature-based carbon sinks 4 . Enhanced rock weathering (ERW), a CDR strategy based on amending soils with crushed calcium- and magnesium-rich silicate rocks, aims to accelerate natural CO 2 sequestration processes 5 , 6 , 7 , 8 . The estimated net global potential for ERW deployed on croplands to draw down CO 2 is substantial, up to 2 GtCO 2 yr − 1 (ref. 6 ), with co-benefits for production 9 , 10 , 11 , soil restoration and ocean acidification 7 , 8 , 12 . Agricultural co-benefits can create demand for ERW deployment that is unaffected by diminishing income from carbon-tax receipts generated by other CDR technologies as the transition to clean energy advances and emissions approach net zero 13 . Global action on CDR, and hence progress towards net zero, requires leadership from early-adopting countries through their development of flexible action plans to support policymakers of other nations. Assessment of the contribution of ERW to the United Kingdom’s net-zero commitment is therefore required, given that it is a CDR strategy for assisting with decarbonization while improving food production and rebuilding soils degraded by intensified land management 9 . Here we examine in detail the technical potential of ERW implementation on UK arable croplands in a national net-zero context and provide a blueprint by which other nations may proceed with this CDR technology as part of their legislated plans for decarbonization. Using coupled climate–carbon–nitrogen (climate–C–N) cycle modelling of ERW (Methods and Extended Data Fig. 1 ), we constructed dynamic UK net 2020–2070 C removal budgets and CDR costs after accounting for secondary CO 2 emissions from the ERW supply chain (Methods and Extended Data Fig. 2 ). Coupled C–N cycle ERW modelling provides the fundamental advance in assessing the effects of cropland N fertilizers on the soil alkalinity balance and mineral weathering kinetics (Methods and Extended Data Fig. 3 ; Supplementary Information ) and ERW-related mitigation of nitrous oxide (N 2 O) emissions from agricultural soils 14 . Nitrous oxide is a key long-lived greenhouse gas and important stratospheric-ozone-depleting substance 15 ; UK agriculture accounts for 75% of N 2 O emissions nationally with high external costs (~£1 billion yr −1 ) 16 . Our analysis, constrained by future energy policies 17 , utilizes basalt as an abundant natural silicate rock suitable for ERW with croplands 9 , 10 , 11 , with low- (S1), medium- (S2) and high- (S3) extraction scenarios between 2035 and 2050 (Methods and Extended Data Fig. 4 ; Supplementary Information ). Patterns of cropland CDR Across basalt supply scenarios S1 to S3, ERW implementation on arable lands was simulated to remove 6–30 MtCO 2 yr −1 by 2050 (Fig. 1a–c ); that is, up to 45% of the CO 2 emissions removal required for UK net-zero emissions (balanced net-zero pathway engineered carbon removal requirement ~58 MtCO 2 yr −1 ; range 45–112 MtCO 2 yr −1 ) 4 . Modelled maximum CDR rates were predominantly governed by the geographical extent of ERW application, which increased as resource provision allowed (Fig. 1a–c ). Year-on-year legacy effects are also important. CDR rates per unit area increased over time with successive annual applications of rock dust, even if the land area of deployment remained constant. These effects are evident in all scenarios when basalt extraction levelled off, and result from slower-weathering silicate minerals continuing to capture CO 2 in years post-application before they are fully dissolved 6 . By quantifying the geochemical dissolution rates governing ERW and legacy effects, our simulations indicated the CDR potential of ERW rise over time to exceed that suggested by previous mass balance estimates 18 , 19 , 20 . Fig. 1: Net CDR by ERW deployed on UK arable croplands. a – c ,", "role": "user" }, { "content": "Adding rock dust to UK agricultural soils could absorb up to 45% of the atmospheric carbon dioxide needed to reach net zero, according to a major new study led by scientists at the University of Sheffield. The study, led by the Leverhulme Centre for Climate Change Mitigation at the University, provides the first detailed analysis of the potential and costs of greenhouse gas removal by enhanced weathering in the UK over the next 50 years. The authors show this technique could make a major overlooked contribution to the UK's requirement for greenhouse gas removal in the coming decades with a removal potential of 6–30 million tons of carbon dioxide annually by 2050. This represents up to 45% of the atmospheric carbon removal required nationally to meet net-zero greenhouse gas emissions alongside emissions reductions. Deployment could be straightforward because the approach uses existing infrastructure and has costs of carbon removal lower than other Carbon Dioxide Removal (CDR) strategies, such as direct air capture with carbon capture storage, and bioenergy crops with carbon capture and storage. A clear advantage of this approach to CDR is the potential to deliver major wins for agriculture in terms of lowering emissions of nitrous oxide, reversing soil acidification that limits yields and reducing demands for imported fertilizers. The advantages of reducing reliance on imported food and fertilizers have been highlighted by the war in Ukraine that has caused the price of food and fertilizers to spike worldwide as exports of both are interrupted. The authors of the study highlight that societal acceptance is required from national politics through to local community and farm scales. While mining operations for producing the basalt rock dust will generate additional employment and could contribute to the UK government's leveling up agenda; however this will need to be done in ways which are both fair and respectful of local community concerns. This new study provides much needed detail of what enhanced rock weathering as a carbon dioxide removal strategy could deliver for the UK's net-zero commitment by 2050. The Committee on Climate Change, which provides independent advice to the government on climate change and carbon budgets, overlooked enhanced weathering in their recent net-zero report because it required further research. The new study now indicates enhanced weathering is comparable to other options on the table and has considerable co-benefits to UK food production and soil health. Professor David Beerling, Director of the Leverhulme Centre for Climate Change Mitigation at the University of Sheffield and senior author of the study, says that their \"analysis highlights the potential of UK agriculture to deliver substantial carbon drawdown by transitioning to managing arable farms with rock dust, with added benefits for soil health and food security.\" Dr. Euripides Kantzas of the Leverhulme Centre for Climate Change Mitigation at the University of Sheffield and lead author, says that \"by quantifying the carbon removal potential and co-benefits of amending crops with crushed rock in the UK, we provide a blueprint for deploying enhanced rock weathering on a national level, adding to the toolbox of solutions for carbon-neutral economies.\" Professor Nick Pidgeon, a partner in the study and Director of the Understanding Risk Group at Cardiff University, says that \"meeting our net zero targets will need widespread changes to the way UK agriculture and land is managed. For this transformation to succeed we will need to fully engage rural communities and farmers in this important journey.\" The research was published in Nature Geoscience. ", "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 Achieving national targets for net-zero carbon emissions will require atmospheric carbon dioxide removal strategies compatible with rising agricultural production. One possible method for delivering on these goals is enhanced rock weathering, which involves modifying soils with crushed silicate rocks, such as basalt. Here we use dynamic carbon budget modelling to assess the carbon dioxide removal potential and agricultural benefits of implementing enhanced rock weathering strategies across UK arable croplands. We find that enhanced rock weathering could deliver net carbon dioxide removal of 6–30 MtCO 2 yr − 1 for the United Kingdom by 2050, representing up to 45% of the atmospheric carbon removal required nationally to meet net-zero emissions. This suggests that enhanced rock weathering could play a crucial role in national climate mitigation strategies if it were to gain acceptance across national political, local community and farm scales. We show that it is feasible to eliminate the energy-demanding requirement for milling rocks to fine particle sizes. Co-benefits of enhanced rock weathering include substantial mitigation of nitrous oxide, the third most important greenhouse gas, widespread reversal of soil acidification and considerable cost savings from reduced fertilizer usage. Our analyses provide a guide for other nations to pursue their carbon dioxide removal ambitions and decarbonize agriculture—a key source of greenhouse gases. Main Governments worldwide are increasingly translating the Paris Agreement under the United Nations Framework Convention on Climate Change into national strategies for achieving net-zero carbon emissions by 2050. More than 120 nations have set full decarbonization goals that account for 51% of global CO 2 emissions, with the United Kingdom among several of these nations legislating for net-zero emissions 1 . The United Kingdom, where the industrial revolution driven by burning fossil fuels originated, is responsible for ~5% of the cumulative CO 2 emissions over the period 1751–2018 that drive climate change 2 . Carbon emissions in the United Kingdom have declined by 43% between 1990 and 2018 owing to the rise of renewables, and the transition from coal to natural gas, while growing the economy by 75% (ref. 3 ). Continued phase-out of emissions is, however, required to meet the United Kingdom’s net-zero commitment, together with the capture and storage of residual emissions using carbon dioxide removal (CDR) technologies and a strengthening of nature-based carbon sinks 4 . Enhanced rock weathering (ERW), a CDR strategy based on amending soils with crushed calcium- and magnesium-rich silicate rocks, aims to accelerate natural CO 2 sequestration processes 5 , 6 , 7 , 8 . The estimated net global potential for ERW deployed on croplands to draw down CO 2 is substantial, up to 2 GtCO 2 yr − 1 (ref. 6 ), with co-benefits for production 9 , 10 , 11 , soil restoration and ocean acidification 7 , 8 , 12 . Agricultural co-benefits can create demand for ERW deployment that is unaffected by diminishing income from carbon-tax receipts generated by other CDR technologies as the transition to clean energy advances and emissions approach net zero 13 . Global action on CDR, and hence progress towards net zero, requires leadership from early-adopting countries through their development of flexible action plans to support policymakers of other nations. Assessment of the contribution of ERW to the United Kingdom’s net-zero commitment is therefore required, given that it is a CDR strategy for assisting with decarbonization while improving food production and rebuilding soils degraded by intensified land management 9 . Here we examine in detail the technical potential of ERW implementation on UK arable croplands in a national net-zero context and provide a blueprint by which other nations may proceed with this CDR technology as part of their legislated plans for decarbonization. Using coupled climate–carbon–nitrogen (climate–C–N) cycle modelling of ERW (Methods and Extended Data Fig. 1 ), we constructed dynamic UK net 2020–2070 C removal budgets and CDR costs after accounting for secondary CO 2 emissions from the ERW supply chain (Methods and Extended Data Fig. 2 ). Coupled C–N cycle ERW modelling provides the fundamental advance in assessing the effects of cropland N fertilizers on the soil alkalinity balance and mineral weathering kinetics (Methods and Extended Data Fig. 3 ; Supplementary Information ) and ERW-related mitigation of nitrous oxide (N 2 O) emissions from agricultural soils 14 . Nitrous oxide is a key long-lived greenhouse gas and important stratospheric-ozone-depleting substance 15 ; UK agriculture accounts for 75% of N 2 O emissions nationally with high external costs (~£1 billion yr −1 ) 16 . Our analysis, constrained by future energy policies 17 , utilizes basalt as an abundant natural silicate rock suitable for ERW with croplands 9 , 10 , 11 , with low- (S1), medium- (S2) and high- (S3) extraction scenarios between 2035 and 2050 (Methods and Extended Data Fig. 4 ; Supplementary Information ). Patterns of cropland CDR Across basalt supply scenarios S1 to S3, ERW implementation on arable lands was simulated to remove 6–30 MtCO 2 yr −1 by 2050 (Fig. 1a–c ); that is, up to 45% of the CO 2 emissions removal required for UK net-zero emissions (balanced net-zero pathway engineered carbon removal requirement ~58 MtCO 2 yr −1 ; range 45–112 MtCO 2 yr −1 ) 4 . Modelled maximum CDR rates were predominantly governed by the geographical extent of ERW application, which increased as resource provision allowed (Fig. 1a–c ). Year-on-year legacy effects are also important. CDR rates per unit area increased over time with successive annual applications of rock dust, even if the land area of deployment remained constant. These effects are evident in all scenarios when basalt extraction levelled off, and result from slower-weathering silicate minerals continuing to capture CO 2 in years post-application before they are fully dissolved 6 . By quantifying the geochemical dissolution rates governing ERW and legacy effects, our simulations indicated the CDR potential of ERW rise over time to exceed that suggested by previous mass balance estimates 18 , 19 , 20 . Fig. 1: Net CDR by ERW deployed on UK arable croplands. a – c ,<|im_end|> <|im_start|>assistant Adding rock dust to UK agricultural soils could absorb up to 45% of the atmospheric carbon dioxide needed to reach net zero, according to a major new study led by scientists at the University of Sheffield. The study, led by the Leverhulme Centre for Climate Change Mitigation at the University, provides the first detailed analysis of the potential and costs of greenhouse gas removal by enhanced weathering in the UK over the next 50 years. The authors show this technique could make a major overlooked contribution to the UK's requirement for greenhouse gas removal in the coming decades with a removal potential of 6–30 million tons of carbon dioxide annually by 2050. This represents up to 45% of the atmospheric carbon removal required nationally to meet net-zero greenhouse gas emissions alongside emissions reductions. Deployment could be straightforward because the approach uses existing infrastructure and has costs of carbon removal lower than other Carbon Dioxide Removal (CDR) strategies, such as direct air capture with carbon capture storage, and bioenergy crops with carbon capture and storage. A clear advantage of this approach to CDR is the potential to deliver major wins for agriculture in terms of lowering emissions of nitrous oxide, reversing soil acidification that limits yields and reducing demands for imported fertilizers. The advantages of reducing reliance on imported food and fertilizers have been highlighted by the war in Ukraine that has caused the price of food and fertilizers to spike worldwide as exports of both are interrupted. The authors of the study highlight that societal acceptance is required from national politics through to local community and farm scales. While mining operations for producing the basalt rock dust will generate additional employment and could contribute to the UK government's leveling up agenda; however this will need to be done in ways which are both fair and respectful of local community concerns. This new study provides much needed detail of what enhanced rock weathering as a carbon dioxide removal strategy could deliver for the UK's net-zero commitment by 2050. The Committee on Climate Change, which provides independent advice to the government on climate change and carbon budgets, overlooked enhanced weathering in their recent net-zero report because it required further research. The new study now indicates enhanced weathering is comparable to other options on the table and has considerable co-benefits to UK food production and soil health. Professor David Beerling, Director of the Leverhulme Centre for Climate Change Mitigation at the University of Sheffield and senior author of the study, says that their "analysis highlights the potential of UK agriculture to deliver substantial carbon drawdown by transitioning to managing arable farms with rock dust, with added benefits for soil health and food security." Dr. Euripides Kantzas of the Leverhulme Centre for Climate Change Mitigation at the University of Sheffield and lead author, says that "by quantifying the carbon removal potential and co-benefits of amending crops with crushed rock in the UK, we provide a blueprint for deploying enhanced rock weathering on a national level, adding to the toolbox of solutions for carbon-neutral economies." Professor Nick Pidgeon, a partner in the study and Director of the Understanding Risk Group at Cardiff University, says that "meeting our net zero targets will need widespread changes to the way UK agriculture and land is managed. For this transformation to succeed we will need to fully engage rural communities and farmers in this important journey." The research was published in Nature Geoscience. <|im_end|>
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220, 806, 1174, 449, 3428, 12, 320, 50, 16, 705, 11298, 12, 320, 50, 17, 8, 323, 1579, 12, 320, 50, 18, 8, 33289, 26350, 1990, 220, 9639, 20, 323, 220, 10866, 15, 320, 18337, 323, 41665, 2956, 23966, 13, 220, 19, 2652, 99371, 8245, 7609, 63823, 315, 14425, 501, 438, 356, 7842, 58237, 3122, 3223, 8312, 26350, 328, 16, 311, 328, 18, 11, 27590, 54, 8292, 389, 802, 481, 12098, 574, 46836, 311, 4148, 220, 21, 4235, 966, 36608, 8445, 220, 17, 43438, 25173, 16, 555, 220, 10866, 15, 320, 30035, 13, 220, 16, 64, 4235, 66, 7048, 430, 374, 11, 709, 311, 220, 1774, 4, 315, 279, 7432, 220, 17, 20748, 17065, 2631, 369, 6560, 4272, 38029, 20748, 320, 59502, 4272, 38029, 38970, 46036, 12782, 17065, 16686, 4056, 2970, 36608, 8445, 220, 17, 43438, 25173, 16, 2652, 2134, 220, 1774, 4235, 7261, 36608, 8445, 220, 17, 43438, 25173, 16, 883, 220, 19, 662, 5008, 839, 7340, 356, 7842, 7969, 1051, 47904, 27800, 555, 279, 54001, 13112, 315, 27590, 54, 3851, 11, 902, 7319, 439, 5211, 17575, 5535, 320, 30035, 13, 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2,063
[ { "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 Reef ecosystems are highly diverse habitats that harbor many ecologically and economically significant species. Yet, globally they are under threat from multiple stressors including overexploitation of predatory fishes and habitat degradation. While these two human-driven activities often occur concomitantly, they are typically studied independently. Using a factorial design, we examined effects of predator presence, habitat complexity, and their interaction on patch reef fish communities in a nearshore ecosystem on Great Abaco Island, The Bahamas. We manipulated the presence of Nassau groupers ( Epinephelus striatus ), a reef predator that is critically endangered largely due to overharvest, and varied patch reef structure (cinder blocks with and without PVC) to reflect high or low complexity-four treatments in total. To assess changes in fish community composition we measured fish abundances, species richness, and evenness. We found that predators present and high reef complexity had an additive, positive effect on total fish abundance: fish abundance increased by ~ 250% and 300%, compared to predators absent and low complexity reef treatments, respectively. Species richness increased with reef complexity. Variation in community structure was explained by the interaction between factors, largely driven by juvenile Tomtate grunt ( Haemulon aurolineatum ) abundances. Specifically, Tomtate grunt abundance was significantly higher on high complexity reefs with predators present, but on low complexity reefs predators present had no effect on Tomtate grunt abundance. Our data suggest that both fisheries management of large-bodied piscivores and reef habitat restoration are critical to the management and conservation of reef ecosystem functions and services. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Introduction Coral dominated reefs are highly productive ecosystems that can harbor large and diverse fish communities, but are threatened worldwide by myriad stressors (Hughes and Connell 1999 ; Hoegh-Guldberg et al. 2007 ). Two primary stressors are overfishing at higher trophic levels and habitat degradation (Dulvy et al. 2004 ; Lee 2006 ). These stressors can fundamentally change processes that act from both the top-down (e.g., trophic cascades) (Baum and Worm 2009 ; Allgeier et al. 2016 ; Valdivia et al. 2017 ) and bottom-up (e.g., nutrient cycling regimes and provision of refugia) of interaction networks (Beukers and Jones 1998 ; Lee 2006 ; Smith et al. 2006 ; Graham and Nash 2013 ). Overexploitation of predators and the loss of habitat complexity are typically concomitant. Yet because these factors are most often studied independently, our understanding of how their simultaneous effects combine or interact to alter reef communities remains limited (but see Wilson et al. 2008 ). Predators and habitat structural complexity play a central role in determining post-settlement coral reef fish communities (Hixon and Carr 1997 ; Steele 1999 ). Direct effects of predators can alter fish communities including species richness (Freestone et al. 2011 ) and overall community composition (Almany 2003 ). Predators also have indirect effects on their surrounding communities, however the outcome is often context-dependent for both predator and prey identity making the effect difficult to predict or generalize (Almany 2004a ; Stallings 2008 ; Chamberlain et al. 2014 ). Additionally, predator impacts on reef communities can be mediated by the structural complexity of reefs (Wilson et al. 2008 ). Specifically, habitat complexity can decrease predators’ direct effects by reducing prey encounter rates (Swisher et al. 1998 ; Almany 2004b ; Warfe and Barmuta 2004 ). In contrast, structural complexity can increase predators’ indirect effects due to predators and their prey residing in close proximity to one another (Grabowski et al. 2008 ). To date, most studies examining predator effects in marine systems have tended to use simplified interaction webs within mesocosms, focused on small-bodied predator species, or a combination of both (Steele 1999 ; Johnson 2006 ; Grabowski et al. 2008 ). However, fishing typically targets large-bodied predators (e.g., sharks, tunas, and groupers) that are more difficult to study. Further complicating this scenario is the challenge of understanding how losses of predators may interact with concomitant changes in habitat complexity that is a result of major shifts in foundation species (e.g., coral to sponge, or macroalgae) that can render reefs flat, reducing available refugia for fauna. This potential interaction has important implications for management and conservation efforts seeking to mitigate human impacts on coral reefs. Here we ask: how do predators present and reef complexity affect reef fish communities in terms of total abundance, species richness, evenness, and overall community composition? We conducted an in situ experiment designed to examine effects of large predator presence, habitat complexity, and their interaction on artificial patch reef communities in a nearshore ecosystem on Great Abaco Island, The Bahamas. Nearshore, patch reef habitats are ideal for this experiment because they are isolated, complex, vertical habitats surrounded by hard or soft low-relief substrate and, being located in nearshore habitats, they are strongly influenced by local stressors (Stallings 2009 ). Artificial patch reefs are particularly ideal because they are relatively easy to manipulate and subsequently study whole community effects (Carr and Hixon 1997 ). In a 2 × 2 factorial design, we manipulated the presence of a locally abundant reef predator, Nassau grouper ( Epinephelus striatus ), on patch reefs of high and low complexity. We used Nassau grouper as our predator species because they are an important fishery species that has experienced drastic population declines throughout the Caribbean from overexploitation (Dahlgren et al. 2016 ; Sherman et al. 2018 ). We hypothesized that reefs with Nassau groupers present would have more fishes compared to those without Nassau groupers due to strong indirect predator effects on smaller-bodied, mesopredator species. Additionally Nassau groupers present would alter fish community composition, i.e., relative abundance of the constituent species, due to a combination of their direct and indirect predator effects. For habitat complexity, we hypothesized that complex reefs would have more fishes as well as more species present than non-complex reefs to do an increase in refugia hole availability and diversity in refugia morphology (shape). Methods Our study occurred in a back-reef system in the Sea of Abaco", "role": "user" }, { "content": "New research highlights two factors that play a critical role in supporting reef fish populations and—ultimately—creating conditions that are more favorable for the growth of both coral reefs and seagrass. \"Previous work has shown mixed results on whether the presence of large predator species benefits reef fish populations, but we found that the presence of Nassau grouper (Epinephelus striatus) had an overall positive effect on fish abundance,\" says Enie Hensel, a former Ph.D. student at North Carolina State University and lead author of a paper on the work. \"We also found that habitat complexity benefits both fish abundance and species richness, likely because it gives fish a larger variety of places to shelter.\" This is consistent with previous work. \"One of the surprises here was that the effect of predator presence on fish abundance was comparable to the effect of habitat complexity,\" Hensel says. To better understand the effect of these variables, researchers constructed 16 artificial \"patch\" reefs in shallow waters off the coast of Great Abaco Island in The Bahamas. Eight of the reefs consisted of cement-filled cinder blocks, mimicking degraded reefs with limited habitat complexity. The remaining eight reefs consisted of unfilled cinder blocks and branching pipe structures, mimicking the more complex physical environment of healthier reefs. Once in place, the researchers waited for groupers to move in and claim the new reef territory. The groupers were large juveniles, ranging in size from 16-33 centimeters. The researchers then removed the groupers from four of the degraded reef sites and from four of the complex reef sites. Groupers that were removed were relocated to distant reefs. Researchers monitored the sites for 60 days to ensure that the grouper-free reefs remained free of groupers. At the end of the 60 days, the researchers assessed the total number of fish at each reef site, as well as the total number of fish species at each site. The differences were significant. Simple artificial reef structures, like that on the left, did little to support fish populations. Complex structures, like the one on the right, helped to support larger communities of fish. Credit: Enie Hensel Fish abundance, or the total number of fish, was highest at sites that had both a resident grouper and complex habitat. Abundance at these sites ranged from 275 fish to more than 500—which is remarkable given that each reef was less than a meter long in any direction. By comparison, sites that had simple structures and no grouper had fewer than 50 fish on average. Simple structures with predators had around 75 fish, while complex sites without grouper had around 100. \"We think the presence of the grouper drives away other predators, which benefits overall fish abundance,\" Hensel says. \"And a complex habitat offers niches of various sizes and shapes, which can shelter more and different kinds of fish than a degraded, simple habitat.\" The presence of grouper had little or no effect on species richness, or the number of different species present at each site. However, habitat complexity made a significant difference. Complex sites had 11-13 species, while degraded sites had around seven. \"We found that the sites with complex habitats and the presence of predators had fish populations that were actually larger than what we see at surrounding, similar-sized natural reefs,\" Hensel says. \"That's because the natural reefs in the area are all degraded due to a variety of stressors. \"We also found that the presence of grouper on complex reefs led to a significant jump in the population of Tomtate grunts (Haemulon aurolineatum),\" Hensel says. \"That's good news, because Tomtates are a species that provides a lot of ecosystem services, which would be good for creating conditions that are more amenable to both coral reef growth and seagrass growth. \"Currently, my colleagues and I are building from these findings in two directions. We're measuring long-term community and ecosystem level responses to coral restoration or the reintroduction of structurally complex habitat; and we are also measuring long-term biological and physiological responses of fishes residing on restored reefs. For the latter, Haley Gambill, an undergraduate at NC State, is measuring changes in the age and growth of grunts. \"It's also worth noting that this is an area that was hit hard by Hurricane Dorian. Because we've done so much reef population work in that area, I'm hoping to return to do some work that can help us understand how extreme weather events can affect these ecosystems.\" ", "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 Reef ecosystems are highly diverse habitats that harbor many ecologically and economically significant species. Yet, globally they are under threat from multiple stressors including overexploitation of predatory fishes and habitat degradation. While these two human-driven activities often occur concomitantly, they are typically studied independently. Using a factorial design, we examined effects of predator presence, habitat complexity, and their interaction on patch reef fish communities in a nearshore ecosystem on Great Abaco Island, The Bahamas. We manipulated the presence of Nassau groupers ( Epinephelus striatus ), a reef predator that is critically endangered largely due to overharvest, and varied patch reef structure (cinder blocks with and without PVC) to reflect high or low complexity-four treatments in total. To assess changes in fish community composition we measured fish abundances, species richness, and evenness. We found that predators present and high reef complexity had an additive, positive effect on total fish abundance: fish abundance increased by ~ 250% and 300%, compared to predators absent and low complexity reef treatments, respectively. Species richness increased with reef complexity. Variation in community structure was explained by the interaction between factors, largely driven by juvenile Tomtate grunt ( Haemulon aurolineatum ) abundances. Specifically, Tomtate grunt abundance was significantly higher on high complexity reefs with predators present, but on low complexity reefs predators present had no effect on Tomtate grunt abundance. Our data suggest that both fisheries management of large-bodied piscivores and reef habitat restoration are critical to the management and conservation of reef ecosystem functions and services. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Introduction Coral dominated reefs are highly productive ecosystems that can harbor large and diverse fish communities, but are threatened worldwide by myriad stressors (Hughes and Connell 1999 ; Hoegh-Guldberg et al. 2007 ). Two primary stressors are overfishing at higher trophic levels and habitat degradation (Dulvy et al. 2004 ; Lee 2006 ). These stressors can fundamentally change processes that act from both the top-down (e.g., trophic cascades) (Baum and Worm 2009 ; Allgeier et al. 2016 ; Valdivia et al. 2017 ) and bottom-up (e.g., nutrient cycling regimes and provision of refugia) of interaction networks (Beukers and Jones 1998 ; Lee 2006 ; Smith et al. 2006 ; Graham and Nash 2013 ). Overexploitation of predators and the loss of habitat complexity are typically concomitant. Yet because these factors are most often studied independently, our understanding of how their simultaneous effects combine or interact to alter reef communities remains limited (but see Wilson et al. 2008 ). Predators and habitat structural complexity play a central role in determining post-settlement coral reef fish communities (Hixon and Carr 1997 ; Steele 1999 ). Direct effects of predators can alter fish communities including species richness (Freestone et al. 2011 ) and overall community composition (Almany 2003 ). Predators also have indirect effects on their surrounding communities, however the outcome is often context-dependent for both predator and prey identity making the effect difficult to predict or generalize (Almany 2004a ; Stallings 2008 ; Chamberlain et al. 2014 ). Additionally, predator impacts on reef communities can be mediated by the structural complexity of reefs (Wilson et al. 2008 ). Specifically, habitat complexity can decrease predators’ direct effects by reducing prey encounter rates (Swisher et al. 1998 ; Almany 2004b ; Warfe and Barmuta 2004 ). In contrast, structural complexity can increase predators’ indirect effects due to predators and their prey residing in close proximity to one another (Grabowski et al. 2008 ). To date, most studies examining predator effects in marine systems have tended to use simplified interaction webs within mesocosms, focused on small-bodied predator species, or a combination of both (Steele 1999 ; Johnson 2006 ; Grabowski et al. 2008 ). However, fishing typically targets large-bodied predators (e.g., sharks, tunas, and groupers) that are more difficult to study. Further complicating this scenario is the challenge of understanding how losses of predators may interact with concomitant changes in habitat complexity that is a result of major shifts in foundation species (e.g., coral to sponge, or macroalgae) that can render reefs flat, reducing available refugia for fauna. This potential interaction has important implications for management and conservation efforts seeking to mitigate human impacts on coral reefs. Here we ask: how do predators present and reef complexity affect reef fish communities in terms of total abundance, species richness, evenness, and overall community composition? We conducted an in situ experiment designed to examine effects of large predator presence, habitat complexity, and their interaction on artificial patch reef communities in a nearshore ecosystem on Great Abaco Island, The Bahamas. Nearshore, patch reef habitats are ideal for this experiment because they are isolated, complex, vertical habitats surrounded by hard or soft low-relief substrate and, being located in nearshore habitats, they are strongly influenced by local stressors (Stallings 2009 ). Artificial patch reefs are particularly ideal because they are relatively easy to manipulate and subsequently study whole community effects (Carr and Hixon 1997 ). In a 2 × 2 factorial design, we manipulated the presence of a locally abundant reef predator, Nassau grouper ( Epinephelus striatus ), on patch reefs of high and low complexity. We used Nassau grouper as our predator species because they are an important fishery species that has experienced drastic population declines throughout the Caribbean from overexploitation (Dahlgren et al. 2016 ; Sherman et al. 2018 ). We hypothesized that reefs with Nassau groupers present would have more fishes compared to those without Nassau groupers due to strong indirect predator effects on smaller-bodied, mesopredator species. Additionally Nassau groupers present would alter fish community composition, i.e., relative abundance of the constituent species, due to a combination of their direct and indirect predator effects. For habitat complexity, we hypothesized that complex reefs would have more fishes as well as more species present than non-complex reefs to do an increase in refugia hole availability and diversity in refugia morphology (shape). Methods Our study occurred in a back-reef system in the Sea of Abaco<|im_end|> <|im_start|>assistant New research highlights two factors that play a critical role in supporting reef fish populations and—ultimately—creating conditions that are more favorable for the growth of both coral reefs and seagrass. "Previous work has shown mixed results on whether the presence of large predator species benefits reef fish populations, but we found that the presence of Nassau grouper (Epinephelus striatus) had an overall positive effect on fish abundance," says Enie Hensel, a former Ph.D. student at North Carolina State University and lead author of a paper on the work. "We also found that habitat complexity benefits both fish abundance and species richness, likely because it gives fish a larger variety of places to shelter." This is consistent with previous work. "One of the surprises here was that the effect of predator presence on fish abundance was comparable to the effect of habitat complexity," Hensel says. To better understand the effect of these variables, researchers constructed 16 artificial "patch" reefs in shallow waters off the coast of Great Abaco Island in The Bahamas. Eight of the reefs consisted of cement-filled cinder blocks, mimicking degraded reefs with limited habitat complexity. The remaining eight reefs consisted of unfilled cinder blocks and branching pipe structures, mimicking the more complex physical environment of healthier reefs. Once in place, the researchers waited for groupers to move in and claim the new reef territory. The groupers were large juveniles, ranging in size from 16-33 centimeters. The researchers then removed the groupers from four of the degraded reef sites and from four of the complex reef sites. Groupers that were removed were relocated to distant reefs. Researchers monitored the sites for 60 days to ensure that the grouper-free reefs remained free of groupers. At the end of the 60 days, the researchers assessed the total number of fish at each reef site, as well as the total number of fish species at each site. The differences were significant. Simple artificial reef structures, like that on the left, did little to support fish populations. Complex structures, like the one on the right, helped to support larger communities of fish. Credit: Enie Hensel Fish abundance, or the total number of fish, was highest at sites that had both a resident grouper and complex habitat. Abundance at these sites ranged from 275 fish to more than 500—which is remarkable given that each reef was less than a meter long in any direction. By comparison, sites that had simple structures and no grouper had fewer than 50 fish on average. Simple structures with predators had around 75 fish, while complex sites without grouper had around 100. "We think the presence of the grouper drives away other predators, which benefits overall fish abundance," Hensel says. "And a complex habitat offers niches of various sizes and shapes, which can shelter more and different kinds of fish than a degraded, simple habitat." The presence of grouper had little or no effect on species richness, or the number of different species present at each site. However, habitat complexity made a significant difference. Complex sites had 11-13 species, while degraded sites had around seven. "We found that the sites with complex habitats and the presence of predators had fish populations that were actually larger than what we see at surrounding, similar-sized natural reefs," Hensel says. "That's because the natural reefs in the area are all degraded due to a variety of stressors. "We also found that the presence of grouper on complex reefs led to a significant jump in the population of Tomtate grunts (Haemulon aurolineatum)," Hensel says. "That's good news, because Tomtates are a species that provides a lot of ecosystem services, which would be good for creating conditions that are more amenable to both coral reef growth and seagrass growth. "Currently, my colleagues and I are building from these findings in two directions. We're measuring long-term community and ecosystem level responses to coral restoration or the reintroduction of structurally complex habitat; and we are also measuring long-term biological and physiological responses of fishes residing on restored reefs. For the latter, Haley Gambill, an undergraduate at NC State, is measuring changes in the age and growth of grunts. "It's also worth noting that this is an area that was hit hard by Hurricane Dorian. Because we've done so much reef population work in that area, I'm hoping to return to do some work that can help us understand how extreme weather events can affect these ecosystems." <|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 Observation of a quantum spin liquid (QSL) state is one of the most important goals in condensed-matter physics, as well as the development of new spintronic devices that support next-generation industries. The QSL in two dimensional quantum spin systems is expected to be due to geometrical magnetic frustration, and thus a kagome-based lattice is the most probable playground for QSL. Here, we report the first experimental results of the QSL state on a square-kagome quantum antiferromagnet, KCu 6 AlBiO 4 (SO 4 ) 5 Cl. Comprehensive experimental studies via magnetic susceptibility, magnetisation, heat capacity, muon spin relaxation ( μ SR), and inelastic neutron scattering (INS) measurements reveal the formation of a gapless QSL at very low temperatures close to the ground state. The QSL behavior cannot be explained fully by a frustrated Heisenberg model with nearest-neighbor exchange interactions, providing a theoretical challenge to unveil the nature of the QSL state. Introduction Magnetic phases of low-dimensional magnets have been studied both theoretically and experimentally in the last half century. Intensive studies of one-dimensional (1D) spin systems have successfully captured the exotic quantum states, such as the Tomonaga–Luttinger spin-liquid state 1 and the Haldane state 2 . Recent progress in synthesising ideal 1D magnets has evolved this research field 3 . On the other hand, in 2D spin systems, the spin-1/2 kagome antiferromagnet is an excellent choice for searching for the QSL state induced by geometrical frustration 4 . A possible compound for QSL in the kagome antiferromagnets was herbertsmithite, which has the Cu 2+ layers with ideal kagome geometry sandwiched by nonmagnetic Zn 2+ layers 5 . To date, no long-range order has been found at any temperature, and a continuum of spin excitations was observed by INS experiments. However, the low-energy magnetic excitation is still unclear as seen in a controversy on gapless 6 or gapped 7 excitation. This is related to the fact that herbertsmithite is obtained by selectively replacing magnetic Cu 2+ ions with nonmagnetic Zn 2+ ions on the triangular-lattice planes of its parent compound clinoatacamite 8 , Cu 2 (OH) 3 Cl. This replacement inevitably causes site mixing 9 . Other materials with the kagome lattice exhibit long-range magnetic or valence-bond crystal (VBC) orders caused by lattice distortions, the DM interaction and further neighbour interactions 10 , 11 , 12 , 13 , 14 . The lack of a suitable model material exhibiting the QSL hinders observations of the QSL state in the 2D spin-1/2 systems. Another highly frustrated 2D quantum spin system expected to be a QSL state is a compound with the square-kagome lattice (SKL). The SKL was introduced by Siddharthan et al. 15 . It has the same coordination number as the kagome lattice ( z = 4), but with a composition of two inequivalent sublattices in contrast to the kagome lattice. Richter et al. reported that the ground state of the spin-1/2 SKL with three equivalent exchange interactions (the case of J 1 = J 2 = J 3 and J X = 0 in Fig. 1 c) is similar to that of the kagome lattice 16 . The ground state of the spin-1/2 J 1 – J 2 SKL antiferromagnet (the case of J 2 = J 3 and J X = 0 in Fig. 1 c) was calculated by Rousochatzakis et al. 17 . It has been predicted to be a crossed-dimer VBC state and a square pinwheels VBC state, depending on J 2 / J 1 . Moreover, there is a possibility that the QSL ground states are realised in the SKL with three nonequivalent exchange interactions (the case of J X = 0 in Fig. 1 c), which lead to the melting of these VBC states 18 . Very recently, it has also predicted to be a topological nematic spin-liquid state 19 . In the magnetic field, the existence of the magnetisation plateaus of M / M sat = 1/3 and 2/3 has theoretically clarified 16 , 17 , 18 , 20 , where M sat is the saturation magnetisation. These plateau phases exhibit VBC, up–up–down structure, and alternate trimerized states. In the high magnetic field and low-temperature regime, a magnetic-field-driven Berezinskii–Kosterlitz–Thouless phase transition exists 21 . However, the lack of a model compound for the SKL system has obstructed a deeper understanding of its spin state. Motivated by the present status on the study of the SKL system, we searched for compounds with the SKL containing Cu 2+ spins, and synthesised the first compound of a SKL antiferromagnet, KCu 6 AlBiO 4 (SO 4 ) 5 Cl, successfully. Here, we use thermodynamic, muon spin relaxation and neutron-scattering experiments on powder samples of KCu 6 AlBiO 4 (SO 4 ) 5 Cl, to demonstrate the absence of magnetic ordering and the presence of gapless continuum of spin excitations. Fig. 1: Spin-1/2 J 1 – J 2 – J 3 square-kagome lattice in KCu 6 AlBiO 4 (SO 4 ) 5 Cl. a Crystal structure of KCu 6 AlBiO 4 (SO 4 ) 5 Cl featuring a large interlayer spacing. b Arrangement of the Cu 2+ orbitals in SKL. The \\({d}_{{x}^{2}-{y}^{2}}\\) orbitals carrying spin-1/2 are depicted on the Cu sites. c Square-kagome lattice of KCu 6 AlBiO 4 (SO 4 ) 5 Cl consisting of Cu 2+ ions with nearest-neighbour exchange couplings J 1 , J 2 , J 3 and next-nearest-neighbour exchange coupling J X . Full size image Results Crystal structure The synthesis of KCu 6 AlBiO 4 (SO 4 ) 5 Cl was conceived following the identification of the naturally occurring mineral atlasovite, KCu 6 FeBiO 4 (SO 4 ) 5 Cl 22 . The space group and structural parameters of KCu 6 AlBiO 4 (SO 4 ) 5 Cl are determined as P 4/ n c c , (the same space group as atlasovite) and a = 9.8248(9) Å, c = 20.5715(24) Å, respectively (see Supplementary Note 1 ). As shown Fig. 1a and b, the SKL in the crystal structure of KCu 6", "role": "user" }, { "content": "Aside from the deep understanding of the natural world that quantum physics theory offers, scientists worldwide are striving to bring forth a technological revolution by leveraging this newfound knowledge in engineering applications. Spintronics is an emerging field that aims to surpass the limits of traditional electronics by using the spin of electrons, which can be roughly seen as their angular rotation, as a means to transmit information. But the design of devices that can operate using spin is extremely challenging and requires the use of new materials in exotic states—even some that scientists do not fully understand and have not experimentally observed yet. In a recent study published in Nature Communications, scientists from the Department of Applied Physics at Tokyo University of Science, Japan, describe a newly synthesized compound with the formula KCu6AlBiO4(SO4)5Cl that may be key in understanding the elusive \"quantum spin liquid (QSL)\" state. Lead scientist Dr. Masayoshi Fujihala explains his motivation: \"Observation of a QSL state is one of the most important goals in condensed-matter physics as well as the development of new spintronic devices. However, the QSL state in two-dimensional (2-D) systems has not been clearly observed in real materials owing to the presence of disorder or deviations from ideal models.\" What is the quantum spin liquid state? In antiferromagnetic materials below specific temperatures, the spins of electrons naturally align into large-scale patterns. In materials in a QSL state, however, the spins are disordered in a way similar to how molecules in liquid water are disordered in comparison to crystalline ice. This disorder arises from a structural phenomenon called frustration, in which there is no possible configuration of spins that is symmetrical and energetically favorable for all electrons. KCu6AlBiO4(SO4)5Cl is a newly synthesized compound whose copper atoms are arranged in a particular 2-D pattern known as the \"square kagome lattice (SKL),\" an arrangement that is expected to produce a QSL state through frustration. Professor Setsuo Mitsuda, co-author of the study, states: \"The lack of a model compound for the SKL system has obstructed a deeper understanding of its spin state. Motivated by this, we synthesized KCu6AlBiO4(SO4)5Cl, the first SKL antiferromagnet, and demonstrated the absence of magnetic ordering at extremely low temperatures—a QSL state.\" However, the experimental results obtained could not be replicated through theoretical calculations using a standard \"J1-J2-J3 SKL Heisenberg\" model. This approach considers the interactions between each copper ion in the crystal network and its nearest neighbors. Co-author Dr. Katsuhiro Morita explains: \"To try to eliminate the discrepancy, we calculated an SKL model considering next-nearest-neighbor interactions using various sets of parameters. Still, we could not reproduce the experimental results. Therefore, to understand the experiment correctly, we need to calculate the model with further interactions.\" This disagreement between experiment and calculations highlights the need for refining existing theoretical approaches, as co-author Prof Takami Tohyama concludes: \"While the SKL antiferromagnet we synthesized is a first candidate to investigate SKL magnetism, we may have to consider longer-range interactions to obtain a quantum spin liquid in our models. This represents a theoretical challenge to unveil the nature of the QSL state.\" Let us hope physicists manage to tackle this challenge to bring us yet another step closer to the wonderful promise of 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 Observation of a quantum spin liquid (QSL) state is one of the most important goals in condensed-matter physics, as well as the development of new spintronic devices that support next-generation industries. The QSL in two dimensional quantum spin systems is expected to be due to geometrical magnetic frustration, and thus a kagome-based lattice is the most probable playground for QSL. Here, we report the first experimental results of the QSL state on a square-kagome quantum antiferromagnet, KCu 6 AlBiO 4 (SO 4 ) 5 Cl. Comprehensive experimental studies via magnetic susceptibility, magnetisation, heat capacity, muon spin relaxation ( μ SR), and inelastic neutron scattering (INS) measurements reveal the formation of a gapless QSL at very low temperatures close to the ground state. The QSL behavior cannot be explained fully by a frustrated Heisenberg model with nearest-neighbor exchange interactions, providing a theoretical challenge to unveil the nature of the QSL state. Introduction Magnetic phases of low-dimensional magnets have been studied both theoretically and experimentally in the last half century. Intensive studies of one-dimensional (1D) spin systems have successfully captured the exotic quantum states, such as the Tomonaga–Luttinger spin-liquid state 1 and the Haldane state 2 . Recent progress in synthesising ideal 1D magnets has evolved this research field 3 . On the other hand, in 2D spin systems, the spin-1/2 kagome antiferromagnet is an excellent choice for searching for the QSL state induced by geometrical frustration 4 . A possible compound for QSL in the kagome antiferromagnets was herbertsmithite, which has the Cu 2+ layers with ideal kagome geometry sandwiched by nonmagnetic Zn 2+ layers 5 . To date, no long-range order has been found at any temperature, and a continuum of spin excitations was observed by INS experiments. However, the low-energy magnetic excitation is still unclear as seen in a controversy on gapless 6 or gapped 7 excitation. This is related to the fact that herbertsmithite is obtained by selectively replacing magnetic Cu 2+ ions with nonmagnetic Zn 2+ ions on the triangular-lattice planes of its parent compound clinoatacamite 8 , Cu 2 (OH) 3 Cl. This replacement inevitably causes site mixing 9 . Other materials with the kagome lattice exhibit long-range magnetic or valence-bond crystal (VBC) orders caused by lattice distortions, the DM interaction and further neighbour interactions 10 , 11 , 12 , 13 , 14 . The lack of a suitable model material exhibiting the QSL hinders observations of the QSL state in the 2D spin-1/2 systems. Another highly frustrated 2D quantum spin system expected to be a QSL state is a compound with the square-kagome lattice (SKL). The SKL was introduced by Siddharthan et al. 15 . It has the same coordination number as the kagome lattice ( z = 4), but with a composition of two inequivalent sublattices in contrast to the kagome lattice. Richter et al. reported that the ground state of the spin-1/2 SKL with three equivalent exchange interactions (the case of J 1 = J 2 = J 3 and J X = 0 in Fig. 1 c) is similar to that of the kagome lattice 16 . The ground state of the spin-1/2 J 1 – J 2 SKL antiferromagnet (the case of J 2 = J 3 and J X = 0 in Fig. 1 c) was calculated by Rousochatzakis et al. 17 . It has been predicted to be a crossed-dimer VBC state and a square pinwheels VBC state, depending on J 2 / J 1 . Moreover, there is a possibility that the QSL ground states are realised in the SKL with three nonequivalent exchange interactions (the case of J X = 0 in Fig. 1 c), which lead to the melting of these VBC states 18 . Very recently, it has also predicted to be a topological nematic spin-liquid state 19 . In the magnetic field, the existence of the magnetisation plateaus of M / M sat = 1/3 and 2/3 has theoretically clarified 16 , 17 , 18 , 20 , where M sat is the saturation magnetisation. These plateau phases exhibit VBC, up–up–down structure, and alternate trimerized states. In the high magnetic field and low-temperature regime, a magnetic-field-driven Berezinskii–Kosterlitz–Thouless phase transition exists 21 . However, the lack of a model compound for the SKL system has obstructed a deeper understanding of its spin state. Motivated by the present status on the study of the SKL system, we searched for compounds with the SKL containing Cu 2+ spins, and synthesised the first compound of a SKL antiferromagnet, KCu 6 AlBiO 4 (SO 4 ) 5 Cl, successfully. Here, we use thermodynamic, muon spin relaxation and neutron-scattering experiments on powder samples of KCu 6 AlBiO 4 (SO 4 ) 5 Cl, to demonstrate the absence of magnetic ordering and the presence of gapless continuum of spin excitations. Fig. 1: Spin-1/2 J 1 – J 2 – J 3 square-kagome lattice in KCu 6 AlBiO 4 (SO 4 ) 5 Cl. a Crystal structure of KCu 6 AlBiO 4 (SO 4 ) 5 Cl featuring a large interlayer spacing. b Arrangement of the Cu 2+ orbitals in SKL. The \({d}_{{x}^{2}-{y}^{2}}\) orbitals carrying spin-1/2 are depicted on the Cu sites. c Square-kagome lattice of KCu 6 AlBiO 4 (SO 4 ) 5 Cl consisting of Cu 2+ ions with nearest-neighbour exchange couplings J 1 , J 2 , J 3 and next-nearest-neighbour exchange coupling J X . Full size image Results Crystal structure The synthesis of KCu 6 AlBiO 4 (SO 4 ) 5 Cl was conceived following the identification of the naturally occurring mineral atlasovite, KCu 6 FeBiO 4 (SO 4 ) 5 Cl 22 . The space group and structural parameters of KCu 6 AlBiO 4 (SO 4 ) 5 Cl are determined as P 4/ n c c , (the same space group as atlasovite) and a = 9.8248(9) Å, c = 20.5715(24) Å, respectively (see Supplementary Note 1 ). As shown Fig. 1a and b, the SKL in the crystal structure of KCu 6<|im_end|> <|im_start|>assistant Aside from the deep understanding of the natural world that quantum physics theory offers, scientists worldwide are striving to bring forth a technological revolution by leveraging this newfound knowledge in engineering applications. Spintronics is an emerging field that aims to surpass the limits of traditional electronics by using the spin of electrons, which can be roughly seen as their angular rotation, as a means to transmit information. But the design of devices that can operate using spin is extremely challenging and requires the use of new materials in exotic states—even some that scientists do not fully understand and have not experimentally observed yet. In a recent study published in Nature Communications, scientists from the Department of Applied Physics at Tokyo University of Science, Japan, describe a newly synthesized compound with the formula KCu6AlBiO4(SO4)5Cl that may be key in understanding the elusive "quantum spin liquid (QSL)" state. Lead scientist Dr. Masayoshi Fujihala explains his motivation: "Observation of a QSL state is one of the most important goals in condensed-matter physics as well as the development of new spintronic devices. However, the QSL state in two-dimensional (2-D) systems has not been clearly observed in real materials owing to the presence of disorder or deviations from ideal models." What is the quantum spin liquid state? In antiferromagnetic materials below specific temperatures, the spins of electrons naturally align into large-scale patterns. In materials in a QSL state, however, the spins are disordered in a way similar to how molecules in liquid water are disordered in comparison to crystalline ice. This disorder arises from a structural phenomenon called frustration, in which there is no possible configuration of spins that is symmetrical and energetically favorable for all electrons. KCu6AlBiO4(SO4)5Cl is a newly synthesized compound whose copper atoms are arranged in a particular 2-D pattern known as the "square kagome lattice (SKL)," an arrangement that is expected to produce a QSL state through frustration. Professor Setsuo Mitsuda, co-author of the study, states: "The lack of a model compound for the SKL system has obstructed a deeper understanding of its spin state. Motivated by this, we synthesized KCu6AlBiO4(SO4)5Cl, the first SKL antiferromagnet, and demonstrated the absence of magnetic ordering at extremely low temperatures—a QSL state." However, the experimental results obtained could not be replicated through theoretical calculations using a standard "J1-J2-J3 SKL Heisenberg" model. This approach considers the interactions between each copper ion in the crystal network and its nearest neighbors. Co-author Dr. Katsuhiro Morita explains: "To try to eliminate the discrepancy, we calculated an SKL model considering next-nearest-neighbor interactions using various sets of parameters. Still, we could not reproduce the experimental results. Therefore, to understand the experiment correctly, we need to calculate the model with further interactions." This disagreement between experiment and calculations highlights the need for refining existing theoretical approaches, as co-author Prof Takami Tohyama concludes: "While the SKL antiferromagnet we synthesized is a first candidate to investigate SKL magnetism, we may have to consider longer-range interactions to obtain a quantum spin liquid in our models. This represents a theoretical challenge to unveil the nature of the QSL state." Let us hope physicists manage to tackle this challenge to bring us yet another step closer to the wonderful promise of spintronics. <|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 The human glycine transporter 1 (GlyT1) regulates glycine-mediated neuronal excitation and inhibition through the sodium- and chloride-dependent reuptake of glycine 1 , 2 , 3 . Inhibition of GlyT1 prolongs neurotransmitter signalling, and has long been a key strategy in the development of therapies for a broad range of disorders of the central nervous system, including schizophrenia and cognitive impairments 4 . Here, using a synthetic single-domain antibody (sybody) and serial synchrotron crystallography, we have determined the structure of GlyT1 in complex with a benzoylpiperazine chemotype inhibitor at 3.4 Å resolution. We find that the inhibitor locks GlyT1 in an inward-open conformation and binds at the intracellular gate of the release pathway, overlapping with the glycine-release site. The inhibitor is likely to reach GlyT1 from the cytoplasmic leaflet of the plasma membrane. Our results define the mechanism of inhibition and enable the rational design of new, clinically efficacious GlyT1 inhibitors. Main Glycine is a conditionally essential amino acid with a dual role in the central nervous system (CNS). It acts as a classical neurotransmitter at inhibitory glycinergic synapses, where it induces hyperpolarizing chloride influx at postsynaptic terminals through ionotropic glycine receptors 1 , 2 . Yet, as the obligatory co-agonist of the N -methyl- d -aspartate (NMDA) receptor, glycine also positively modulates calcium-dependent neuronal excitation and plasticity at glutamatergic synapses 1 , 3 . Glycine homeostasis is tightly regulated by reuptake transporters—including the glycine-specific GlyT1 and GlyT2—that belong to the secondary active neurotransmitter/sodium symporters (NSSs) of the solute carrier 6 (SLC6) transport family 5 . GlyT1 (encoded by the SLC6A9 gene), GlyT2 (encoded by SLC6A5 ) and the other members of the NSS family, such as the serotonin transporter (SERT), dopamine transporter (DAT) and γ-aminobutyric acid (GABA) transporter (GAT), share a sequence identity of approximately 50%. GlyT1 is located on presynaptic neurons and astrocytes surrounding both inhibitory glycinergic and excitatory glutamatergic synapses, and is considered the main regulator of extracellular levels of glycine in the brain 1 , 6 . At glutamatergic synapses, GlyT1 has a key role in maintaining subsaturating concentrations of regulatory glycine for the NMDA receptor 7 , 8 . Hypofunction of the NMDA receptor has been implicated in the pathophysiology of schizophrenia 9 , but pharmacological interventions to directly enhance neurotransmission via this receptor in patients with the condition have been unsuccessful 10 , 11 . Selective inhibition of glycine reuptake by GlyT1 is an alternative approach to increase endogenous extracellular levels of glycine and potentiate NMDA transmission 1 , 4 . Several chemotypes of potent and selective GlyT1 inhibitors, such as bitopertin, have been developed to achieve antipsychotic and procognitive activity for the treatment of schizophrenia 4 , 12 . Bitopertin has shown clear signs of enhancing neuroplasticity 13 , 14 via the glycine-binding site of the NMDA receptor; however, it failed to show efficacy in phase III clinical trials (at a reduced dose), and a drug candidate that targets GlyT1 has yet to emerge. Studies of NSS and homologues have revealed an alternating-access mechanism 15 , which involves a binding and occlusion of the extracellular substrate, dependent on a Na + (and Cl − in eukaryotic NSS) gradient. Binding is followed by a rearrangement to an inward-facing state and subsequent intracellular opening and release of bound ions and substrate. Conformational rearrangements of transmembrane helices during the transport cycle expose the substrate-binding site to either side of the membrane 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 . Bitopertin behaves functionally as a non-competitive inhibitor of glycine reuptake 24 ; nevertheless, detailed structural information on the inhibitor’s binding site, selectivity and underlying molecular mechanism of glycine reuptake inhibition have yet to be obtained. Here we present the structure of human GlyT1 in complex with a highly selective bitopertin analogue 25 , 26 , Cmpd1, and an inhibition-state-selective synthetic nanobody (sybody). Cmpd1 has been patented as a more potent inhibitor targeting GlyT1 that contains a benzoylisoindoline scaffold originating from the bitopertin chemical series 26 . The structure of GlyT1 reveals the molecular determinants and mechanism of action underlying the inhibition of glycine reuptake. Stabilization and crystal structure of GlyT1 Wild-type human GlyT1 (encoded by SLC6A9 ) is unstable when extracted from the membrane, and contains unstructured termini and a large, flexible extracellular loop 2 (EL2). To enable structure determination, we screened for point mutations that increase thermal stability while preserving ligand-binding activity. For the final crystallization construct, we combined the point mutations L153A, S297A, I368A and C633A with a shortened EL2 (Δ240–256) and truncated amino and carboxyl termini (Δ1–90 and Δ685–706) (see Methods ), and were able to measure persistent transport activity, albeit 42-fold decreased compared with that of wild-type GlyT1 (Extended Data Fig. 1 ). Adding the selective GlyT1 inhibitor Cmpd1 increases the thermal stability of the transporter further by 30.5 °C (Fig. 1a ). Indicative of high-affinity binding with a stabilizing effect, we measured a half-maximal inhibitory concentration (IC 50 ) for Cmpd1 of 12.9 ± 0.9 nM and 7.2 ± 0.4 nM on human and mouse GlyT1, respectively (Fig. 1b ), in a membrane-based competition assay with the [ 3 H]Org24598 compound 27 (a non-competitive GlyT1 inhibitor). We therefore purified GlyT1 in the presence of Cmpd1 and generated sybodies to further stabilize the transporter in the inhibition-state conformation, identifying sybody Sb_GlyT1#7 to bind GlyT1 with an affinity of 9 nM (ref. 28 ). We then obtained microcrystals of GlyT1 in complex with Sb_GlyT1#7 and Cpmd1 in lipidic cubic phase. Merging the oscillation patterns collected from 409 mounted loops containing microcrystals by a serial synchrotron crystallography approach yielded a complete dataset at 3.4 Å resolution. The structure was determined by molecular replacement using structures of the inward-occluded bacterial multiple hydrophobic amino acid transporter (MhsT; Protein Data Bank identification code (PDB ID) 4US3) and the inward-open human SERT (PDB ID 6DZZ) 17 , 19 . The high quality of the resulting electron density maps enabled us to unambiguously model human GlyT1 in complex with the sybody and", "role": "user" }, { "content": "Glycine can stimulate or inhibit neurons in the brain, thereby controlling complex functions. Unraveling the three-dimensional structure of the glycine transporter, researchers have now come a big step closer to understanding the regulation of glycine in the brain. These results, which have been published in Nature, open up opportunities to find effective drugs that inhibit GlyT1 function, with major implications for the treatment of schizophrenia and other mental disorders. Glycine is the smallest amino acid and a building block of proteins, and also a critical neurotransmitter that can both stimulate or inhibit neurons in the brain and thereby control complex brain functions. Termination of a glycine signal is mediated by glycine transporters that reuptake and clear glycine from the synapses between neurons. Glycine transporter GlyT1 is the main regulator of neurotransmitter glycine levels in the brain, and also important for e.g. blood cells, where glycine is required for the synthesis of heme. The N-methyl-D-aspartate (NMDA) receptor is activated by glycine, and its poor performance is implicated in schizophrenia. Over the past twenty years, many pharmaceutical companies and academic research laboratories therefore have focused on influencing glycinergic signaling and glycine reuptake delay as a way of activating the NMDA receptor in search of a cure for schizophrenia and other psychiatric disorders. Indeed, several potent and selective GlyT1 inhibitors achieve antipsychotic and pro-cognitive effects alleviating many symptoms of schizophrenia, and have advanced into clinical trials. However, a successful drug candidate has yet to emerge, and GlyT1 inhibition in blood cells is a concern for side effects. Structural insight into the binding of inhibitors to GlyT1 would provide insight in finding new strategies in drug design. To gain better knowledge about the three-dimensional structure and inhibition mechanisms of the GlyT1 transporter, researchers from the companies Roche and Linkster, and from the European Molecular Biology Laboratory (EMBL) Hamburg, University of Zurich and Aarhus University, have therefore collaborated on investigating one of the most advanced GlyT1 inhibitors. Using a synthetic single-domain antibody (Linkster therapeutics' sybody) for GlyT1, the research team managed to grow microcrystals of the inhibited GlyT1 complex. By employing a Serial Synchrotron Crystallography (SSX) approach, the team lead by Assistant Professor Azadeh Shahsavar and Professor Poul Nissen from the Department of Molecular Biology and Genetics/DANDRITE, Aarhus University, determined the structure of human GlyT1 using X-ray diffraction data from hundreds of microcrystals. The SSX method is particularly suitable as a method fornew, powerful X-ray sources and opens up for new approaches to, among other things, the development of drugs for various purposes. The structure is reported in the leading scientific journal Nature and also unveils a new mechanism of inhibition in neurotransmitter transporters in general. Mechanisms have previously been uncovered for, for example, inhibition of the serotonin transporter (which has many similarities to GlyT1) with antidepressant drugs, but it is a quite different inhibition mechanism now found for GlyT1. It provides background knowledge for the further development of small molecules and antibodies as selective inhibitors targeted at GlyT1 and possibly also for new ideas for the development of inhibitors of other neurotrandmitter carriers that can be used to treat other mental disorders. Azadeh Shahsavar's team continues the studies of GlyT1 and will be investigating further aspects of its function and inhibition and the effect of GlyT1 inhibitors 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 The human glycine transporter 1 (GlyT1) regulates glycine-mediated neuronal excitation and inhibition through the sodium- and chloride-dependent reuptake of glycine 1 , 2 , 3 . Inhibition of GlyT1 prolongs neurotransmitter signalling, and has long been a key strategy in the development of therapies for a broad range of disorders of the central nervous system, including schizophrenia and cognitive impairments 4 . Here, using a synthetic single-domain antibody (sybody) and serial synchrotron crystallography, we have determined the structure of GlyT1 in complex with a benzoylpiperazine chemotype inhibitor at 3.4 Å resolution. We find that the inhibitor locks GlyT1 in an inward-open conformation and binds at the intracellular gate of the release pathway, overlapping with the glycine-release site. The inhibitor is likely to reach GlyT1 from the cytoplasmic leaflet of the plasma membrane. Our results define the mechanism of inhibition and enable the rational design of new, clinically efficacious GlyT1 inhibitors. Main Glycine is a conditionally essential amino acid with a dual role in the central nervous system (CNS). It acts as a classical neurotransmitter at inhibitory glycinergic synapses, where it induces hyperpolarizing chloride influx at postsynaptic terminals through ionotropic glycine receptors 1 , 2 . Yet, as the obligatory co-agonist of the N -methyl- d -aspartate (NMDA) receptor, glycine also positively modulates calcium-dependent neuronal excitation and plasticity at glutamatergic synapses 1 , 3 . Glycine homeostasis is tightly regulated by reuptake transporters—including the glycine-specific GlyT1 and GlyT2—that belong to the secondary active neurotransmitter/sodium symporters (NSSs) of the solute carrier 6 (SLC6) transport family 5 . GlyT1 (encoded by the SLC6A9 gene), GlyT2 (encoded by SLC6A5 ) and the other members of the NSS family, such as the serotonin transporter (SERT), dopamine transporter (DAT) and γ-aminobutyric acid (GABA) transporter (GAT), share a sequence identity of approximately 50%. GlyT1 is located on presynaptic neurons and astrocytes surrounding both inhibitory glycinergic and excitatory glutamatergic synapses, and is considered the main regulator of extracellular levels of glycine in the brain 1 , 6 . At glutamatergic synapses, GlyT1 has a key role in maintaining subsaturating concentrations of regulatory glycine for the NMDA receptor 7 , 8 . Hypofunction of the NMDA receptor has been implicated in the pathophysiology of schizophrenia 9 , but pharmacological interventions to directly enhance neurotransmission via this receptor in patients with the condition have been unsuccessful 10 , 11 . Selective inhibition of glycine reuptake by GlyT1 is an alternative approach to increase endogenous extracellular levels of glycine and potentiate NMDA transmission 1 , 4 . Several chemotypes of potent and selective GlyT1 inhibitors, such as bitopertin, have been developed to achieve antipsychotic and procognitive activity for the treatment of schizophrenia 4 , 12 . Bitopertin has shown clear signs of enhancing neuroplasticity 13 , 14 via the glycine-binding site of the NMDA receptor; however, it failed to show efficacy in phase III clinical trials (at a reduced dose), and a drug candidate that targets GlyT1 has yet to emerge. Studies of NSS and homologues have revealed an alternating-access mechanism 15 , which involves a binding and occlusion of the extracellular substrate, dependent on a Na + (and Cl − in eukaryotic NSS) gradient. Binding is followed by a rearrangement to an inward-facing state and subsequent intracellular opening and release of bound ions and substrate. Conformational rearrangements of transmembrane helices during the transport cycle expose the substrate-binding site to either side of the membrane 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 . Bitopertin behaves functionally as a non-competitive inhibitor of glycine reuptake 24 ; nevertheless, detailed structural information on the inhibitor’s binding site, selectivity and underlying molecular mechanism of glycine reuptake inhibition have yet to be obtained. Here we present the structure of human GlyT1 in complex with a highly selective bitopertin analogue 25 , 26 , Cmpd1, and an inhibition-state-selective synthetic nanobody (sybody). Cmpd1 has been patented as a more potent inhibitor targeting GlyT1 that contains a benzoylisoindoline scaffold originating from the bitopertin chemical series 26 . The structure of GlyT1 reveals the molecular determinants and mechanism of action underlying the inhibition of glycine reuptake. Stabilization and crystal structure of GlyT1 Wild-type human GlyT1 (encoded by SLC6A9 ) is unstable when extracted from the membrane, and contains unstructured termini and a large, flexible extracellular loop 2 (EL2). To enable structure determination, we screened for point mutations that increase thermal stability while preserving ligand-binding activity. For the final crystallization construct, we combined the point mutations L153A, S297A, I368A and C633A with a shortened EL2 (Δ240–256) and truncated amino and carboxyl termini (Δ1–90 and Δ685–706) (see Methods ), and were able to measure persistent transport activity, albeit 42-fold decreased compared with that of wild-type GlyT1 (Extended Data Fig. 1 ). Adding the selective GlyT1 inhibitor Cmpd1 increases the thermal stability of the transporter further by 30.5 °C (Fig. 1a ). Indicative of high-affinity binding with a stabilizing effect, we measured a half-maximal inhibitory concentration (IC 50 ) for Cmpd1 of 12.9 ± 0.9 nM and 7.2 ± 0.4 nM on human and mouse GlyT1, respectively (Fig. 1b ), in a membrane-based competition assay with the [ 3 H]Org24598 compound 27 (a non-competitive GlyT1 inhibitor). We therefore purified GlyT1 in the presence of Cmpd1 and generated sybodies to further stabilize the transporter in the inhibition-state conformation, identifying sybody Sb_GlyT1#7 to bind GlyT1 with an affinity of 9 nM (ref. 28 ). We then obtained microcrystals of GlyT1 in complex with Sb_GlyT1#7 and Cpmd1 in lipidic cubic phase. Merging the oscillation patterns collected from 409 mounted loops containing microcrystals by a serial synchrotron crystallography approach yielded a complete dataset at 3.4 Å resolution. The structure was determined by molecular replacement using structures of the inward-occluded bacterial multiple hydrophobic amino acid transporter (MhsT; Protein Data Bank identification code (PDB ID) 4US3) and the inward-open human SERT (PDB ID 6DZZ) 17 , 19 . The high quality of the resulting electron density maps enabled us to unambiguously model human GlyT1 in complex with the sybody and<|im_end|> <|im_start|>assistant Glycine can stimulate or inhibit neurons in the brain, thereby controlling complex functions. Unraveling the three-dimensional structure of the glycine transporter, researchers have now come a big step closer to understanding the regulation of glycine in the brain. These results, which have been published in Nature, open up opportunities to find effective drugs that inhibit GlyT1 function, with major implications for the treatment of schizophrenia and other mental disorders. Glycine is the smallest amino acid and a building block of proteins, and also a critical neurotransmitter that can both stimulate or inhibit neurons in the brain and thereby control complex brain functions. Termination of a glycine signal is mediated by glycine transporters that reuptake and clear glycine from the synapses between neurons. Glycine transporter GlyT1 is the main regulator of neurotransmitter glycine levels in the brain, and also important for e.g. blood cells, where glycine is required for the synthesis of heme. The N-methyl-D-aspartate (NMDA) receptor is activated by glycine, and its poor performance is implicated in schizophrenia. Over the past twenty years, many pharmaceutical companies and academic research laboratories therefore have focused on influencing glycinergic signaling and glycine reuptake delay as a way of activating the NMDA receptor in search of a cure for schizophrenia and other psychiatric disorders. Indeed, several potent and selective GlyT1 inhibitors achieve antipsychotic and pro-cognitive effects alleviating many symptoms of schizophrenia, and have advanced into clinical trials. However, a successful drug candidate has yet to emerge, and GlyT1 inhibition in blood cells is a concern for side effects. Structural insight into the binding of inhibitors to GlyT1 would provide insight in finding new strategies in drug design. To gain better knowledge about the three-dimensional structure and inhibition mechanisms of the GlyT1 transporter, researchers from the companies Roche and Linkster, and from the European Molecular Biology Laboratory (EMBL) Hamburg, University of Zurich and Aarhus University, have therefore collaborated on investigating one of the most advanced GlyT1 inhibitors. Using a synthetic single-domain antibody (Linkster therapeutics' sybody) for GlyT1, the research team managed to grow microcrystals of the inhibited GlyT1 complex. By employing a Serial Synchrotron Crystallography (SSX) approach, the team lead by Assistant Professor Azadeh Shahsavar and Professor Poul Nissen from the Department of Molecular Biology and Genetics/DANDRITE, Aarhus University, determined the structure of human GlyT1 using X-ray diffraction data from hundreds of microcrystals. The SSX method is particularly suitable as a method fornew, powerful X-ray sources and opens up for new approaches to, among other things, the development of drugs for various purposes. The structure is reported in the leading scientific journal Nature and also unveils a new mechanism of inhibition in neurotransmitter transporters in general. Mechanisms have previously been uncovered for, for example, inhibition of the serotonin transporter (which has many similarities to GlyT1) with antidepressant drugs, but it is a quite different inhibition mechanism now found for GlyT1. It provides background knowledge for the further development of small molecules and antibodies as selective inhibitors targeted at GlyT1 and possibly also for new ideas for the development of inhibitors of other neurotrandmitter carriers that can be used to treat other mental disorders. Azadeh Shahsavar's team continues the studies of GlyT1 and will be investigating further aspects of its function and inhibition and the effect of GlyT1 inhibitors in the body. <|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 Metal nanoclusters composed of noble elements such as gold (Au) or silver (Ag) are regarded as superatoms. In recent years, the understanding of the materials composed of superatoms, which are often called superatomic molecules, has gradually progressed for Au-based materials. However, there is still little information on Ag-based superatomic molecules. In the present study, we synthesise two di-superatomic molecules with Ag as the main constituent element and reveal the three essential conditions for the formation and isolation of a superatomic molecule comprising two Ag 13− x M x structures (M = Ag or other metal; x = number of M) connected by vertex sharing. The effects of the central atom and the type of bridging halogen on the electronic structure of the resulting superatomic molecule are also clarified in detail. These findings are expected to provide clear design guidelines for the creation of superatomic molecules with various properties and functions. Introduction Metal nanoclusters (NCs) 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 composed of noble metal elements such as gold (Au) and silver (Ag) are stabilised when the total number of valence electrons satisfies the closed-shell electronic structure, as in conventional atoms 15 , 16 . Such metal NCs are regarded as superatoms (artificial atoms). If superatoms are used to assemble materials, it might be possible to create materials with physicochemical properties and functions that are different from those of conventional materials 17 . Regarding such materials composed of superatoms (often called superatomic molecules 18 , 19 ), since the 1980s, there have been many reports of Au-based superatomic molecules, which Teo and Zhang called clusters of clusters 20 . Subsequent work by groups such as Tsukuda 21 , Nobusada 22 , Jin 23 and Zhu 24 has gradually improved our understanding of the types of superatomic molecules that can be produced and the electronic structures that can be created 25 . Ag NCs have multiple properties and functions that are superior to those of Au NCs, including photoluminescence (PL) with high quantum yield 26 and selective catalytic activity for carbon dioxide reduction 27 . However, there are only a limited number of reports, including the report 28 by the authors, on Ag-based superatomic molecules 29 , 30 , 31 , 32 . To construct substances using superatomic molecules and create new materials, it is essential to gain a deeper understanding of the types of superatomic molecules that can be produced and the electronic structures that can be created, even for Ag-based superatomic molecules. In the present study, we focus on Ag-based 13-atom NCs (Ag 13− x M x ; M = Ag or other metal; x = number of M) as superatoms, and aim to elucidate the key factors in the formation of di-superatomic molecules by vertex sharing 33 and the electronic structure of the obtained di-superatomic molecules. Platinum (Pt) or palladium (Pd) was used as the element that substitutes part of the Ag, and chloride (Cl) or bromide (Br) was used as the bridging ligand to support the connection of the two 13-atom NCs. To achieve our purpose, in addition to two previously reported di-superatomic molecules ([Ag 23 Pt 2 (PPh 3 ) 10 Cl 7 ] 0 ( 1 ); Fig. 1a ; PPh 3 = triphenylphosphine) 31 and ([Ag 23 Pd 2 (PPh 3 ) 10 Cl 7 ] 0 ( 2 ); Fig. 1b ) 28 , we synthesised two new superatomic molecules with Br as the bridging ligand ([Ag 23 Pt 2 (PPh 3 ) 10 Br 7 ] 0 ( 3 ) and [Ag 23 Pd 2 (PPh 3 ) 10 Br 7 ] 0 ( 4 ); Table 1 ). We investigated their geometric/electronic structures and their stabilities with regard to degradation in solution. Consequently, we confirmed that 3 and 4 both have a geometric/electronic structure that qualifies them as superatomic molecules. Regarding the electronic structure, we further observed that (1) there is a peak attributable to the metal core at approximately 600 nm in the optical absorption spectra of all the superatomic molecules; (2) such peaks shift to longer wavelengths when M is changed from Pt to Pd; (3) all 1 − 4 exhibit PL in visible-to-near infra-red (NIR) region; and (4) PL peaks shift to longer wavelengths when M is changed from Pt to Pd. With respect to the stability of the superatomic molecule described by [Ag 23 M 2 (PPh 3 ) 10 X 7 ] z (M = Ag, Pd, or Pt; X = Cl or Br; z = 2+ or 0), we found that the stability decreases in the order 1 > 3 > 2 > 4 (which can be synthesised) > [Ag 25 (PPh 3 ) 10 X 7 ] 2+ (X = Cl or Br; which are not so stable in solution). Based on these results and reports on the related superatomic molecules, we concluded that the following three conditions are essential for the formation and isolation of a superatomic molecule consisting of two Ag 13− x M x structures (M = Ag or other metal) connected by vertex sharing ([Ag 25− x M x (PR 3 ) 10 X y ] z ; PR 3 = phosphine; y = number of X): (1) a halogen ligand of a size that can maintain a moderate distance between two Ag 13− x M x structures is used as the bridging ligand; (2) an icosahedral core, which is stronger than Ag 13 , is formed by heteroatom substitution; and (3) [Ag 25− x M x (PR 3 ) 10 X y ] z comprises substituted heteroatoms and bridging halogens such that the total number of valence electrons is 16 when they are cationic or neutral. Fig. 1: Comparison of the geometric structures. a 1 . b 2 . c 3 . d 4 . The geometric structure of 1 and 2 are reproduced from ref. 28 ,", "role": "user" }, { "content": "Superatomic molecules containing noble metal elements like gold and silver are studied for their potential in the synthesis of superatomic materials. However, the understanding of silver-based superatomic molecules has been limited. Addressing this gap, researchers from Japan studied two bimetallic superatomic molecules with silver as a main constituent to determine the key factors that enabled their formation. Their findings are expected to advance the development of novel materials in the future. In the past few decades, metal nanoclusters composed of noble metal elements such as gold (Au) and silver (Ag) have gained attention as superatoms for the synthesis of materials with unique properties and potential new applications. These superatoms (also known as \"artificial atoms\") typically consist of a cluster of a few to several hundred atoms and exhibit properties that are significantly different from their bulk, conventional counterparts. However, much like real atoms, the stability of these superatoms is determined by the formation of a closed-shell electron structure. Ag-based superatoms are known for their superior properties and functions, including photoluminescence and selective catalytic activity, compared to those of Au-based superatoms. However, most of the research in this field has been primarily focused on Au-based superatomic molecules. To overcome this research gap, researchers from Japan studied the formation of superatomic molecules composed of Ag and evaluated the factors involved in this formation. This study was published in the journal Communications Chemistry on March 28, 2023. Speaking of the motivation behind studying Ag-based superatoms, Prof. Negishi says, \"So far, we humans have created a variety of useful materials from the elements available to us on Earth. However, looking at a future with complex energy and environmental issues, the development of materials with new properties and functions is desired.\" To this end, the researchers synthesized two di-superatomic molecules with bromine (Br) as the bridging ligand: ([Ag23Pt2(PPh3)10Br7]0 and [Ag23Pd2(PPh3)10Br7]0 (PPh3 = Triphenylphosphine). The former consisted of two icosahedral Ag12Pt superatoms connected by vertex sharing with platinum atoms (Pt) occupying the central position in each superatom. In contrast, the other superatomic molecule consisted of two icosahedral Ag12Pd structures with palladium (Pd) as the central atom. The geometric/electronic structure and stability of these two nanoclusters was then analyzed and compared with [Ag23Pt2(PPh3)10Cl7]0 (1) and [Ag23Pd2(PPh3)10Cl7]0 (2)—two nanoclusters with geometrical similarity to the synthesized nanoclusters, consisting of chlorine (Cl) as the bridging atom. On examining the geometric structures of the four nanoclusters, the researchers observed a twist between the two icosahedral structures containing Br as the bridging ligand. The researchers suggest that this twist stabilizes the nanocluster by shortening the distance between the two icosahedral structures. Additionally, the larger Br atom was found to introduce steric hindrance in the molecule, causing both the PPh3 molecule to be positioned further from the long axis of the metal nanocluster and, a change in the bond length of the Ag-P and Ag-Ag bonds. These findings indicate that although the type of bridging halogen slightly affects the geometric structures of the metal nanoclusters, it does not hinder their formation. \"The type of bridging halogen appears to have little effect on whether superatomic molecules can be formed or not, as long as the bridging halogen is large enough to maintain a moderate distance between the two Ag12M structures,\" explains Prof. Negishi. However, the stability of the nanocluster was largely dependent on the number of bridging halogens attached to it. Like atoms, stable metallic nanoclusters require a filled valence shell. In the case of the prepared nanoclusters—which had a total of 16 valence electrons—the researchers were only able to attach a maximum of five bridging halogens to maintain the metal nanocluster in a stable neutral or cationic state. The presence of Pd and Pt central atoms was found to be due to the formation of metallic nanoclusters. Substituting the central atom of Ag13 with Pt or Pd led to an increase in the average binding energy within the nanoclusters, making it favorable for the formation of superatomic molecules. Overall, the researchers identified three key requirements for the formation and isolation of superatomic molecules consisting of two Ag13−xMx structures connected by vertex sharing. These include the presence of a bridging halogen that can maintain an optimal distance between the two structures, a combination of heteroatoms and bridging halogens that results in 16 valence electrons, and the formation of an icosahedral core that is stronger than Ag13. In the words of Prof. Negishi, \"These findings offer clear design guidelines for the creation of molecular devices with various properties and functions, and can potentially contribute to resolving pressing concerns regarding clean energy and 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 Metal nanoclusters composed of noble elements such as gold (Au) or silver (Ag) are regarded as superatoms. In recent years, the understanding of the materials composed of superatoms, which are often called superatomic molecules, has gradually progressed for Au-based materials. However, there is still little information on Ag-based superatomic molecules. In the present study, we synthesise two di-superatomic molecules with Ag as the main constituent element and reveal the three essential conditions for the formation and isolation of a superatomic molecule comprising two Ag 13− x M x structures (M = Ag or other metal; x = number of M) connected by vertex sharing. The effects of the central atom and the type of bridging halogen on the electronic structure of the resulting superatomic molecule are also clarified in detail. These findings are expected to provide clear design guidelines for the creation of superatomic molecules with various properties and functions. Introduction Metal nanoclusters (NCs) 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 composed of noble metal elements such as gold (Au) and silver (Ag) are stabilised when the total number of valence electrons satisfies the closed-shell electronic structure, as in conventional atoms 15 , 16 . Such metal NCs are regarded as superatoms (artificial atoms). If superatoms are used to assemble materials, it might be possible to create materials with physicochemical properties and functions that are different from those of conventional materials 17 . Regarding such materials composed of superatoms (often called superatomic molecules 18 , 19 ), since the 1980s, there have been many reports of Au-based superatomic molecules, which Teo and Zhang called clusters of clusters 20 . Subsequent work by groups such as Tsukuda 21 , Nobusada 22 , Jin 23 and Zhu 24 has gradually improved our understanding of the types of superatomic molecules that can be produced and the electronic structures that can be created 25 . Ag NCs have multiple properties and functions that are superior to those of Au NCs, including photoluminescence (PL) with high quantum yield 26 and selective catalytic activity for carbon dioxide reduction 27 . However, there are only a limited number of reports, including the report 28 by the authors, on Ag-based superatomic molecules 29 , 30 , 31 , 32 . To construct substances using superatomic molecules and create new materials, it is essential to gain a deeper understanding of the types of superatomic molecules that can be produced and the electronic structures that can be created, even for Ag-based superatomic molecules. In the present study, we focus on Ag-based 13-atom NCs (Ag 13− x M x ; M = Ag or other metal; x = number of M) as superatoms, and aim to elucidate the key factors in the formation of di-superatomic molecules by vertex sharing 33 and the electronic structure of the obtained di-superatomic molecules. Platinum (Pt) or palladium (Pd) was used as the element that substitutes part of the Ag, and chloride (Cl) or bromide (Br) was used as the bridging ligand to support the connection of the two 13-atom NCs. To achieve our purpose, in addition to two previously reported di-superatomic molecules ([Ag 23 Pt 2 (PPh 3 ) 10 Cl 7 ] 0 ( 1 ); Fig. 1a ; PPh 3 = triphenylphosphine) 31 and ([Ag 23 Pd 2 (PPh 3 ) 10 Cl 7 ] 0 ( 2 ); Fig. 1b ) 28 , we synthesised two new superatomic molecules with Br as the bridging ligand ([Ag 23 Pt 2 (PPh 3 ) 10 Br 7 ] 0 ( 3 ) and [Ag 23 Pd 2 (PPh 3 ) 10 Br 7 ] 0 ( 4 ); Table 1 ). We investigated their geometric/electronic structures and their stabilities with regard to degradation in solution. Consequently, we confirmed that 3 and 4 both have a geometric/electronic structure that qualifies them as superatomic molecules. Regarding the electronic structure, we further observed that (1) there is a peak attributable to the metal core at approximately 600 nm in the optical absorption spectra of all the superatomic molecules; (2) such peaks shift to longer wavelengths when M is changed from Pt to Pd; (3) all 1 − 4 exhibit PL in visible-to-near infra-red (NIR) region; and (4) PL peaks shift to longer wavelengths when M is changed from Pt to Pd. With respect to the stability of the superatomic molecule described by [Ag 23 M 2 (PPh 3 ) 10 X 7 ] z (M = Ag, Pd, or Pt; X = Cl or Br; z = 2+ or 0), we found that the stability decreases in the order 1 > 3 > 2 > 4 (which can be synthesised) > [Ag 25 (PPh 3 ) 10 X 7 ] 2+ (X = Cl or Br; which are not so stable in solution). Based on these results and reports on the related superatomic molecules, we concluded that the following three conditions are essential for the formation and isolation of a superatomic molecule consisting of two Ag 13− x M x structures (M = Ag or other metal) connected by vertex sharing ([Ag 25− x M x (PR 3 ) 10 X y ] z ; PR 3 = phosphine; y = number of X): (1) a halogen ligand of a size that can maintain a moderate distance between two Ag 13− x M x structures is used as the bridging ligand; (2) an icosahedral core, which is stronger than Ag 13 , is formed by heteroatom substitution; and (3) [Ag 25− x M x (PR 3 ) 10 X y ] z comprises substituted heteroatoms and bridging halogens such that the total number of valence electrons is 16 when they are cationic or neutral. Fig. 1: Comparison of the geometric structures. a 1 . b 2 . c 3 . d 4 . The geometric structure of 1 and 2 are reproduced from ref. 28 ,<|im_end|> <|im_start|>assistant Superatomic molecules containing noble metal elements like gold and silver are studied for their potential in the synthesis of superatomic materials. However, the understanding of silver-based superatomic molecules has been limited. Addressing this gap, researchers from Japan studied two bimetallic superatomic molecules with silver as a main constituent to determine the key factors that enabled their formation. Their findings are expected to advance the development of novel materials in the future. In the past few decades, metal nanoclusters composed of noble metal elements such as gold (Au) and silver (Ag) have gained attention as superatoms for the synthesis of materials with unique properties and potential new applications. These superatoms (also known as "artificial atoms") typically consist of a cluster of a few to several hundred atoms and exhibit properties that are significantly different from their bulk, conventional counterparts. However, much like real atoms, the stability of these superatoms is determined by the formation of a closed-shell electron structure. Ag-based superatoms are known for their superior properties and functions, including photoluminescence and selective catalytic activity, compared to those of Au-based superatoms. However, most of the research in this field has been primarily focused on Au-based superatomic molecules. To overcome this research gap, researchers from Japan studied the formation of superatomic molecules composed of Ag and evaluated the factors involved in this formation. This study was published in the journal Communications Chemistry on March 28, 2023. Speaking of the motivation behind studying Ag-based superatoms, Prof. Negishi says, "So far, we humans have created a variety of useful materials from the elements available to us on Earth. However, looking at a future with complex energy and environmental issues, the development of materials with new properties and functions is desired." To this end, the researchers synthesized two di-superatomic molecules with bromine (Br) as the bridging ligand: ([Ag23Pt2(PPh3)10Br7]0 and [Ag23Pd2(PPh3)10Br7]0 (PPh3 = Triphenylphosphine). The former consisted of two icosahedral Ag12Pt superatoms connected by vertex sharing with platinum atoms (Pt) occupying the central position in each superatom. In contrast, the other superatomic molecule consisted of two icosahedral Ag12Pd structures with palladium (Pd) as the central atom. The geometric/electronic structure and stability of these two nanoclusters was then analyzed and compared with [Ag23Pt2(PPh3)10Cl7]0 (1) and [Ag23Pd2(PPh3)10Cl7]0 (2)—two nanoclusters with geometrical similarity to the synthesized nanoclusters, consisting of chlorine (Cl) as the bridging atom. On examining the geometric structures of the four nanoclusters, the researchers observed a twist between the two icosahedral structures containing Br as the bridging ligand. The researchers suggest that this twist stabilizes the nanocluster by shortening the distance between the two icosahedral structures. Additionally, the larger Br atom was found to introduce steric hindrance in the molecule, causing both the PPh3 molecule to be positioned further from the long axis of the metal nanocluster and, a change in the bond length of the Ag-P and Ag-Ag bonds. These findings indicate that although the type of bridging halogen slightly affects the geometric structures of the metal nanoclusters, it does not hinder their formation. "The type of bridging halogen appears to have little effect on whether superatomic molecules can be formed or not, as long as the bridging halogen is large enough to maintain a moderate distance between the two Ag12M structures," explains Prof. Negishi. However, the stability of the nanocluster was largely dependent on the number of bridging halogens attached to it. Like atoms, stable metallic nanoclusters require a filled valence shell. In the case of the prepared nanoclusters—which had a total of 16 valence electrons—the researchers were only able to attach a maximum of five bridging halogens to maintain the metal nanocluster in a stable neutral or cationic state. The presence of Pd and Pt central atoms was found to be due to the formation of metallic nanoclusters. Substituting the central atom of Ag13 with Pt or Pd led to an increase in the average binding energy within the nanoclusters, making it favorable for the formation of superatomic molecules. Overall, the researchers identified three key requirements for the formation and isolation of superatomic molecules consisting of two Ag13−xMx structures connected by vertex sharing. These include the presence of a bridging halogen that can maintain an optimal distance between the two structures, a combination of heteroatoms and bridging halogens that results in 16 valence electrons, and the formation of an icosahedral core that is stronger than Ag13. In the words of Prof. Negishi, "These findings offer clear design guidelines for the creation of molecular devices with various properties and functions, and can potentially contribute to resolving pressing concerns regarding clean energy and the environment." <|im_end|>
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12005, 9219, 1419, 35956, 17, 5417, 3438, 18, 8, 605, 6971, 22, 60, 15, 323, 510, 9219, 1419, 47, 67, 17, 5417, 3438, 18, 8, 605, 6971, 22, 60, 15, 320, 47, 3438, 18, 284, 12639, 15112, 4010, 764, 24527, 483, 570, 578, 4846, 44660, 315, 1403, 220, 17038, 1494, 36620, 4701, 717, 35956, 2307, 66650, 8599, 555, 12202, 11821, 449, 63327, 33299, 320, 35956, 8, 72280, 279, 8792, 2361, 304, 1855, 2307, 22612, 13, 763, 13168, 11, 279, 1023, 2307, 6756, 43030, 44660, 315, 1403, 220, 17038, 1494, 36620, 4701, 717, 47, 67, 14726, 449, 67597, 13786, 320, 47, 67, 8, 439, 279, 8792, 19670, 13, 578, 53584, 16954, 772, 8535, 6070, 323, 20334, 315, 1521, 1403, 20622, 62868, 14947, 574, 1243, 30239, 323, 7863, 449, 510, 9219, 1419, 35956, 17, 5417, 3438, 18, 8, 605, 5176, 22, 60, 15, 320, 16, 8, 323, 510, 9219, 1419, 47, 67, 17, 5417, 3438, 18, 8, 605, 5176, 22, 60, 15, 320, 17, 68850, 20375, 20622, 62868, 14947, 449, 69086, 12381, 38723, 311, 279, 92106, 20622, 62868, 14947, 11, 31706, 315, 85206, 320, 5176, 8, 439, 279, 77847, 3252, 19670, 13, 1952, 38936, 279, 53584, 14726, 315, 279, 3116, 20622, 62868, 14947, 11, 279, 12074, 13468, 264, 27744, 1990, 279, 1403, 220, 17038, 1494, 36620, 14726, 8649, 3320, 439, 279, 77847, 3252, 29413, 438, 13, 578, 12074, 4284, 430, 420, 27744, 27276, 4861, 279, 20622, 62868, 5100, 555, 2875, 6147, 279, 6138, 1990, 279, 1403, 220, 17038, 1494, 36620, 14726, 13, 23212, 11, 279, 8294, 3320, 19670, 574, 1766, 311, 19678, 357, 11893, 48419, 35206, 304, 279, 43030, 11, 14718, 2225, 279, 393, 3438, 18, 43030, 311, 387, 35328, 4726, 505, 279, 1317, 8183, 315, 279, 9501, 20622, 62868, 5100, 323, 11, 264, 2349, 304, 279, 11049, 3160, 315, 279, 4701, 9483, 323, 4701, 6830, 70, 27460, 13, 4314, 14955, 13519, 430, 8051, 279, 955, 315, 77847, 3252, 15104, 11968, 10284, 22223, 279, 53584, 14726, 315, 279, 9501, 20622, 62868, 14947, 11, 433, 1587, 539, 57780, 872, 18488, 13, 330, 791, 955, 315, 77847, 3252, 15104, 11968, 8111, 311, 617, 2697, 2515, 389, 3508, 2307, 6756, 35715, 649, 387, 14454, 477, 539, 11, 439, 1317, 439, 279, 77847, 3252, 15104, 11968, 374, 3544, 3403, 311, 10519, 264, 24070, 6138, 1990, 279, 1403, 4701, 717, 44, 14726, 1359, 15100, 8626, 13, 24952, 39476, 13, 4452, 11, 279, 20334, 315, 279, 20622, 62868, 5100, 574, 14090, 18222, 389, 279, 1396, 315, 77847, 3252, 15104, 57118, 12673, 311, 433, 13, 9086, 33299, 11, 15528, 46258, 20622, 62868, 14947, 1397, 264, 10409, 1062, 768, 12811, 13, 763, 279, 1162, 315, 279, 10235, 20622, 62868, 14947, 50004, 1047, 264, 2860, 315, 220, 845, 1062, 768, 57678, 22416, 12074, 1051, 1193, 3025, 311, 15866, 264, 7340, 315, 4330, 77847, 3252, 15104, 57118, 311, 10519, 279, 9501, 20622, 62868, 5100, 304, 264, 15528, 21277, 477, 272, 367, 292, 1614, 13, 578, 9546, 315, 393, 67, 323, 52170, 8792, 33299, 574, 1766, 311, 387, 4245, 311, 279, 18488, 315, 46258, 20622, 62868, 14947, 13, 3804, 3781, 10831, 279, 8792, 19670, 315, 4701, 1032, 449, 52170, 477, 393, 67, 6197, 311, 459, 5376, 304, 279, 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2,481
[ { "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 human genome reference sequence remains incomplete owing to the challenge of assembling long tracts of near-identical tandem repeats in centromeres. We implemented a nanopore sequencing strategy to generate high-quality reads that span hundreds of kilobases of highly repetitive DNA in a human Y chromosome centromere. Combining these data with short-read variant validation, we assembled and characterized the centromeric region of a human Y chromosome. Main Centromeres facilitate spindle attachment and ensure proper chromosome segregation during cell division. Normal human centromeres are enriched with AT-rich ∼ 171-bp tandem repeats known as alpha satellite DNA 1 . Most alpha satellite DNAs are organized into higher order repeats (HORs), in which chromosome-specific alpha satellite repeat units, or monomers, are reiterated as a single repeat structure hundreds or thousands of times with high (>99%) sequence conservation to form extensive arrays 2 . Characterizing both the sequence composition of individual HOR structures and the extent of repeat variation is crucial to understanding kinetochore assembly and centromere identity 3 , 4 , 5 . However, no sequencing technology (including single-molecule real-time (SMRT) sequencing or synthetic long-read technologies) or a combination of sequencing technologies has been able to assemble centromeric regions because extremely high-quality, long reads are needed to confidently traverse low-copy sequence variants. As a result, human centromeric regions remain absent from even the most complete chromosome assemblies. Here we apply nanopore long-read sequencing to produce high-quality reads that span hundreds of kilobases of highly repetitive DNA ( Supplementary Fig. 1 ). We focus on the haploid satellite array present on the Y centromere (DYZ3), as it is particularly suitable for assembly owing to its tractable size, well-characterized HOR structure, and previous physical mapping data 6 , 7 , 8 . We devised a transposase-based method that we named 'longboard strategy' to produce high-read coverage of full-length bacterial artificial chromosome (BAC) DNA with nanopore sequencing (MinION sequencing device, Mk1B, Oxford Nanopore Technologies). In our longboard strategy, we linearize the circular BAC with a single cut site, then add sequencing adaptors ( Fig. 1a ). The BAC DNA passes through the pore, resulting in complete, end-to-end sequence coverage of the entire insert. Plots of read length versus megabase yield revealed an increase in megabase yield for full-length BAC DNA sequences ( Fig. 1b and Supplementary Fig. 2 ). We present more than 3,500 full-length '1D' reads (that is, one strand of the DNA is sequenced) from ten BACs (two control BACs from Xq24 and Yp11.2; eight BACs in the DYZ3 locus 9 ; Supplementary Table 1 ). Figure 1: BAC-based longboard nanopore sequencing strategy on the MinION. ( a ) Optimized strategy to cut each circular BAC once with transposase results in a linear and complete DNA fragment of the BAC for nanopore sequencing. ( b ) Yield plot of BAC DNA (RP11-648J18). ( c ) High-quality BAC consensus sequences were generated by multiple alignment of 60 full-length 1D reads (shown as blue and yellow for both orientations), sampled at random with ten iterations, followed by polishing steps (green) with the entire nanopore long-read data and Illumina data. ( d ) Circos representation 20 of the polished RP11-718M18 BAC consensus sequence. Blue arrowheads indicate the position and orientation of HORs. Purple tiles in yellow background mark the position of the Illumina-validated variants. Additional purple highlight extending from select Illumina-validated variants are used to identify single-nucleotide-sequence variants and mark the site of the DYZ3 repeat structural variants (6 kb) in tandem. Full size image Correct assembly across the centromeric locus requires overlap among a few sequence variants, meaning that accuracy of base-calls is important. Individual reads (MinION R9.4 chemistry, Albacore v1.1.1) provide insufficient sequence identity (median alignment identity of 84.8% for control BAC, RP11-482A22 reads) to ensure correct repeat assembly 10 . To improve overall base quality, we produced a consensus sequence from 10 iterations of 60 randomly sampled alignments of full-length 1D reads that spanned the full insert length for each BAC ( Fig. 1c ). To polish sequences, we realigned full-length nanopore reads to each BAC-derived consensus (99.2% observed for control BAC, RP11-482A22; and an observed range of 99.4–99.8% for vector sequences in DYZ3-containing BACs). To provide a truth set of array sequence variants and to evaluate any inherent nanopore sequence biases, we used Illumina BAC resequencing (Online Methods ). We used eight BAC-polished sequences (e.g., 209 kb for RP11-718M18; Fig. 1d ) to guide the ordered assembly of BACs from p-arm to q-arm, which includes an entire Y centromere. We ordered the DYZ3-containing BACs using 16 Illumina-validated HOR variants, resulting in 365 kb of assembled alpha satellite DNA ( Fig. 2a and Supplementary Data 1 ). The centromeric locus contains a 301-kb array that is composed of the DYZ3 HOR, with a 5.8-kb consensus sequence, repeated in a head-to-tail orientation without repeat inversions or transposable element interruptions 6 , 11 , 12 . The assembled length of the RP11 DYZ3 array is consistent with estimates for 96 individuals from the same Y haplogroup (R1b) ( Supplementary Fig. 3 ; mean: 315 kb; median: 350 kb) 13 , 14 . This finding is in agreement with pulsed-field gel electrophoresis (PFGE) DYZ3 size estimates from previous physical maps, and from a Y-haplogroup matched cell line ( Supplementary Fig. 4 ). Figure 2: Linear assembly of the RP11 Y centromere. ( a ) Ordering of nine DYZ3-containing BACs spanning from proximal p-arm to proximal q-arm. The majority of the centromeric locus is defined by the DYZ3 conical 5.8-kb HOR (light blue). Highly divergent monomeric alpha satellite is indicated in dark blue. HOR variants (6.0 kb) indicated in purple. ( b ) The genomic location of the functional Y centromere is defined by the enrichment of centromere protein A (CENP-A), where enrichment ( ∼ 5–6×) is attributed predominantly to the DYZ3 HOR array. Full size image Pairwise comparisons among the 52 HORs in the assembled DYZ3 array revealed limited sequence divergence between copies (mean 99.7% pairwise identity). In agreement with a previous assessment of sequence variation within", "role": "user" }, { "content": "Fifteen years ago, the Human Genome Project announced they had cracked the code of life. Nonetheless, the published human genome map was incomplete and parts of our DNA remained to be deciphered. Now, a new study published in the journal Nature Biotechnology brings us closer to a complete genetic blueprint by using a nanotechnology-based sequencing technique. Like ancient Egyptian ruins covered in mysterious hieroglyphics, the letters and words in our genetic code remained unutterable for a long time. In an effort to solve this genetic cipher, the Human Genome Project, a collaborative international consortium, was created. The goal was to read out the DNA sequence – made up of four letters, or bases, A,T,G and C – of all human genes (genome). In 2003, a near-complete map of the human genome was reported. The scientific community hailed the momentous event as a turning point, perhaps overshadowed only by the discovery of the double-helix structure of DNA. Indeed, for the first time in human history, we could read and understand the language of our \"being\". Yet, the assembled genome represented only 92% of all human genes. Gaps remained that could not be easily decrypted. For many researchers, that elusive 8% of the genome is a holy grail. The dark matter inside us all The unmappable genome is associated with \"heterochromatin\" (dark matter of the genome, highly condensed), unlike \"euchromatin\" (light matter, more loosely wound part of the genome). Euchromatin is gene-rich while heterochromatin refers to the silent, repressed regions of our DNA. Euchromatin is full of unique DNA sequences. This means that finding a single- or low-copy DNA sequence, with all the same DNA bases in the same order, at more than one location in our genome is highly unlikely. These discrete DNA sequences are easily distinguishable and serve distinct purposes within our cells. No wonder the human genome has almost 20,000 different genes with limited redundancy. Now, visualize a human chromosome as a big \"X\", made of coiled-up DNA, with two arms attached at a constriction. Heterochromatin is mostly localised near the point of attachment (centromere) and the tips of the arms (telomeres). In fact, the centromere becomes indispensable when cells divide, dragging along one chromosome arm into each of the newly formed daughter cells. DNA sequencing technologies operate by reading each base of DNA, one at a time, and spitting out short \"reads\" that spell out the sequence being read. Thus, decoding unique, non-identical euchromatic DNA is facile because one stretch apart from other with little ambiguity. The problem arises when we try to enunciate heterochromatic sequences comprising strings of DNA that look like each other. Arranged in tandem arrays or dispersed throughout our genome, these highly repetitive stretches of DNA amount to garbled gibberish after conventional DNA sequencing. One small chunk of DNA (monomer) at the centromere resembles other identical chunks flanking it and so on. In the resulting quagmire, the base-composition & precise position of any given repeated sequence cannot be ascertained in a long polymer of repeats. Made up of millions of repeating A,T,G,C bases, the centromeres of human chromosomes evaded biologists and explain holes in our current DNA map. Threading the genome into a tiny needle The new study, from the team of Dr. Karen Miga at University of California (Santa Cruz), has managed to uncover the centromere of the Y chromosome – the male-specific chromosome and also the smallest chromosome in our genome (something worth thinking about). The researchers were able to insert a longer stretch of DNA into a nano-pore (like thread passed through the eye of a needle), \"resulting in complete, end-to-end sequence coverage of the entire insert\". Using this nanopore-sequencing method, the researchers can now decipher a long, muddled DNA stretch full of repeats. This \"long-read\" strategy allowed them to string together longer pieces of DNA (made up of variable repeat monomer lengths). It turns out that when all these chunks are laid out, certain clues help reconstruct the repetitive-sequence. Walking along the centromere, from left to right, context is provided by surrounding monomers in the same tandem array and by flanking non-repetitive DNA. Like a neatly laid section of railroad, the authors pieced together a chain of contiguous DNA sequences and solved the jigsaw puzzle of the Y chromosome centromere. This recent work, published in Nature Biotechnology journal, plugs holes in the existing human DNA map. In the future, finding out the DNA sequences that define other centromeres will allow researchers to rewrite, manipulate, alter or duplicate these key structures. Given that the centromere is essential for cells to divide and segregate their genetic content to future generations, the Y centromere assembly represents an exciting step forward in modern biology. ", "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 human genome reference sequence remains incomplete owing to the challenge of assembling long tracts of near-identical tandem repeats in centromeres. We implemented a nanopore sequencing strategy to generate high-quality reads that span hundreds of kilobases of highly repetitive DNA in a human Y chromosome centromere. Combining these data with short-read variant validation, we assembled and characterized the centromeric region of a human Y chromosome. Main Centromeres facilitate spindle attachment and ensure proper chromosome segregation during cell division. Normal human centromeres are enriched with AT-rich ∼ 171-bp tandem repeats known as alpha satellite DNA 1 . Most alpha satellite DNAs are organized into higher order repeats (HORs), in which chromosome-specific alpha satellite repeat units, or monomers, are reiterated as a single repeat structure hundreds or thousands of times with high (>99%) sequence conservation to form extensive arrays 2 . Characterizing both the sequence composition of individual HOR structures and the extent of repeat variation is crucial to understanding kinetochore assembly and centromere identity 3 , 4 , 5 . However, no sequencing technology (including single-molecule real-time (SMRT) sequencing or synthetic long-read technologies) or a combination of sequencing technologies has been able to assemble centromeric regions because extremely high-quality, long reads are needed to confidently traverse low-copy sequence variants. As a result, human centromeric regions remain absent from even the most complete chromosome assemblies. Here we apply nanopore long-read sequencing to produce high-quality reads that span hundreds of kilobases of highly repetitive DNA ( Supplementary Fig. 1 ). We focus on the haploid satellite array present on the Y centromere (DYZ3), as it is particularly suitable for assembly owing to its tractable size, well-characterized HOR structure, and previous physical mapping data 6 , 7 , 8 . We devised a transposase-based method that we named 'longboard strategy' to produce high-read coverage of full-length bacterial artificial chromosome (BAC) DNA with nanopore sequencing (MinION sequencing device, Mk1B, Oxford Nanopore Technologies). In our longboard strategy, we linearize the circular BAC with a single cut site, then add sequencing adaptors ( Fig. 1a ). The BAC DNA passes through the pore, resulting in complete, end-to-end sequence coverage of the entire insert. Plots of read length versus megabase yield revealed an increase in megabase yield for full-length BAC DNA sequences ( Fig. 1b and Supplementary Fig. 2 ). We present more than 3,500 full-length '1D' reads (that is, one strand of the DNA is sequenced) from ten BACs (two control BACs from Xq24 and Yp11.2; eight BACs in the DYZ3 locus 9 ; Supplementary Table 1 ). Figure 1: BAC-based longboard nanopore sequencing strategy on the MinION. ( a ) Optimized strategy to cut each circular BAC once with transposase results in a linear and complete DNA fragment of the BAC for nanopore sequencing. ( b ) Yield plot of BAC DNA (RP11-648J18). ( c ) High-quality BAC consensus sequences were generated by multiple alignment of 60 full-length 1D reads (shown as blue and yellow for both orientations), sampled at random with ten iterations, followed by polishing steps (green) with the entire nanopore long-read data and Illumina data. ( d ) Circos representation 20 of the polished RP11-718M18 BAC consensus sequence. Blue arrowheads indicate the position and orientation of HORs. Purple tiles in yellow background mark the position of the Illumina-validated variants. Additional purple highlight extending from select Illumina-validated variants are used to identify single-nucleotide-sequence variants and mark the site of the DYZ3 repeat structural variants (6 kb) in tandem. Full size image Correct assembly across the centromeric locus requires overlap among a few sequence variants, meaning that accuracy of base-calls is important. Individual reads (MinION R9.4 chemistry, Albacore v1.1.1) provide insufficient sequence identity (median alignment identity of 84.8% for control BAC, RP11-482A22 reads) to ensure correct repeat assembly 10 . To improve overall base quality, we produced a consensus sequence from 10 iterations of 60 randomly sampled alignments of full-length 1D reads that spanned the full insert length for each BAC ( Fig. 1c ). To polish sequences, we realigned full-length nanopore reads to each BAC-derived consensus (99.2% observed for control BAC, RP11-482A22; and an observed range of 99.4–99.8% for vector sequences in DYZ3-containing BACs). To provide a truth set of array sequence variants and to evaluate any inherent nanopore sequence biases, we used Illumina BAC resequencing (Online Methods ). We used eight BAC-polished sequences (e.g., 209 kb for RP11-718M18; Fig. 1d ) to guide the ordered assembly of BACs from p-arm to q-arm, which includes an entire Y centromere. We ordered the DYZ3-containing BACs using 16 Illumina-validated HOR variants, resulting in 365 kb of assembled alpha satellite DNA ( Fig. 2a and Supplementary Data 1 ). The centromeric locus contains a 301-kb array that is composed of the DYZ3 HOR, with a 5.8-kb consensus sequence, repeated in a head-to-tail orientation without repeat inversions or transposable element interruptions 6 , 11 , 12 . The assembled length of the RP11 DYZ3 array is consistent with estimates for 96 individuals from the same Y haplogroup (R1b) ( Supplementary Fig. 3 ; mean: 315 kb; median: 350 kb) 13 , 14 . This finding is in agreement with pulsed-field gel electrophoresis (PFGE) DYZ3 size estimates from previous physical maps, and from a Y-haplogroup matched cell line ( Supplementary Fig. 4 ). Figure 2: Linear assembly of the RP11 Y centromere. ( a ) Ordering of nine DYZ3-containing BACs spanning from proximal p-arm to proximal q-arm. The majority of the centromeric locus is defined by the DYZ3 conical 5.8-kb HOR (light blue). Highly divergent monomeric alpha satellite is indicated in dark blue. HOR variants (6.0 kb) indicated in purple. ( b ) The genomic location of the functional Y centromere is defined by the enrichment of centromere protein A (CENP-A), where enrichment ( ∼ 5–6×) is attributed predominantly to the DYZ3 HOR array. Full size image Pairwise comparisons among the 52 HORs in the assembled DYZ3 array revealed limited sequence divergence between copies (mean 99.7% pairwise identity). In agreement with a previous assessment of sequence variation within<|im_end|> <|im_start|>assistant Fifteen years ago, the Human Genome Project announced they had cracked the code of life. Nonetheless, the published human genome map was incomplete and parts of our DNA remained to be deciphered. Now, a new study published in the journal Nature Biotechnology brings us closer to a complete genetic blueprint by using a nanotechnology-based sequencing technique. Like ancient Egyptian ruins covered in mysterious hieroglyphics, the letters and words in our genetic code remained unutterable for a long time. In an effort to solve this genetic cipher, the Human Genome Project, a collaborative international consortium, was created. The goal was to read out the DNA sequence – made up of four letters, or bases, A,T,G and C – of all human genes (genome). In 2003, a near-complete map of the human genome was reported. The scientific community hailed the momentous event as a turning point, perhaps overshadowed only by the discovery of the double-helix structure of DNA. Indeed, for the first time in human history, we could read and understand the language of our "being". Yet, the assembled genome represented only 92% of all human genes. Gaps remained that could not be easily decrypted. For many researchers, that elusive 8% of the genome is a holy grail. The dark matter inside us all The unmappable genome is associated with "heterochromatin" (dark matter of the genome, highly condensed), unlike "euchromatin" (light matter, more loosely wound part of the genome). Euchromatin is gene-rich while heterochromatin refers to the silent, repressed regions of our DNA. Euchromatin is full of unique DNA sequences. This means that finding a single- or low-copy DNA sequence, with all the same DNA bases in the same order, at more than one location in our genome is highly unlikely. These discrete DNA sequences are easily distinguishable and serve distinct purposes within our cells. No wonder the human genome has almost 20,000 different genes with limited redundancy. Now, visualize a human chromosome as a big "X", made of coiled-up DNA, with two arms attached at a constriction. Heterochromatin is mostly localised near the point of attachment (centromere) and the tips of the arms (telomeres). In fact, the centromere becomes indispensable when cells divide, dragging along one chromosome arm into each of the newly formed daughter cells. DNA sequencing technologies operate by reading each base of DNA, one at a time, and spitting out short "reads" that spell out the sequence being read. Thus, decoding unique, non-identical euchromatic DNA is facile because one stretch apart from other with little ambiguity. The problem arises when we try to enunciate heterochromatic sequences comprising strings of DNA that look like each other. Arranged in tandem arrays or dispersed throughout our genome, these highly repetitive stretches of DNA amount to garbled gibberish after conventional DNA sequencing. One small chunk of DNA (monomer) at the centromere resembles other identical chunks flanking it and so on. In the resulting quagmire, the base-composition & precise position of any given repeated sequence cannot be ascertained in a long polymer of repeats. Made up of millions of repeating A,T,G,C bases, the centromeres of human chromosomes evaded biologists and explain holes in our current DNA map. Threading the genome into a tiny needle The new study, from the team of Dr. Karen Miga at University of California (Santa Cruz), has managed to uncover the centromere of the Y chromosome – the male-specific chromosome and also the smallest chromosome in our genome (something worth thinking about). The researchers were able to insert a longer stretch of DNA into a nano-pore (like thread passed through the eye of a needle), "resulting in complete, end-to-end sequence coverage of the entire insert". Using this nanopore-sequencing method, the researchers can now decipher a long, muddled DNA stretch full of repeats. This "long-read" strategy allowed them to string together longer pieces of DNA (made up of variable repeat monomer lengths). It turns out that when all these chunks are laid out, certain clues help reconstruct the repetitive-sequence. Walking along the centromere, from left to right, context is provided by surrounding monomers in the same tandem array and by flanking non-repetitive DNA. Like a neatly laid section of railroad, the authors pieced together a chain of contiguous DNA sequences and solved the jigsaw puzzle of the Y chromosome centromere. This recent work, published in Nature Biotechnology journal, plugs holes in the existing human DNA map. In the future, finding out the DNA sequences that define other centromeres will allow researchers to rewrite, manipulate, alter or duplicate these key structures. Given that the centromere is essential for cells to divide and segregate their genetic content to future generations, the Y centromere assembly represents an exciting step forward in modern biology. <|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 Dirac semimetals, the materials featuring fourfold degenerate Dirac points, are critical states of topologically distinct phases. Such gapless topological states have been accomplished by a band-inversion mechanism, in which the Dirac points can be annihilated pairwise by perturbations without changing the symmetry of the system. Here, we report an experimental observation of Dirac points that are enforced completely by the crystal symmetry using a nonsymmorphic three-dimensional phononic crystal. Intriguingly, our Dirac phononic crystal hosts four spiral topological surface states, in which the surface states of opposite helicities intersect gaplessly along certain momentum lines, as confirmed by additional surface measurements. The novel Dirac system may release new opportunities for studying elusive (pseudo) and offer a unique prototype platform for acoustic applications. Introduction The discovery of new topological states of matter has become a vital goal in fundamental physics and material science 1 , 2 . A three-dimensional (3D) Dirac semimetal (DSM) 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , accommodating many exotic transport properties such as anomalous magnetoresistance and ultrahigh mobility 14 , 15 , is an exceptional platform for exploring topological phase transitions and other novel topological quantum states. It is also of fundamental interest to serve as a solid-state realization of a (3 + 1)-dimensional Dirac vacuum. A DSM phase may appear accidentally at the quantum transition between normal and topological insulators 16 , 17 . The approach to such a single critical point demands the fine-tuning of the alloy’s chemical composition, which limits the experimental accessibility to the fascinating physics of 3D Dirac fermions. 3D DSMs can also emerge without fine-tuning parameters and are distinguished into two classes 3 , 4 . The first one, already realized in Na 3 Bi 7 , 8 and Cd 3 As 2 9 , 10 , occurs due to band inversion 5 , 6 . The Dirac points, lying on the generic momenta of a specific rotation symmetry axis, always come in pairs and could be eliminated by their merger and pairwise annihilation through the continuous tuning of parameters 3 , 4 that preserve the symmetry of the system. The second class features Dirac points that are pinned stably to discrete high-symmetry points on the surface of the Brillouin zone (BZ). Markedly different from the first class of DSMs, the occurrence of Dirac points is an unavoidable result of the nonsymmorphic space group of the material 11 , 12 , 13 , which cannot be removed without changing the crystal symmetry. Although some solid-state candidate materials have been proposed 4 , 11 , 12 , symmetry-enforced 3D DSMs have never been experimentally realized because of the great challenge in synthesizing materials 4 , 7 . Recently, numerous distinct topological states have been demonstrated in classical wave systems 18 , 19 , such as photonic crystals 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 and phononic crystals 29 , 30 , 31 , 32 , 33 , 34 , which offer opportunities for exploring topological physics in a fully controllable manner. Here, we report an experimental realization of a 3D phononic crystal that hosts symmetry-enforced Dirac points at the BZ corners. The fourfold degeneracy is protected by a nonsymmorphic space group that couples point operations (rotations and mirrors) with nonprimitive lattice translations. In addition to the Dirac points identified directly by angle-resolved transmission measurements, highly intricate quad-helicoid surface states are unveiled by our surface measurements and associated Fourier spectra. Specifically, the surface states are composed of four gaplessly crossed spiral branches 13 and thus are strikingly different than the double Fermi arc surface states observed recently in electronic 8 and photonic systems 28 . Excellent agreement is found between our experiments and simulations. As illustrated in Fig. 1a , our Dirac phononic crystal has a body-centered-cubic (bcc) lattice associated with the lattice constant a = 2.8 cm. The main body of the building block consists of four inequivalent resin cylinders, which are labeled with different colors and oriented along different bcc lattice vector directions. All the cylinders have a regular hexagonal cross section with a side length of 0.42 cm. To facilitate sample fabrication, these cylinders are connected with short hexagonal bars with side lengths of 0.21 cm. The remainder of the volume is filled with air. Numerically, the photosensitive resin material used for printing the acoustic structure is treated as rigid, and sound propagates only in air (at speed 342 m/s), considering the great acoustic impedance mismatch between the resin and air. Fig. 1: Symmetry-enforced Dirac points and quad-helicoid topological surface states in a nonsymmorphic phononic crystal. a Schematics of the bcc unit (left panel) of the phononic crystal and its (010) surface (right panel) featured with two glide mirrors G x and G z . b 3D bcc BZ and its (010) surface BZ. The colored spheres highlight the bulk Dirac points with equal frequency and their projections onto the surface BZ. c Bulk bands simulated along several high-symmetry directions. d Schematic of the quad-helicoid surface state dispersions (color surfaces), where the gray cone labels the projection of bulk states. e Surface bands simulated along a circular momentum loop of radius 0.4 π / a (as shown in f ) centered at \\({\\bar{\\mathrm P}}\\) . The shadow regions indicate the projected bulk states. f 3D plot of the surface dispersion simulated in the first quadrant of the surface BZ. Bulk band projections are not shown for clarity Full size image The crosslinked network structure belongs to the nonsymmorphic space group 230 \\((Ia\\bar 3d)\\) , featuring inversion symmetry and multiple screw rotations and glide reflections. The crystal symmetry enables rich point and line degeneracies (see Supplementary Materials). Interestingly, the small group at P and P’, a pair of time-reversal related Brillouin zone (BZ) corners (Fig. 1b ), has 24 group elements and supports only fourfold degeneracy. This finding is confirmed by the band structure in Fig. 1c", "role": "user" }, { "content": "Dirac semimetals are critical states of topologically distinct phases. Such gapless topological states have been accomplished by a band-inversion mechanism, in which the Dirac points can be annihilated pairwise by perturbations without changing the symmetry of the system. Here, scientists in China report an experimental observation of Dirac points that are enforced completely by the crystal symmetry using a nonsymmorphic phononic crystal. Novel topological surface states are demonstrated in their experiments. The discovery of new topological states of matter has become a vital goal in fundamental physics and material science. A three-dimensional (3-D) Dirac semimetal (DSM), accommodating many exotic transport properties such as anomalous magnetoresistance and ultrahigh mobility, is an exceptional platform for exploring topological phase transitions and other novel topological quantum states. It is also of fundamental interest to serve as a solid-state realization of a (3+1)-dimensional Dirac vacuum. So far the realized Dirac points always come in pairs and could be eliminated by their merger and pairwise annihilation through the continuous tuning of parameters that preserve the symmetry of the system. In a new paper published in Light Science & Applications, scientists from the Key Laboratory of Artificial Micro- and Nano-Structures of the Ministry of Education and School of Physics and Technology, Wuhan University, China, we report an experimental realization of a 3-D phononic crystal that hosts symmetry-enforced Dirac points at the Brillouin zone corners. Markedly different from existing DSMs, the occurrence of Dirac points is an unavoidable result of the nonsymmorphic space group of the material, which cannot be removed without changing the crystal symmetry. In addition to the Dirac points identified directly by angle-resolved transmission measurements, highly intricate quad-helicoid surface states are unveiled by our surface measurements and associated Fourier spectra. Specifically, the surface states are composed of four gaplessly crossed spiral branches and thus are strikingly different than the double Fermi arc surface states observed recently in electronic and photonic systems. \"This study may open up new manners for controlling sound, such as realizing unusual sound scattering and radiation, considering the conical dispersion and vanishing density of states around the Dirac points. The dispersion around the Dirac point is isotropic, and thus, our macroscopic system serves as a good platform to simulate relativistic Dirac physics,\" the scientists forecast. ", "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 Dirac semimetals, the materials featuring fourfold degenerate Dirac points, are critical states of topologically distinct phases. Such gapless topological states have been accomplished by a band-inversion mechanism, in which the Dirac points can be annihilated pairwise by perturbations without changing the symmetry of the system. Here, we report an experimental observation of Dirac points that are enforced completely by the crystal symmetry using a nonsymmorphic three-dimensional phononic crystal. Intriguingly, our Dirac phononic crystal hosts four spiral topological surface states, in which the surface states of opposite helicities intersect gaplessly along certain momentum lines, as confirmed by additional surface measurements. The novel Dirac system may release new opportunities for studying elusive (pseudo) and offer a unique prototype platform for acoustic applications. Introduction The discovery of new topological states of matter has become a vital goal in fundamental physics and material science 1 , 2 . A three-dimensional (3D) Dirac semimetal (DSM) 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , accommodating many exotic transport properties such as anomalous magnetoresistance and ultrahigh mobility 14 , 15 , is an exceptional platform for exploring topological phase transitions and other novel topological quantum states. It is also of fundamental interest to serve as a solid-state realization of a (3 + 1)-dimensional Dirac vacuum. A DSM phase may appear accidentally at the quantum transition between normal and topological insulators 16 , 17 . The approach to such a single critical point demands the fine-tuning of the alloy’s chemical composition, which limits the experimental accessibility to the fascinating physics of 3D Dirac fermions. 3D DSMs can also emerge without fine-tuning parameters and are distinguished into two classes 3 , 4 . The first one, already realized in Na 3 Bi 7 , 8 and Cd 3 As 2 9 , 10 , occurs due to band inversion 5 , 6 . The Dirac points, lying on the generic momenta of a specific rotation symmetry axis, always come in pairs and could be eliminated by their merger and pairwise annihilation through the continuous tuning of parameters 3 , 4 that preserve the symmetry of the system. The second class features Dirac points that are pinned stably to discrete high-symmetry points on the surface of the Brillouin zone (BZ). Markedly different from the first class of DSMs, the occurrence of Dirac points is an unavoidable result of the nonsymmorphic space group of the material 11 , 12 , 13 , which cannot be removed without changing the crystal symmetry. Although some solid-state candidate materials have been proposed 4 , 11 , 12 , symmetry-enforced 3D DSMs have never been experimentally realized because of the great challenge in synthesizing materials 4 , 7 . Recently, numerous distinct topological states have been demonstrated in classical wave systems 18 , 19 , such as photonic crystals 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 and phononic crystals 29 , 30 , 31 , 32 , 33 , 34 , which offer opportunities for exploring topological physics in a fully controllable manner. Here, we report an experimental realization of a 3D phononic crystal that hosts symmetry-enforced Dirac points at the BZ corners. The fourfold degeneracy is protected by a nonsymmorphic space group that couples point operations (rotations and mirrors) with nonprimitive lattice translations. In addition to the Dirac points identified directly by angle-resolved transmission measurements, highly intricate quad-helicoid surface states are unveiled by our surface measurements and associated Fourier spectra. Specifically, the surface states are composed of four gaplessly crossed spiral branches 13 and thus are strikingly different than the double Fermi arc surface states observed recently in electronic 8 and photonic systems 28 . Excellent agreement is found between our experiments and simulations. As illustrated in Fig. 1a , our Dirac phononic crystal has a body-centered-cubic (bcc) lattice associated with the lattice constant a = 2.8 cm. The main body of the building block consists of four inequivalent resin cylinders, which are labeled with different colors and oriented along different bcc lattice vector directions. All the cylinders have a regular hexagonal cross section with a side length of 0.42 cm. To facilitate sample fabrication, these cylinders are connected with short hexagonal bars with side lengths of 0.21 cm. The remainder of the volume is filled with air. Numerically, the photosensitive resin material used for printing the acoustic structure is treated as rigid, and sound propagates only in air (at speed 342 m/s), considering the great acoustic impedance mismatch between the resin and air. Fig. 1: Symmetry-enforced Dirac points and quad-helicoid topological surface states in a nonsymmorphic phononic crystal. a Schematics of the bcc unit (left panel) of the phononic crystal and its (010) surface (right panel) featured with two glide mirrors G x and G z . b 3D bcc BZ and its (010) surface BZ. The colored spheres highlight the bulk Dirac points with equal frequency and their projections onto the surface BZ. c Bulk bands simulated along several high-symmetry directions. d Schematic of the quad-helicoid surface state dispersions (color surfaces), where the gray cone labels the projection of bulk states. e Surface bands simulated along a circular momentum loop of radius 0.4 π / a (as shown in f ) centered at \({\bar{\mathrm P}}\) . The shadow regions indicate the projected bulk states. f 3D plot of the surface dispersion simulated in the first quadrant of the surface BZ. Bulk band projections are not shown for clarity Full size image The crosslinked network structure belongs to the nonsymmorphic space group 230 \((Ia\bar 3d)\) , featuring inversion symmetry and multiple screw rotations and glide reflections. The crystal symmetry enables rich point and line degeneracies (see Supplementary Materials). Interestingly, the small group at P and P’, a pair of time-reversal related Brillouin zone (BZ) corners (Fig. 1b ), has 24 group elements and supports only fourfold degeneracy. This finding is confirmed by the band structure in Fig. 1c<|im_end|> <|im_start|>assistant Dirac semimetals are critical states of topologically distinct phases. Such gapless topological states have been accomplished by a band-inversion mechanism, in which the Dirac points can be annihilated pairwise by perturbations without changing the symmetry of the system. Here, scientists in China report an experimental observation of Dirac points that are enforced completely by the crystal symmetry using a nonsymmorphic phononic crystal. Novel topological surface states are demonstrated in their experiments. The discovery of new topological states of matter has become a vital goal in fundamental physics and material science. A three-dimensional (3-D) Dirac semimetal (DSM), accommodating many exotic transport properties such as anomalous magnetoresistance and ultrahigh mobility, is an exceptional platform for exploring topological phase transitions and other novel topological quantum states. It is also of fundamental interest to serve as a solid-state realization of a (3+1)-dimensional Dirac vacuum. So far the realized Dirac points always come in pairs and could be eliminated by their merger and pairwise annihilation through the continuous tuning of parameters that preserve the symmetry of the system. In a new paper published in Light Science & Applications, scientists from the Key Laboratory of Artificial Micro- and Nano-Structures of the Ministry of Education and School of Physics and Technology, Wuhan University, China, we report an experimental realization of a 3-D phononic crystal that hosts symmetry-enforced Dirac points at the Brillouin zone corners. Markedly different from existing DSMs, the occurrence of Dirac points is an unavoidable result of the nonsymmorphic space group of the material, which cannot be removed without changing the crystal symmetry. In addition to the Dirac points identified directly by angle-resolved transmission measurements, highly intricate quad-helicoid surface states are unveiled by our surface measurements and associated Fourier spectra. Specifically, the surface states are composed of four gaplessly crossed spiral branches and thus are strikingly different than the double Fermi arc surface states observed recently in electronic and photonic systems. "This study may open up new manners for controlling sound, such as realizing unusual sound scattering and radiation, considering the conical dispersion and vanishing density of states around the Dirac points. The dispersion around the Dirac point is isotropic, and thus, our macroscopic system serves as a good platform to simulate relativistic Dirac physics," the scientists forecast. <|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 Stomata are orifices that connect the drier atmosphere with the interconnected network of more humid air spaces that surround the cells within a leaf. Accurate values of the humidities inside the substomatal cavity, w i , and in the air, w a , are needed to estimate stomatal conductance and the CO 2 concentration in the internal air spaces of leaves. Both are vital factors in the understanding of plant physiology and climate, ecological and crop systems. However, there is no easy way to measure w i directly. Out of necessity, w i has been taken as the saturation water vapour concentration at leaf temperature, w sat , and applied to the whole leaf intercellular air spaces. We explored the occurrence of unsaturation by examining gas exchange of leaves exposed to various magnitudes of w sat − w a , or Δ w , using a double-sided, clamp-on chamber, and estimated degrees of unsaturation from the gradient of CO 2 across the leaf that was required to sustain the rate of CO 2 assimilation through the upper surface. The relative humidity in the substomatal cavities dropped to about 97% under mild Δ w and as dry as around 80% when Δ w was large. Measurements of the diffusion of noble gases across the leaf indicated that there were still regions of near 100% humidity distal from the stomatal pores. We suggest that as Δ w increases, the saturation edge retreats into the intercellular air spaces, accompanied by the progressive closure of mesophyll aquaporins to maintain the cytosolic water potential. Main The question of whether the internal spaces of a leaf can become undersaturated under high evaporative conditions has remained unresolved for decades. In such a situation, the transpiration rate has to be reduced by mechanisms other than stomatal closure. Jarvis and Slatyer 1 discussed mechanisms proposed to account for non-stomatal control of transpiration, should it occur. The preferred option was “incipient drying” 2 —the retreat of evaporation sites into the mesophyll cell walls, relying on increasingly smaller pore throats and the Kelvin effect. Jarvis and Slatyer 1 measured the resistances to the diffusion of nitrous oxide introduced to one side of a cotton leaf and compared them with the corresponding water vapour resistances of the same leaf, and suggested that relative humidity (RH) inside the leaf could be as low as 70%. This RH would require a water potential of the liquid water of −49 MPa, but most plants lose turgor at −2 to −5 MPa and reach a lethal leaf water potential not much after the turgor loss point. These researchers expressed the reduction in humidity as the product of the transpiration flux and a “wall resistance” but gave no explanation of the resistance. In contrast, Farquhar and Raschke 3 performed a similar experiment with cotton and other species using helium but saw no evidence of a resistance to transpiration within the leaves, suggesting that the humidity inside the substomatal cavity, w i , was near saturation and the water potential was close to zero. Egorov and Karpushkin 4 measured transpiration rates in air and in mixtures of helium and oxygen and concluded that the intercellular RH could be 90% to 85%. Canny and Huang 5 collected Eucalyptus pauciflora leaf discs at midday during late summer and concluded that intercellular RH could be as low as 90%. If the substomatal cavities are unsaturated, then in the standard gas exchange calculations 6 , 7 , the estimation of critical values such as apparent leaf conductance to water vapour, g , and the CO 2 concentration in substomatal cavities, c i , would give lower values than the true ones. In 2008, we found gradients of c i in several species that seemed to be incompatible with the 100% RH assumption of the gas exchange calculations. This led to further efforts over subsequent years to corroborate these results. As a consequence, Cernusak et al. 8 measured the oxygen isotope composition of transpiration and CO 2 assimilation and concluded that water-stressed conifers were experiencing intercellular RH as low as 80%. This was followed by the examination, using the same isotopic techniques, of wild-type Populus leaves as well as a transgenic variety insensitive to abscisic acid that fails to close stomata at high transpiration rates. As humidity decreased, the abscisic-acid-insensitive plants lost saturation 9 . Holloway-Phillips et al. 10 used a two-source method of contrasting oxygen isotopic composition and similarly found that in some cases intercellular RH appeared less than 100%. Despite these recent findings, there has been considerable scepticism 11 because of the lack of a known mechanism 12 to enforce the very low water potentials required to sustain unsaturation in the intercellular mesophyll air space. Theory For evaporation to occur, there will be a water vapour concentration gradient from the sites of evaporation through the stomatal pores to the ambient air. The question becomes: at what depth in the interior of the leaf is the air space saturated? The need for humidity gradients within the substomatal cavity to support vapour flux to the stomatal pore implies that where the saturation water vapour concentration at leaf temperature, w sat , is found depends on the stomatal aperture and the difference between w sat and the humidity in the air ( w a ), Δ w . However, it is reasonable to assume that under low Δ w (for example, Δ w < 8 mmol mol −1 ), the saturation edge is a surface around the entry of the stomatal pore within the leaf. We will refer to this surface as the saturation front ( w sat ). Thus, under a low Δ w , we assume that the whole intercellular air space is saturated so that w i = w sat (Fig. 1a ). In this condition, we assume that the pathway for water vapour and CO 2 between w sat and the atmosphere over the leaf surface ( w s ) is the same 13 , through the stomatal pore", "role": "user" }, { "content": "Scientists from The Australian National University (ANU) and James Cook University (JCU) have identified an \"exquisite\" natural mechanism that helps plants limit their water loss with little effect on carbon dioxide (CO2) intake—an essential process for photosynthesis, plant growth and crop yield. The discovery, led by Dr. Chin Wong from ANU, is expected to help agricultural scientists and plant breeders develop more water-efficient crops. Study co-author Dr. Diego Marquez from ANU said the findings will have significant implications for the agricultural industry and could lead to more resilient crops that are capable of withstanding extreme weather events, including drought. \"Plants continuously lose water through pores in the 'skin' of their leaves. These same pores allow CO2 to enter the leaves and are critical to their survival,\" Dr. Marquez said. \"For every unit of CO2 gained, plants typically lose hundreds of units of water. This is why plants require a lot of water in order to grow and survive. \"The mechanism we have demonstrated is activated when the environment is dry, such as on a hot summer day, to allow the plant to reduce water loss with little effect on CO2 uptake.\" The researchers believe this water preserving mechanism can be manipulated and, in turn, may hold the key to breeding more water-efficient crops. According to lead author Dr. Wong, the ANU team's findings are a \"dream discovery\" from a scientific and agricultural perspective. \"The agriculture industry has long held high hopes for scientists to come up with a way to deliver highly productive crops that use water efficiently,\" Dr. Wong said. \"Plant scientists have been dealing with this big question of how to increase CO2 uptake and reduce water loss without negatively affecting yields. \"Having this mechanism that can reduce water loss with little effect on CO2 uptake presents an opportunity for agricultural scientists and plant breeders researching ways to improve water use efficiency and create drought-tolerant crops.\" Although the researchers have confirmed there is a system in place that is working to limit the amount of water being lost from the leaf, they still don't know what's causing it. \"Our main target now is to identify the structures inside the plant that allow this control. We think that water conduits, called aquaporins, located in the cell membranes are responsible,\" Dr. Marquez said. \"Once we're able to confirm this, we can then start thinking about how we can manipulate these systems and turn them into an asset for the agricultural industry.\" Co-author Distinguished Professor Graham Farquhar from ANU said: \"Finding the mechanism itself was one step, a big one, but there is still work to do to translate this discovery into the industry. \"We expect that both government and industry will see the value of contributing funds to achieve this goal.\" Dr. Wong first alluded to this water preserving mechanism 14 years ago, but the research team has only now been able to officially confirm its existence thanks to years of experimentation and corroboration of their results. The research is published in Nature Plants. ", "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 Stomata are orifices that connect the drier atmosphere with the interconnected network of more humid air spaces that surround the cells within a leaf. Accurate values of the humidities inside the substomatal cavity, w i , and in the air, w a , are needed to estimate stomatal conductance and the CO 2 concentration in the internal air spaces of leaves. Both are vital factors in the understanding of plant physiology and climate, ecological and crop systems. However, there is no easy way to measure w i directly. Out of necessity, w i has been taken as the saturation water vapour concentration at leaf temperature, w sat , and applied to the whole leaf intercellular air spaces. We explored the occurrence of unsaturation by examining gas exchange of leaves exposed to various magnitudes of w sat − w a , or Δ w , using a double-sided, clamp-on chamber, and estimated degrees of unsaturation from the gradient of CO 2 across the leaf that was required to sustain the rate of CO 2 assimilation through the upper surface. The relative humidity in the substomatal cavities dropped to about 97% under mild Δ w and as dry as around 80% when Δ w was large. Measurements of the diffusion of noble gases across the leaf indicated that there were still regions of near 100% humidity distal from the stomatal pores. We suggest that as Δ w increases, the saturation edge retreats into the intercellular air spaces, accompanied by the progressive closure of mesophyll aquaporins to maintain the cytosolic water potential. Main The question of whether the internal spaces of a leaf can become undersaturated under high evaporative conditions has remained unresolved for decades. In such a situation, the transpiration rate has to be reduced by mechanisms other than stomatal closure. Jarvis and Slatyer 1 discussed mechanisms proposed to account for non-stomatal control of transpiration, should it occur. The preferred option was “incipient drying” 2 —the retreat of evaporation sites into the mesophyll cell walls, relying on increasingly smaller pore throats and the Kelvin effect. Jarvis and Slatyer 1 measured the resistances to the diffusion of nitrous oxide introduced to one side of a cotton leaf and compared them with the corresponding water vapour resistances of the same leaf, and suggested that relative humidity (RH) inside the leaf could be as low as 70%. This RH would require a water potential of the liquid water of −49 MPa, but most plants lose turgor at −2 to −5 MPa and reach a lethal leaf water potential not much after the turgor loss point. These researchers expressed the reduction in humidity as the product of the transpiration flux and a “wall resistance” but gave no explanation of the resistance. In contrast, Farquhar and Raschke 3 performed a similar experiment with cotton and other species using helium but saw no evidence of a resistance to transpiration within the leaves, suggesting that the humidity inside the substomatal cavity, w i , was near saturation and the water potential was close to zero. Egorov and Karpushkin 4 measured transpiration rates in air and in mixtures of helium and oxygen and concluded that the intercellular RH could be 90% to 85%. Canny and Huang 5 collected Eucalyptus pauciflora leaf discs at midday during late summer and concluded that intercellular RH could be as low as 90%. If the substomatal cavities are unsaturated, then in the standard gas exchange calculations 6 , 7 , the estimation of critical values such as apparent leaf conductance to water vapour, g , and the CO 2 concentration in substomatal cavities, c i , would give lower values than the true ones. In 2008, we found gradients of c i in several species that seemed to be incompatible with the 100% RH assumption of the gas exchange calculations. This led to further efforts over subsequent years to corroborate these results. As a consequence, Cernusak et al. 8 measured the oxygen isotope composition of transpiration and CO 2 assimilation and concluded that water-stressed conifers were experiencing intercellular RH as low as 80%. This was followed by the examination, using the same isotopic techniques, of wild-type Populus leaves as well as a transgenic variety insensitive to abscisic acid that fails to close stomata at high transpiration rates. As humidity decreased, the abscisic-acid-insensitive plants lost saturation 9 . Holloway-Phillips et al. 10 used a two-source method of contrasting oxygen isotopic composition and similarly found that in some cases intercellular RH appeared less than 100%. Despite these recent findings, there has been considerable scepticism 11 because of the lack of a known mechanism 12 to enforce the very low water potentials required to sustain unsaturation in the intercellular mesophyll air space. Theory For evaporation to occur, there will be a water vapour concentration gradient from the sites of evaporation through the stomatal pores to the ambient air. The question becomes: at what depth in the interior of the leaf is the air space saturated? The need for humidity gradients within the substomatal cavity to support vapour flux to the stomatal pore implies that where the saturation water vapour concentration at leaf temperature, w sat , is found depends on the stomatal aperture and the difference between w sat and the humidity in the air ( w a ), Δ w . However, it is reasonable to assume that under low Δ w (for example, Δ w < 8 mmol mol −1 ), the saturation edge is a surface around the entry of the stomatal pore within the leaf. We will refer to this surface as the saturation front ( w sat ). Thus, under a low Δ w , we assume that the whole intercellular air space is saturated so that w i = w sat (Fig. 1a ). In this condition, we assume that the pathway for water vapour and CO 2 between w sat and the atmosphere over the leaf surface ( w s ) is the same 13 , through the stomatal pore<|im_end|> <|im_start|>assistant Scientists from The Australian National University (ANU) and James Cook University (JCU) have identified an "exquisite" natural mechanism that helps plants limit their water loss with little effect on carbon dioxide (CO2) intake—an essential process for photosynthesis, plant growth and crop yield. The discovery, led by Dr. Chin Wong from ANU, is expected to help agricultural scientists and plant breeders develop more water-efficient crops. Study co-author Dr. Diego Marquez from ANU said the findings will have significant implications for the agricultural industry and could lead to more resilient crops that are capable of withstanding extreme weather events, including drought. "Plants continuously lose water through pores in the 'skin' of their leaves. These same pores allow CO2 to enter the leaves and are critical to their survival," Dr. Marquez said. "For every unit of CO2 gained, plants typically lose hundreds of units of water. This is why plants require a lot of water in order to grow and survive. "The mechanism we have demonstrated is activated when the environment is dry, such as on a hot summer day, to allow the plant to reduce water loss with little effect on CO2 uptake." The researchers believe this water preserving mechanism can be manipulated and, in turn, may hold the key to breeding more water-efficient crops. According to lead author Dr. Wong, the ANU team's findings are a "dream discovery" from a scientific and agricultural perspective. "The agriculture industry has long held high hopes for scientists to come up with a way to deliver highly productive crops that use water efficiently," Dr. Wong said. "Plant scientists have been dealing with this big question of how to increase CO2 uptake and reduce water loss without negatively affecting yields. "Having this mechanism that can reduce water loss with little effect on CO2 uptake presents an opportunity for agricultural scientists and plant breeders researching ways to improve water use efficiency and create drought-tolerant crops." Although the researchers have confirmed there is a system in place that is working to limit the amount of water being lost from the leaf, they still don't know what's causing it. "Our main target now is to identify the structures inside the plant that allow this control. We think that water conduits, called aquaporins, located in the cell membranes are responsible," Dr. Marquez said. "Once we're able to confirm this, we can then start thinking about how we can manipulate these systems and turn them into an asset for the agricultural industry." Co-author Distinguished Professor Graham Farquhar from ANU said: "Finding the mechanism itself was one step, a big one, but there is still work to do to translate this discovery into the industry. "We expect that both government and industry will see the value of contributing funds to achieve this goal." Dr. Wong first alluded to this water preserving mechanism 14 years ago, but the research team has only now been able to officially confirm its existence thanks to years of experimentation and corroboration of their results. The research is published in Nature Plants. <|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 Two-dimensional crystals with angstrom-scale pores are widely considered as candidates for a next generation of molecular separation technologies aiming to provide extreme, exponentially large selectivity combined with high flow rates. No such pores have been demonstrated experimentally. Here we study gas transport through individual graphene pores created by low intensity exposure to low kV electrons. Helium and hydrogen permeate easily through these pores whereas larger species such as xenon and methane are practically blocked. Permeating gases experience activation barriers that increase quadratically with molecules’ kinetic diameter, and the effective diameter of the created pores is estimated as ∼ 2 angstroms, about one missing carbon ring. Our work reveals stringent conditions for achieving the long sought-after exponential selectivity using porous two-dimensional membranes and suggests limits on their possible performance. Introduction Two-dimensional (2D) membranes with a high density of angstrom-scale pores can be made by engineering defects in 2D crystals 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 or, perhaps more realistically in terms of applications, by growing intrinsically porous crystals such as, e.g., graphynes 10 , 11 , 12 . Interest in angstroporous 2D materials is strongly stimulated by potential applications, particularly for gas separation as an alternative to polymeric membranes employed by industry 3 , 13 . On one hand, the atomic thickness of 2D materials implies a relatively high permeability as compared to traditional 3D membranes. On the other hand, angstrom-scale pores with effective sizes d P smaller than the kinetic diameter d K of molecules should pose substantial barriers for their translocation, which is predicted to result in colossal selectivities S > 10 10 , even for gases with fractionally ( ∼ 25%) different d K such as, for example, H 2 and CH 4 1 , 14 , 15 . This unique combination of material properties holds a promise of better selectivity-permeability tradeoffs than those possible by conventional membranes 3 , 13 . At present, this optimistic assessment is based mostly on theoretical modeling. Experimental clarity has so far been achieved only for the classical regime of d P > d K where the flow is governed by the Knudsen equation, and the resulting modest selectivities arise from differences in thermal velocities of gases having different molecular masses m 7 , 8 , 9 , 16 . For smaller pores with d P ≈ d K , S up to 10–100 have been reported for monolayer graphene 5 , 8 , and even higher selectivities ( ∼ 10 4 ) were found for some defects with an estimated diameter of ∼ 3.5 Å in bilayer graphene 4 . Still, this is many orders of magnitude smaller than S predicted for the activated-transport regime, d P < d K 1 , 14 , 15 . Little remains known about the latter regime, which has proven to be extremely difficult to reach in experiment 5 , 8 , 9 . Indeed, even monovacancies in dichalcogenide monolayers were suggested to exhibit the conventional Knudsen flow 9 . The experimental difficulties and lack of understanding are further exacerbated by prohibitive computational costs of simulating molecular permeation in the activated regime 17 , 18 , 19 , 20 . In this work, we achieve the activated regime by creating individual angstrom-scale pores in monolayer graphene by its short exposure to a low-energy electron beam. Gas permeation measurements reveal exponentially large selectivities with activation barriers that depend quadratically on gas molecules’ kinetic diameter. Results Experimental devices Our devices were micrometer-size cavities sealed with monolayer graphene (Fig. 1a ). The microcavities were fabricated from graphite monocrystals, using lithography and dry etching, and had internal diameters of 1–3 μm and depth of ∼ 100 nm (“Methods”). Large, exfoliated graphene crystals were then transferred in air on top of the microcavities, creating “atomically tight” sealing 21 . The sealing was tested by placing the devices into a He atmosphere and monitoring changes in graphene membrane’s position by atomic force microscopy (AFM) (Fig. 1b ). We selected only the devices that were completely impermeable to He (“Methods”; ref. 21 ). Next, the He-tight membranes were subjected to electron radiation using a scanning electron microscope. The accelerating voltage was chosen to be ≤10 kV, and the beam current was set at 10 pA. In a single exposure lasting 3–5 s and using magnification of 700, an area of ~150 × 150 μm 2 was radiated, which translated into an electron dose of 0.1–0.2 μC cm −2 or only ∼ 1 electron per 100 nm 2 . After the exposure, the devices were He-leak tested again. The procedure was repeated several times, until a leak appeared indicating a damage induced by electrons (Fig. 1c ). Fig. 1: Creating defects in suspended graphene. a Schematic of our devices. Left: Monolayer graphene sealing a microcavity was bombarded with electrons. Initially, the membrane sagged inside the cavity due to adhesion to the side walls 4 , 5 , 21 . Right: After pressurization, defected membranes bulged out. b AFM images of the same device before (left) and after (right) its exposure to 10 keV electrons; dose of 0.5 μC cm −2 . Both images were taken after storing the device in Kr at 3 bar for 10 days. The white curves are height profiles along the membrane diameter 21 . σ is the membrane’s central position measured with respect to graphite’s top surface. The gray scale is given by σ ≈ −15 and +24 nm in the left and right images, respectively. c Examples of σ as a function of radiation dose and acceleration voltage. Each point is taken after pressurizing the devices in 3-bar Kr. Dashed lines: guides to the eye; short black lines: σ = 0. d σ ( t ) for a device with the medium-size pore denoted as type 2, after pressurizing it with various gases (color coded). Solid curves: best linear fits. Inset: representative height profiles for a deflating device with Ar inside. Full size image Number", "role": "user" }, { "content": "By crafting atomic-scale holes in atomically thin membranes, it should be possible to create molecular sieves for precise and efficient gas separation, including extraction of carbon dioxide from air, University of Manchester researchers have found. If a pore size in a membrane is comparable to the size of atoms and molecules, they can either pass through the membrane or be rejected, allowing separation of gases according to their molecular diameters. Industrial gas separation technologies widely use this principle, often relying on polymer membranes with different porosity. There is always a trade-off between the accuracy of separation and its efficiency: the finer you adjust the pore sizes, the less gas flow such sieves allow. It has long been speculated that, using two-dimensional membranes similar in thickness to graphene, one can reach much better trade-offs than currently achievable because, unlike conventional membranes, atomically thin ones should allow easier gas flows for the same selectivity. Now a research team led by Professor Sir Andre Geim at The University of Manchester, in collaboration with scientists from Belgium and China, have used low-energy electrons to punch individual atomic-scale holes in suspended graphene. The holes came in sizes down to about two angstroms, smaller than even the smallest atoms such as helium and hydrogen. In December's issue of Nature Communications, the researchers report that they achieved practically perfect selectivity (better than 99.9%) for such gases as helium or hydrogen with respect to nitrogen, methane or xenon. Also, air molecules (oxygen and nitrogen) pass through the pores easily relative to carbon dioxide, which is >95% captured. The scientists point out that to make two-dimensional membranes practical, it is essential to find atomically thin materials with intrinsic pores, that is, pores within the crystal lattice itself. \"Precision sieves for gases are certainly possible and, in fact, they are conceptually not dissimilar to those used to sieve sand and granular materials. However, to make this technology industrially relevant, we need membranes with densely spaced pores, not individual holes created in our study to prove the concept for the first time. Only then are the high flows required for industrial gas separation achievable,\" says Dr. Pengzhan Sun, a lead author of the paper. The research team now plans to search for such two-dimensional materials with large intrinsic pores to find those most promising for future gas separation technologies. Such materials do exist. For example, there are various graphynes, which are also atomically thin allotropes of carbon but not yet manufactured at scale. These look like graphene but have larger carbon rings, similar in size to the individual defects created and studied by the Manchester researchers. The right size may make graphynes perfectly suited for gas separation. ", "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-dimensional crystals with angstrom-scale pores are widely considered as candidates for a next generation of molecular separation technologies aiming to provide extreme, exponentially large selectivity combined with high flow rates. No such pores have been demonstrated experimentally. Here we study gas transport through individual graphene pores created by low intensity exposure to low kV electrons. Helium and hydrogen permeate easily through these pores whereas larger species such as xenon and methane are practically blocked. Permeating gases experience activation barriers that increase quadratically with molecules’ kinetic diameter, and the effective diameter of the created pores is estimated as ∼ 2 angstroms, about one missing carbon ring. Our work reveals stringent conditions for achieving the long sought-after exponential selectivity using porous two-dimensional membranes and suggests limits on their possible performance. Introduction Two-dimensional (2D) membranes with a high density of angstrom-scale pores can be made by engineering defects in 2D crystals 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 or, perhaps more realistically in terms of applications, by growing intrinsically porous crystals such as, e.g., graphynes 10 , 11 , 12 . Interest in angstroporous 2D materials is strongly stimulated by potential applications, particularly for gas separation as an alternative to polymeric membranes employed by industry 3 , 13 . On one hand, the atomic thickness of 2D materials implies a relatively high permeability as compared to traditional 3D membranes. On the other hand, angstrom-scale pores with effective sizes d P smaller than the kinetic diameter d K of molecules should pose substantial barriers for their translocation, which is predicted to result in colossal selectivities S > 10 10 , even for gases with fractionally ( ∼ 25%) different d K such as, for example, H 2 and CH 4 1 , 14 , 15 . This unique combination of material properties holds a promise of better selectivity-permeability tradeoffs than those possible by conventional membranes 3 , 13 . At present, this optimistic assessment is based mostly on theoretical modeling. Experimental clarity has so far been achieved only for the classical regime of d P > d K where the flow is governed by the Knudsen equation, and the resulting modest selectivities arise from differences in thermal velocities of gases having different molecular masses m 7 , 8 , 9 , 16 . For smaller pores with d P ≈ d K , S up to 10–100 have been reported for monolayer graphene 5 , 8 , and even higher selectivities ( ∼ 10 4 ) were found for some defects with an estimated diameter of ∼ 3.5 Å in bilayer graphene 4 . Still, this is many orders of magnitude smaller than S predicted for the activated-transport regime, d P < d K 1 , 14 , 15 . Little remains known about the latter regime, which has proven to be extremely difficult to reach in experiment 5 , 8 , 9 . Indeed, even monovacancies in dichalcogenide monolayers were suggested to exhibit the conventional Knudsen flow 9 . The experimental difficulties and lack of understanding are further exacerbated by prohibitive computational costs of simulating molecular permeation in the activated regime 17 , 18 , 19 , 20 . In this work, we achieve the activated regime by creating individual angstrom-scale pores in monolayer graphene by its short exposure to a low-energy electron beam. Gas permeation measurements reveal exponentially large selectivities with activation barriers that depend quadratically on gas molecules’ kinetic diameter. Results Experimental devices Our devices were micrometer-size cavities sealed with monolayer graphene (Fig. 1a ). The microcavities were fabricated from graphite monocrystals, using lithography and dry etching, and had internal diameters of 1–3 μm and depth of ∼ 100 nm (“Methods”). Large, exfoliated graphene crystals were then transferred in air on top of the microcavities, creating “atomically tight” sealing 21 . The sealing was tested by placing the devices into a He atmosphere and monitoring changes in graphene membrane’s position by atomic force microscopy (AFM) (Fig. 1b ). We selected only the devices that were completely impermeable to He (“Methods”; ref. 21 ). Next, the He-tight membranes were subjected to electron radiation using a scanning electron microscope. The accelerating voltage was chosen to be ≤10 kV, and the beam current was set at 10 pA. In a single exposure lasting 3–5 s and using magnification of 700, an area of ~150 × 150 μm 2 was radiated, which translated into an electron dose of 0.1–0.2 μC cm −2 or only ∼ 1 electron per 100 nm 2 . After the exposure, the devices were He-leak tested again. The procedure was repeated several times, until a leak appeared indicating a damage induced by electrons (Fig. 1c ). Fig. 1: Creating defects in suspended graphene. a Schematic of our devices. Left: Monolayer graphene sealing a microcavity was bombarded with electrons. Initially, the membrane sagged inside the cavity due to adhesion to the side walls 4 , 5 , 21 . Right: After pressurization, defected membranes bulged out. b AFM images of the same device before (left) and after (right) its exposure to 10 keV electrons; dose of 0.5 μC cm −2 . Both images were taken after storing the device in Kr at 3 bar for 10 days. The white curves are height profiles along the membrane diameter 21 . σ is the membrane’s central position measured with respect to graphite’s top surface. The gray scale is given by σ ≈ −15 and +24 nm in the left and right images, respectively. c Examples of σ as a function of radiation dose and acceleration voltage. Each point is taken after pressurizing the devices in 3-bar Kr. Dashed lines: guides to the eye; short black lines: σ = 0. d σ ( t ) for a device with the medium-size pore denoted as type 2, after pressurizing it with various gases (color coded). Solid curves: best linear fits. Inset: representative height profiles for a deflating device with Ar inside. Full size image Number<|im_end|> <|im_start|>assistant By crafting atomic-scale holes in atomically thin membranes, it should be possible to create molecular sieves for precise and efficient gas separation, including extraction of carbon dioxide from air, University of Manchester researchers have found. If a pore size in a membrane is comparable to the size of atoms and molecules, they can either pass through the membrane or be rejected, allowing separation of gases according to their molecular diameters. Industrial gas separation technologies widely use this principle, often relying on polymer membranes with different porosity. There is always a trade-off between the accuracy of separation and its efficiency: the finer you adjust the pore sizes, the less gas flow such sieves allow. It has long been speculated that, using two-dimensional membranes similar in thickness to graphene, one can reach much better trade-offs than currently achievable because, unlike conventional membranes, atomically thin ones should allow easier gas flows for the same selectivity. Now a research team led by Professor Sir Andre Geim at The University of Manchester, in collaboration with scientists from Belgium and China, have used low-energy electrons to punch individual atomic-scale holes in suspended graphene. The holes came in sizes down to about two angstroms, smaller than even the smallest atoms such as helium and hydrogen. In December's issue of Nature Communications, the researchers report that they achieved practically perfect selectivity (better than 99.9%) for such gases as helium or hydrogen with respect to nitrogen, methane or xenon. Also, air molecules (oxygen and nitrogen) pass through the pores easily relative to carbon dioxide, which is >95% captured. The scientists point out that to make two-dimensional membranes practical, it is essential to find atomically thin materials with intrinsic pores, that is, pores within the crystal lattice itself. "Precision sieves for gases are certainly possible and, in fact, they are conceptually not dissimilar to those used to sieve sand and granular materials. However, to make this technology industrially relevant, we need membranes with densely spaced pores, not individual holes created in our study to prove the concept for the first time. Only then are the high flows required for industrial gas separation achievable," says Dr. Pengzhan Sun, a lead author of the paper. The research team now plans to search for such two-dimensional materials with large intrinsic pores to find those most promising for future gas separation technologies. Such materials do exist. For example, there are various graphynes, which are also atomically thin allotropes of carbon but not yet manufactured at scale. These look like graphene but have larger carbon rings, similar in size to the individual defects created and studied by the Manchester researchers. The right size may make graphynes perfectly suited for gas separation. <|im_end|>
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10508, 863, 66934, 220, 1691, 662, 578, 66934, 574, 12793, 555, 25012, 279, 7766, 1139, 264, 1283, 16975, 323, 16967, 4442, 304, 66192, 39654, 753, 2361, 555, 25524, 5457, 92914, 320, 8440, 44, 8, 320, 30035, 13, 220, 16, 65, 7609, 1226, 4183, 1193, 279, 7766, 430, 1051, 6724, 17190, 2727, 481, 311, 1283, 27179, 18337, 66545, 2098, 13, 220, 1691, 7609, 9479, 11, 279, 1283, 2442, 492, 79348, 1051, 38126, 311, 17130, 25407, 1701, 264, 36201, 17130, 73757, 13, 578, 69741, 22465, 574, 12146, 311, 387, 38394, 605, 597, 53, 11, 323, 279, 24310, 1510, 574, 743, 520, 220, 605, 281, 32, 13, 763, 264, 3254, 14675, 29869, 220, 18, 4235, 20, 274, 323, 1701, 8622, 2461, 315, 220, 7007, 11, 459, 3158, 315, 4056, 3965, 25800, 220, 3965, 33983, 76, 220, 17, 574, 12164, 660, 11, 902, 25548, 1139, 459, 17130, 19660, 315, 220, 15, 13, 16, 4235, 15, 13, 17, 33983, 34, 10166, 25173, 17, 477, 1193, 12264, 120, 220, 16, 17130, 824, 220, 1041, 26807, 220, 17, 662, 4740, 279, 14675, 11, 279, 7766, 1051, 1283, 31307, 587, 12793, 1578, 13, 578, 10537, 574, 11763, 3892, 3115, 11, 3156, 264, 24237, 9922, 19392, 264, 5674, 36572, 555, 57678, 320, 30035, 13, 220, 16, 66, 7609, 23966, 13, 220, 16, 25, 32406, 42655, 304, 22340, 66192, 13, 264, 328, 82149, 315, 1057, 7766, 13, 14043, 25, 3206, 337, 1155, 66192, 66934, 264, 8162, 66, 11980, 574, 13054, 21632, 449, 57678, 13, 59656, 11, 279, 39654, 30811, 3640, 4871, 279, 56429, 4245, 311, 1008, 59738, 311, 279, 3185, 14620, 220, 19, 1174, 220, 20, 1174, 220, 1691, 662, 10291, 25, 4740, 3577, 324, 2065, 11, 711, 1599, 79348, 7173, 3640, 704, 13, 293, 20479, 44, 5448, 315, 279, 1890, 3756, 1603, 320, 2414, 8, 323, 1306, 320, 1315, 8, 1202, 14675, 311, 220, 605, 2004, 53, 57678, 26, 19660, 315, 220, 15, 13, 20, 33983, 34, 10166, 25173, 17, 662, 11995, 5448, 1051, 4529, 1306, 28672, 279, 3756, 304, 16852, 520, 220, 18, 3703, 369, 220, 605, 2919, 13, 578, 4251, 37033, 527, 2673, 21542, 3235, 279, 39654, 23899, 220, 1691, 662, 48823, 374, 279, 39654, 753, 8792, 2361, 17303, 449, 5201, 311, 95273, 753, 1948, 7479, 13, 578, 18004, 5569, 374, 2728, 555, 48823, 118792, 25173, 868, 323, 489, 1187, 26807, 304, 279, 2163, 323, 1314, 5448, 11, 15947, 13, 272, 26379, 315, 48823, 439, 264, 734, 315, 25407, 19660, 323, 31903, 22465, 13, 9062, 1486, 374, 4529, 1306, 3577, 324, 4954, 279, 7766, 304, 220, 18, 16150, 16852, 13, 423, 13883, 5238, 25, 28292, 311, 279, 8071, 26, 2875, 3776, 5238, 25, 48823, 284, 220, 15, 13, 294, 48823, 320, 259, 883, 369, 264, 3756, 449, 279, 11298, 7321, 97551, 3453, 9437, 439, 955, 220, 17, 11, 1306, 3577, 324, 4954, 433, 449, 5370, 45612, 320, 3506, 47773, 570, 22925, 37033, 25, 1888, 13790, 18809, 13, 763, 751, 25, 18740, 2673, 21542, 369, 264, 711, 75, 1113, 3756, 449, 1676, 4871, 13, 8797, 1404, 2217, 5742, 128257, 198, 128256, 78191, 198, 1383, 45167, 25524, 13230, 20349, 304, 19670, 2740, 15792, 79348, 11, 433, 1288, 387, 3284, 311, 1893, 31206, 10112, 2396, 369, 24473, 323, 11297, 6962, 25768, 11, 2737, 33289, 315, 12782, 40589, 505, 3805, 11, 3907, 315, 19922, 12074, 617, 1766, 13, 1442, 264, 97551, 1404, 304, 264, 39654, 374, 30139, 311, 279, 1404, 315, 33299, 323, 35715, 11, 814, 649, 3060, 1522, 1555, 279, 39654, 477, 387, 18010, 11, 10923, 25768, 315, 45612, 4184, 311, 872, 31206, 13047, 2481, 13, 25563, 6962, 25768, 14645, 13882, 1005, 420, 17966, 11, 3629, 39661, 389, 47393, 79348, 449, 2204, 4247, 22828, 13, 2684, 374, 2744, 264, 6696, 12744, 1990, 279, 13708, 315, 25768, 323, 1202, 15374, 25, 279, 73886, 499, 7652, 279, 97551, 12562, 11, 279, 2753, 6962, 6530, 1778, 10112, 2396, 2187, 13, 1102, 706, 1317, 1027, 74877, 430, 11, 1701, 1403, 33520, 79348, 4528, 304, 26839, 311, 66192, 11, 832, 649, 5662, 1790, 2731, 6696, 65039, 1109, 5131, 89253, 1606, 11, 20426, 21349, 79348, 11, 19670, 2740, 15792, 6305, 1288, 2187, 8831, 6962, 28555, 369, 279, 1890, 3373, 1968, 13, 4800, 264, 3495, 2128, 6197, 555, 17054, 17177, 27525, 4323, 318, 520, 578, 3907, 315, 19922, 11, 304, 20632, 449, 14248, 505, 34061, 323, 5734, 11, 617, 1511, 3428, 65487, 57678, 311, 21004, 3927, 25524, 13230, 20349, 304, 22340, 66192, 13, 578, 20349, 3782, 304, 12562, 1523, 311, 922, 1403, 6590, 35155, 82, 11, 9333, 1109, 1524, 279, 25655, 33299, 1778, 439, 97607, 323, 35784, 13, 763, 6790, 596, 4360, 315, 22037, 26545, 11, 279, 12074, 1934, 430, 814, 17427, 32367, 4832, 3373, 1968, 320, 58234, 1109, 220, 1484, 13, 24, 11587, 369, 1778, 45612, 439, 97607, 477, 35784, 449, 5201, 311, 47503, 11, 61083, 477, 53265, 263, 13, 7429, 11, 3805, 35715, 320, 78, 19472, 323, 47503, 8, 1522, 1555, 279, 72028, 6847, 8844, 311, 12782, 40589, 11, 902, 374, 871, 2721, 4, 17439, 13, 578, 14248, 1486, 704, 430, 311, 1304, 1403, 33520, 79348, 15325, 11, 433, 374, 7718, 311, 1505, 19670, 2740, 15792, 7384, 449, 47701, 72028, 11, 430, 374, 11, 72028, 2949, 279, 26110, 55372, 5196, 13, 330, 56601, 10112, 2396, 369, 45612, 527, 7995, 3284, 323, 11, 304, 2144, 11, 814, 527, 7434, 1870, 539, 14091, 79962, 311, 1884, 1511, 311, 75436, 9462, 323, 16109, 1299, 7384, 13, 4452, 11, 311, 1304, 420, 5557, 67965, 750, 9959, 11, 584, 1205, 79348, 449, 97617, 64928, 72028, 11, 539, 3927, 20349, 3549, 304, 1057, 4007, 311, 12391, 279, 7434, 369, 279, 1176, 892, 13, 8442, 1243, 527, 279, 1579, 28555, 2631, 369, 13076, 6962, 25768, 89253, 1359, 2795, 2999, 13, 52150, 89, 10118, 8219, 11, 264, 3063, 3229, 315, 279, 5684, 13, 578, 3495, 2128, 1457, 6787, 311, 2778, 369, 1778, 1403, 33520, 7384, 449, 3544, 47701, 72028, 311, 1505, 1884, 1455, 26455, 369, 3938, 6962, 25768, 14645, 13, 15483, 7384, 656, 3073, 13, 1789, 3187, 11, 1070, 527, 5370, 4876, 84267, 11, 902, 527, 1101, 19670, 2740, 15792, 85274, 897, 288, 315, 12782, 719, 539, 3686, 28648, 520, 5569, 13, 4314, 1427, 1093, 66192, 719, 617, 8294, 12782, 25562, 11, 4528, 304, 1404, 311, 279, 3927, 42655, 3549, 323, 20041, 555, 279, 19922, 12074, 13, 578, 1314, 1404, 1253, 1304, 4876, 84267, 14268, 32599, 369, 6962, 25768, 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 Immune-mediated anti-tumoral responses, elicited by oncolytic viruses and augmented with checkpoint inhibition, may be an effective treatment approach for glioblastoma. Here in this multicenter phase 1/2 study we evaluated the combination of intratumoral delivery of oncolytic virus DNX-2401 followed by intravenous anti-PD-1 antibody pembrolizumab in recurrent glioblastoma, first in a dose-escalation and then in a dose-expansion phase, in 49 patients. The primary endpoints were overall safety and objective response rate. The primary safety endpoint was met, whereas the primary efficacy endpoint was not met. There were no dose-limiting toxicities, and full dose combined treatment was well tolerated. The objective response rate was 10.4% (90% confidence interval (CI) 4.2–20.7%), which was not statistically greater than the prespecified control rate of 5%. The secondary endpoint of overall survival at 12 months was 52.7% (95% CI 40.1–69.2%), which was statistically greater than the prespecified control rate of 20%. Median overall survival was 12.5 months (10.7–13.5 months). Objective responses led to longer survival (hazard ratio 0.20, 95% CI 0.05–0.87). A total of 56.2% (95% CI 41.1–70.5%) of patients had a clinical benefit defined as stable disease or better. Three patients completed treatment with durable responses and remain alive at 45, 48 and 60 months. Exploratory mutational, gene-expression and immunophenotypic analyses revealed that the balance between immune cell infiltration and expression of checkpoint inhibitors may potentially inform on response to treatment and mechanisms of resistance. Overall, the combination of intratumoral DNX-2401 followed by pembrolizumab was safe with notable survival benefit in select patients (ClinicalTrials.gov registration: NCT02798406). Main Glioblastoma is the most common and lethal adult primary brain tumor. The standard of care treatment for newly diagnosed patients includes surgical resection followed by concomitant chemoradiotherapy and adjuvant temozolomide 1 . Despite maximal multimodal therapy, patients invariably experience recurrence of their disease 7 months after diagnosis, on average 1 . Unfortunately, treatment options at recurrence are scarce. Existing salvage therapies have very limited efficacy, with median survival being in the range of only 6–8 months after tumor progression 2 . Effective treatments for recurrent disease are urgently needed. While immune checkpoint blockade by anti-PD1 or anti-PD-L1 antibodies have improved outcomes with objective responses in a variety of other cancers, including those in the brain such as metastatic melanoma 3 , they have had limited efficacy as monotherapy for recurrent glioblastoma where the microenvironment is innately immunosuppressive (that is, immunologically ‘cold’) 4 , 5 . Oncolytic viruses are capable of reconditioning the tumor microenvironment toward a ‘hot’ phenotype, providing rationale for combinatorial therapy with checkpoint inhibitors, which has been shown to improve outcomes in other cancers 6 , 7 . DNX-2401 (tasadenoturev; Delta-24-RGD) is a conditionally replicative oncolytic adenovirus engineered to treat high-grade malignant gliomas 8 , 9 . The virus contains two stable genetic changes in the adenovirus dsDNA genome that cause it to selectively and efficiently replicate in cancerous cells. A dose-escalation phase 1 study demonstrated that stereotactic delivery of DNX-2401 into patients with high-grade gliomas was safe and induced cell death initially by direct oncolysis and subsequently by antitumor response from infiltrated immune cells, with durable responses after a single intratumoral dose 10 . In this Article, we report the results of CAPTIVE (2401BT-002P; KEYNOTE-192; NCT02798406 ), a two-part, phase 1/2, multicenter, open-label clinical trial of combined intratumoral injection of DNX-2401 with systemic pembrolizumab for patients with recurrent glioblastoma. This is the first in-human investigation of combined oncolytic virus with immune checkpoint blockade for recurrent glioblastoma. Results Patient demographics and baseline characteristics A total of 49 patients from 13 of the 15 participating institutions were enrolled between 28 September 2016 and 17 January 2019 (Fig. 1a ). The demographic and baseline clinical characteristics of all patients enrolled are reported in Table 1 . The median age of patients was 53 years, and 41% were women. The majority of patients (80%) presented after first recurrence, and 18% of patients were using steroids at baseline. All patients had histopathological diagnosis of glioblastomas, except one patient enrolled with gliosarcoma (2%). Most patients (90%, N = 44) had reported IDH1 wild-type tumors, four (8%) had IDH1 mutant tumors and IDH1 mutation status was not known for one patient. All patients had received prior treatment with temozolomide and radiotherapy, six (12%) patients had prior bevacizumab treatment and five (10%) had prior treatment with a tumor-treating fields device. Fig. 1: Survival and response to treatment. a , Patient flow in trial. b , Waterfall plot that displays the maximal change in tumor size for all patients who received full-dose DNX-2401 treatment ( n = 42). Bars represent the maximal tumor change from baseline on the basis of contrast-enhanced MRI. Bars are colored according to responses classified according to mRANO criteria. c , Survival for each patient by DNX-2401 dose. The bar colors show the response to treatment according to the mRANO criteria. Arrows indicate that the patient remains alive. d , Overall survival for the intent to treat population. Crosses denote censored data. Full size image Table 1 Patient demographics and baseline characteristics Full size table Safety Forty-eight of 49 (98%) patients were treated with one dose of DNX-2401 after a standard biopsy, which was then followed by pembrolizumab starting 7 days later. One patient enrolled in the first dose cohort received 5 × 10 8 viral particles (v.p.) DNX-2401 but did not start pembrolizumab due to delirium, which was attributed by the investigators to anesthesia used during biopsy, unrelated to treatment. This patient was included in the safety analysis set only, per protocol. There were no dose-limiting toxicities observed, and the maximal dose tested (5 × 10 10 v.p. DNX-2401) was selected as the declared dose for the dose-expansion phase. In total, across both dose-escalation and dose-expansion phases, patients were treated with 5 × 10 8 ( n = 4), 5 × 10 9 ( n = 3) and 5 × 10 10 v.p. DNX-2401 ( n = 42). The median duration of exposure to treatment with DNX-2401 and pembrolizumab was 153 days (range 21–753 days), including three patients", "role": "user" }, { "content": "A new international study published in Nature Medicine and presented as a late-breaking abstract at the American Association of Neurological Surgeons (AANS) annual conference, shows great promise for patients with glioblastoma. Drs. Farshad Nassiri and Gelareh Zadeh, neurosurgeons at the University Health Network (UHN) in Toronto, published the results of a Phase 1/2 clinical trial investigating the safety and effectiveness of a novel therapy which combines the injection of an oncolytic virus—a virus that targets and kills cancer cells—directly into the tumor, with intravenous immunotherapy. The authors found that this novel combination therapy can eradicate the tumor in select patients, with evidence of prolonged survival. Investigative work by the authors also revealed a new genetic signature within tumor samples that has the potential to predict which patients with glioblastoma are most likely to respond to treatment. \"The initial clinical trial results are promising,\" says Dr. Zadeh, who is also Co-Director of the Krembil Brain Institute and a Senior Scientist at the Princess Margaret Cancer Center. \"We are cautiously optimistic about the long-term clinical benefits for patients.\" Glioblastoma is a notoriously difficult-to-treat primary brain cancer. Despite aggressive treatment, which typically involves surgical removal of the tumor and multiple chemotherapy drugs, the cancer often returns, at which point treatment options are limited. Immune checkpoint inhibitors are effective treatments for a variety of cancers, but they have had limited success in treating recurrent glioblastoma. This novel therapy involves the combination of an oncolytic virus and immune checkpoint inhibition, using an anti-PD-1 antibody as a targeted immunotherapy. First, the team delivered the virus by accurately localizing the tumor using stereotactic techniques and injecting the virus through a small hole and a purpose-built catheter. Then, patients received an anti-PD-1 antibody intravenously, every three weeks, starting one week after surgery. \"These drugs work by preventing cancer's ability to evade the body's natural immune response, so they have little benefit when the tumor is immunologically inactive—as is the case in glioblastoma,\" explains Dr. Zadeh. \"Oncolytic viruses can overcome this limitation by creating a more favorable tumor microenvironment, which then helps to boost anti-tumor immune responses.\" The combination of the oncolytic virus and immune-checkpoint inhibition results in a \"double hit\" to tumors; the virus directly causes cancer cell death, but also stimulates local immune activity causing inflammation, leaving the cancer cells more vulnerable to targeted immunotherapy. Dr. Zadeh and colleagues evaluated the innovative therapy in 49 patients with recurrent disease, from 15 hospital sites across North America. UHN, which is the largest research and teaching hospital in Canada and the only Canadian institution involved in the study, treated the majority of the patients enrolled in the trial. The results, published in Nature Medicine, show that this combination therapy is safe, well tolerated and prolongs patient survival. The therapy had no major unexpected adverse effects and yielded a median survival of 12.5 months—considerably longer than the six to eight months typically seen with existing therapies. \"We're very encouraged by these results,\" says Dr. Farshad Nassiri, first author of the study and a senior neurosurgery resident at the University of Toronto. \"Over half of our patients achieved a clinical benefit—stable disease or better—and we saw some remarkable responses with tumors shrinking, and some even disappearing completely. Three patients remain alive at 45, 48 and 60 months after starting the clinical trial.\" \"The findings of the study are particularly meaningful as the patients in the trial did not have tumor resection at recurrence—only injection of the virus—which is a novel treatment approach for glioblastoma. So, it's really remarkable to see these responses,\" says Dr. Zadeh. \"We believe the key to our success was delivering the virus directly into the tumor prior to using systemic immunotherapy. Our results clearly signal that this can be a safe and effective approach,\" adds Dr. Nassiri. The team also performed experiments to define mutations, gene expression, and immune features of each patient's tumor. They discovered key immune features which could eventually help clinicians predict treatment responses and understand the mechanisms of glioblastoma resistance. \"In general, the drugs that are used in cancer treatment do not work for every patient, but we believe there is a sub-population of glioblastoma patients that will respond well to this treatment,\" says Dr. Zadeh. \"I believe this translational work, combining basic bench science and clinical trials, is key to moving personalized treatments for glioblastoma forward.\" This is one of the few clinical trials with favorable results for glioblastoma over the last decade, and it was truly a team effort. \"The trial would not have been possible without our incredible OR teams, research safety teams and researchers—including Dr. Warren Mason and his team at Princess Margaret Cancer Center—and our brave patients and their families. We're also grateful to the Wilkins Family for providing the funds to enable us to complete trials that advance care for our patients,\" says Dr. Zadeh. The next steps for the group are to test the effectiveness of the combination therapy against other treatments in a randomized clinical trial. \"We are encouraged by these results, but there is still a lot of work ahead of us,\" says Dr. Nassiri. \"Our goal, as always, is to help our patients. That's what motivates us to continue this research.\" ", "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-mediated anti-tumoral responses, elicited by oncolytic viruses and augmented with checkpoint inhibition, may be an effective treatment approach for glioblastoma. Here in this multicenter phase 1/2 study we evaluated the combination of intratumoral delivery of oncolytic virus DNX-2401 followed by intravenous anti-PD-1 antibody pembrolizumab in recurrent glioblastoma, first in a dose-escalation and then in a dose-expansion phase, in 49 patients. The primary endpoints were overall safety and objective response rate. The primary safety endpoint was met, whereas the primary efficacy endpoint was not met. There were no dose-limiting toxicities, and full dose combined treatment was well tolerated. The objective response rate was 10.4% (90% confidence interval (CI) 4.2–20.7%), which was not statistically greater than the prespecified control rate of 5%. The secondary endpoint of overall survival at 12 months was 52.7% (95% CI 40.1–69.2%), which was statistically greater than the prespecified control rate of 20%. Median overall survival was 12.5 months (10.7–13.5 months). Objective responses led to longer survival (hazard ratio 0.20, 95% CI 0.05–0.87). A total of 56.2% (95% CI 41.1–70.5%) of patients had a clinical benefit defined as stable disease or better. Three patients completed treatment with durable responses and remain alive at 45, 48 and 60 months. Exploratory mutational, gene-expression and immunophenotypic analyses revealed that the balance between immune cell infiltration and expression of checkpoint inhibitors may potentially inform on response to treatment and mechanisms of resistance. Overall, the combination of intratumoral DNX-2401 followed by pembrolizumab was safe with notable survival benefit in select patients (ClinicalTrials.gov registration: NCT02798406). Main Glioblastoma is the most common and lethal adult primary brain tumor. The standard of care treatment for newly diagnosed patients includes surgical resection followed by concomitant chemoradiotherapy and adjuvant temozolomide 1 . Despite maximal multimodal therapy, patients invariably experience recurrence of their disease 7 months after diagnosis, on average 1 . Unfortunately, treatment options at recurrence are scarce. Existing salvage therapies have very limited efficacy, with median survival being in the range of only 6–8 months after tumor progression 2 . Effective treatments for recurrent disease are urgently needed. While immune checkpoint blockade by anti-PD1 or anti-PD-L1 antibodies have improved outcomes with objective responses in a variety of other cancers, including those in the brain such as metastatic melanoma 3 , they have had limited efficacy as monotherapy for recurrent glioblastoma where the microenvironment is innately immunosuppressive (that is, immunologically ‘cold’) 4 , 5 . Oncolytic viruses are capable of reconditioning the tumor microenvironment toward a ‘hot’ phenotype, providing rationale for combinatorial therapy with checkpoint inhibitors, which has been shown to improve outcomes in other cancers 6 , 7 . DNX-2401 (tasadenoturev; Delta-24-RGD) is a conditionally replicative oncolytic adenovirus engineered to treat high-grade malignant gliomas 8 , 9 . The virus contains two stable genetic changes in the adenovirus dsDNA genome that cause it to selectively and efficiently replicate in cancerous cells. A dose-escalation phase 1 study demonstrated that stereotactic delivery of DNX-2401 into patients with high-grade gliomas was safe and induced cell death initially by direct oncolysis and subsequently by antitumor response from infiltrated immune cells, with durable responses after a single intratumoral dose 10 . In this Article, we report the results of CAPTIVE (2401BT-002P; KEYNOTE-192; NCT02798406 ), a two-part, phase 1/2, multicenter, open-label clinical trial of combined intratumoral injection of DNX-2401 with systemic pembrolizumab for patients with recurrent glioblastoma. This is the first in-human investigation of combined oncolytic virus with immune checkpoint blockade for recurrent glioblastoma. Results Patient demographics and baseline characteristics A total of 49 patients from 13 of the 15 participating institutions were enrolled between 28 September 2016 and 17 January 2019 (Fig. 1a ). The demographic and baseline clinical characteristics of all patients enrolled are reported in Table 1 . The median age of patients was 53 years, and 41% were women. The majority of patients (80%) presented after first recurrence, and 18% of patients were using steroids at baseline. All patients had histopathological diagnosis of glioblastomas, except one patient enrolled with gliosarcoma (2%). Most patients (90%, N = 44) had reported IDH1 wild-type tumors, four (8%) had IDH1 mutant tumors and IDH1 mutation status was not known for one patient. All patients had received prior treatment with temozolomide and radiotherapy, six (12%) patients had prior bevacizumab treatment and five (10%) had prior treatment with a tumor-treating fields device. Fig. 1: Survival and response to treatment. a , Patient flow in trial. b , Waterfall plot that displays the maximal change in tumor size for all patients who received full-dose DNX-2401 treatment ( n = 42). Bars represent the maximal tumor change from baseline on the basis of contrast-enhanced MRI. Bars are colored according to responses classified according to mRANO criteria. c , Survival for each patient by DNX-2401 dose. The bar colors show the response to treatment according to the mRANO criteria. Arrows indicate that the patient remains alive. d , Overall survival for the intent to treat population. Crosses denote censored data. Full size image Table 1 Patient demographics and baseline characteristics Full size table Safety Forty-eight of 49 (98%) patients were treated with one dose of DNX-2401 after a standard biopsy, which was then followed by pembrolizumab starting 7 days later. One patient enrolled in the first dose cohort received 5 × 10 8 viral particles (v.p.) DNX-2401 but did not start pembrolizumab due to delirium, which was attributed by the investigators to anesthesia used during biopsy, unrelated to treatment. This patient was included in the safety analysis set only, per protocol. There were no dose-limiting toxicities observed, and the maximal dose tested (5 × 10 10 v.p. DNX-2401) was selected as the declared dose for the dose-expansion phase. In total, across both dose-escalation and dose-expansion phases, patients were treated with 5 × 10 8 ( n = 4), 5 × 10 9 ( n = 3) and 5 × 10 10 v.p. DNX-2401 ( n = 42). The median duration of exposure to treatment with DNX-2401 and pembrolizumab was 153 days (range 21–753 days), including three patients<|im_end|> <|im_start|>assistant A new international study published in Nature Medicine and presented as a late-breaking abstract at the American Association of Neurological Surgeons (AANS) annual conference, shows great promise for patients with glioblastoma. Drs. Farshad Nassiri and Gelareh Zadeh, neurosurgeons at the University Health Network (UHN) in Toronto, published the results of a Phase 1/2 clinical trial investigating the safety and effectiveness of a novel therapy which combines the injection of an oncolytic virus—a virus that targets and kills cancer cells—directly into the tumor, with intravenous immunotherapy. The authors found that this novel combination therapy can eradicate the tumor in select patients, with evidence of prolonged survival. Investigative work by the authors also revealed a new genetic signature within tumor samples that has the potential to predict which patients with glioblastoma are most likely to respond to treatment. "The initial clinical trial results are promising," says Dr. Zadeh, who is also Co-Director of the Krembil Brain Institute and a Senior Scientist at the Princess Margaret Cancer Center. "We are cautiously optimistic about the long-term clinical benefits for patients." Glioblastoma is a notoriously difficult-to-treat primary brain cancer. Despite aggressive treatment, which typically involves surgical removal of the tumor and multiple chemotherapy drugs, the cancer often returns, at which point treatment options are limited. Immune checkpoint inhibitors are effective treatments for a variety of cancers, but they have had limited success in treating recurrent glioblastoma. This novel therapy involves the combination of an oncolytic virus and immune checkpoint inhibition, using an anti-PD-1 antibody as a targeted immunotherapy. First, the team delivered the virus by accurately localizing the tumor using stereotactic techniques and injecting the virus through a small hole and a purpose-built catheter. Then, patients received an anti-PD-1 antibody intravenously, every three weeks, starting one week after surgery. "These drugs work by preventing cancer's ability to evade the body's natural immune response, so they have little benefit when the tumor is immunologically inactive—as is the case in glioblastoma," explains Dr. Zadeh. "Oncolytic viruses can overcome this limitation by creating a more favorable tumor microenvironment, which then helps to boost anti-tumor immune responses." The combination of the oncolytic virus and immune-checkpoint inhibition results in a "double hit" to tumors; the virus directly causes cancer cell death, but also stimulates local immune activity causing inflammation, leaving the cancer cells more vulnerable to targeted immunotherapy. Dr. Zadeh and colleagues evaluated the innovative therapy in 49 patients with recurrent disease, from 15 hospital sites across North America. UHN, which is the largest research and teaching hospital in Canada and the only Canadian institution involved in the study, treated the majority of the patients enrolled in the trial. The results, published in Nature Medicine, show that this combination therapy is safe, well tolerated and prolongs patient survival. The therapy had no major unexpected adverse effects and yielded a median survival of 12.5 months—considerably longer than the six to eight months typically seen with existing therapies. "We're very encouraged by these results," says Dr. Farshad Nassiri, first author of the study and a senior neurosurgery resident at the University of Toronto. "Over half of our patients achieved a clinical benefit—stable disease or better—and we saw some remarkable responses with tumors shrinking, and some even disappearing completely. Three patients remain alive at 45, 48 and 60 months after starting the clinical trial." "The findings of the study are particularly meaningful as the patients in the trial did not have tumor resection at recurrence—only injection of the virus—which is a novel treatment approach for glioblastoma. So, it's really remarkable to see these responses," says Dr. Zadeh. "We believe the key to our success was delivering the virus directly into the tumor prior to using systemic immunotherapy. Our results clearly signal that this can be a safe and effective approach," adds Dr. Nassiri. The team also performed experiments to define mutations, gene expression, and immune features of each patient's tumor. They discovered key immune features which could eventually help clinicians predict treatment responses and understand the mechanisms of glioblastoma resistance. "In general, the drugs that are used in cancer treatment do not work for every patient, but we believe there is a sub-population of glioblastoma patients that will respond well to this treatment," says Dr. Zadeh. "I believe this translational work, combining basic bench science and clinical trials, is key to moving personalized treatments for glioblastoma forward." This is one of the few clinical trials with favorable results for glioblastoma over the last decade, and it was truly a team effort. "The trial would not have been possible without our incredible OR teams, research safety teams and researchers—including Dr. Warren Mason and his team at Princess Margaret Cancer Center—and our brave patients and their families. We're also grateful to the Wilkins Family for providing the funds to enable us to complete trials that advance care for our patients," says Dr. Zadeh. The next steps for the group are to test the effectiveness of the combination therapy against other treatments in a randomized clinical trial. "We are encouraged by these results, but there is still a lot of work ahead of us," says Dr. Nassiri. "Our goal, as always, is to help our patients. That's what motivates us to continue this research." <|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 ability to estimate the distance of objects from one’s self and from each other is fundamental to a variety of behaviours from grasping objects to navigating. The main cue to distance, stereopsis, relies on the slight offsets between the images derived from our left and right eyes, also termed disparities. Here we ask whether the precision of stereopsis varies with professional experience with precise manual tasks. We measured stereo-acuities of dressmakers and non-dressmakers for both absolute and relative disparities. We used a stereoscope and a computerized test removing monocular cues. We also measured vergence noise and bias using the Nonius line technique. We demonstrate that dressmakers’ stereoscopic acuities are better than those of non-dressmakers, for both absolute and relative disparities. In contrast, vergence noise and bias were comparable in the two groups. Two non-exclusive mechanisms may be at the source of the group difference we document: (i) self-selection or the fact that stereo-vision is functionally important to become a dressmaker, and (ii) plasticity, or the fact that training on demanding stereovision tasks improves stereo-acuity. Introduction Depth perception is an important human visual ability allowing people to interact easily with their environment. It relies substantially on the stereoscopic depth information, which itself is based on image binocular disparities. These disparities are caused by the different viewpoints of the two eyes. Monocular cues to depth (e.g. motion parallax, shadows, occlusion) also contribute to depth perception 1 . The functional role of stereopsis has been the subject of much debate. It has been theorized to guide the fine movements of the hands in reaching and grasping 2 , 3 , 4 . Indeed, object placement 5 , 6 and grasping 7 , 8 , 9 , 10 are more precise with binocular viewing than monocular viewing (at least in the centre of the visual field 11 ). However, most of the evidence is based on comparing binocular and monocular viewing conditions, which differ not only in the absence of stereopsis, but also in an absence of binocular vergence and summation, and a decreased field of view. It is known that decreasing the field of view affects reaching 12 . Yet, there remains a binocular advantage in object prehension even when controlling for the field of view 13 . There is also a growing body of confirmatory evidence, including studies showing that binocular cues to depth are crucial to prehension 14 , that binocular cues are given more weight than monocular cues when placing objects 15 , and that the binocular advantage in object placement correlates with stereo-acuity 5 . Previous studies 6 , 16 have shown that binocular vision is more efficient than monocular vision in delicate manual tasks like threading a needle. Some have argued that stereopsis can only be useful for slow motions requiring extreme precision 17 . However, past studies have not shown better stereo-acuities for professions based on slow motions requiring extreme precision, like surgeons 18 or dentists 19 , 20 , although stereoblind surgeons performed a simulated surgical task significantly worse than the stereo-normal ones 21 . Furthermore, stereo-acuity when entering a school of dentistry was not linked with later student grades 22 . In the current study, we tested stereoscopic acuities of a sample of dressmakers, and compared these acuities with those of a non-dressmaker group. Given the likely advantage given by stereopsis in fine eye-hand tasks, we reasoned that dressmakers may display better stereo-acuities. This could result either through self-selection or through the development of expertise given that their daily work involves constantly estimating small changes in visual depth. Indeed, stereoscopic vision is known to undergo some training-dependent plasticity. For example, stereo-perception can be ameliorated by training on a depth task with random dot stereograms 23 , 24 , 25 , or a depth task with local stereograms, involving edges, squares, lines, dots, or Gabor patches 24 , 26 , 27 , 28 , 29 . In addition, persons with strabismus and amblyopia, who often suffer from stereo-blindness, have been trained to recover stereoscopic vision with various rates of success (for a review, see ref. 4 ), using techniques such as patching 30 , monocular 31 or dichoptic perceptual learning 32 , 33 , monocular 34 or dichoptic video gaming 30 , 35 , 36 , and stereo-training 37 , 38 , 39 . However, it is not known whether manual actions, in particular, the kind of fine actions involved in sewing can increase stereoscopic depth perception, or whether having poor (or no) stereopsis would deter individuals from professions such as dressmaking. Although we have discussed stereoscopic acuity as if it were a unitary concept, it is well known that there are two different types of disparity: absolute disparity and relative disparity. An object’s absolute disparity is the difference between the angle subtended by the target at the two entrance pupils of the eyes and the angle of convergence. Absolute disparity is important for judging the depth distance of an object from one’s self (Fig. 1 ). The difference between the absolute disparities of two objects is called relative disparity (Fig. 1 ). Relative disparity is important for judging the depth distance between two (or more) objects. It is well known that human observers are better at judging relative disparity than at judging absolute disparity 40 . We and others have argued that the source of this difference is an absence of conscious readout for absolute disparities. We refer to this as the absolute disparity anomaly 41 . Despite this anomaly, humans should have a high sensitivity for absolute disparities, given that both vergence eye movements 42 , 43 , 44 , 45 and relative disparities are based on absolute disparities 41 , 46 , 47 . The plasticity studies discussed above were all conducted with relative disparities. Therefore, it is not clear whether absolute disparity acuity (or readout) can be improved by learning. On the one hand, in a recent study 41 , we have found very little evidence for rapid learning of", "role": "user" }, { "content": "Haute couture can be credited for enhancing more than catwalks and red carpets. New research from UC Berkeley suggests that the 3-D or \"stereoscopic\" vision of dressmakers is as sharp as their needles. Stereoscopic vision is the brain's ability to decode the flat 2-D optical information received by both eyes to give us the depth of perception needed to thread a needle, catch a ball, park a car and generally navigate a 3-D world. Using computerized perceptual tasks, researchers from UC Berkeley and the University of Geneva, Switzerland, tested the stereoscopic vision of dressmakers and other professionals, and found dressmakers to be the most eagle-eyed. The results, published in the June 13 issue of the journal Scientific Reports, show dressmakers to be 80 percent more accurate than non-dressmakers at calculating the distance between themselves and the objects they were looking at, and 43 percent better at estimating the distance between objects. \"We found dressmakers have superior stereovision, perhaps because of the direct feedback involved with fine needlework,\" said study lead author Adrien Chopin, a postdoctoral researcher in visual neuroscience at UC Berkeley. What researchers are still determining is whether dressmaking sharpens stereoscopic vision, or whether dressmakers are drawn to the trade because of their visual stereo-acuity, Chopin said. Credit: University of California - Berkeley To experience what it means to have stereoscopic vision, focus on a visual target. Now blink one eye while still staring at your target. Then blink the other eye. The background should appear to shift position. With stereoscopic vision, the brain's visual cortex merges the 2-D viewpoints of each eye into one 3-D image. It has generally been assumed that surgeons, dentists and other medical professionals who perform precise manual procedures would have superior stereovision. But previous studies have shown this not to be the case. That spurred Chopin to investigate which professions would produce or attract people with superior stereovision, and led him to dressmakers. A better understanding of dressmakers' stereoscopic superpowers will inform ongoing efforts to train people with visual impairments such as amblyopia or \"lazy eye\" to strengthen their stereoscopic vision, Chopin said. In addition to helping people with sight disorders, improved stereoscopic vision may be key to the success of military fighters, athletes and other occupations that require keen hand-eye coordination. An estimated 10 percent of people suffer from some form of stereoscopic impairment, and 5 percent suffer from full stereo blindness, Chopin said. For example, the 17th-century Dutch painter Rembrandt, whose self-portraits occasionally showed him with one lazy eye, is thought to have suffered from stereo blindness, rendering him with flat vision. Some vision scientists have posited that painters tend to have poorer stereovision, which gives them an advantage working in 2-D. For the study, participants viewed objects on a computer screen through a stereoscope and judged the distances between objects, and between themselves and the objects. Researchers recorded their visual precision and found that, overall, dressmakers performed markedly better than their non-dressmaker counterparts in visual acuity. ", "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 ability to estimate the distance of objects from one’s self and from each other is fundamental to a variety of behaviours from grasping objects to navigating. The main cue to distance, stereopsis, relies on the slight offsets between the images derived from our left and right eyes, also termed disparities. Here we ask whether the precision of stereopsis varies with professional experience with precise manual tasks. We measured stereo-acuities of dressmakers and non-dressmakers for both absolute and relative disparities. We used a stereoscope and a computerized test removing monocular cues. We also measured vergence noise and bias using the Nonius line technique. We demonstrate that dressmakers’ stereoscopic acuities are better than those of non-dressmakers, for both absolute and relative disparities. In contrast, vergence noise and bias were comparable in the two groups. Two non-exclusive mechanisms may be at the source of the group difference we document: (i) self-selection or the fact that stereo-vision is functionally important to become a dressmaker, and (ii) plasticity, or the fact that training on demanding stereovision tasks improves stereo-acuity. Introduction Depth perception is an important human visual ability allowing people to interact easily with their environment. It relies substantially on the stereoscopic depth information, which itself is based on image binocular disparities. These disparities are caused by the different viewpoints of the two eyes. Monocular cues to depth (e.g. motion parallax, shadows, occlusion) also contribute to depth perception 1 . The functional role of stereopsis has been the subject of much debate. It has been theorized to guide the fine movements of the hands in reaching and grasping 2 , 3 , 4 . Indeed, object placement 5 , 6 and grasping 7 , 8 , 9 , 10 are more precise with binocular viewing than monocular viewing (at least in the centre of the visual field 11 ). However, most of the evidence is based on comparing binocular and monocular viewing conditions, which differ not only in the absence of stereopsis, but also in an absence of binocular vergence and summation, and a decreased field of view. It is known that decreasing the field of view affects reaching 12 . Yet, there remains a binocular advantage in object prehension even when controlling for the field of view 13 . There is also a growing body of confirmatory evidence, including studies showing that binocular cues to depth are crucial to prehension 14 , that binocular cues are given more weight than monocular cues when placing objects 15 , and that the binocular advantage in object placement correlates with stereo-acuity 5 . Previous studies 6 , 16 have shown that binocular vision is more efficient than monocular vision in delicate manual tasks like threading a needle. Some have argued that stereopsis can only be useful for slow motions requiring extreme precision 17 . However, past studies have not shown better stereo-acuities for professions based on slow motions requiring extreme precision, like surgeons 18 or dentists 19 , 20 , although stereoblind surgeons performed a simulated surgical task significantly worse than the stereo-normal ones 21 . Furthermore, stereo-acuity when entering a school of dentistry was not linked with later student grades 22 . In the current study, we tested stereoscopic acuities of a sample of dressmakers, and compared these acuities with those of a non-dressmaker group. Given the likely advantage given by stereopsis in fine eye-hand tasks, we reasoned that dressmakers may display better stereo-acuities. This could result either through self-selection or through the development of expertise given that their daily work involves constantly estimating small changes in visual depth. Indeed, stereoscopic vision is known to undergo some training-dependent plasticity. For example, stereo-perception can be ameliorated by training on a depth task with random dot stereograms 23 , 24 , 25 , or a depth task with local stereograms, involving edges, squares, lines, dots, or Gabor patches 24 , 26 , 27 , 28 , 29 . In addition, persons with strabismus and amblyopia, who often suffer from stereo-blindness, have been trained to recover stereoscopic vision with various rates of success (for a review, see ref. 4 ), using techniques such as patching 30 , monocular 31 or dichoptic perceptual learning 32 , 33 , monocular 34 or dichoptic video gaming 30 , 35 , 36 , and stereo-training 37 , 38 , 39 . However, it is not known whether manual actions, in particular, the kind of fine actions involved in sewing can increase stereoscopic depth perception, or whether having poor (or no) stereopsis would deter individuals from professions such as dressmaking. Although we have discussed stereoscopic acuity as if it were a unitary concept, it is well known that there are two different types of disparity: absolute disparity and relative disparity. An object’s absolute disparity is the difference between the angle subtended by the target at the two entrance pupils of the eyes and the angle of convergence. Absolute disparity is important for judging the depth distance of an object from one’s self (Fig. 1 ). The difference between the absolute disparities of two objects is called relative disparity (Fig. 1 ). Relative disparity is important for judging the depth distance between two (or more) objects. It is well known that human observers are better at judging relative disparity than at judging absolute disparity 40 . We and others have argued that the source of this difference is an absence of conscious readout for absolute disparities. We refer to this as the absolute disparity anomaly 41 . Despite this anomaly, humans should have a high sensitivity for absolute disparities, given that both vergence eye movements 42 , 43 , 44 , 45 and relative disparities are based on absolute disparities 41 , 46 , 47 . The plasticity studies discussed above were all conducted with relative disparities. Therefore, it is not clear whether absolute disparity acuity (or readout) can be improved by learning. On the one hand, in a recent study 41 , we have found very little evidence for rapid learning of<|im_end|> <|im_start|>assistant Haute couture can be credited for enhancing more than catwalks and red carpets. New research from UC Berkeley suggests that the 3-D or "stereoscopic" vision of dressmakers is as sharp as their needles. Stereoscopic vision is the brain's ability to decode the flat 2-D optical information received by both eyes to give us the depth of perception needed to thread a needle, catch a ball, park a car and generally navigate a 3-D world. Using computerized perceptual tasks, researchers from UC Berkeley and the University of Geneva, Switzerland, tested the stereoscopic vision of dressmakers and other professionals, and found dressmakers to be the most eagle-eyed. The results, published in the June 13 issue of the journal Scientific Reports, show dressmakers to be 80 percent more accurate than non-dressmakers at calculating the distance between themselves and the objects they were looking at, and 43 percent better at estimating the distance between objects. "We found dressmakers have superior stereovision, perhaps because of the direct feedback involved with fine needlework," said study lead author Adrien Chopin, a postdoctoral researcher in visual neuroscience at UC Berkeley. What researchers are still determining is whether dressmaking sharpens stereoscopic vision, or whether dressmakers are drawn to the trade because of their visual stereo-acuity, Chopin said. Credit: University of California - Berkeley To experience what it means to have stereoscopic vision, focus on a visual target. Now blink one eye while still staring at your target. Then blink the other eye. The background should appear to shift position. With stereoscopic vision, the brain's visual cortex merges the 2-D viewpoints of each eye into one 3-D image. It has generally been assumed that surgeons, dentists and other medical professionals who perform precise manual procedures would have superior stereovision. But previous studies have shown this not to be the case. That spurred Chopin to investigate which professions would produce or attract people with superior stereovision, and led him to dressmakers. A better understanding of dressmakers' stereoscopic superpowers will inform ongoing efforts to train people with visual impairments such as amblyopia or "lazy eye" to strengthen their stereoscopic vision, Chopin said. In addition to helping people with sight disorders, improved stereoscopic vision may be key to the success of military fighters, athletes and other occupations that require keen hand-eye coordination. An estimated 10 percent of people suffer from some form of stereoscopic impairment, and 5 percent suffer from full stereo blindness, Chopin said. For example, the 17th-century Dutch painter Rembrandt, whose self-portraits occasionally showed him with one lazy eye, is thought to have suffered from stereo blindness, rendering him with flat vision. Some vision scientists have posited that painters tend to have poorer stereovision, which gives them an advantage working in 2-D. For the study, participants viewed objects on a computer screen through a stereoscope and judged the distances between objects, and between themselves and the objects. Researchers recorded their visual precision and found that, overall, dressmakers performed markedly better than their non-dressmaker counterparts in visual acuity. <|im_end|>
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1,968
[ { "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 Timescale comparison between optical atomic clocks over ground-to-space and terrestrial free-space laser links will have enormous benefits for fundamental and applied sciences. However, atmospheric turbulence creates phase noise and beam wander that degrade the measurement precision. Here we report on phase-stabilized optical frequency transfer over a 265 m horizontal point-to-point free-space link between optical terminals with active tip-tilt mirrors to suppress beam wander, in a compact, human-portable set-up. A phase-stabilized 715 m underground optical fiber link between the two terminals is used to measure the performance of the free-space link. The active optical terminals enable continuous, cycle-slip free, coherent transmission over periods longer than an hour. In this work, we achieve residual instabilities of 2.7 × 10 −6 rad 2 Hz −1 at 1 Hz in phase, and 1.6 × 10 −19 at 40 s of integration in fractional frequency; this performance surpasses the best optical atomic clocks, ensuring clock-limited frequency comparison over turbulent free-space links. Introduction Modern optical atomic clocks have the potential to revolutionize high-precision measurements in fundamental and applied sciences 1 , 2 , 3 , 4 , 5 , 6 , 7 . The ability to realize remote timescale comparison in situations where fiber links are impractical or impossible, specifically, between ground- and space-based optical atomic clocks 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , will enable significant advances in fundamental physics and practical applications including tests of the variability of fundamental constants 23 , 24 , general relativity 25 , 26 , searches for dark matter 27 , geodesy 28 , 29 , 30 , 31 , 32 , 33 , 34 , and global navigation satellite systems 35 among others 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 . These efforts build on optical timing links developed for timescale comparison between microwave atomic clocks 47 , 48 , 49 , and efforts are underway to develop optical clocks that can be deployed on the International Space Station 50 and on dedicated spacecraft 51 . Similarly, timescale comparisons between mobile terrestrial optical clocks 1 , 52 , 53 , 54 , 55 , where one or more mobile clocks are able to be deployed and moved over an area of interest, enable ground tests of general relativity and local geopotential measurements for research in geophysics, environmental monitoring, surveying, and resource exploration. Comparison of both ground- and space-based clocks, and mobile terrestrial clocks, requires frequency transfer over free-space optical links. Just as with timescale comparison over optical fiber links, free-space frequency transfer should have residual instabilities better than those of the optical clocks. However, atmospheric turbulence induces much greater phase noise than a comparable length of fiber 12 , 19 , 56 , 57 . In addition, free-space links through the turbulent atmosphere must also overcome periodic deep fades of the signal amplitude due to beam wander and scintillation. When the size of the optical beam is smaller than the Fried scale of the atmospheric turbulence, the centroid of the beam can wander off the detector, while in the case where the beam is larger than the Fried scale, destructive interference within the beam (speckle) can result in loss of signal (scintillation) and so loss of timescale synchronization 19 , 58 , 59 . These deep fades can occur 10s to 100s of times per second for vertical links between the ground and space, and also on horizontal links on the order of 10 km 12 , 17 . One method to overcome deep fades of the signal is to transmit a series of optical pulses from an optical frequency comb and compare them with another optical frequency comb at the remote site 21 . While deep fades will result in the loss of some pulses, the time and phase information can be reconstructed from the remaining pulses. Another method to overcome deep fades is to stabilize the spatial noise caused by atmospheric turbulence by active correction of the emitted and received wave front. In general, tip-tilt correction is sufficient when using apertures that are small compared to the Fried scale as beam wander will dominate the deep fades. For large apertures, the effects of speckle scintillation increase and higher-order corrections using adaptive optics may be necessary. Tip-tilt stabilization of beam wander for comparison of atomic clocks has previously been demonstrated over 12 km with 50 mm scale optics 17 and 18 km with larger 250 mm telescopes 8 . A further practical concern for the deployment of free-space links is the ability of the system to acquire and track a moving object 10 , 60 . In that case, tip-tilt capability is mandatory, and additionally such a system must be robust while also having as low a size, weight, and power as possible for ease of deployment in spacecraft, airborne relay terminals, or mobile ground segments. In this work, we describe phase-stabilized optical frequency transfer via a 265 m point-to-point free-space link between two portable optical terminals. Both terminals have 50 mm apertures and utilize tip-tilt active optics to enable link acquisition and continuous atmospheric spatial noise suppression. The terminals are human-portable and ruggedized for daily field deployment to demonstrate the suitability for remote optical timescale comparison. The performance of the phase stabilization system was determined using a separate 715 m, phase-stabilized optical fiber link between the two terminals. The phase-stabilized free-space optical transfer exhibits an 80 dB improvement in phase noise at 1 Hz, down to 2.7 × 10 −6 rad 2 Hz −1 , compared to the unstabilized optical transmission. The active spatial stabilization used at each terminal is effective at suppressing beam wander caused by the atmospheric turbulence, allowing continuous, cycle-slip and deep-fade free, coherent transmission over periods longer than an hour. The resulting fractional-frequency stability of the phase-stabilized optical transfer reaches 1.6 × 10 −19", "role": "user" }, { "content": "Scientists from the International Centre for Radio Astronomy Research (ICRAR) and the University of Western Australia (UWA) have set a world record for the most stable transmission of a laser signal through the atmosphere. In a study published today in the journal Nature Communications, Australian researchers teamed up with researchers from the French National Centre for Space Studies (CNES) and the French metrology lab Systèmes de Référence Temps-Espace (SYRTE) at Paris Observatory. The team set the world record for the most stable laser transmission by combining the Aussies' phase stabilization technology with advanced self-guiding optical terminals. Together, these technologies allowed laser signals to be sent from one point to another without interference from the atmosphere. Lead author Benjamin Dix-Matthews, a Ph.D. student at ICRAR and UWA, said the technique effectively eliminates atmospheric turbulence. \"We can correct for atmospheric turbulence in 3-D, that is, left-right, up-down and, critically, along the line of flight,\" he said. \"It's as if the moving atmosphere has been removed and doesn't exist. It allows us to send highly stable laser signals through the atmosphere while retaining the quality of the original signal.\" The result is the world's most precise method for comparing the flow of time between two separate locations using a laser system transmitted through the atmosphere. One of the self-guiding optical terminals on its telescope mount on the roof of a building at the CNES campus in Toulouse. Credit: ICRAR/UWA ICRAR-UWA senior researcher Dr. Sascha Schediwy said the research has exciting applications. \"If you have one of these optical terminals on the ground and another on a satellite in space, then you can start to explore fundamental physics,\" he said. \"Everything from testing Einstein's theory of general relativity more precisely than ever before, to discovering if fundamental physical constants change over time.\" The technology's precise measurements also have practical uses in earth science and geophysics. \"For instance, this technology could improve satellite-based studies of how the water table changes over time, or to look for ore deposits underground,\" Dr. Schediwy said. There are further potential benefits for optical communications, an emerging field that uses light to carry information. Optical communications can securely transmit data between satellites and Earth with much higher data rates than current radio communications. \"Our technology could help us increase the data rate from satellites to ground by orders of magnitude,\" Dr. Schediwy said. \"The next generation of big data-gathering satellites would be able to get critical information to the ground faster.\" The phase stabilization technology behind the record-breaking link was originally developed to synchronize incoming signals for the Square Kilometer Array telescope. The multi-billion-dollar telescope is set to be built in Western Australia and South Africa from 2021. ", "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 Timescale comparison between optical atomic clocks over ground-to-space and terrestrial free-space laser links will have enormous benefits for fundamental and applied sciences. However, atmospheric turbulence creates phase noise and beam wander that degrade the measurement precision. Here we report on phase-stabilized optical frequency transfer over a 265 m horizontal point-to-point free-space link between optical terminals with active tip-tilt mirrors to suppress beam wander, in a compact, human-portable set-up. A phase-stabilized 715 m underground optical fiber link between the two terminals is used to measure the performance of the free-space link. The active optical terminals enable continuous, cycle-slip free, coherent transmission over periods longer than an hour. In this work, we achieve residual instabilities of 2.7 × 10 −6 rad 2 Hz −1 at 1 Hz in phase, and 1.6 × 10 −19 at 40 s of integration in fractional frequency; this performance surpasses the best optical atomic clocks, ensuring clock-limited frequency comparison over turbulent free-space links. Introduction Modern optical atomic clocks have the potential to revolutionize high-precision measurements in fundamental and applied sciences 1 , 2 , 3 , 4 , 5 , 6 , 7 . The ability to realize remote timescale comparison in situations where fiber links are impractical or impossible, specifically, between ground- and space-based optical atomic clocks 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , will enable significant advances in fundamental physics and practical applications including tests of the variability of fundamental constants 23 , 24 , general relativity 25 , 26 , searches for dark matter 27 , geodesy 28 , 29 , 30 , 31 , 32 , 33 , 34 , and global navigation satellite systems 35 among others 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 . These efforts build on optical timing links developed for timescale comparison between microwave atomic clocks 47 , 48 , 49 , and efforts are underway to develop optical clocks that can be deployed on the International Space Station 50 and on dedicated spacecraft 51 . Similarly, timescale comparisons between mobile terrestrial optical clocks 1 , 52 , 53 , 54 , 55 , where one or more mobile clocks are able to be deployed and moved over an area of interest, enable ground tests of general relativity and local geopotential measurements for research in geophysics, environmental monitoring, surveying, and resource exploration. Comparison of both ground- and space-based clocks, and mobile terrestrial clocks, requires frequency transfer over free-space optical links. Just as with timescale comparison over optical fiber links, free-space frequency transfer should have residual instabilities better than those of the optical clocks. However, atmospheric turbulence induces much greater phase noise than a comparable length of fiber 12 , 19 , 56 , 57 . In addition, free-space links through the turbulent atmosphere must also overcome periodic deep fades of the signal amplitude due to beam wander and scintillation. When the size of the optical beam is smaller than the Fried scale of the atmospheric turbulence, the centroid of the beam can wander off the detector, while in the case where the beam is larger than the Fried scale, destructive interference within the beam (speckle) can result in loss of signal (scintillation) and so loss of timescale synchronization 19 , 58 , 59 . These deep fades can occur 10s to 100s of times per second for vertical links between the ground and space, and also on horizontal links on the order of 10 km 12 , 17 . One method to overcome deep fades of the signal is to transmit a series of optical pulses from an optical frequency comb and compare them with another optical frequency comb at the remote site 21 . While deep fades will result in the loss of some pulses, the time and phase information can be reconstructed from the remaining pulses. Another method to overcome deep fades is to stabilize the spatial noise caused by atmospheric turbulence by active correction of the emitted and received wave front. In general, tip-tilt correction is sufficient when using apertures that are small compared to the Fried scale as beam wander will dominate the deep fades. For large apertures, the effects of speckle scintillation increase and higher-order corrections using adaptive optics may be necessary. Tip-tilt stabilization of beam wander for comparison of atomic clocks has previously been demonstrated over 12 km with 50 mm scale optics 17 and 18 km with larger 250 mm telescopes 8 . A further practical concern for the deployment of free-space links is the ability of the system to acquire and track a moving object 10 , 60 . In that case, tip-tilt capability is mandatory, and additionally such a system must be robust while also having as low a size, weight, and power as possible for ease of deployment in spacecraft, airborne relay terminals, or mobile ground segments. In this work, we describe phase-stabilized optical frequency transfer via a 265 m point-to-point free-space link between two portable optical terminals. Both terminals have 50 mm apertures and utilize tip-tilt active optics to enable link acquisition and continuous atmospheric spatial noise suppression. The terminals are human-portable and ruggedized for daily field deployment to demonstrate the suitability for remote optical timescale comparison. The performance of the phase stabilization system was determined using a separate 715 m, phase-stabilized optical fiber link between the two terminals. The phase-stabilized free-space optical transfer exhibits an 80 dB improvement in phase noise at 1 Hz, down to 2.7 × 10 −6 rad 2 Hz −1 , compared to the unstabilized optical transmission. The active spatial stabilization used at each terminal is effective at suppressing beam wander caused by the atmospheric turbulence, allowing continuous, cycle-slip and deep-fade free, coherent transmission over periods longer than an hour. The resulting fractional-frequency stability of the phase-stabilized optical transfer reaches 1.6 × 10 −19<|im_end|> <|im_start|>assistant Scientists from the International Centre for Radio Astronomy Research (ICRAR) and the University of Western Australia (UWA) have set a world record for the most stable transmission of a laser signal through the atmosphere. In a study published today in the journal Nature Communications, Australian researchers teamed up with researchers from the French National Centre for Space Studies (CNES) and the French metrology lab Systèmes de Référence Temps-Espace (SYRTE) at Paris Observatory. The team set the world record for the most stable laser transmission by combining the Aussies' phase stabilization technology with advanced self-guiding optical terminals. Together, these technologies allowed laser signals to be sent from one point to another without interference from the atmosphere. Lead author Benjamin Dix-Matthews, a Ph.D. student at ICRAR and UWA, said the technique effectively eliminates atmospheric turbulence. "We can correct for atmospheric turbulence in 3-D, that is, left-right, up-down and, critically, along the line of flight," he said. "It's as if the moving atmosphere has been removed and doesn't exist. It allows us to send highly stable laser signals through the atmosphere while retaining the quality of the original signal." The result is the world's most precise method for comparing the flow of time between two separate locations using a laser system transmitted through the atmosphere. One of the self-guiding optical terminals on its telescope mount on the roof of a building at the CNES campus in Toulouse. Credit: ICRAR/UWA ICRAR-UWA senior researcher Dr. Sascha Schediwy said the research has exciting applications. "If you have one of these optical terminals on the ground and another on a satellite in space, then you can start to explore fundamental physics," he said. "Everything from testing Einstein's theory of general relativity more precisely than ever before, to discovering if fundamental physical constants change over time." The technology's precise measurements also have practical uses in earth science and geophysics. "For instance, this technology could improve satellite-based studies of how the water table changes over time, or to look for ore deposits underground," Dr. Schediwy said. There are further potential benefits for optical communications, an emerging field that uses light to carry information. Optical communications can securely transmit data between satellites and Earth with much higher data rates than current radio communications. "Our technology could help us increase the data rate from satellites to ground by orders of magnitude," Dr. Schediwy said. "The next generation of big data-gathering satellites would be able to get critical information to the ground faster." The phase stabilization technology behind the record-breaking link was originally developed to synchronize incoming signals for the Square Kilometer Array telescope. The multi-billion-dollar telescope is set to be built in Western Australia and South Africa from 2021. <|im_end|>
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1,904
[ { "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 the first time it is shown that carbon black inks on ancient Egyptian papyri from different time periods and geographical regions contain copper. The inks have been investigated using synchrotron-based micro X-ray fluorescence (XRF) and micro X-ray absorption near-edge structure spectroscopy (XANES) at the European Synchrotron Radiation Facility (ESRF). The composition of the copper-containing carbon inks showed no significant differences that could be related to time periods or the geographical locations. This renders it probable that the same technology for ink production was used throughout Egypt for a period spanning at least 300 years. It is argued that the black pigment material (soot) for these inks was obtained as by-products of technical metallurgy. The copper (Cu) can be correlated with the following three main components: cuprite (Cu 2 O), azurite (Cu 3 [CO 3 ] 2 [OH] 2 ) and malachite (Cu 2 CO 3 [OH] 2 ). Introduction Two of the most profound technological advances in human intellectual history were the twin inventions of ink and papyrus, the ancient precursor of modern paper, by the Egyptians about 5.000 years ago. The advent of writing allowed information to be expanded beyond the mental capacity of any single individual and to be shared across time and space. The two inventions spread throughout the ancient Mediterranean to Greece, Rome and beyond. The chemistry of the black inks used in the ancient world has been only scantily studied so far, leaving gaps in our knowledge of one of the fundamental inventions in the history of civilization 1 . Thus, until recently, it was assumed that the ink used for writing was primarily carbon-based at least until the 4 th to the 5 th century CE. However, micro XRF analyses of two papyrus fragments from Herculaneum have shown that lead compounds were added to black ink already in 1 st century CE, thereby modifying our knowledge of ink manufacture in Antiquity 2 , 3 . Here, we report on the chemical composition of black ink inscribed on papyrus fragments from ancient Egypt using micro XRF and XANES. The fragments form parts of larger manuscripts belonging to the Papyrus Carlsberg Collection, University of Copenhagen, and can be divided into two groups: The first group comes from southern Egypt and consists of the private papers of an Egyptian soldier, Horus, who was stationed at the military camp of Pathyris, located at modern Gebelein some 30 km south of Luxor. Pathyris was destroyed in 88 BCE during a civil war and thousands of papyri have been preserved in the ruins until modern times and are now conserved in papyrus collections around the world, including Berlin, Cairo, Heidelberg and Turin, as well as Copenhagen. Our archive consists of 50 Greek and Egyptian papyri that date to the late 2 nd and early 1 st century BCE. They were bought on the antiquities market in 1924 by the manuscript collector Elkan Nathan Adler (1861–1941) according to whom they had been found inside a sealed jar at the ancient settlement 4 . This is the only archive from Pathyris that have come down to posterity substantially intact 5 . The second group derives from the only large scale institutional library to survive from ancient Egypt, the Tebtunis temple library. The assemblage includes an estimated 400–500 papyrus manuscripts which span the 1 st through the early 3 rd century CE, with the bulk dating to the late 1 st and 2 nd centuries. It was discovered within two small cellars inside the main temple precinct at Tebtunis, modern Umm el-Breigât, which is located in the south of the Fayum depression, some 100 km south-west of Cairo. The dry and brittle manuscripts are all poorly preserved and the material as a whole now consists of many thousands of smaller fragments, which are preserved in papyrus collections around the world, including Copenhagen, Florence, Berlin, Berkeley, Oxford and Yale. Whole columns or pages are only rarely preserved, and the difficult and time consuming process of sorting and identifying fragments of specific manuscripts is still ongoing. Published texts indicate that on average less than 10% of a manuscript is likely to have been preserved. The papyri selected for analysis were acquired for the Papyrus Carlsberg Collection between 1931 and 1938 on the antiquities market in Cairo 6 . Recently, the chemical composition of papyri and ink from the two localities was studied using a combination of laboratory XRF point analysis, Raman spectroscopy and scanning electron microscopy-energy dispersive x-ray spectroscopy (SEM-EDXS). Despite their distance in time, space, and social context, the study concluded that the black inks of Pathyris and Tebtunis revealed similar traits and that – besides carbon ink – two other distinct types of black ink were used for at least a period of 300 years: lead-containing carbon ink and copper-containing carbon ink. However, this preliminary characterization was limited to conventional XRF (few points), Raman and SEM-EDXS (small area maps) techniques and the chemical nature of the lead (Pb) and copper (Cu) compounds detected in the black inks could not be ascertained through the experimental setup 7 . Experimental Samples In total, the research was conducted on a corpus of 12 fragments. The papyri are of a light brown color and the inks range from deep black to light grey or brown (cf. the visible light pictures shown in the figures). The papyrus medium itself is approximately 0.3 mm thick and made of two layers of papyrus strips – in one instance, where two sheets overlap, of four layers (sample 1). The macro XRF elemental maps, discussed below, showed either no contrast between the inked areas and the papyrus, indicating soot or finely powdered charcoal as the origin of the black color, or the presence of Cu or Pb compounds in the pigments. In Fig. 1 , an example of a XRF fit is shown, which demonstrates that the main elements can be identified with certainty. Figure 1 Example of a XRF fit (sample 1). Full size image Out of the 12", "role": "user" }, { "content": "Until recently, it was assumed that the ink used for writing was primarily carbon-based at least until the fourth and fifth centuries AD. But in a new University of Copenhagen study, analyses of 2,000-year-old papyri fragments with X-ray microscopy show that black ink used by Egyptian scribes also contained copper - an element previously not identified in ancient ink. In a study published today in Scientific Reports, a cross-disciplinary team of researchers show that Egyptians used carbon inks that contained copper, which has not been identified in ancient ink before. Although the analysed papyri fragments were written over a period of 300 years and from different geographical regions, the results did not vary significantly: The papyri fragments were investigated with advanced synchrotron radiation based X-ray microscopy equipment at the European Synchrotron Radiation Facility in Grenoble as part of the cross-disciplinary CoNext project, and the particles found in the inks indicate that they were by-products of the extraction of copper from sulphurous ores. \"The composition of the copper-containing carbon inks showed no significant differences that could be related to time periods or geographical locations, which suggests that the ancient Egyptians used the same technology for ink production throughout Egypt from roughly 200 BC to 100 AD,\" says Egyptologist and first author of the study Thomas Christiansen from the University of Copenhagen. No unique ink signature The studied papyri fragments all form part of larger manuscripts belonging to the Papyrus Carlsberg Collection at the University of Copenhagen, more specifically from two primary sources: the private papers of an Egyptian soldier named Horus, who was stationed at a military camp in Pathyris, and from the Tebtunis temple library, which is the only surviving large-scale institutional library from ancient Egypt. \"None of the four inks studied here was completely identical, and there can even be variations within a single papyrus fragment, suggesting that the composition of ink produced at the same location could vary a great deal. This makes it impossible to produce maps of ink signatures that otherwise could have been used to date and place papyri fragments of uncertain provenance,\" explains Thomas Christiansen but adds: \"However, as many papyri have been handed down to us as fragments, the observation that ink used on individual manuscripts can differ from other manuscripts from the same source is good news insofar as it might facilitate the identification of fragments belonging to specific manuscripts or sections thereof.\" According to the researchers, their results will also be useful for conservation purposes as detailed knowledge of the material's composition could help museums and collections make the right decisions regarding conservation and storage of papyri, thus ensuring their preservation and longevity. ", "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 the first time it is shown that carbon black inks on ancient Egyptian papyri from different time periods and geographical regions contain copper. The inks have been investigated using synchrotron-based micro X-ray fluorescence (XRF) and micro X-ray absorption near-edge structure spectroscopy (XANES) at the European Synchrotron Radiation Facility (ESRF). The composition of the copper-containing carbon inks showed no significant differences that could be related to time periods or the geographical locations. This renders it probable that the same technology for ink production was used throughout Egypt for a period spanning at least 300 years. It is argued that the black pigment material (soot) for these inks was obtained as by-products of technical metallurgy. The copper (Cu) can be correlated with the following three main components: cuprite (Cu 2 O), azurite (Cu 3 [CO 3 ] 2 [OH] 2 ) and malachite (Cu 2 CO 3 [OH] 2 ). Introduction Two of the most profound technological advances in human intellectual history were the twin inventions of ink and papyrus, the ancient precursor of modern paper, by the Egyptians about 5.000 years ago. The advent of writing allowed information to be expanded beyond the mental capacity of any single individual and to be shared across time and space. The two inventions spread throughout the ancient Mediterranean to Greece, Rome and beyond. The chemistry of the black inks used in the ancient world has been only scantily studied so far, leaving gaps in our knowledge of one of the fundamental inventions in the history of civilization 1 . Thus, until recently, it was assumed that the ink used for writing was primarily carbon-based at least until the 4 th to the 5 th century CE. However, micro XRF analyses of two papyrus fragments from Herculaneum have shown that lead compounds were added to black ink already in 1 st century CE, thereby modifying our knowledge of ink manufacture in Antiquity 2 , 3 . Here, we report on the chemical composition of black ink inscribed on papyrus fragments from ancient Egypt using micro XRF and XANES. The fragments form parts of larger manuscripts belonging to the Papyrus Carlsberg Collection, University of Copenhagen, and can be divided into two groups: The first group comes from southern Egypt and consists of the private papers of an Egyptian soldier, Horus, who was stationed at the military camp of Pathyris, located at modern Gebelein some 30 km south of Luxor. Pathyris was destroyed in 88 BCE during a civil war and thousands of papyri have been preserved in the ruins until modern times and are now conserved in papyrus collections around the world, including Berlin, Cairo, Heidelberg and Turin, as well as Copenhagen. Our archive consists of 50 Greek and Egyptian papyri that date to the late 2 nd and early 1 st century BCE. They were bought on the antiquities market in 1924 by the manuscript collector Elkan Nathan Adler (1861–1941) according to whom they had been found inside a sealed jar at the ancient settlement 4 . This is the only archive from Pathyris that have come down to posterity substantially intact 5 . The second group derives from the only large scale institutional library to survive from ancient Egypt, the Tebtunis temple library. The assemblage includes an estimated 400–500 papyrus manuscripts which span the 1 st through the early 3 rd century CE, with the bulk dating to the late 1 st and 2 nd centuries. It was discovered within two small cellars inside the main temple precinct at Tebtunis, modern Umm el-Breigât, which is located in the south of the Fayum depression, some 100 km south-west of Cairo. The dry and brittle manuscripts are all poorly preserved and the material as a whole now consists of many thousands of smaller fragments, which are preserved in papyrus collections around the world, including Copenhagen, Florence, Berlin, Berkeley, Oxford and Yale. Whole columns or pages are only rarely preserved, and the difficult and time consuming process of sorting and identifying fragments of specific manuscripts is still ongoing. Published texts indicate that on average less than 10% of a manuscript is likely to have been preserved. The papyri selected for analysis were acquired for the Papyrus Carlsberg Collection between 1931 and 1938 on the antiquities market in Cairo 6 . Recently, the chemical composition of papyri and ink from the two localities was studied using a combination of laboratory XRF point analysis, Raman spectroscopy and scanning electron microscopy-energy dispersive x-ray spectroscopy (SEM-EDXS). Despite their distance in time, space, and social context, the study concluded that the black inks of Pathyris and Tebtunis revealed similar traits and that – besides carbon ink – two other distinct types of black ink were used for at least a period of 300 years: lead-containing carbon ink and copper-containing carbon ink. However, this preliminary characterization was limited to conventional XRF (few points), Raman and SEM-EDXS (small area maps) techniques and the chemical nature of the lead (Pb) and copper (Cu) compounds detected in the black inks could not be ascertained through the experimental setup 7 . Experimental Samples In total, the research was conducted on a corpus of 12 fragments. The papyri are of a light brown color and the inks range from deep black to light grey or brown (cf. the visible light pictures shown in the figures). The papyrus medium itself is approximately 0.3 mm thick and made of two layers of papyrus strips – in one instance, where two sheets overlap, of four layers (sample 1). The macro XRF elemental maps, discussed below, showed either no contrast between the inked areas and the papyrus, indicating soot or finely powdered charcoal as the origin of the black color, or the presence of Cu or Pb compounds in the pigments. In Fig. 1 , an example of a XRF fit is shown, which demonstrates that the main elements can be identified with certainty. Figure 1 Example of a XRF fit (sample 1). Full size image Out of the 12<|im_end|> <|im_start|>assistant Until recently, it was assumed that the ink used for writing was primarily carbon-based at least until the fourth and fifth centuries AD. But in a new University of Copenhagen study, analyses of 2,000-year-old papyri fragments with X-ray microscopy show that black ink used by Egyptian scribes also contained copper - an element previously not identified in ancient ink. In a study published today in Scientific Reports, a cross-disciplinary team of researchers show that Egyptians used carbon inks that contained copper, which has not been identified in ancient ink before. Although the analysed papyri fragments were written over a period of 300 years and from different geographical regions, the results did not vary significantly: The papyri fragments were investigated with advanced synchrotron radiation based X-ray microscopy equipment at the European Synchrotron Radiation Facility in Grenoble as part of the cross-disciplinary CoNext project, and the particles found in the inks indicate that they were by-products of the extraction of copper from sulphurous ores. "The composition of the copper-containing carbon inks showed no significant differences that could be related to time periods or geographical locations, which suggests that the ancient Egyptians used the same technology for ink production throughout Egypt from roughly 200 BC to 100 AD," says Egyptologist and first author of the study Thomas Christiansen from the University of Copenhagen. No unique ink signature The studied papyri fragments all form part of larger manuscripts belonging to the Papyrus Carlsberg Collection at the University of Copenhagen, more specifically from two primary sources: the private papers of an Egyptian soldier named Horus, who was stationed at a military camp in Pathyris, and from the Tebtunis temple library, which is the only surviving large-scale institutional library from ancient Egypt. "None of the four inks studied here was completely identical, and there can even be variations within a single papyrus fragment, suggesting that the composition of ink produced at the same location could vary a great deal. This makes it impossible to produce maps of ink signatures that otherwise could have been used to date and place papyri fragments of uncertain provenance," explains Thomas Christiansen but adds: "However, as many papyri have been handed down to us as fragments, the observation that ink used on individual manuscripts can differ from other manuscripts from the same source is good news insofar as it might facilitate the identification of fragments belonging to specific manuscripts or sections thereof." According to the researchers, their results will also be useful for conservation purposes as detailed knowledge of the material's composition could help museums and collections make the right decisions regarding conservation and storage of papyri, thus ensuring their preservation and longevity. <|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 Ångström-sized probe of the scanning transmission electron microscope can visualize and collect spectra from single atoms. This can unambiguously resolve the chemical structure of materials, but not their isotopic composition. Here we differentiate between two isotopes of the same element by quantifying how likely the energetic imaging electrons are to eject atoms. First, we measure the displacement probability in graphene grown from either 12 C or 13 C and describe the process using a quantum mechanical model of lattice vibrations coupled with density functional theory simulations. We then test our spatial resolution in a mixed sample by ejecting individual atoms from nanoscale areas spanning an interface region that is far from atomically sharp, mapping the isotope concentration with a precision better than 20%. Although we use a scanning instrument, our method may be applicable to any atomic resolution transmission electron microscope and to other low-dimensional materials. Introduction Spectroscopy and microscopy are two fundamental pillars of materials science. By overcoming the diffraction limit of light, electron microscopy has emerged as a particularly powerful tool for studying low-dimensional materials such as graphene 1 , in which each atom can be distinguished. Through advances in aberration-corrected scanning transmission electron microscopy 2 , 3 (STEM) and electron energy loss spectroscopy 4 , 5 , the vision of a ‘synchrotron in a microscope’ 6 has now been realized. Spectroscopy of single atoms, including their spin state 7 , has together with Z-contrast imaging 3 allowed the identity and bonding of individual atoms to be unambiguously determined 4 , 8 , 9 , 10 . However, discerning the isotopes of a particular element has not been possible—a technique that might be called ‘mass spectrometer in a microscope’. Here we show how the quantum mechanical description of lattice vibrations lets us accurately model the stochastic ejection of single atoms 11 , 12 from graphene consisting of either of the two stable carbon isotopes. Our technique rests on a crucial difference between electrons and photons when used as a microscopy probe: due to their finite mass, electrons can transfer significant amounts of momentum. When a highly energetic electron is scattered by the electrostatic potential of an atomic nucleus, a maximal amount of kinetic energy (inversely proportional to the mass of the nucleus, ∝ ) can be transferred when the electron backscatters. When this energy is comparable to the energy required to eject an atom from the material, defined as the displacement threshold energy T d —for instance, when probing pristine 11 or doped 13 single-layer graphene with 60–100 keV electrons—atomic vibrations become important in activating otherwise energetically prohibited processes due to the motion of the nucleus in the direction of the electron beam. The intrinsic capability of STEM for imaging further allows us to map the isotope concentration in selected nanoscale areas of a mixed sample, demonstrating the spatial resolution of our technique. The ability to do mass analysis in the transmission electron microscope thus expands the possibilities for studying materials on the atomic scale. Results Quantum description of vibrations The velocities of atoms in a solid are distributed based on a temperature-dependent velocity distribution, defined by the vibrational modes of the material. Due to the geometry of a typical transmission electron microscopy (TEM) study of a two-dimensional material, the out-of-plane velocity v z , whose distribution is characterized by the mean square velocity , is here of particular interest. In an earlier study 11 this was estimated using a Debye approximation for the out-of-plane phonon density of states 14 (DOS) g z ( ω ), where ω is the phonon frequency. A better justified estimate can be achieved by calculating the kinetic energy of the atoms via the thermodynamic internal energy, evaluated using the full phonon DOS. As a starting point, we calculate the partition function Z =Tr{ e − H /( kT ) }, where Tr denotes the trace operation and k is the Boltzmann constant and T the absolute temperature. We evaluate this trace for the second-quantized Hamiltonian H describing harmonic lattice vibrations 15 : where ħ is the reduced Planck constant, k the phonon wave vector, j the phonon branch index running to 3 r ( r being the number of atoms in the unit cell), ω j ( k ) the eigenvalue of the j th mode at k , and n j ( k ) the number of phonons with frequency ω j ( k ). After computing the internal energy from the partition function via the Helmholtz free energy F =− kT ln Z , we obtain the Planck distribution function describing the occupation of the phonon bands (Methods). We must then explicitly separate the energy into the in-plane U p and out-of-plane U z components, and take into account that half the thermal energy equals the kinetic energy of the atoms. This gives the out-of-plane mean square velocity of a single atom in a two-atom unit cell as where M is the mass of the vibrating atom, ω z is the highest out-of-plane mode frequency, and the correct normalization of the number of modes is included in the DOS. Phonon dispersion To estimate the phonon DOS, we calculated through density functional theory (DFT; GPAW package 16 , 17 ) the graphene phonon band structure 18 , 19 via the dynamical matrix using the ‘frozen phonon method’ (Methods; Supplementary Fig. 1 ). Taking the density of the components corresponding to the out-of-plane acoustic (ZA) and optical (ZO) phonon modes ( Supplementary Data 1 ) and solving equation 2 numerically, we obtain a mean square velocity m 2 s −2 for a 12 C atom in normal graphene. This description can be extended to ‘heavy graphene’ (consisting of 13 C instead of a natural isotope mixture). A heavier atomic mass affects the velocity through two effects: the phonon band structure is scaled by the square root of the mass ratio (from the mass prefactor of the dynamical matrix), and the squared velocity is scaled by the mass ratio itself (equation", "role": "user" }, { "content": "The different elements found in nature each have their distinct isotopes. For carbon, there are 99 atoms of the lighter stable carbon isotope 12C for each 13C atom, which has one more neutron in its nucleus. Apart from this natural variation, materials can be grown from isotope-enriched chemicals. This allows scientists to study how the atoms arrange into solids, for example to improve their synthesis. Yet, most traditional techniques to measure the isotope ratio require the decomposition of the material or are limited to a resolution of hundreds of nanometers, obscuring important details. In the new study, led by Jani Kotakoski, the University of Vienna researchers used the advanced scanning transmission electron microscope Nion UltraSTEM100 to measure isotopes in nanometer-sized areas of a graphene sample. The same energetic electrons that form an image of the graphene structure can also eject one atom at a time due to scattering at a carbon nucleus. Because of the greater mass of the 13C isotope, an electron can give a 12C atom a slightly harder kick, knocking it out more easily. How many electrons are on average required gives an estimate of the local isotope concentration. \"The key to making this work was combining accurate experiments with an improved theoretical model of the process\", says Toma Susi, the lead author of the study. Publishing in Nature Communications allowed the team to fully embrace open science. In addition to releasing the peer review reports alongside the article, a comprehensive description of the methods and analyses is included. However, the researchers went one step further and uploaded their microscopy data onto the open repository figshare. Anyone with an Internet connection can thus freely access, use and cite the gigabytes of high-quality images. Toma Susi continues: \"To our knowledge, this is the first time electron microscopy data have been openly shared at this scale.\" The results show that atomic-resolution electron microscopes can distinguish between different isotopes of carbon. Although the method was now demonstrated only for graphene, it can in principle be extended for other two-dimensional materials, and the researchers have a patent pending on this invention. \"Modern microscopes already allow us to resolve all atomic distances in solids and to see which chemical elements compose them. Now we can add isotopes to the list\", Jani Kotakoski concludes. The lighter the atom, the fewer electrons are on everage needed to eject it. Credit: Copyright: Koponen+Hildén, Creative Commons BY 4.0 ", "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 Ångström-sized probe of the scanning transmission electron microscope can visualize and collect spectra from single atoms. This can unambiguously resolve the chemical structure of materials, but not their isotopic composition. Here we differentiate between two isotopes of the same element by quantifying how likely the energetic imaging electrons are to eject atoms. First, we measure the displacement probability in graphene grown from either 12 C or 13 C and describe the process using a quantum mechanical model of lattice vibrations coupled with density functional theory simulations. We then test our spatial resolution in a mixed sample by ejecting individual atoms from nanoscale areas spanning an interface region that is far from atomically sharp, mapping the isotope concentration with a precision better than 20%. Although we use a scanning instrument, our method may be applicable to any atomic resolution transmission electron microscope and to other low-dimensional materials. Introduction Spectroscopy and microscopy are two fundamental pillars of materials science. By overcoming the diffraction limit of light, electron microscopy has emerged as a particularly powerful tool for studying low-dimensional materials such as graphene 1 , in which each atom can be distinguished. Through advances in aberration-corrected scanning transmission electron microscopy 2 , 3 (STEM) and electron energy loss spectroscopy 4 , 5 , the vision of a ‘synchrotron in a microscope’ 6 has now been realized. Spectroscopy of single atoms, including their spin state 7 , has together with Z-contrast imaging 3 allowed the identity and bonding of individual atoms to be unambiguously determined 4 , 8 , 9 , 10 . However, discerning the isotopes of a particular element has not been possible—a technique that might be called ‘mass spectrometer in a microscope’. Here we show how the quantum mechanical description of lattice vibrations lets us accurately model the stochastic ejection of single atoms 11 , 12 from graphene consisting of either of the two stable carbon isotopes. Our technique rests on a crucial difference between electrons and photons when used as a microscopy probe: due to their finite mass, electrons can transfer significant amounts of momentum. When a highly energetic electron is scattered by the electrostatic potential of an atomic nucleus, a maximal amount of kinetic energy (inversely proportional to the mass of the nucleus, ∝ ) can be transferred when the electron backscatters. When this energy is comparable to the energy required to eject an atom from the material, defined as the displacement threshold energy T d —for instance, when probing pristine 11 or doped 13 single-layer graphene with 60–100 keV electrons—atomic vibrations become important in activating otherwise energetically prohibited processes due to the motion of the nucleus in the direction of the electron beam. The intrinsic capability of STEM for imaging further allows us to map the isotope concentration in selected nanoscale areas of a mixed sample, demonstrating the spatial resolution of our technique. The ability to do mass analysis in the transmission electron microscope thus expands the possibilities for studying materials on the atomic scale. Results Quantum description of vibrations The velocities of atoms in a solid are distributed based on a temperature-dependent velocity distribution, defined by the vibrational modes of the material. Due to the geometry of a typical transmission electron microscopy (TEM) study of a two-dimensional material, the out-of-plane velocity v z , whose distribution is characterized by the mean square velocity , is here of particular interest. In an earlier study 11 this was estimated using a Debye approximation for the out-of-plane phonon density of states 14 (DOS) g z ( ω ), where ω is the phonon frequency. A better justified estimate can be achieved by calculating the kinetic energy of the atoms via the thermodynamic internal energy, evaluated using the full phonon DOS. As a starting point, we calculate the partition function Z =Tr{ e − H /( kT ) }, where Tr denotes the trace operation and k is the Boltzmann constant and T the absolute temperature. We evaluate this trace for the second-quantized Hamiltonian H describing harmonic lattice vibrations 15 : where ħ is the reduced Planck constant, k the phonon wave vector, j the phonon branch index running to 3 r ( r being the number of atoms in the unit cell), ω j ( k ) the eigenvalue of the j th mode at k , and n j ( k ) the number of phonons with frequency ω j ( k ). After computing the internal energy from the partition function via the Helmholtz free energy F =− kT ln Z , we obtain the Planck distribution function describing the occupation of the phonon bands (Methods). We must then explicitly separate the energy into the in-plane U p and out-of-plane U z components, and take into account that half the thermal energy equals the kinetic energy of the atoms. This gives the out-of-plane mean square velocity of a single atom in a two-atom unit cell as where M is the mass of the vibrating atom, ω z is the highest out-of-plane mode frequency, and the correct normalization of the number of modes is included in the DOS. Phonon dispersion To estimate the phonon DOS, we calculated through density functional theory (DFT; GPAW package 16 , 17 ) the graphene phonon band structure 18 , 19 via the dynamical matrix using the ‘frozen phonon method’ (Methods; Supplementary Fig. 1 ). Taking the density of the components corresponding to the out-of-plane acoustic (ZA) and optical (ZO) phonon modes ( Supplementary Data 1 ) and solving equation 2 numerically, we obtain a mean square velocity m 2 s −2 for a 12 C atom in normal graphene. This description can be extended to ‘heavy graphene’ (consisting of 13 C instead of a natural isotope mixture). A heavier atomic mass affects the velocity through two effects: the phonon band structure is scaled by the square root of the mass ratio (from the mass prefactor of the dynamical matrix), and the squared velocity is scaled by the mass ratio itself (equation<|im_end|> <|im_start|>assistant The different elements found in nature each have their distinct isotopes. For carbon, there are 99 atoms of the lighter stable carbon isotope 12C for each 13C atom, which has one more neutron in its nucleus. Apart from this natural variation, materials can be grown from isotope-enriched chemicals. This allows scientists to study how the atoms arrange into solids, for example to improve their synthesis. Yet, most traditional techniques to measure the isotope ratio require the decomposition of the material or are limited to a resolution of hundreds of nanometers, obscuring important details. In the new study, led by Jani Kotakoski, the University of Vienna researchers used the advanced scanning transmission electron microscope Nion UltraSTEM100 to measure isotopes in nanometer-sized areas of a graphene sample. The same energetic electrons that form an image of the graphene structure can also eject one atom at a time due to scattering at a carbon nucleus. Because of the greater mass of the 13C isotope, an electron can give a 12C atom a slightly harder kick, knocking it out more easily. How many electrons are on average required gives an estimate of the local isotope concentration. "The key to making this work was combining accurate experiments with an improved theoretical model of the process", says Toma Susi, the lead author of the study. Publishing in Nature Communications allowed the team to fully embrace open science. In addition to releasing the peer review reports alongside the article, a comprehensive description of the methods and analyses is included. However, the researchers went one step further and uploaded their microscopy data onto the open repository figshare. Anyone with an Internet connection can thus freely access, use and cite the gigabytes of high-quality images. Toma Susi continues: "To our knowledge, this is the first time electron microscopy data have been openly shared at this scale." The results show that atomic-resolution electron microscopes can distinguish between different isotopes of carbon. Although the method was now demonstrated only for graphene, it can in principle be extended for other two-dimensional materials, and the researchers have a patent pending on this invention. "Modern microscopes already allow us to resolve all atomic distances in solids and to see which chemical elements compose them. Now we can add isotopes to the list", Jani Kotakoski concludes. The lighter the atom, the fewer electrons are on everage needed to eject it. Credit: Copyright: Koponen+Hildén, Creative Commons BY 4.0 <|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 An apparent absence of Silurian fishes more than half-a-metre in length has been viewed as evidence that gnathostomes were restricted in size and diversity prior to the Devonian. Here we describe the largest pre-Devonian vertebrate ( Megamastax amblyodus gen. et sp. nov.), a predatory marine osteichthyan from the Silurian Kuanti Formation (late Ludlow, ~423 million years ago) of Yunnan, China, with an estimated length of about 1 meter. The unusual dentition of the new form suggests a durophagous diet which, combined with its large size, indicates a considerable degree of trophic specialisation among early osteichthyans. The lack of large Silurian vertebrates has recently been used as constraint in palaeoatmospheric modelling, with purported lower oxygen levels imposing a physiological size limit. Regardless of the exact causal relationship between oxygen availability and evolutionary success, this finding refutes the assumption that pre-Emsian vertebrates were restricted to small body sizes. Introduction The Devonian Period has been considered to mark a major transition in the size and diversity of early gnathostomes (jawed vertebrates), including the earliest appearance of large vertebrate predators 1 . In contrast to the rich Devonian fossil record, gnathostomes from earlier strata have long been represented by scarce and highly fragmentary remains 2 . Traditional depictions of Silurian marine faunas typically either lack fish altogether 3 or are dominated by diminutive jawless forms 4 . In addition to this apparent low diversity, the maximum size of pre-Devonian gnathostomes and vertebrates in general, has been noted as being considerably smaller than later periods 1 . Until recently, the largest known Silurian gnathostomes were the osteichthyan Guiyu 5 and the antiarch placoderm Silurolepis 6 from the Ludlow Kuanti Formation of Yunnan, both with total body lengths of roughly 35 cm. Beyond the Silurian, the Ordovician agnathan Sacabambaspis from Bolivia is of comparable size 7 . The absence of pre-Devonian gnathostomes more than a few tens of centimeters in length, coupled with an apparent increase in size and diversity in the Early Devonian, has led to suggestions that jawed vertebrates were minor components of aquatic faunas prior to the Emsian 1 , 8 . Such an extended period of time with no apparent increase in body size is striking, given that the gnathostome fossil record may extend as far back as the Ordovician 9 , 10 . Recent discoveries reveal that Silurian gnathostomes were far more diverse and widely distributed than previously recognized 10 , 11 . Of particular importance is Xiaoxiang fauna of Yunnan Province, southwestern China, based on fossils from a series of marine sediments of which the Kuanti Formation is by far the most productive 12 , 13 . This unit has produced a diverse assemblage of early fishes, including the only articulated specimens of pre-Devonian gnathostomes. Here we present a bony fish from the Kuanti Formation ( Fig. 1 ) with an estimated length of about 1 meter, revealing that pre-Devonian gnathostomes could attain comparatively large sizes. The likely specialized predatory feeding habits of this form and anatomical disparity to other early osteichthyans, reinforce earlier indications of a significant degree of morphological and ecological diversity among gnathostomes well before the Devonian 10 , 14 . Figure 1 Silurian sequence in Qujing (Yunnan, China) with stratigraphic position of Megamastax amblyodus gen. et sp. nov. and other vertebrate taxa (modified from ref. 5 , using Adobe Illustrator 10). Full size image The apparent small size and limited diversity of Silurian gnathostomes has recently been employed as a constraint in paleoatmospheric reconstruction 1 , 8 . Models of atmospheric history based on geochemical data indicate a mid-Palaeozoic episode of global oceanic oxygenation, likely linked to the formation of a global terrestrial vascular flora and the concurrent widespread burial of organic matter 15 , 16 and roughly coinciding with the appearance of large gnathostomes in the fossil record. Our new finding refutes suggestions that there were significant environmental constraints to vertebrate body size prior to the Emsian (~400 Ma). Results Systematic palaeontology Gnathostomata, Gegenbaur, 1874 Osteichthyes, Huxley, 1880 Sarcopterygii, Romer, 1955 Megamastax amblyodus gen. et sp. nov. Etymology Genus named from megalos and mastax (Greek), meaning “big mouth”. The specific epithet is derived from amblys and odous (Greek) meaning “blunt tooth”. Holotype Institute of Vertebrate Paleontology and Paleoanthropology (IVPP) V18499.1, complete left mandible. Referred material IVPP V18499.2, partial left mandible; IVPP V18499.3, right maxilla. Type locality and horizon The Kuanti Formation, at a hill close to the Xiaoxiang Reservoir, Qujing, Yunnan, southwestern China ( Fig. 1 ), dating to the late Ludlow (Ludfordian Stage) 11 , 12 , 13 , with a youngest age of ~423 million years ago 17 . The fossils were collected from a horizon immediately below the first appearance of the conodont Ozarkodina crispa . Other fishes from this horizon include the galeaspid Dunyu 18 , the remarkable placoderm Entelognathus 19 and the osteichthyan Guiyu 5 , 20 . Diagnosis Osteichthyan with multiple rows of closely packed conical teeth on the marginal jaw bones and widely spaced pairs of blunt teeth fused to each of the four coronoids. Coronoids fused to the lingual face of the mandible with the posterior three flanked by an elongate anterior ramus of the prearticular. Outer surfaces of the mandible and maxilla covered in cosmine with numerous embedded pores. Description The external faces of the mandible ( Fig. 2A, F ) and maxilla ( Fig. 2I ) have a cosmine surface with numerous pores, as in Achoania and Psarolepis 21 . The mandible is long and low in overall shape, tapering anteriorly as in some Devonian limbed tetrapods 22 . It is gently convex in longitudinal and vertical axes, with slight medial curvature in dorsal view suggesting a narrow tapering snout. The sutured margins of the dermal bones are not clearly visible, although a small notch on the anteroventral jaw margin likely marks the posteromedial boundary of the splenial as in Achoania and Psarolepis 21 . There is a shallow semi-lunate overlap area for the maxilla and quadratojugal, while a horizontal pit-line runs almost end", "role": "user" }, { "content": "A team of researchers working at China's Kuanti formation has unearthed the largest known example of a jawed vertebrate from the early Dvonian, commonly known as the Silurian period. In their paper published in Scientific Reports, the team describes the predatory fish as being approximately 1 meter long with two types of teeth, one for catching prey, the other for crushing hard shells. The discovery adds new evidence to the theory that animals with backbones and jaws first developed in what is now China and also disrupts current theories regarding atmospheric oxygen levels during early Earth history. The researchers believe the fish, Big Mouth, Blunt Tooth (Megamastax amblyodus), lived approximately 423 million years ago—a time period that until this new discovery was thought to be characterized by low atmospheric oxygen levels. But a large fish such as Megamastax couldn't survive under such conditions, thus, levels must have been higher. The find actually consisted of three fossils from three different fish—one a whole lower jaw, the other two, both fragments of an upper jaw—all found at the Yunnan province dig site. The size of the jaw and teeth allowed the researchers to suggest the entire fish, when alive, would have been approximately 1 meter long. The teeth in front were sharp, for grabbing, while those in the back were clearly meant for grinding, likely hard shelled prey. The jaw was approximately 16 cm in length. Megamastax lower jaw: Holotype mandible (IVPP V18499.1) of Megamastax amblyodus gen. et sp. nov. in lateral, lingular, and dorsal views. Credit: Min Zhu Fossils of Megamastax amblyodus gen. et sp. nov. (A–E) Holotype mandible (IVPP V18499.1) in (A) lateral, (B) lingular, and (C) dorsal views; close-up of prearticular bone, showing surface ridges (D), and close-up of the marginal dentition in lingual view (E). (F–H) Partial mandible (V18499.2) in (F) lateral, (G) lingular, and (H) dorsal views. (I) Right maxilla (V18499.3) in lateral view. (J) Reconstruction of (i1) Guiyu oneiros alongside hypothetical silhouettes of (J2–3) Megamastax with superimposed fossil outlines. The (J2) smaller fish is based on the V18499.1 and V18499.3, the (J3) larger on V.18499.2. Credit, Min Zhu The researchers believe the fish was likely the largest predator in its environment—about triple the size of any other known fish from that time period—making it the dominant fish in the sea. During the Silurian period, the part of China where the fish was unearthed was part of the South China Sea. Fossil finds from the region predate jawed vertebrates found anywhere else thus far, suggesting the area was the birthplace of such creatures. They also believe that the reason Megamastax grew so large was because of intense competition between the many types of fish that existed at the time. But making it possible was the amount of oxygen available. Prior to the Silurian period, levels would have been too low. Interestingly, the most recent climate models used to depict early Earth conditions during the same period have also indicated higher atmospheric oxygen levels—this latest fossil find now backs that up. ", "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 An apparent absence of Silurian fishes more than half-a-metre in length has been viewed as evidence that gnathostomes were restricted in size and diversity prior to the Devonian. Here we describe the largest pre-Devonian vertebrate ( Megamastax amblyodus gen. et sp. nov.), a predatory marine osteichthyan from the Silurian Kuanti Formation (late Ludlow, ~423 million years ago) of Yunnan, China, with an estimated length of about 1 meter. The unusual dentition of the new form suggests a durophagous diet which, combined with its large size, indicates a considerable degree of trophic specialisation among early osteichthyans. The lack of large Silurian vertebrates has recently been used as constraint in palaeoatmospheric modelling, with purported lower oxygen levels imposing a physiological size limit. Regardless of the exact causal relationship between oxygen availability and evolutionary success, this finding refutes the assumption that pre-Emsian vertebrates were restricted to small body sizes. Introduction The Devonian Period has been considered to mark a major transition in the size and diversity of early gnathostomes (jawed vertebrates), including the earliest appearance of large vertebrate predators 1 . In contrast to the rich Devonian fossil record, gnathostomes from earlier strata have long been represented by scarce and highly fragmentary remains 2 . Traditional depictions of Silurian marine faunas typically either lack fish altogether 3 or are dominated by diminutive jawless forms 4 . In addition to this apparent low diversity, the maximum size of pre-Devonian gnathostomes and vertebrates in general, has been noted as being considerably smaller than later periods 1 . Until recently, the largest known Silurian gnathostomes were the osteichthyan Guiyu 5 and the antiarch placoderm Silurolepis 6 from the Ludlow Kuanti Formation of Yunnan, both with total body lengths of roughly 35 cm. Beyond the Silurian, the Ordovician agnathan Sacabambaspis from Bolivia is of comparable size 7 . The absence of pre-Devonian gnathostomes more than a few tens of centimeters in length, coupled with an apparent increase in size and diversity in the Early Devonian, has led to suggestions that jawed vertebrates were minor components of aquatic faunas prior to the Emsian 1 , 8 . Such an extended period of time with no apparent increase in body size is striking, given that the gnathostome fossil record may extend as far back as the Ordovician 9 , 10 . Recent discoveries reveal that Silurian gnathostomes were far more diverse and widely distributed than previously recognized 10 , 11 . Of particular importance is Xiaoxiang fauna of Yunnan Province, southwestern China, based on fossils from a series of marine sediments of which the Kuanti Formation is by far the most productive 12 , 13 . This unit has produced a diverse assemblage of early fishes, including the only articulated specimens of pre-Devonian gnathostomes. Here we present a bony fish from the Kuanti Formation ( Fig. 1 ) with an estimated length of about 1 meter, revealing that pre-Devonian gnathostomes could attain comparatively large sizes. The likely specialized predatory feeding habits of this form and anatomical disparity to other early osteichthyans, reinforce earlier indications of a significant degree of morphological and ecological diversity among gnathostomes well before the Devonian 10 , 14 . Figure 1 Silurian sequence in Qujing (Yunnan, China) with stratigraphic position of Megamastax amblyodus gen. et sp. nov. and other vertebrate taxa (modified from ref. 5 , using Adobe Illustrator 10). Full size image The apparent small size and limited diversity of Silurian gnathostomes has recently been employed as a constraint in paleoatmospheric reconstruction 1 , 8 . Models of atmospheric history based on geochemical data indicate a mid-Palaeozoic episode of global oceanic oxygenation, likely linked to the formation of a global terrestrial vascular flora and the concurrent widespread burial of organic matter 15 , 16 and roughly coinciding with the appearance of large gnathostomes in the fossil record. Our new finding refutes suggestions that there were significant environmental constraints to vertebrate body size prior to the Emsian (~400 Ma). Results Systematic palaeontology Gnathostomata, Gegenbaur, 1874 Osteichthyes, Huxley, 1880 Sarcopterygii, Romer, 1955 Megamastax amblyodus gen. et sp. nov. Etymology Genus named from megalos and mastax (Greek), meaning “big mouth”. The specific epithet is derived from amblys and odous (Greek) meaning “blunt tooth”. Holotype Institute of Vertebrate Paleontology and Paleoanthropology (IVPP) V18499.1, complete left mandible. Referred material IVPP V18499.2, partial left mandible; IVPP V18499.3, right maxilla. Type locality and horizon The Kuanti Formation, at a hill close to the Xiaoxiang Reservoir, Qujing, Yunnan, southwestern China ( Fig. 1 ), dating to the late Ludlow (Ludfordian Stage) 11 , 12 , 13 , with a youngest age of ~423 million years ago 17 . The fossils were collected from a horizon immediately below the first appearance of the conodont Ozarkodina crispa . Other fishes from this horizon include the galeaspid Dunyu 18 , the remarkable placoderm Entelognathus 19 and the osteichthyan Guiyu 5 , 20 . Diagnosis Osteichthyan with multiple rows of closely packed conical teeth on the marginal jaw bones and widely spaced pairs of blunt teeth fused to each of the four coronoids. Coronoids fused to the lingual face of the mandible with the posterior three flanked by an elongate anterior ramus of the prearticular. Outer surfaces of the mandible and maxilla covered in cosmine with numerous embedded pores. Description The external faces of the mandible ( Fig. 2A, F ) and maxilla ( Fig. 2I ) have a cosmine surface with numerous pores, as in Achoania and Psarolepis 21 . The mandible is long and low in overall shape, tapering anteriorly as in some Devonian limbed tetrapods 22 . It is gently convex in longitudinal and vertical axes, with slight medial curvature in dorsal view suggesting a narrow tapering snout. The sutured margins of the dermal bones are not clearly visible, although a small notch on the anteroventral jaw margin likely marks the posteromedial boundary of the splenial as in Achoania and Psarolepis 21 . There is a shallow semi-lunate overlap area for the maxilla and quadratojugal, while a horizontal pit-line runs almost end<|im_end|> <|im_start|>assistant A team of researchers working at China's Kuanti formation has unearthed the largest known example of a jawed vertebrate from the early Dvonian, commonly known as the Silurian period. In their paper published in Scientific Reports, the team describes the predatory fish as being approximately 1 meter long with two types of teeth, one for catching prey, the other for crushing hard shells. The discovery adds new evidence to the theory that animals with backbones and jaws first developed in what is now China and also disrupts current theories regarding atmospheric oxygen levels during early Earth history. The researchers believe the fish, Big Mouth, Blunt Tooth (Megamastax amblyodus), lived approximately 423 million years ago—a time period that until this new discovery was thought to be characterized by low atmospheric oxygen levels. But a large fish such as Megamastax couldn't survive under such conditions, thus, levels must have been higher. The find actually consisted of three fossils from three different fish—one a whole lower jaw, the other two, both fragments of an upper jaw—all found at the Yunnan province dig site. The size of the jaw and teeth allowed the researchers to suggest the entire fish, when alive, would have been approximately 1 meter long. The teeth in front were sharp, for grabbing, while those in the back were clearly meant for grinding, likely hard shelled prey. The jaw was approximately 16 cm in length. Megamastax lower jaw: Holotype mandible (IVPP V18499.1) of Megamastax amblyodus gen. et sp. nov. in lateral, lingular, and dorsal views. Credit: Min Zhu Fossils of Megamastax amblyodus gen. et sp. nov. (A–E) Holotype mandible (IVPP V18499.1) in (A) lateral, (B) lingular, and (C) dorsal views; close-up of prearticular bone, showing surface ridges (D), and close-up of the marginal dentition in lingual view (E). (F–H) Partial mandible (V18499.2) in (F) lateral, (G) lingular, and (H) dorsal views. (I) Right maxilla (V18499.3) in lateral view. (J) Reconstruction of (i1) Guiyu oneiros alongside hypothetical silhouettes of (J2–3) Megamastax with superimposed fossil outlines. The (J2) smaller fish is based on the V18499.1 and V18499.3, the (J3) larger on V.18499.2. Credit, Min Zhu The researchers believe the fish was likely the largest predator in its environment—about triple the size of any other known fish from that time period—making it the dominant fish in the sea. During the Silurian period, the part of China where the fish was unearthed was part of the South China Sea. Fossil finds from the region predate jawed vertebrates found anywhere else thus far, suggesting the area was the birthplace of such creatures. They also believe that the reason Megamastax grew so large was because of intense competition between the many types of fish that existed at the time. But making it possible was the amount of oxygen available. Prior to the Silurian period, levels would have been too low. Interestingly, the most recent climate models used to depict early Earth conditions during the same period have also indicated higher atmospheric oxygen levels—this latest fossil find now backs that up. <|im_end|>
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2,266
[ { "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 the mortality impact of COVID-19 requires not only counting the dead, but analyzing how premature the deaths are. We calculate years of life lost (YLL) across 81 countries due to COVID-19 attributable deaths, and also conduct an analysis based on estimated excess deaths. We find that over 20.5 million years of life have been lost to COVID-19 globally. As of January 6, 2021, YLL in heavily affected countries are 2–9 times the average seasonal influenza; three quarters of the YLL result from deaths in ages below 75 and almost a third from deaths below 55; and men have lost 45% more life years than women. The results confirm the large mortality impact of COVID-19 among the elderly. They also call for heightened awareness in devising policies that protect vulnerable demographics losing the largest number of life-years. Introduction The large direct and indirect effects of the COVID-19 pandemic have necessitated the delivery of policy responses that, when reasonable, are a balancing act between minimizing the immediate health impact of the pandemic, and containing the long-term damage to the society that may arise from the protective policies. A key input parameter in the calculation of how restrictive policies might be justified is the mortality impact of COVID-19. Attempts to evaluate the total mortality impact of COVID-19 are proceeding on several fronts. Progress is being made in estimating the infection fatality rate of COVID-19 and how this might vary across sub-populations 1 . Large, coordinated international collaborations have been set up to collect data that records COVID-19 attributable deaths. Attempts to estimate total excess mortality related to the COVID-19 are underway, and emphasized as an important measure 2 , 3 . Each of these research avenues and their associated health measures (infection rate, deaths and excess deaths) is important in informing the public and policymakers about the mortality impact of COVID-19. However, each come with their own limitations. Infection fatality rates apply only to the relatively small sub-population that has been confirmed to have the disease, and without knowledge about the true number of infected, these rates are inherently difficult to estimate. COVID-19 attributable deaths may over- or underestimate the true number of deaths that are due to the disease, as both policies and practices about coding the deaths are only being developed and standardized. Excess death approaches that compare mortality rates during the COVID-19 outbreak to a baseline depend on correctly estimating the baseline. The most important limitation in COVID-19 attributable death or excess death approaches, however, is that these approaches do not provide information on how many life years have been lost. Deaths at very old ages can be considered to result in fewer life years lost, when compared to deaths at very young ages. In fact, several policy responses (or non-responses) have been motivated with the argument that COVID-19 is mostly killing individuals who, even in the absence of COVID-19, would have had few life years remaining. However, comprehensive evaluation of the true mortality impact of COVID-19 has not been conducted. We analyze the premature mortality impact of COVID-19 by calculating the amount of life-years lost across 81 countries covering over 1,279,866 deaths. We base our analysis on two large recently established and continuously growing databases 4 , 5 and on two different methodological approaches, one based on COVID-19 attributable deaths, and, for selected countries, one based on estimated excess deaths comparing recent mortality levels to an estimated baseline. We are not able to solve the measurement limitations of either of these approaches, but the complementary nature of the two ways of measuring COVID-19 deaths makes these concerns explicit and allows us to evaluate the implications. This study is also limited to premature mortality only; a full health impact evaluation might consider for instance, the burden of disability associated with the disease 6 . This latter dimension requires thorough understanding of sequelae associated with COVID-19, for which data are limited at this point on a cross-country, comparable level. As such, we focus on premature mortality here. Methods Country death counts by age and gender due to COVID-19 come from the COVerAge-DB 4 ; the analysis includes all countries with at least one COVID-19 related death in 4 at the time of the study. Population data are drawn from the Human Mortality Database 5 and the World Population Prospects 7 . Country life expectancies are from the life tables in the World Population Prospects for the period 2015-2020. The dates at which data are collected, and death counts by country are reported in the Supplementary information materials (SI Table S1 ). Projections for total number of deaths due to COVID-19 by country are from the Imperial College 8 . Death counts due to other causes of mortality are from data in Global Burden of Disease 9 . Finally, we use weekly excess mortality data from the Short-Term Mortality Fluctuations Database (STMF, from the Human Mortality Database 5 ). A full description of the data, its sources, and the methodology is provided in the Supplementary Information. Results In total, 20,507,518 years of life have been lost to COVID-19 among the studied 81 countries, due to 1,279,866 deaths from the disease. The average years of life lost per death is 16 years. As countries are at different stages of the pandemic trajectory, this study is a snapshot of the impacts of COVID-19 on years of life lost (YLL) as of January 6, 2021 (a complete list of countries and their dates at measurement is in the Supplementary Information). In 35 of the countries in our sample, coverage of the data spans at least 9 months; in such cases, this suggests that the full impacts of the pandemic in 2020, or at least the first waves of the pandemic, are likely captured. For other countries still on an upwards incline of transmission rates or for which data is yet forthcoming for end of 2020, the YLL experienced are likely to further increase substantially in the next few months. We encourage context-based interpretation", "role": "user" }, { "content": "Over 20.5 million years of life may have been lost due to COVID-19 globally, with an average of 16 years lost per death, according to a study published in Scientific Reports. Years of life lost (YLL)—the difference between an individual's age at death and their life expectancy—due to COVID-19 in heavily affected countries may be two to nine times higher than YLL due to average seasonal influenza. Héctor Pifarré i Arolas, Mikko Mÿrskyla and colleagues estimated YLL due to COVID-19 using data on over 1,279,866 deaths in 81 countries, as well as life expectancy data and projections for total deaths of COVID-19 by country. The authors estimate that in total, 20,507,518 years of life may have been lost due to COVID-19 in the 81 countries included in this study—16 years per individual death. Of the total YLL, 44.9% seems to have occurred in individuals between 55 and 75 years of age, 30.2% in individuals younger than 55, and 25% in those older than 75. In countries for which death counts by gender were available, YLL was 44% higher in men than in women. Compared with other global common causes of death, YLL associated with COVID-19 is two to nine times greater than YLL associated with seasonal flu, and between a quarter and a half as much as the YLL attributable to heart conditions. The authors caution that the results need to be understood in the context of an ongoing pandemic: they provide a snapshot of the possible impacts of COVID-19 on YLL as of 6 January, 2021. Estimates of YLL may be over- or under-estimates due to the difficulty of accurately recording COVID-19-related deaths. ", "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 the mortality impact of COVID-19 requires not only counting the dead, but analyzing how premature the deaths are. We calculate years of life lost (YLL) across 81 countries due to COVID-19 attributable deaths, and also conduct an analysis based on estimated excess deaths. We find that over 20.5 million years of life have been lost to COVID-19 globally. As of January 6, 2021, YLL in heavily affected countries are 2–9 times the average seasonal influenza; three quarters of the YLL result from deaths in ages below 75 and almost a third from deaths below 55; and men have lost 45% more life years than women. The results confirm the large mortality impact of COVID-19 among the elderly. They also call for heightened awareness in devising policies that protect vulnerable demographics losing the largest number of life-years. Introduction The large direct and indirect effects of the COVID-19 pandemic have necessitated the delivery of policy responses that, when reasonable, are a balancing act between minimizing the immediate health impact of the pandemic, and containing the long-term damage to the society that may arise from the protective policies. A key input parameter in the calculation of how restrictive policies might be justified is the mortality impact of COVID-19. Attempts to evaluate the total mortality impact of COVID-19 are proceeding on several fronts. Progress is being made in estimating the infection fatality rate of COVID-19 and how this might vary across sub-populations 1 . Large, coordinated international collaborations have been set up to collect data that records COVID-19 attributable deaths. Attempts to estimate total excess mortality related to the COVID-19 are underway, and emphasized as an important measure 2 , 3 . Each of these research avenues and their associated health measures (infection rate, deaths and excess deaths) is important in informing the public and policymakers about the mortality impact of COVID-19. However, each come with their own limitations. Infection fatality rates apply only to the relatively small sub-population that has been confirmed to have the disease, and without knowledge about the true number of infected, these rates are inherently difficult to estimate. COVID-19 attributable deaths may over- or underestimate the true number of deaths that are due to the disease, as both policies and practices about coding the deaths are only being developed and standardized. Excess death approaches that compare mortality rates during the COVID-19 outbreak to a baseline depend on correctly estimating the baseline. The most important limitation in COVID-19 attributable death or excess death approaches, however, is that these approaches do not provide information on how many life years have been lost. Deaths at very old ages can be considered to result in fewer life years lost, when compared to deaths at very young ages. In fact, several policy responses (or non-responses) have been motivated with the argument that COVID-19 is mostly killing individuals who, even in the absence of COVID-19, would have had few life years remaining. However, comprehensive evaluation of the true mortality impact of COVID-19 has not been conducted. We analyze the premature mortality impact of COVID-19 by calculating the amount of life-years lost across 81 countries covering over 1,279,866 deaths. We base our analysis on two large recently established and continuously growing databases 4 , 5 and on two different methodological approaches, one based on COVID-19 attributable deaths, and, for selected countries, one based on estimated excess deaths comparing recent mortality levels to an estimated baseline. We are not able to solve the measurement limitations of either of these approaches, but the complementary nature of the two ways of measuring COVID-19 deaths makes these concerns explicit and allows us to evaluate the implications. This study is also limited to premature mortality only; a full health impact evaluation might consider for instance, the burden of disability associated with the disease 6 . This latter dimension requires thorough understanding of sequelae associated with COVID-19, for which data are limited at this point on a cross-country, comparable level. As such, we focus on premature mortality here. Methods Country death counts by age and gender due to COVID-19 come from the COVerAge-DB 4 ; the analysis includes all countries with at least one COVID-19 related death in 4 at the time of the study. Population data are drawn from the Human Mortality Database 5 and the World Population Prospects 7 . Country life expectancies are from the life tables in the World Population Prospects for the period 2015-2020. The dates at which data are collected, and death counts by country are reported in the Supplementary information materials (SI Table S1 ). Projections for total number of deaths due to COVID-19 by country are from the Imperial College 8 . Death counts due to other causes of mortality are from data in Global Burden of Disease 9 . Finally, we use weekly excess mortality data from the Short-Term Mortality Fluctuations Database (STMF, from the Human Mortality Database 5 ). A full description of the data, its sources, and the methodology is provided in the Supplementary Information. Results In total, 20,507,518 years of life have been lost to COVID-19 among the studied 81 countries, due to 1,279,866 deaths from the disease. The average years of life lost per death is 16 years. As countries are at different stages of the pandemic trajectory, this study is a snapshot of the impacts of COVID-19 on years of life lost (YLL) as of January 6, 2021 (a complete list of countries and their dates at measurement is in the Supplementary Information). In 35 of the countries in our sample, coverage of the data spans at least 9 months; in such cases, this suggests that the full impacts of the pandemic in 2020, or at least the first waves of the pandemic, are likely captured. For other countries still on an upwards incline of transmission rates or for which data is yet forthcoming for end of 2020, the YLL experienced are likely to further increase substantially in the next few months. We encourage context-based interpretation<|im_end|> <|im_start|>assistant Over 20.5 million years of life may have been lost due to COVID-19 globally, with an average of 16 years lost per death, according to a study published in Scientific Reports. Years of life lost (YLL)—the difference between an individual's age at death and their life expectancy—due to COVID-19 in heavily affected countries may be two to nine times higher than YLL due to average seasonal influenza. Héctor Pifarré i Arolas, Mikko Mÿrskyla and colleagues estimated YLL due to COVID-19 using data on over 1,279,866 deaths in 81 countries, as well as life expectancy data and projections for total deaths of COVID-19 by country. The authors estimate that in total, 20,507,518 years of life may have been lost due to COVID-19 in the 81 countries included in this study—16 years per individual death. Of the total YLL, 44.9% seems to have occurred in individuals between 55 and 75 years of age, 30.2% in individuals younger than 55, and 25% in those older than 75. In countries for which death counts by gender were available, YLL was 44% higher in men than in women. Compared with other global common causes of death, YLL associated with COVID-19 is two to nine times greater than YLL associated with seasonal flu, and between a quarter and a half as much as the YLL attributable to heart conditions. The authors caution that the results need to be understood in the context of an ongoing pandemic: they provide a snapshot of the possible impacts of COVID-19 on YLL as of 6 January, 2021. Estimates of YLL may be over- or under-estimates due to the difficulty of accurately recording COVID-19-related deaths. <|im_end|>
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1,671
[ { "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 connectomics, the study of the network structure of connected neurons, great advances are being made on two different scales: that of macro- and meso-scale connectomics, studying the connectivity between populations of neurons, and that of micro-scale connectomics, studying connectivity between individual neurons. We combine these two complementary views of connectomics to build a first draft statistical model of the micro-connectome of a whole mouse neocortex based on available data on region-to-region connectivity and individual whole-brain axon reconstructions. This process reveals a targeting principle that allows us to predict the innervation logic of individual axons from meso-scale data. The resulting connectome recreates biological trends of targeting on all scales and predicts that an established principle of scale invariant topological organization of connectivity can be extended down to the level of individual neurons. It can serve as a powerful null model and as a substrate for whole-brain simulations. Introduction The study of connectomics has to date largely taken place on two separate levels with disjunct methods and results: macro-connectomics, studying the structure and strength of long-range projections between brain regions, and micro-connectomics, studying the topology of individual neuron-to-neuron connectivity within a region. In macro-connectomics, the absence or presence and strength of projections between brain regions are measured using for example, histological pathway tracing, retrograde 1 , 2 or anterograde 3 tracers, or MR diffusion tractography 4 , 5 . While recent advances made it possible to turn such data into connectome models with a resolution of 100 μm 6 , this is still far away from single-neuron resolution. In micro-connectomics, two complementary approaches prevail: stochastic models and direct measures of synaptic connectivity using, for example, electron microscopy. The first uses biological findings to formulate principles that rule out certain classes of wiring diagrams and prescribe probabilities to the remaining ones, while with electron microscopy, snapshots of individual biological wiring diagrams are taken 7 , 8 , 9 , 10 , 11 , 12 , 13 . However, published reconstructed volumes at this point only contain incomplete dendritic trees, and therefore incomplete connectivity. To gain a full understanding of, for example the role of an individual neuron or small groups of neurons in a given behavior, we will have to integrate the advantages of both scales: single-neuron resolution on a whole-brain or at least whole-neocortex level. This has been recognized before 14 , but steps toward this goal have until now remained limited. At this point, electron-microscopic reconstructions at that scale are not viable, leaving only statistical approaches to dense micro-connectivity, based on identifying biological principles in the data. Scaling it up to a whole-neocortex level will amplify the uncertainty about the biological accuracy of the results, as many of the resulting connections will be between rarely studied brain regions with little available biological data. Nevertheless, it can serve as a first draft micro-connectome defining a null model to compare and evaluate future findings against. It will also allow us to perform full-neocortex simulations at cellular resolution to gain insights, as to which brain function can or cannot be explained with a given connectome. We have completed such a first-draft connectome of mouse neocortex by using an improved version of our previously published circuit and connectivity modeling pipeline 15 . It has been improved to place neurons in brain-atlas defined 3d spaces instead of hexagonal prisms, taking into account the geometry and cellular composition of individual brain regions. However, this did not include long-range connections between brain regions, especially the ones formed via projections along the white matter. We therefore set out to identify possible principles, hypotheses of rules constraining the long-range connectivity, and develop stochastic methods to instantiate micro-connectomes fulfilling them. A first constraint was given by the data on macro- or mesoscale connectivity, which is often reported as a region-to-region connection matrix, yielding a measure proportional to the total number of synapses forming a projection between pairs of brain regions 1 , 14 , 16 , 17 . We used for this purpose, the recently published mesoscale mouse brain connectome of Harris et al. 3 . This data set splits the mouse neocortex into 86 separate regions (43 per hemisphere) and further splits each region when considered as a source of a projection into five individual projection classes, by layer or pathway (Layer 23IT, Layer 4IT, Layer 5IT, Layer 5PT, and Layer 6CT). IT refers to intratelencephalic projections, targeting the ipsilateral and contralateral cortex and striatum; PT refers to pyramidal tract projections, predominantly targeting subcortical structures, but also ipsilateral cortex; CT refers to corticothalamic projections. From here on, we will leave out this additional distinction for projections from layers 2/3, 4, and 6, where only one class is specified in the data of ref. 3 . While the data set does not include GABAergic projection neurons 18 , it provides the most comprehensive information on connection strengths of individual projection classes to date. We further constrained the spatial structure of each projection within the target region. Along the vertical axis (orthogonal to layer boundaries), this was achieved by assigning a layer profile to each projection, as provided by Harris et al. 3 . Along the horizontal axes, we assumed a generalized topographical mapping between regions, parameterized using a voxelized (resolution 100 μm) version of the data provided by Knox et al. 6 . As a final constraint, we applied rules on the number and identity of brain regions innervated by individual neurons in a given source region. To this end, we analyzed the brain regions innervated by individual in vivo reconstructions of whole-brain axons in a published data set (MouseLight project at Janelia, mouselight.janelia.org 19 ). Based on the analysis, we conceptualized and parameterized a decision tree of long-range axon targeting that reproduced the targeting rules found in the in vivo data. This approach was generalized to other brain regions for which few or no axonal reconstructions are available. Finally, we implemented a stochastic algorithm that connected morphologically detailed neurons in a 3d-volume representing the entire mouse neocortex. Synapses", "role": "user" }, { "content": "Researchers at EPFL's Blue Brain Project, a Swiss brain research Initiative, have combined two high profile, large-scale datasets to produce something completely new—a first draft model of the rules guiding neuron-to-neuron connectivity of a whole mouse neocortex. They generated statistical instances of the micro-connectome of 10 million neurons, a model spanning five orders of magnitude and containing 88 billion synaptic connections. A basis for the world's largest-scale simulations of detailed neural circuits. Identifying the connections across all neurons in every region of the neocortex The structure of synaptic connections between neurons shapes their activity and function. Measuring a comprehensive snapshot of this so-called connectome has so far only been accomplished within tiny volumes, smaller than the head of a pin. For larger volumes, the long-range connectivity, formed by bundles of extremely thin but long fibers, has only been studied for small numbers of individual neurons, which is far from a complete picture. Alternatively, it has been studied at the macro-scale, a 'zoomed-out' view of average features that does not provide single-cell resolution. In a paper published in Nature Communications, the Blue Brain researchers have shown that the trick lies in combining these two views. By integrating data from two recent datasets—the Allen Mouse Brain Connectivity Atlas and Janelia MouseLight—the researchers identified some of the key rules that dictate which individual neurons can form connections over large distances within the neocortex. This was possible because the two datasets complemented each other in terms of entirety of the neocortex and the cellular resolution provided. Emergence of a surprisingly complex structure at single-cell resolution Building on their previous work in modelling local brain circuits, the researchers were then able to parameterize these principles of neocortical connectivity and generate statistical connectome instances compatible with them. When they studied the resulting structure, they found something fascinating; at cellular resolution, a surprisingly complex structure that had so far only been seen between neighboring neurons now also tied together neurons in different regions and at opposite ends of the brain. This was comparable to a rule of self-similarity that has been previously found in the human brain (MRI data) and predicts that it extends all the way down to the level of individual neurons. \"This made me re-think how I think about these long-range connections,\" reveals lead researcher Michael Reimann. \"They have been depicted as these blunt cables, connecting or synchronizing whole brain regions. But maybe there is more to them, more specific targeting of individual neurons. And this is what we learned from just a few, relatively course-grained principles. I expect that with improved methods we will find more in the future.\" Researchers at EPFL's Blue Brain Project, a Swiss brain research Initiative have combined two high profile, large-scale datasets to produce something completely new - a first draft model of the rules guiding neuron-to-neuron connectivity of a whole mouse neocortex. Credit: Blue Brain Project / EPFL Openly accessible connectome can serve as a powerful null model to compare experimental findings \"We have completed such a first-draft connectome of mouse neocortex by using an improved version of our previously published circuit building pipeline (Markram et al., 2015),\" explains Michael Reimann. \"It has been improved to place neurons in brain-atlas defined 3d spaces instead of hexagonal prisms, taking into account the geometry and cellular composition of individual brain regions. The composition was based on data from the open source Blue Brain Cell Atlas. Further constraints were derived from other openly accessible datasets. Additional constraints that are so far unknown are likely to limit long-range connectivity even more. To start a process of iterative refinement, we made the model and data available to the public. The parameterized constraints on projection strength, mapping, layer profiles and individual axon targeting (i.e. the projection recipe), as well as stochastic instantiations of whole-neocortex micro-connectomes can be found under https://portal.bluebrain.epfl.ch/resources/models/mouse-projections\". This openly accessible connectome can serve as a powerful null model to compare experimental findings to and as a substrate for whole-brain simulations of detailed neural networks. Sparse connection matrices of several instances of the predicted null model of neocortical long-range connectivity have also been publicly available as this result actively demonstrates the power of making datasets available to the public. Further advancing the case for Simulation The simulation (in-silico) method allowed the scientists to target volumes several orders of magnitude smaller, than would be possible with experimental methods, right down to the innervation of individual neurons with sub-cellular resolution. Going forward, this will allow the simulation of the electrical activity of individual neurons, entire regions or of the entire neocortex. \"This paper builds upon Blue Brain's earlier work on evaluating morphological constraints on connectivity, \"Morphological Diversity Strongly Constrains Synaptic Connectivity and Plasticity,\" (Cerebral Cortex, 2017) and \"Reconstruction and Simulation of Neocortical Microcircuitry' (Cell 2015) explains Blue Brain Founder and Director Prof. Henry Markram. \"The findings enable us continue our simulation experiments at an exponentially increasing rate meaning, we can now build biologically accurate brain models of bigger and bigger brain regions and at a higher and higher resolution thereby further advancing the case for simulation.\" ", "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 connectomics, the study of the network structure of connected neurons, great advances are being made on two different scales: that of macro- and meso-scale connectomics, studying the connectivity between populations of neurons, and that of micro-scale connectomics, studying connectivity between individual neurons. We combine these two complementary views of connectomics to build a first draft statistical model of the micro-connectome of a whole mouse neocortex based on available data on region-to-region connectivity and individual whole-brain axon reconstructions. This process reveals a targeting principle that allows us to predict the innervation logic of individual axons from meso-scale data. The resulting connectome recreates biological trends of targeting on all scales and predicts that an established principle of scale invariant topological organization of connectivity can be extended down to the level of individual neurons. It can serve as a powerful null model and as a substrate for whole-brain simulations. Introduction The study of connectomics has to date largely taken place on two separate levels with disjunct methods and results: macro-connectomics, studying the structure and strength of long-range projections between brain regions, and micro-connectomics, studying the topology of individual neuron-to-neuron connectivity within a region. In macro-connectomics, the absence or presence and strength of projections between brain regions are measured using for example, histological pathway tracing, retrograde 1 , 2 or anterograde 3 tracers, or MR diffusion tractography 4 , 5 . While recent advances made it possible to turn such data into connectome models with a resolution of 100 μm 6 , this is still far away from single-neuron resolution. In micro-connectomics, two complementary approaches prevail: stochastic models and direct measures of synaptic connectivity using, for example, electron microscopy. The first uses biological findings to formulate principles that rule out certain classes of wiring diagrams and prescribe probabilities to the remaining ones, while with electron microscopy, snapshots of individual biological wiring diagrams are taken 7 , 8 , 9 , 10 , 11 , 12 , 13 . However, published reconstructed volumes at this point only contain incomplete dendritic trees, and therefore incomplete connectivity. To gain a full understanding of, for example the role of an individual neuron or small groups of neurons in a given behavior, we will have to integrate the advantages of both scales: single-neuron resolution on a whole-brain or at least whole-neocortex level. This has been recognized before 14 , but steps toward this goal have until now remained limited. At this point, electron-microscopic reconstructions at that scale are not viable, leaving only statistical approaches to dense micro-connectivity, based on identifying biological principles in the data. Scaling it up to a whole-neocortex level will amplify the uncertainty about the biological accuracy of the results, as many of the resulting connections will be between rarely studied brain regions with little available biological data. Nevertheless, it can serve as a first draft micro-connectome defining a null model to compare and evaluate future findings against. It will also allow us to perform full-neocortex simulations at cellular resolution to gain insights, as to which brain function can or cannot be explained with a given connectome. We have completed such a first-draft connectome of mouse neocortex by using an improved version of our previously published circuit and connectivity modeling pipeline 15 . It has been improved to place neurons in brain-atlas defined 3d spaces instead of hexagonal prisms, taking into account the geometry and cellular composition of individual brain regions. However, this did not include long-range connections between brain regions, especially the ones formed via projections along the white matter. We therefore set out to identify possible principles, hypotheses of rules constraining the long-range connectivity, and develop stochastic methods to instantiate micro-connectomes fulfilling them. A first constraint was given by the data on macro- or mesoscale connectivity, which is often reported as a region-to-region connection matrix, yielding a measure proportional to the total number of synapses forming a projection between pairs of brain regions 1 , 14 , 16 , 17 . We used for this purpose, the recently published mesoscale mouse brain connectome of Harris et al. 3 . This data set splits the mouse neocortex into 86 separate regions (43 per hemisphere) and further splits each region when considered as a source of a projection into five individual projection classes, by layer or pathway (Layer 23IT, Layer 4IT, Layer 5IT, Layer 5PT, and Layer 6CT). IT refers to intratelencephalic projections, targeting the ipsilateral and contralateral cortex and striatum; PT refers to pyramidal tract projections, predominantly targeting subcortical structures, but also ipsilateral cortex; CT refers to corticothalamic projections. From here on, we will leave out this additional distinction for projections from layers 2/3, 4, and 6, where only one class is specified in the data of ref. 3 . While the data set does not include GABAergic projection neurons 18 , it provides the most comprehensive information on connection strengths of individual projection classes to date. We further constrained the spatial structure of each projection within the target region. Along the vertical axis (orthogonal to layer boundaries), this was achieved by assigning a layer profile to each projection, as provided by Harris et al. 3 . Along the horizontal axes, we assumed a generalized topographical mapping between regions, parameterized using a voxelized (resolution 100 μm) version of the data provided by Knox et al. 6 . As a final constraint, we applied rules on the number and identity of brain regions innervated by individual neurons in a given source region. To this end, we analyzed the brain regions innervated by individual in vivo reconstructions of whole-brain axons in a published data set (MouseLight project at Janelia, mouselight.janelia.org 19 ). Based on the analysis, we conceptualized and parameterized a decision tree of long-range axon targeting that reproduced the targeting rules found in the in vivo data. This approach was generalized to other brain regions for which few or no axonal reconstructions are available. Finally, we implemented a stochastic algorithm that connected morphologically detailed neurons in a 3d-volume representing the entire mouse neocortex. Synapses<|im_end|> <|im_start|>assistant Researchers at EPFL's Blue Brain Project, a Swiss brain research Initiative, have combined two high profile, large-scale datasets to produce something completely new—a first draft model of the rules guiding neuron-to-neuron connectivity of a whole mouse neocortex. They generated statistical instances of the micro-connectome of 10 million neurons, a model spanning five orders of magnitude and containing 88 billion synaptic connections. A basis for the world's largest-scale simulations of detailed neural circuits. Identifying the connections across all neurons in every region of the neocortex The structure of synaptic connections between neurons shapes their activity and function. Measuring a comprehensive snapshot of this so-called connectome has so far only been accomplished within tiny volumes, smaller than the head of a pin. For larger volumes, the long-range connectivity, formed by bundles of extremely thin but long fibers, has only been studied for small numbers of individual neurons, which is far from a complete picture. Alternatively, it has been studied at the macro-scale, a 'zoomed-out' view of average features that does not provide single-cell resolution. In a paper published in Nature Communications, the Blue Brain researchers have shown that the trick lies in combining these two views. By integrating data from two recent datasets—the Allen Mouse Brain Connectivity Atlas and Janelia MouseLight—the researchers identified some of the key rules that dictate which individual neurons can form connections over large distances within the neocortex. This was possible because the two datasets complemented each other in terms of entirety of the neocortex and the cellular resolution provided. Emergence of a surprisingly complex structure at single-cell resolution Building on their previous work in modelling local brain circuits, the researchers were then able to parameterize these principles of neocortical connectivity and generate statistical connectome instances compatible with them. When they studied the resulting structure, they found something fascinating; at cellular resolution, a surprisingly complex structure that had so far only been seen between neighboring neurons now also tied together neurons in different regions and at opposite ends of the brain. This was comparable to a rule of self-similarity that has been previously found in the human brain (MRI data) and predicts that it extends all the way down to the level of individual neurons. "This made me re-think how I think about these long-range connections," reveals lead researcher Michael Reimann. "They have been depicted as these blunt cables, connecting or synchronizing whole brain regions. But maybe there is more to them, more specific targeting of individual neurons. And this is what we learned from just a few, relatively course-grained principles. I expect that with improved methods we will find more in the future." Researchers at EPFL's Blue Brain Project, a Swiss brain research Initiative have combined two high profile, large-scale datasets to produce something completely new - a first draft model of the rules guiding neuron-to-neuron connectivity of a whole mouse neocortex. Credit: Blue Brain Project / EPFL Openly accessible connectome can serve as a powerful null model to compare experimental findings "We have completed such a first-draft connectome of mouse neocortex by using an improved version of our previously published circuit building pipeline (Markram et al., 2015)," explains Michael Reimann. "It has been improved to place neurons in brain-atlas defined 3d spaces instead of hexagonal prisms, taking into account the geometry and cellular composition of individual brain regions. The composition was based on data from the open source Blue Brain Cell Atlas. Further constraints were derived from other openly accessible datasets. Additional constraints that are so far unknown are likely to limit long-range connectivity even more. To start a process of iterative refinement, we made the model and data available to the public. The parameterized constraints on projection strength, mapping, layer profiles and individual axon targeting (i.e. the projection recipe), as well as stochastic instantiations of whole-neocortex micro-connectomes can be found under https://portal.bluebrain.epfl.ch/resources/models/mouse-projections". This openly accessible connectome can serve as a powerful null model to compare experimental findings to and as a substrate for whole-brain simulations of detailed neural networks. Sparse connection matrices of several instances of the predicted null model of neocortical long-range connectivity have also been publicly available as this result actively demonstrates the power of making datasets available to the public. Further advancing the case for Simulation The simulation (in-silico) method allowed the scientists to target volumes several orders of magnitude smaller, than would be possible with experimental methods, right down to the innervation of individual neurons with sub-cellular resolution. Going forward, this will allow the simulation of the electrical activity of individual neurons, entire regions or of the entire neocortex. "This paper builds upon Blue Brain's earlier work on evaluating morphological constraints on connectivity, "Morphological Diversity Strongly Constrains Synaptic Connectivity and Plasticity," (Cerebral Cortex, 2017) and "Reconstruction and Simulation of Neocortical Microcircuitry' (Cell 2015) explains Blue Brain Founder and Director Prof. Henry Markram. "The findings enable us continue our simulation experiments at an exponentially increasing rate meaning, we can now build biologically accurate brain models of bigger and bigger brain regions and at a higher and higher resolution thereby further advancing the case for simulation." <|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 investigation of two-dimensional atomically thin superconductors—especially those hosting topological states—attracts growing interest in condensed-matter physics. Here we report the observation of spin–orbit–parity coupled superconducting state in centrosymmetric atomically thin 2M-WS 2 , a material that has been predicted to exhibit topological band inversions. Our magnetotransport measurements show that the in-plane upper critical field not only exceeds the Pauli paramagnetic limit but also exhibits a strongly anisotropic two-fold symmetry in response to the in-plane magnetic field direction. Furthermore, tunnelling spectroscopy measurements conducted under high in-plane magnetic fields reveal that the superconducting gap possesses an anisotropic magnetic response along different in-plane magnetic field directions, and it persists much above the Pauli limit. Self-consistent mean-field calculations show that this unusual behaviour originates from the strong spin–orbit–parity coupling arising from the topological band inversion in 2M-WS 2 , which effectively pins the spin of states near the topological band crossing and gives rise to an anisotropic renormalization of the effect of external Zeeman fields. Our results identify the unconventional superconductivity in atomically thin 2M-WS 2 , which serves as a promising platform for exploring the interplay between superconductivity, topology and strong spin–orbit–parity coupling. Main Two-dimensional (2D) crystalline superconductors serve as wonderful platforms 1 , 2 for the search of intriguing quantum phenomena, such as quantum metallic ground state 3 , 4 , non-reciprocal charge transport 5 , 6 , 7 and large in-plane upper critical field \\(B_{{\\mathrm{C2}}}^{||}\\) (refs. 8 , 9 , 10 , 11 , 12 ). In non-centrosymmetric superconductors, the spin–orbit coupling (SOC) lifts spin degeneracies of the electronic bands, which enhances \\(B_{{\\mathrm{C2}}}^{||}\\) and gives rise to the Zeeman-protected superconductivity 2 , 8 , 10 , 11 , 12 , 13 . One particular example is the Ising superconductivity in liquid-gated MoS 2 (molybdenum disulfide) (refs. 8 , 10 ), 2D NbSe 2 (niobium diselenide) (refs. 11 , 12 ) and monolayer TaS 2 (tantalum disulfide) (ref. 13 ). Beyond non-centrosymmetric superconductors, the study of Ising-protected superconductivity has recently been extended to centrosymmetric superconductors, such as stanene 9 and PdTe 2 (palladium ditelluride) (ref. 14 ) thin films, where the SOC induces spin–orbit locking near the Γ point 15 and generates enhanced \\(B_{{\\mathrm{C2}}}^{||}\\) . In general, exploring and understanding the microscopic origin of the novel superconducting states that are resilient to large magnetic fields is of great interest to both fundamental and applied physics. When combining superconductivity and topology, topological superconducting states with Majorana fermions can emerge, which is the central component for fault-tolerant quantum computing 16 , 17 , 18 . Moreover, the further presence of inversion symmetry can enrich the topological structure of a system and enable the manifestation of topological crystalline superconductors 19 , 20 , 21 . Recently, a theory proposed that 2D centrosymmetric superconductors with a topological band inversion 22 , such as the 1T′-WTe 2 (refs. 23 , 24 , 25 , 26 , 27 ), exhibit a distinct type of superconductivity termed as spin–orbit–parity coupled superconductivity 28 . As depicted in Fig. 1a , near the topological band inversion where bands with opposite parities invert, a topological gap opens. In this scenario, the conventional SOC terms that involve only spin and momentum are forbidden by inversion symmetry, but the spin, momentum and parities of the electronic states are allowed to couple together near the topological band inversion, referred to as spin–orbit–parity coupling (SOPC). This SOPC is predicted to produce novel superconductivity near the topological band crossing with both largely enhanced \\(B_{{\\mathrm{C2}}}^{||}\\) and anisotropic spin susceptibility with respect to in-plane magnetic field directions 28 . Experimentally, the emergent van der Waals superconductor 2M-WS 2 (2M phase tungsten disulfide) (ref. 29 ) is believed to be a promising candidate for spin–orbit–parity coupled superconductivity. Monolayer 2M-WS 2 shares an identical structure with 1T′-WTe 2 , but it possesses a stacking mode distinct from other transition metal dichalcogenides 30 . Its bulk material exhibits a high superconducting transition temperature T C of 8.8 K (ref. 30 ) and hosts many intriguing phenomena, including the evidence of anisotropic Majorana bound states 31 and topological surface states 32 . Furthermore, theoretical calculations predict that 2M-WS 2 holds topological edge states with band inversion in the atomically thin limit 33 , 34 , making it an attractive platform to explore exotic superconducting states. Fig. 1: Crystal structure and characterizations of 2M-WS 2 . a , Schematic plot of two bands of opposite parity getting inverted at Γ with colour indicating different orbitals (represented by dark blue and red, respectively). The spectrum after projection is depicted to show such topological band inversion that can give rise to edge states. The SOPC superconductivity appears when cooper pairs are formed with the states near the topological band crossing (such as near Fermi level E F ), where SOPC is strong and crucial. b , Top and side views of the crystal structure of 2M-WS 2 , where the a axis (purple dashed line), b axis (pink dashed line), c axis (light blue dashed line) and c* axis (dark blue dashed line oriented perpendicular to the {001} planes) are marked. Tungsten atoms are shifted from their octahedral sites due to the strong intermetallic bonding, forming the visible zigzag metal–metal chains along the a axis. c , Density functional theory calculated d states for the tungsten atoms and p states for the sulfur atoms projected onto the monolayer (left) and bilayer (right) electronic bands of the 2M-WS 2 , where a clear band inversion between W and S bands can be observed around the Γ point. d , Optical images of few-layer flakes of 2M-WS 2 cleaved on a SiO 2 /Si substrate. The number of layers (L) is labelled in the left image and the a axis of each crystal is marked by cyan dashed lines in both the left and right images. Scale bars, 4 μm. e , TEM bright-field image taken from a section of an exfoliated 2M-WS 2 ribbon-like flake, with the inset being the selected area electron diffraction pattern. It", "role": "user" }, { "content": "In recent years, many physicists and material scientists have been studying superconductors, materials that can conduct direct current electricity without energy loss when cooled under a particular temperature. These materials could have numerous valuable applications, for instance generating energy for imaging machines (e.g., MRI scanners), trains, and other technological systems. Researchers at Fudan University, Shanghai Qi Zhi Institute, Hong Kong University of Science and Technology, and other institutes in China have recently uncovered a new mechanism to generate anisotropically-enhanced in-plane upper critical field in atomically thin centrosymmetric superconductors with topological band inversions. Their paper, published in Nature Physics, specifically demonstrated this mechanism on a thin layer of 2M-WS2, a material that has recently attracted much research attention. \"In 2020, a paper by our theoretical collaborator Prof. K.T. Law proposed that 2D centrosymmetric superconductors with a topological band inversion, such as 1T′-WTe2 exhibit a distinct type of superconductivity, called spin-orbit-parity coupled (SOPC) superconductivity,\" Enze Zhang, one of the researchers who carried out the study, told Phys.org. \"SOPC is predicted to produce novel superconductivity near the topological band crossing with both largely enhanced and anisotropic spin susceptibility with respect to in-plane magnetic field directions. At that time, we were conducting research on the superconducting properties of atomically thin 2M-WS2, so after talking with Prof. K.T. Law, we felt that the emergent van der Waals superconductor 2M-WS2 would most likely be a promising candidate for spin-orbit-parity coupled superconductivity.\" The structure of monolayer 2M-WS2 is identical to that of 1T′-WTe2, the material previously investigated by Prof. Law and his team. 2M-WS2, however, has a unique stacking mode, which distinguishes it from other transition metal dichalcogenides. The researchers previously found that in its bulk form, this material exhibit a high superconducting transition temperature TC of 8.8 K. In addition, theoretical calculations suggested that atomically thin layers of 2M-WS2 hold topological edge states with band inversion. In their experiments, Zhang and his colleagues measured the in-plane upper critical field at a high magnetic field and confirmed the violation of the Pauli limit law. They also observed a strongly anisotropic two-fold symmetry in the material, in response to the in-plane magnetic field direction. \"Tunneling experiments conducted under high in-plane magnetic fields also showed that the superconducting gap in atomically thin 2M-WS2 possesses an anisotropic magnetic response along different in-plane magnetic field directions, and it persists much above the Pauli limit,\" Zhang explained. \"Using self-consistent mean-field calculations, our theoretical collaborators conclude that these unusual behaviors originate from the strong spin-orbit-parity coupling arising from the topological band inversion in 2M-WS2.\" The researchers' experiments spanned across several steps. Firstly, the team performed magneto-transport measurements on atomically thin 2M-WS2 and found that its in-plane upper critical field is not only far beyond the Pauli paramagnetic limit, but also exhibits a strongly anisotropic two-fold symmetry in response to the in-plane magnetic field direction. Subsequently, they used tunneling spectroscopy to collect measurements under high in-plane magnetic fields. These measurements revealed that the superconducting gap in atomically thin 2M-WS2 possesses an anisotropic magnetic response along different in-plane magnetic field directions, which persists much above the Pauli limit. Finally, the researchers performed a series of self-consistent mean-field calculations to better understand the origin of the unusual behaviors they observed in their sample. Based on their results, they concluded that these behaviors originate from the strong spin-orbit-parity coupling arising from the topological band inversion in 2M-WS2, which effectively pins the spin of states near the topological band crossing and renormalizes the effect of external Zeeman fields anisotropically. \"We uncovered a new mechanism for generating an anisotropically-enhanced in-plane upper critical field in atomically thin centrosymmetric superconductors with topological band inversions, highlighting 2D 2M-WS2 as a wonderful platform for the study of exotic superconducting phenomena such as higher-order topological superconductivity and further device applications,\" Zhang said. \"The novel properties found here are highly nontrivial as they directly reflect a strong SOPC inheriting from the topological band inversion in the normal state of 2M-WS2, which had been ignored for many years in previous studies of centrosymmetric superconductors.\" In recent years, more research teams worldwide have been exploring the properties and mechanisms of centrosymmetric superconducting transition metal dichalcogenides (TMDs), such as monolayer superconducting 1T′-MoS2, and 1T′-WTe2, due to the characteristic co-existence of topological band structure and superconductivity within them. The recent paper by Zhang and his colleagues could pave the way towards the exploration of large enhanced and strongly anisotropic in-plane upper critical fields, which could further improve the current understanding of these materials' exotic physics. \"We now plan to explore the usual superconducting properties (such as the in-plane upper critical field and tunneling spectroscopy behavior at high magnetic field) of more atomically thin centrosymmetric superconductors with topological band inversions,\" Zhang added. ", "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 investigation of two-dimensional atomically thin superconductors—especially those hosting topological states—attracts growing interest in condensed-matter physics. Here we report the observation of spin–orbit–parity coupled superconducting state in centrosymmetric atomically thin 2M-WS 2 , a material that has been predicted to exhibit topological band inversions. Our magnetotransport measurements show that the in-plane upper critical field not only exceeds the Pauli paramagnetic limit but also exhibits a strongly anisotropic two-fold symmetry in response to the in-plane magnetic field direction. Furthermore, tunnelling spectroscopy measurements conducted under high in-plane magnetic fields reveal that the superconducting gap possesses an anisotropic magnetic response along different in-plane magnetic field directions, and it persists much above the Pauli limit. Self-consistent mean-field calculations show that this unusual behaviour originates from the strong spin–orbit–parity coupling arising from the topological band inversion in 2M-WS 2 , which effectively pins the spin of states near the topological band crossing and gives rise to an anisotropic renormalization of the effect of external Zeeman fields. Our results identify the unconventional superconductivity in atomically thin 2M-WS 2 , which serves as a promising platform for exploring the interplay between superconductivity, topology and strong spin–orbit–parity coupling. Main Two-dimensional (2D) crystalline superconductors serve as wonderful platforms 1 , 2 for the search of intriguing quantum phenomena, such as quantum metallic ground state 3 , 4 , non-reciprocal charge transport 5 , 6 , 7 and large in-plane upper critical field \(B_{{\mathrm{C2}}}^{||}\) (refs. 8 , 9 , 10 , 11 , 12 ). In non-centrosymmetric superconductors, the spin–orbit coupling (SOC) lifts spin degeneracies of the electronic bands, which enhances \(B_{{\mathrm{C2}}}^{||}\) and gives rise to the Zeeman-protected superconductivity 2 , 8 , 10 , 11 , 12 , 13 . One particular example is the Ising superconductivity in liquid-gated MoS 2 (molybdenum disulfide) (refs. 8 , 10 ), 2D NbSe 2 (niobium diselenide) (refs. 11 , 12 ) and monolayer TaS 2 (tantalum disulfide) (ref. 13 ). Beyond non-centrosymmetric superconductors, the study of Ising-protected superconductivity has recently been extended to centrosymmetric superconductors, such as stanene 9 and PdTe 2 (palladium ditelluride) (ref. 14 ) thin films, where the SOC induces spin–orbit locking near the Γ point 15 and generates enhanced \(B_{{\mathrm{C2}}}^{||}\) . In general, exploring and understanding the microscopic origin of the novel superconducting states that are resilient to large magnetic fields is of great interest to both fundamental and applied physics. When combining superconductivity and topology, topological superconducting states with Majorana fermions can emerge, which is the central component for fault-tolerant quantum computing 16 , 17 , 18 . Moreover, the further presence of inversion symmetry can enrich the topological structure of a system and enable the manifestation of topological crystalline superconductors 19 , 20 , 21 . Recently, a theory proposed that 2D centrosymmetric superconductors with a topological band inversion 22 , such as the 1T′-WTe 2 (refs. 23 , 24 , 25 , 26 , 27 ), exhibit a distinct type of superconductivity termed as spin–orbit–parity coupled superconductivity 28 . As depicted in Fig. 1a , near the topological band inversion where bands with opposite parities invert, a topological gap opens. In this scenario, the conventional SOC terms that involve only spin and momentum are forbidden by inversion symmetry, but the spin, momentum and parities of the electronic states are allowed to couple together near the topological band inversion, referred to as spin–orbit–parity coupling (SOPC). This SOPC is predicted to produce novel superconductivity near the topological band crossing with both largely enhanced \(B_{{\mathrm{C2}}}^{||}\) and anisotropic spin susceptibility with respect to in-plane magnetic field directions 28 . Experimentally, the emergent van der Waals superconductor 2M-WS 2 (2M phase tungsten disulfide) (ref. 29 ) is believed to be a promising candidate for spin–orbit–parity coupled superconductivity. Monolayer 2M-WS 2 shares an identical structure with 1T′-WTe 2 , but it possesses a stacking mode distinct from other transition metal dichalcogenides 30 . Its bulk material exhibits a high superconducting transition temperature T C of 8.8 K (ref. 30 ) and hosts many intriguing phenomena, including the evidence of anisotropic Majorana bound states 31 and topological surface states 32 . Furthermore, theoretical calculations predict that 2M-WS 2 holds topological edge states with band inversion in the atomically thin limit 33 , 34 , making it an attractive platform to explore exotic superconducting states. Fig. 1: Crystal structure and characterizations of 2M-WS 2 . a , Schematic plot of two bands of opposite parity getting inverted at Γ with colour indicating different orbitals (represented by dark blue and red, respectively). The spectrum after projection is depicted to show such topological band inversion that can give rise to edge states. The SOPC superconductivity appears when cooper pairs are formed with the states near the topological band crossing (such as near Fermi level E F ), where SOPC is strong and crucial. b , Top and side views of the crystal structure of 2M-WS 2 , where the a axis (purple dashed line), b axis (pink dashed line), c axis (light blue dashed line) and c* axis (dark blue dashed line oriented perpendicular to the {001} planes) are marked. Tungsten atoms are shifted from their octahedral sites due to the strong intermetallic bonding, forming the visible zigzag metal–metal chains along the a axis. c , Density functional theory calculated d states for the tungsten atoms and p states for the sulfur atoms projected onto the monolayer (left) and bilayer (right) electronic bands of the 2M-WS 2 , where a clear band inversion between W and S bands can be observed around the Γ point. d , Optical images of few-layer flakes of 2M-WS 2 cleaved on a SiO 2 /Si substrate. The number of layers (L) is labelled in the left image and the a axis of each crystal is marked by cyan dashed lines in both the left and right images. Scale bars, 4 μm. e , TEM bright-field image taken from a section of an exfoliated 2M-WS 2 ribbon-like flake, with the inset being the selected area electron diffraction pattern. It<|im_end|> <|im_start|>assistant In recent years, many physicists and material scientists have been studying superconductors, materials that can conduct direct current electricity without energy loss when cooled under a particular temperature. These materials could have numerous valuable applications, for instance generating energy for imaging machines (e.g., MRI scanners), trains, and other technological systems. Researchers at Fudan University, Shanghai Qi Zhi Institute, Hong Kong University of Science and Technology, and other institutes in China have recently uncovered a new mechanism to generate anisotropically-enhanced in-plane upper critical field in atomically thin centrosymmetric superconductors with topological band inversions. Their paper, published in Nature Physics, specifically demonstrated this mechanism on a thin layer of 2M-WS2, a material that has recently attracted much research attention. "In 2020, a paper by our theoretical collaborator Prof. K.T. Law proposed that 2D centrosymmetric superconductors with a topological band inversion, such as 1T′-WTe2 exhibit a distinct type of superconductivity, called spin-orbit-parity coupled (SOPC) superconductivity," Enze Zhang, one of the researchers who carried out the study, told Phys.org. "SOPC is predicted to produce novel superconductivity near the topological band crossing with both largely enhanced and anisotropic spin susceptibility with respect to in-plane magnetic field directions. At that time, we were conducting research on the superconducting properties of atomically thin 2M-WS2, so after talking with Prof. K.T. Law, we felt that the emergent van der Waals superconductor 2M-WS2 would most likely be a promising candidate for spin-orbit-parity coupled superconductivity." The structure of monolayer 2M-WS2 is identical to that of 1T′-WTe2, the material previously investigated by Prof. Law and his team. 2M-WS2, however, has a unique stacking mode, which distinguishes it from other transition metal dichalcogenides. The researchers previously found that in its bulk form, this material exhibit a high superconducting transition temperature TC of 8.8 K. In addition, theoretical calculations suggested that atomically thin layers of 2M-WS2 hold topological edge states with band inversion. In their experiments, Zhang and his colleagues measured the in-plane upper critical field at a high magnetic field and confirmed the violation of the Pauli limit law. They also observed a strongly anisotropic two-fold symmetry in the material, in response to the in-plane magnetic field direction. "Tunneling experiments conducted under high in-plane magnetic fields also showed that the superconducting gap in atomically thin 2M-WS2 possesses an anisotropic magnetic response along different in-plane magnetic field directions, and it persists much above the Pauli limit," Zhang explained. "Using self-consistent mean-field calculations, our theoretical collaborators conclude that these unusual behaviors originate from the strong spin-orbit-parity coupling arising from the topological band inversion in 2M-WS2." The researchers' experiments spanned across several steps. Firstly, the team performed magneto-transport measurements on atomically thin 2M-WS2 and found that its in-plane upper critical field is not only far beyond the Pauli paramagnetic limit, but also exhibits a strongly anisotropic two-fold symmetry in response to the in-plane magnetic field direction. Subsequently, they used tunneling spectroscopy to collect measurements under high in-plane magnetic fields. These measurements revealed that the superconducting gap in atomically thin 2M-WS2 possesses an anisotropic magnetic response along different in-plane magnetic field directions, which persists much above the Pauli limit. Finally, the researchers performed a series of self-consistent mean-field calculations to better understand the origin of the unusual behaviors they observed in their sample. Based on their results, they concluded that these behaviors originate from the strong spin-orbit-parity coupling arising from the topological band inversion in 2M-WS2, which effectively pins the spin of states near the topological band crossing and renormalizes the effect of external Zeeman fields anisotropically. "We uncovered a new mechanism for generating an anisotropically-enhanced in-plane upper critical field in atomically thin centrosymmetric superconductors with topological band inversions, highlighting 2D 2M-WS2 as a wonderful platform for the study of exotic superconducting phenomena such as higher-order topological superconductivity and further device applications," Zhang said. "The novel properties found here are highly nontrivial as they directly reflect a strong SOPC inheriting from the topological band inversion in the normal state of 2M-WS2, which had been ignored for many years in previous studies of centrosymmetric superconductors." In recent years, more research teams worldwide have been exploring the properties and mechanisms of centrosymmetric superconducting transition metal dichalcogenides (TMDs), such as monolayer superconducting 1T′-MoS2, and 1T′-WTe2, due to the characteristic co-existence of topological band structure and superconductivity within them. The recent paper by Zhang and his colleagues could pave the way towards the exploration of large enhanced and strongly anisotropic in-plane upper critical fields, which could further improve the current understanding of these materials' exotic physics. "We now plan to explore the usual superconducting properties (such as the in-plane upper critical field and tunneling spectroscopy behavior at high magnetic field) of more atomically thin centrosymmetric superconductors with topological band inversions," Zhang added. <|im_end|>
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2307, 77752, 1105, 11, 7384, 430, 649, 6929, 2167, 1510, 18200, 2085, 4907, 4814, 994, 65410, 1234, 264, 4040, 9499, 13, 4314, 7384, 1436, 617, 12387, 15525, 8522, 11, 369, 2937, 24038, 4907, 369, 32758, 12933, 320, 68, 1326, 2637, 52460, 95146, 705, 28788, 11, 323, 1023, 30116, 6067, 13, 59250, 520, 435, 664, 276, 3907, 11, 38147, 58094, 1901, 6151, 10181, 11, 19730, 18711, 3907, 315, 10170, 323, 12053, 11, 323, 1023, 94812, 304, 5734, 617, 6051, 43522, 264, 502, 17383, 311, 7068, 459, 285, 354, 897, 2740, 84182, 4979, 304, 90649, 8582, 9200, 2115, 304, 19670, 2740, 15792, 2960, 3714, 30559, 2307, 77752, 1105, 449, 1948, 5848, 7200, 1558, 36379, 13, 11205, 5684, 11, 4756, 304, 22037, 28415, 11, 11951, 21091, 420, 17383, 389, 264, 15792, 6324, 315, 220, 17, 44, 12, 7585, 17, 11, 264, 3769, 430, 706, 6051, 29123, 1790, 3495, 6666, 13, 330, 644, 220, 2366, 15, 11, 264, 5684, 555, 1057, 32887, 11430, 859, 8626, 13, 735, 844, 13, 7658, 11223, 430, 220, 17, 35, 2960, 3714, 30559, 2307, 77752, 1105, 449, 264, 1948, 5848, 7200, 47588, 11, 1778, 439, 220, 16, 51, 39615, 12, 54, 6777, 17, 31324, 264, 12742, 955, 315, 2307, 77752, 1968, 11, 2663, 12903, 27609, 4590, 58098, 488, 34356, 320, 50, 3143, 34, 8, 2307, 77752, 1968, 1359, 2998, 3059, 37120, 11, 832, 315, 279, 12074, 889, 11953, 704, 279, 4007, 11, 3309, 13101, 2726, 13, 330, 50, 3143, 34, 374, 19698, 311, 8356, 11775, 2307, 77752, 1968, 3221, 279, 1948, 5848, 7200, 27736, 449, 2225, 14090, 24872, 323, 459, 285, 79432, 12903, 88636, 449, 5201, 311, 304, 90649, 24924, 2115, 18445, 13, 2468, 430, 892, 11, 584, 1051, 31474, 3495, 389, 279, 2307, 77752, 287, 6012, 315, 19670, 2740, 15792, 220, 17, 44, 12, 7585, 17, 11, 779, 1306, 7556, 449, 8626, 13, 735, 844, 13, 7658, 11, 584, 6612, 430, 279, 7425, 306, 5355, 2761, 29614, 1147, 2307, 444, 36869, 220, 17, 44, 12, 7585, 17, 1053, 1455, 4461, 387, 264, 26455, 9322, 369, 12903, 27609, 4590, 58098, 488, 34356, 2307, 77752, 1968, 1210, 578, 6070, 315, 1647, 337, 1155, 220, 17, 44, 12, 7585, 17, 374, 20086, 311, 430, 315, 220, 16, 51, 39615, 12, 54, 6777, 17, 11, 279, 3769, 8767, 27313, 555, 8626, 13, 7658, 323, 813, 2128, 13, 220, 17, 44, 12, 7585, 17, 11, 4869, 11, 706, 264, 5016, 75172, 3941, 11, 902, 19512, 21168, 433, 505, 1023, 9320, 9501, 29953, 17356, 11968, 3422, 13, 578, 12074, 8767, 1766, 430, 304, 1202, 20155, 1376, 11, 420, 3769, 31324, 264, 1579, 2307, 77752, 287, 9320, 9499, 25610, 315, 220, 23, 13, 23, 735, 13, 763, 5369, 11, 32887, 29217, 12090, 430, 19670, 2740, 15792, 13931, 315, 220, 17, 44, 12, 7585, 17, 3412, 1948, 5848, 6964, 5415, 449, 7200, 47588, 13, 763, 872, 21896, 11, 37120, 323, 813, 18105, 17303, 279, 304, 90649, 8582, 9200, 2115, 520, 264, 1579, 24924, 2115, 323, 11007, 279, 20535, 315, 279, 7043, 72, 4017, 2383, 13, 2435, 1101, 13468, 264, 16917, 459, 285, 79432, 1403, 24325, 46220, 304, 279, 3769, 11, 304, 2077, 311, 279, 304, 90649, 24924, 2115, 5216, 13, 330, 51, 41392, 287, 21896, 13375, 1234, 1579, 304, 90649, 24924, 5151, 1101, 8710, 430, 279, 2307, 77752, 287, 13225, 304, 19670, 2740, 15792, 220, 17, 44, 12, 7585, 17, 50326, 459, 459, 285, 79432, 24924, 2077, 3235, 2204, 304, 90649, 24924, 2115, 18445, 11, 323, 433, 67145, 1790, 3485, 279, 7043, 72, 4017, 1359, 37120, 11497, 13, 330, 16834, 659, 69604, 18620, 3152, 19677, 29217, 11, 1057, 32887, 79119, 32194, 430, 1521, 19018, 28198, 82316, 505, 279, 3831, 12903, 27609, 4590, 58098, 488, 59086, 40986, 505, 279, 1948, 5848, 7200, 47588, 304, 220, 17, 44, 12, 7585, 17, 1210, 578, 12074, 6, 21896, 9575, 19212, 4028, 3892, 7504, 13, 77795, 11, 279, 2128, 10887, 8622, 11269, 12, 27543, 22323, 389, 19670, 2740, 15792, 220, 17, 44, 12, 7585, 17, 323, 1766, 430, 1202, 304, 90649, 8582, 9200, 2115, 374, 539, 1193, 3117, 7953, 279, 7043, 72, 1719, 39100, 4017, 11, 719, 1101, 50829, 264, 16917, 459, 285, 79432, 1403, 24325, 46220, 304, 2077, 311, 279, 304, 90649, 24924, 2115, 5216, 13, 3804, 39742, 11, 814, 1511, 26711, 287, 66425, 51856, 311, 6667, 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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 Fibre and bulk optical isolators are widely used to stabilize laser cavities by preventing unwanted feedback. However, their integrated counterparts have been slow to be adopted. Although several strategies for on-chip optical isolation have been realized, these rely on either integration of magneto-optic materials or high-frequency modulation with acousto-optic or electro-optic modulators. Here we demonstrate an integrated approach for passively isolating a continuous-wave laser using the intrinsically non-reciprocal Kerr nonlinearity in ring resonators. Using silicon nitride as a model platform, we achieve single ring isolation of 17–23 dB with 1.8–5.5-dB insertion loss, and a cascaded ring isolation of 35 dB with 5-dB insertion loss. Employing these devices, we demonstrate hybrid integration and isolation with a semiconductor laser chip. Main The effort to integrate high-performance optical systems on-chip has made tremendous progress in recent years. Advances in ultra-low-loss photonic platforms 1 , nonlinear photonics 2 and heterogeneous material integration 1 , 3 have enabled fully integrated turnkey frequency-comb sources 1 , 4 , on-chip lasers with hertz linewidth 5 , terabits-per-second (Tbps) communications on-chip 6 , 7 , on-chip optical amplifiers 8 and much more. Although these systems will continue to improve, a lack of integrated optical isolation limits their performance. Optical isolators allow for the transmission of light in one direction while preventing transmission in the other. This non-reciprocal behaviour is critical in optical systems in order to stabilize lasers and reduce noise by preventing unwanted back-reflection 9 . In traditional fibre and bulk optical systems, non-reciprocal transmission is achieved by the use of Faraday-effect-induced non-reciprocal polarization rotation under an external magnetic field 9 , 10 , 11 . This approach can be replicated on-chip by integrating magneto-optic materials into waveguides 10 . However, the scalability of the approach remains a substantial challenge due to the required custom material fabrication and lack of complementary metal–oxide–semiconductor (CMOS) compatibility. Furthermore, magneto-optic materials require a very strong magnet for their operation due to their weak effects in the visible to near-infrared (NIR) wavelength range 12 , 13 and are therefore difficult to operate in an integrated platform. More recently, there has been remarkable progress in integrating magnet-free isolators using an active drive to break reciprocity. This drive has taken the form of a synthetic magnet 14 , 15 , stimulated Brillouin scattering 16 , 17 and spatio-temporal modulation 18 , 19 , 20 . However, the requirement for an external drive increases the system complexity, often requires additional fabrication, and consumes power. Additionally, high-power radiofrequency drives contribute large amounts of electromagnetic background that can interfere with the sensitive electronics and photodetection in photonic integrated circuits. This poses inevitable challenges to the scalability and adoption of such devices. Therefore, to maximize the scalability and integration into current photonic integrated circuits, an ideal isolator would be fully passive and magnet-free. Optical nonlinearity is a promising path towards breaking reciprocity 21 , 22 , 23 , 24 , 25 , and is inherently present in most widely utilized photonic platforms, such as silicon nitride 2 , 26 , silicon 22 , gallium phosphide 27 , tantala 28 , silicon carbide 29 , 30 and lithium niobate 31 , 32 . Unfortunately, due to dynamic reciprocity, many proposals for non-reciprocal transmission using optical nonlinearities cannot function as isolators 33 . However, by carefully choosing the mode of operation, isolation using optical nonlinearity is possible and has been demonstrated with discrete components 24 . In this Article we demonstrate integrated continuous-wave isolators using the Kerr effect present in thin-film silicon-nitride ring resonators. The Kerr effect breaks the degeneracy between the clockwise and counterclockwise modes of the ring and allows for nonreciprocal transmission. These devices are fully passive and require no input besides the laser that is being isolated. As such, the only power overhead is the small insertion loss from coupling of the ring resonator. Additionally, many integrated optical systems that would benefit from isolators already have high-quality silicon-nitride or commensurate components and could easily integrate this type of isolator with CMOS-compatible fabrication 1 . By varying the coupling of the ring resonators we can trade off insertion loss and isolation. As two examples, we demonstrate devices with a peak isolation of 23 dB with 4.6-dB insertion loss and isolation of 17 dB with a 1.3-dB insertion loss with 90 mW of optical power. As we are using an integrated photonics platform, we can reproducibly fabricate and cascade multiple isolators on the same chip, allowing us to demonstrate two cascaded isolators with an overall isolation ratio of 35 dB. Finally, we butt-couple a semiconductor laser-diode chip to the silicon-nitride isolators and demonstrate optical isolation in a system on a chip. Theory of operation The Kerr effect is the change in refractive index of a material due to its third-order nonlinearity in susceptibility, χ (3) . In the presence of two electric fields, the nonlinear polarization corresponding to this term is given by \\({P}^{(3)}{(t)}={\\epsilon }_{0}{\\chi }^{(3)}{({E}_{1}{\\rm{e}}^{-i{\\omega }_{1}t}+{E}_{2}{\\rm{e}}^{-i{\\omega }_{2}t}+{\\rm{c.c.}})}^{3}\\) . Expanding this polynomial and keeping only the terms with the same frequencies, we find that \\({P}^{(3)}({\\omega }_{1})={3}{\\epsilon }_{0}{\\chi }^{(3)}(| {E}_{1}{| }^{2}+{2}| {E}_{2}{| }^{2}){E}_{1}{\\rm{e}}^{-i{\\omega }_{1}t}\\) and \\({P}^{(3)}({\\omega }_{2})={3}{\\epsilon }_{0}{\\chi }^{(3)}({2}| {E}_{1}{| }^{2}+| {E}_{2}{| }^{2}){E}_{2}{\\rm{e}}^{-i{\\omega }_{1}t}\\) . Thus, there is an effective increase in the refractive index proportional to the optical intensity. Critically, the index change differs by a factor of two depending on the source of the optical power. The field that is degenerate with the mode under consideration contributes a refractive index increase of 3 ϵ 0 χ (3) | E | 2 , self-phase modulation (SPM). The field that is non-degenerate contributes a refractive index increase of 6 ϵ 0 χ (3) | E | 2 , cross-phase modulation (XPM). This difference provides an intrinsic non-reciprocity. If a strong pump beam is sent through a waveguide, and a weak probe is sent through in the other direction, the probe will accrue an additional phase shift due to the Kerr effect that is twice that of the pump. We can apply the same principle to construct an isolator. Consider", "role": "user" }, { "content": "Lasers are transformational devices, but one technical challenge prevents them from being even more so. The light they emit can reflect back into the laser itself and destabilize or even disable it. At real-world scales, this challenge is solved by bulky devices that use magnetism to block the harmful reflections. At chip scale, however, where engineers hope lasers will one day transform computer circuitry, effective isolators have proved elusive. Against that backdrop, researchers at Stanford University say they have created a simple and effective chip-scale isolator that can be laid down in a layer of semiconductor-based material hundreds of times thinner than a sheet of paper. \"Chip-scale isolation is one of the great open challenges in photonics,\" said Jelena Vučković, a professor of electrical engineering at Stanford and senior author of the study appearing Dec. 1 in the journal Nature Photonics. \"Every laser needs an isolator to stop back reflections from coming into and destabilizing the laser,\" said Alexander White, a doctoral candidate in Vučković's lab and co-first author of the paper, adding that the device has implications for everyday computing, but could also influence next-generation technologies, like quantum computing. Small and passive The nanoscale isolator is promising for several reasons. First, this isolator is \"passive.\" It requires no external inputs, complicated electronics, or magnetics—technical challenges that have stymied progress in chip-scale lasers to date. These additional mechanisms lead to devices that are too bulky for integrated photonics applications and can cause electrical interference that compromises other components on the chips. Another advantage is that the new isolator is also made from common and well-known semiconductor-based material and can be manufactured using existing semiconductor processing technologies, potentially easing its path to mass production. The new isolator is shaped like a ring. It is made of silicon nitride, a material based on the most commonly used semiconductor—silicon. The strong primary laser beam enters the ring and the photons begin to spin around the ring in a clockwise direction. At the same time, a back-reflected beam would be sent back into the ring in the opposite direction, spinning in a counterclockwise fashion. \"The laser power that we put in circulates many times and this allows us to build up inside the ring. This increasing power alters the weaker beam, while the stronger one continues unaffected,\" explains co-first author Geun Ho Ahn, a doctoral candidate in electrical engineering of the phenomenon that causes the weaker beam to stop resonating. \"The reflected light, and only the reflected light, is effectively canceled.\" The primary laser then exits the ring and is \"isolated\" in the desired direction. Vučković and team have built a prototype as a proof of concept and were able to couple two ring isolators in a cascade to achieve better performance. \"Next steps include working on isolators for different frequencies of light,\" said co-author Kasper Van Gasse, a post-doctoral scholar in Vučković's lab. \"As well as tighter integration of components at chip scale to explore other uses of the isolator and improve performance.\" ", "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 Fibre and bulk optical isolators are widely used to stabilize laser cavities by preventing unwanted feedback. However, their integrated counterparts have been slow to be adopted. Although several strategies for on-chip optical isolation have been realized, these rely on either integration of magneto-optic materials or high-frequency modulation with acousto-optic or electro-optic modulators. Here we demonstrate an integrated approach for passively isolating a continuous-wave laser using the intrinsically non-reciprocal Kerr nonlinearity in ring resonators. Using silicon nitride as a model platform, we achieve single ring isolation of 17–23 dB with 1.8–5.5-dB insertion loss, and a cascaded ring isolation of 35 dB with 5-dB insertion loss. Employing these devices, we demonstrate hybrid integration and isolation with a semiconductor laser chip. Main The effort to integrate high-performance optical systems on-chip has made tremendous progress in recent years. Advances in ultra-low-loss photonic platforms 1 , nonlinear photonics 2 and heterogeneous material integration 1 , 3 have enabled fully integrated turnkey frequency-comb sources 1 , 4 , on-chip lasers with hertz linewidth 5 , terabits-per-second (Tbps) communications on-chip 6 , 7 , on-chip optical amplifiers 8 and much more. Although these systems will continue to improve, a lack of integrated optical isolation limits their performance. Optical isolators allow for the transmission of light in one direction while preventing transmission in the other. This non-reciprocal behaviour is critical in optical systems in order to stabilize lasers and reduce noise by preventing unwanted back-reflection 9 . In traditional fibre and bulk optical systems, non-reciprocal transmission is achieved by the use of Faraday-effect-induced non-reciprocal polarization rotation under an external magnetic field 9 , 10 , 11 . This approach can be replicated on-chip by integrating magneto-optic materials into waveguides 10 . However, the scalability of the approach remains a substantial challenge due to the required custom material fabrication and lack of complementary metal–oxide–semiconductor (CMOS) compatibility. Furthermore, magneto-optic materials require a very strong magnet for their operation due to their weak effects in the visible to near-infrared (NIR) wavelength range 12 , 13 and are therefore difficult to operate in an integrated platform. More recently, there has been remarkable progress in integrating magnet-free isolators using an active drive to break reciprocity. This drive has taken the form of a synthetic magnet 14 , 15 , stimulated Brillouin scattering 16 , 17 and spatio-temporal modulation 18 , 19 , 20 . However, the requirement for an external drive increases the system complexity, often requires additional fabrication, and consumes power. Additionally, high-power radiofrequency drives contribute large amounts of electromagnetic background that can interfere with the sensitive electronics and photodetection in photonic integrated circuits. This poses inevitable challenges to the scalability and adoption of such devices. Therefore, to maximize the scalability and integration into current photonic integrated circuits, an ideal isolator would be fully passive and magnet-free. Optical nonlinearity is a promising path towards breaking reciprocity 21 , 22 , 23 , 24 , 25 , and is inherently present in most widely utilized photonic platforms, such as silicon nitride 2 , 26 , silicon 22 , gallium phosphide 27 , tantala 28 , silicon carbide 29 , 30 and lithium niobate 31 , 32 . Unfortunately, due to dynamic reciprocity, many proposals for non-reciprocal transmission using optical nonlinearities cannot function as isolators 33 . However, by carefully choosing the mode of operation, isolation using optical nonlinearity is possible and has been demonstrated with discrete components 24 . In this Article we demonstrate integrated continuous-wave isolators using the Kerr effect present in thin-film silicon-nitride ring resonators. The Kerr effect breaks the degeneracy between the clockwise and counterclockwise modes of the ring and allows for nonreciprocal transmission. These devices are fully passive and require no input besides the laser that is being isolated. As such, the only power overhead is the small insertion loss from coupling of the ring resonator. Additionally, many integrated optical systems that would benefit from isolators already have high-quality silicon-nitride or commensurate components and could easily integrate this type of isolator with CMOS-compatible fabrication 1 . By varying the coupling of the ring resonators we can trade off insertion loss and isolation. As two examples, we demonstrate devices with a peak isolation of 23 dB with 4.6-dB insertion loss and isolation of 17 dB with a 1.3-dB insertion loss with 90 mW of optical power. As we are using an integrated photonics platform, we can reproducibly fabricate and cascade multiple isolators on the same chip, allowing us to demonstrate two cascaded isolators with an overall isolation ratio of 35 dB. Finally, we butt-couple a semiconductor laser-diode chip to the silicon-nitride isolators and demonstrate optical isolation in a system on a chip. Theory of operation The Kerr effect is the change in refractive index of a material due to its third-order nonlinearity in susceptibility, χ (3) . In the presence of two electric fields, the nonlinear polarization corresponding to this term is given by \({P}^{(3)}{(t)}={\epsilon }_{0}{\chi }^{(3)}{({E}_{1}{\rm{e}}^{-i{\omega }_{1}t}+{E}_{2}{\rm{e}}^{-i{\omega }_{2}t}+{\rm{c.c.}})}^{3}\) . Expanding this polynomial and keeping only the terms with the same frequencies, we find that \({P}^{(3)}({\omega }_{1})={3}{\epsilon }_{0}{\chi }^{(3)}(| {E}_{1}{| }^{2}+{2}| {E}_{2}{| }^{2}){E}_{1}{\rm{e}}^{-i{\omega }_{1}t}\) and \({P}^{(3)}({\omega }_{2})={3}{\epsilon }_{0}{\chi }^{(3)}({2}| {E}_{1}{| }^{2}+| {E}_{2}{| }^{2}){E}_{2}{\rm{e}}^{-i{\omega }_{1}t}\) . Thus, there is an effective increase in the refractive index proportional to the optical intensity. Critically, the index change differs by a factor of two depending on the source of the optical power. The field that is degenerate with the mode under consideration contributes a refractive index increase of 3 ϵ 0 χ (3) | E | 2 , self-phase modulation (SPM). The field that is non-degenerate contributes a refractive index increase of 6 ϵ 0 χ (3) | E | 2 , cross-phase modulation (XPM). This difference provides an intrinsic non-reciprocity. If a strong pump beam is sent through a waveguide, and a weak probe is sent through in the other direction, the probe will accrue an additional phase shift due to the Kerr effect that is twice that of the pump. We can apply the same principle to construct an isolator. Consider<|im_end|> <|im_start|>assistant Lasers are transformational devices, but one technical challenge prevents them from being even more so. The light they emit can reflect back into the laser itself and destabilize or even disable it. At real-world scales, this challenge is solved by bulky devices that use magnetism to block the harmful reflections. At chip scale, however, where engineers hope lasers will one day transform computer circuitry, effective isolators have proved elusive. Against that backdrop, researchers at Stanford University say they have created a simple and effective chip-scale isolator that can be laid down in a layer of semiconductor-based material hundreds of times thinner than a sheet of paper. "Chip-scale isolation is one of the great open challenges in photonics," said Jelena Vučković, a professor of electrical engineering at Stanford and senior author of the study appearing Dec. 1 in the journal Nature Photonics. "Every laser needs an isolator to stop back reflections from coming into and destabilizing the laser," said Alexander White, a doctoral candidate in Vučković's lab and co-first author of the paper, adding that the device has implications for everyday computing, but could also influence next-generation technologies, like quantum computing. Small and passive The nanoscale isolator is promising for several reasons. First, this isolator is "passive." It requires no external inputs, complicated electronics, or magnetics—technical challenges that have stymied progress in chip-scale lasers to date. These additional mechanisms lead to devices that are too bulky for integrated photonics applications and can cause electrical interference that compromises other components on the chips. Another advantage is that the new isolator is also made from common and well-known semiconductor-based material and can be manufactured using existing semiconductor processing technologies, potentially easing its path to mass production. The new isolator is shaped like a ring. It is made of silicon nitride, a material based on the most commonly used semiconductor—silicon. The strong primary laser beam enters the ring and the photons begin to spin around the ring in a clockwise direction. At the same time, a back-reflected beam would be sent back into the ring in the opposite direction, spinning in a counterclockwise fashion. "The laser power that we put in circulates many times and this allows us to build up inside the ring. This increasing power alters the weaker beam, while the stronger one continues unaffected," explains co-first author Geun Ho Ahn, a doctoral candidate in electrical engineering of the phenomenon that causes the weaker beam to stop resonating. "The reflected light, and only the reflected light, is effectively canceled." The primary laser then exits the ring and is "isolated" in the desired direction. Vučković and team have built a prototype as a proof of concept and were able to couple two ring isolators in a cascade to achieve better performance. "Next steps include working on isolators for different frequencies of light," said co-author Kasper Van Gasse, a post-doctoral scholar in Vučković's lab. "As well as tighter integration of components at chip scale to explore other uses of the isolator and improve performance." <|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 simulations and experiments have shown that shear-thickening of dense particle suspensions corresponds to a frictional transition. Based on this understanding, non-monotonic rheological laws have been proposed and successfully tested in rheometers. These recent advances offer a unique opportunity for moving beyond rheometry and tackling quantitatively hydrodynamic flows of shear-thickening suspensions. Here, we investigate the flow of a shear-thickening suspension down an inclined plane and show that, at large volume fractions, surface kinematic waves can spontaneously emerge. Curiously, the instability develops at low Reynolds numbers, and therefore does not fit into the classical framework of Kapitza or ‘roll-waves’ instabilities based on inertia. We show that this instability, that we call ‘Oobleck waves’, arises from the sole coupling between the non-monotonic (S-shape) rheological laws of shear-thickening suspensions and the flow free surface. Introduction How microscopic interactions affect the macroscopic flow behavior of complex fluids is at the core of soft matter physics. Recently, it has been shown that shear-thickening in dense particulate suspensions corresponds to a frictional transition at the microscopic scale; when the imposed shear stress exceeds the inter-particle short-range repulsive force, the grain contact interaction transits from frictionless to frictional 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 . During this transition, the proliferation of frictional contacts can be so massive that it triggers a remarkable macroscopic rheological response: the rate of shear of the suspension decreases when the imposed shear stress is increased. As a result, highly concentrated shear-thickening suspensions have peculiar S-shape rheological laws 9 , 10 , which have been rationalized by a frictional transition model 3 , 11 , 12 . So far, the consequences of the frictional transition and its associated S-shape rheology have been essentially investigated in rheometers, where instabilities, shear bands and spatiotemporal patterns have been documented 11 , 13 , 14 , 15 . By contrast, very little is known about the behavior of shear-thickening suspensions in real hydrodynamic flow configurations beyond rheometry, in spite of the numerous applications 16 , 17 , 18 . An archetypical case, which is widely encountered in industrial and geophysical applications, is the incline plane flow configuration. As previously reported 19 and illustrated in Fig. 1 a (see also Supplementary movie 2 ), when a thin layer of shear-thickening suspension flows down an inclined plane, surface waves of wavelengths much larger than the thickness can develop spontaneously and grow as they propagate downstream. This longwave free-surface instability may seem reminiscent of the Kapitza instability observed when a thin liquid film flows down a slope 20 , 21 , or more generally of the so called “roll waves” instability observed from turbulent flows in open channels 22 , 23 , 24 , to avalanches of complex fluids like mud 25 , 26 or granular media 27 . These latter two instabilities rely on the same primary mechanism: the amplification of kinematic surface waves at high velocity owing to inertial effects 28 . For a Newtonian liquid in the laminar regime, the destabilization occurs only when the Reynolds number of the flow, R e = ρ u 0 h 0 / η , where ρ is the fluid density, u 0 its mean velocity, h 0 the flow thickness and η the fluid viscosity, exceeds the Kapitza threshold, \\(R{e}_{K}=5/(6\\tan \\theta )\\) , which is typically much larger than 1 for a small tilting angle θ of the incline 29 , 30 , 31 . By contrast, the growth of surface waves observed in Fig. 1 a for a dense shear-thickening suspension occurs at a Reynolds number of only ≈1, i.e., far below the Kapitza threshold R e K ≈ 5 predicted for θ = 10 ∘ (see also ref. 19 ). This suggests that a different instability mechanism is at play for dense shear-thickening suspensions, yet its origin remains an open question. Fig. 1: Experimental characterization of the instability onset. a Non-inertial surface waves emerging spontaneously when a concentrated suspension of cornstarch particles flows down an incline (volume fraction ϕ = 0.45, inclination angle θ = 10 ∘ and normalized flow Reynold number R e / R e K ≈ 0.2). b Sketch of the experimental setup. We use the progressive drainage of the reservoir to quasi-steadily vary the flow rate. The instability onset is determined by measuring the wave amplitudes both at the top and at the bottom of the incline with two laser sheets and cameras. For ϕ ≤ 0.4, an oscillation of the gate is added to impose a controlled perturbation. c Spatiotemporal plots of the laser sheet transverse-position versus time, indicating the vertical oscillations (blue and red arrows) of the free surface, at the top and at the bottom of the incline ( ϕ = 0.33, θ = 2 ∘ , R e ≈ 37). d Reynolds number of the flow, R e , and e amplitude of the perturbation at the top, Δ h 1 , and at the bottom, Δ h 2 , during the drainage of the suspension reservoir ( ϕ = 0.36, θ = 3 ∘ ). The instability onset ( Δ h 1 = Δ h 2 ) is given by R e c ≈ 28 (black-dashed-line). Full size image Here, we investigate the origin of this instability by studying the flow of a shear-thickening suspension down an inclined plane over a wide range of volume fractions and flow rates. We confirm that this instability is not inertial and fundamentally different than the classical Kapitza or Roll waves instabilities. We provide experimental evidence together with a theoretical explanation, which show that this destabilization arises from the coupling between the flow free surface and the non-monotonic (S-shape) rheological laws of shear-thickening suspensions. Results and discussion Evidence of an instability distinct from the classical Kapitza or roll waves instabilities We perform experiments with shear-thickening aqueous suspensions of commercial native cornstarch (Maisita®, ). We vary the particle volume fraction over a wide range (0.30 < ϕ < 0.48) and characterize the onset of", "role": "user" }, { "content": "\"Oobleck\" is a strange fluid made of equal parts of cornstarch and water. It flows like milk when gently stirred, but turns rock-solid when impacted at high speed. This fascinating phenomenon, known as shear-thickening, results in spectacular demonstrations like running on a pool of Oobleck without submerging into it, as long as the runner doesn't stop. Researchers from Aix-Marseille University in France have now studied the regular and prominent surface waves that form when a Oobleck flows down an inclined slope (see Figure 1). Similar waves can be observed on gutters and windows on rainy days. However, the scientists noted qualitative differences with water waves; waves in Oobleck grow and saturate much faster. In order to unveil the origin of Oobleck waves, they conducted careful experiments with a mixture of cornstarch and water down an inclined plane. The researchers measured the onset of wave appearance and their speed using controlled perturbation of the flow and laser detection to estimate the fluid film thickness. These experiments revealed that for concentrated Oobleck, the onset of destabilization is different for destabilization in a Newtonian fluid such as water. This surprising observation led the team to look for a scenario to explain their formation. Their results are presented in a paper published on December 18 in Communication Physics. In this article, they conclude that for Oobleck, waves do not arise from the effect of inertia, as for water, but from Oobleck's specific flowing properties. Under impact, as shown by recent studies, Oobleck suddenly changes from liquid to solid because of the activation of frictional contacts between the starch particles. When flowing down a slope, this proliferation of frictional contacts leads to a very curious behavior: The flow velocity of the suspension decreased when the imposed stress increased—like stepping on the gas pedal causing a car to decelerate. Researchers have shown that this effect couples to the flow free surface and can spontaneously generate a regular wave pattern. The proposed mechanism is generic. These findings could thus provide new grounds to understand other flow instabilities observed in various configurations, particularly in industrial processes facing problematic flow instabilities when conveying Oobleck-like materials such as concrete, chocolate or vinyl 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 Recent simulations and experiments have shown that shear-thickening of dense particle suspensions corresponds to a frictional transition. Based on this understanding, non-monotonic rheological laws have been proposed and successfully tested in rheometers. These recent advances offer a unique opportunity for moving beyond rheometry and tackling quantitatively hydrodynamic flows of shear-thickening suspensions. Here, we investigate the flow of a shear-thickening suspension down an inclined plane and show that, at large volume fractions, surface kinematic waves can spontaneously emerge. Curiously, the instability develops at low Reynolds numbers, and therefore does not fit into the classical framework of Kapitza or ‘roll-waves’ instabilities based on inertia. We show that this instability, that we call ‘Oobleck waves’, arises from the sole coupling between the non-monotonic (S-shape) rheological laws of shear-thickening suspensions and the flow free surface. Introduction How microscopic interactions affect the macroscopic flow behavior of complex fluids is at the core of soft matter physics. Recently, it has been shown that shear-thickening in dense particulate suspensions corresponds to a frictional transition at the microscopic scale; when the imposed shear stress exceeds the inter-particle short-range repulsive force, the grain contact interaction transits from frictionless to frictional 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 . During this transition, the proliferation of frictional contacts can be so massive that it triggers a remarkable macroscopic rheological response: the rate of shear of the suspension decreases when the imposed shear stress is increased. As a result, highly concentrated shear-thickening suspensions have peculiar S-shape rheological laws 9 , 10 , which have been rationalized by a frictional transition model 3 , 11 , 12 . So far, the consequences of the frictional transition and its associated S-shape rheology have been essentially investigated in rheometers, where instabilities, shear bands and spatiotemporal patterns have been documented 11 , 13 , 14 , 15 . By contrast, very little is known about the behavior of shear-thickening suspensions in real hydrodynamic flow configurations beyond rheometry, in spite of the numerous applications 16 , 17 , 18 . An archetypical case, which is widely encountered in industrial and geophysical applications, is the incline plane flow configuration. As previously reported 19 and illustrated in Fig. 1 a (see also Supplementary movie 2 ), when a thin layer of shear-thickening suspension flows down an inclined plane, surface waves of wavelengths much larger than the thickness can develop spontaneously and grow as they propagate downstream. This longwave free-surface instability may seem reminiscent of the Kapitza instability observed when a thin liquid film flows down a slope 20 , 21 , or more generally of the so called “roll waves” instability observed from turbulent flows in open channels 22 , 23 , 24 , to avalanches of complex fluids like mud 25 , 26 or granular media 27 . These latter two instabilities rely on the same primary mechanism: the amplification of kinematic surface waves at high velocity owing to inertial effects 28 . For a Newtonian liquid in the laminar regime, the destabilization occurs only when the Reynolds number of the flow, R e = ρ u 0 h 0 / η , where ρ is the fluid density, u 0 its mean velocity, h 0 the flow thickness and η the fluid viscosity, exceeds the Kapitza threshold, \(R{e}_{K}=5/(6\tan \theta )\) , which is typically much larger than 1 for a small tilting angle θ of the incline 29 , 30 , 31 . By contrast, the growth of surface waves observed in Fig. 1 a for a dense shear-thickening suspension occurs at a Reynolds number of only ≈1, i.e., far below the Kapitza threshold R e K ≈ 5 predicted for θ = 10 ∘ (see also ref. 19 ). This suggests that a different instability mechanism is at play for dense shear-thickening suspensions, yet its origin remains an open question. Fig. 1: Experimental characterization of the instability onset. a Non-inertial surface waves emerging spontaneously when a concentrated suspension of cornstarch particles flows down an incline (volume fraction ϕ = 0.45, inclination angle θ = 10 ∘ and normalized flow Reynold number R e / R e K ≈ 0.2). b Sketch of the experimental setup. We use the progressive drainage of the reservoir to quasi-steadily vary the flow rate. The instability onset is determined by measuring the wave amplitudes both at the top and at the bottom of the incline with two laser sheets and cameras. For ϕ ≤ 0.4, an oscillation of the gate is added to impose a controlled perturbation. c Spatiotemporal plots of the laser sheet transverse-position versus time, indicating the vertical oscillations (blue and red arrows) of the free surface, at the top and at the bottom of the incline ( ϕ = 0.33, θ = 2 ∘ , R e ≈ 37). d Reynolds number of the flow, R e , and e amplitude of the perturbation at the top, Δ h 1 , and at the bottom, Δ h 2 , during the drainage of the suspension reservoir ( ϕ = 0.36, θ = 3 ∘ ). The instability onset ( Δ h 1 = Δ h 2 ) is given by R e c ≈ 28 (black-dashed-line). Full size image Here, we investigate the origin of this instability by studying the flow of a shear-thickening suspension down an inclined plane over a wide range of volume fractions and flow rates. We confirm that this instability is not inertial and fundamentally different than the classical Kapitza or Roll waves instabilities. We provide experimental evidence together with a theoretical explanation, which show that this destabilization arises from the coupling between the flow free surface and the non-monotonic (S-shape) rheological laws of shear-thickening suspensions. Results and discussion Evidence of an instability distinct from the classical Kapitza or roll waves instabilities We perform experiments with shear-thickening aqueous suspensions of commercial native cornstarch (Maisita®, ). We vary the particle volume fraction over a wide range (0.30 < ϕ < 0.48) and characterize the onset of<|im_end|> <|im_start|>assistant "Oobleck" is a strange fluid made of equal parts of cornstarch and water. It flows like milk when gently stirred, but turns rock-solid when impacted at high speed. This fascinating phenomenon, known as shear-thickening, results in spectacular demonstrations like running on a pool of Oobleck without submerging into it, as long as the runner doesn't stop. Researchers from Aix-Marseille University in France have now studied the regular and prominent surface waves that form when a Oobleck flows down an inclined slope (see Figure 1). Similar waves can be observed on gutters and windows on rainy days. However, the scientists noted qualitative differences with water waves; waves in Oobleck grow and saturate much faster. In order to unveil the origin of Oobleck waves, they conducted careful experiments with a mixture of cornstarch and water down an inclined plane. The researchers measured the onset of wave appearance and their speed using controlled perturbation of the flow and laser detection to estimate the fluid film thickness. These experiments revealed that for concentrated Oobleck, the onset of destabilization is different for destabilization in a Newtonian fluid such as water. This surprising observation led the team to look for a scenario to explain their formation. Their results are presented in a paper published on December 18 in Communication Physics. In this article, they conclude that for Oobleck, waves do not arise from the effect of inertia, as for water, but from Oobleck's specific flowing properties. Under impact, as shown by recent studies, Oobleck suddenly changes from liquid to solid because of the activation of frictional contacts between the starch particles. When flowing down a slope, this proliferation of frictional contacts leads to a very curious behavior: The flow velocity of the suspension decreased when the imposed stress increased—like stepping on the gas pedal causing a car to decelerate. Researchers have shown that this effect couples to the flow free surface and can spontaneously generate a regular wave pattern. The proposed mechanism is generic. These findings could thus provide new grounds to understand other flow instabilities observed in various configurations, particularly in industrial processes facing problematic flow instabilities when conveying Oobleck-like materials such as concrete, chocolate or vinyl 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 Efficient generation of human induced pluripotent stem cell (hiPSC)-derived human intestinal organoids (HIOs) would facilitate the development of in vitro models for a variety of diseases that affect the gastrointestinal tract, such as inflammatory bowel disease or Cystic Fibrosis. Here, we report a directed differentiation protocol for the generation of mesenchyme-free HIOs that can be primed towards more colonic or proximal intestinal lineages in serum-free defined conditions. Using a CDX2 eGFP iPSC knock-in reporter line to track the emergence of hindgut progenitors, we follow the kinetics of CDX2 expression throughout directed differentiation, enabling the purification of intestinal progenitors and robust generation of mesenchyme-free organoids expressing characteristic markers of small intestinal or colonic epithelium. We employ HIOs generated in this way to measure CFTR function using cystic fibrosis patient-derived iPSC lines before and after correction of the CFTR mutation, demonstrating their future potential for disease modeling and therapeutic screening applications. Introduction Three-dimensional tissue-specific organoids represent a powerful tool to study both normal development and disease. Organoids have been generated from a variety of primary tissue samples, including small intestine 1 , 2 , stomach 3 , colon 4 , and pancreas 5 . Since the discovery of the Wnt-activated LGR5 + stem cell niche at the base of small intestinal and colonic crypts 1 , previous studies have reported the generation of 3D intestinal organoids containing crypt-like structures from murine and human LGR5 + intestinal stem cells in the presence of Wnt stimulation, epidermal growth factor (EGF) signaling, and Noggin 2 . However, the invasive procedures to obtain intestinal and colonic biopsy samples present a major challenge for larger scale applications of human intestinal organoids. The discovery of induced pluripotent stem cells (iPSCs) 6 has led to the development of multiple directed differentiation protocols, resulting in the in vitro generation of various endoderm-derived tissue types of interest, including liver 7 , stomach 8 , pancreas 9 , proximal 10 , 11 , 12 and distal 13 lung, kidney 14 , as well as intestine 15 . Moreover, the three-dimensional culture systems that generate organoids allow cells to self-organize, promoting further maturation and differentiation into target cell types that more closely resemble their in vivo counterparts 16 , 17 . The efficient generation of iPSC-derived human intestinal organoids (HIOs) serves not only as a relevant tool to study development, but has great potential for patient-specific in vitro disease modeling and high-throughput drug screening applications. HIOs positive for intestinal markers such as the intestinal homeobox transcription factor Cdx2 18 , 19 and intestinal epithelium marker Cdh17 have been generated from iPSCs using activin A to derive SOX17 + /FOXA2 + endoderm, followed by Wnt3A and FGF4 (with serum) to specify CDX2 + hindgut (Hindgut Medium), and R-spondin, EGF, and the BMP inhibitor, noggin (Intestinal Medium or IM) to promote intestinal specification and crypt-like formation 15 . More recently, distal patterning of iPSC-derived HIOs to generate SATB2 + colonic organoids was achieved through BMP2 stimulation 20 . These factors have all been shown to play a role in intestinal specification and epithelial proliferation during embryonic development 21 . Interestingly, this protocol often generates HIOs containing both epithelial and mesenchymal stromal cells 15 , 20 , necessitating a FACS-based approach to isolate epithelial cell adhesion molecule positive (EpCAM + ) cells in order to interrogate epithelial-specific populations 22 , complicating their use in disease modeling or drug screening applications to isolate epithelial-specific factors. The derivation of HIOs from intestinal crypts using the LGR5 + adult stem cell population can generate organoids in the absence of mesenchyme 2 , raising questions as to whether intestinal progenitors derived from iPSCs are comparable to native crypts in generating HIOs. Moreover, a directed differentiation protocol using fully defined culture conditions is still lacking, as current protocols rely on the addition of exogenous serum. Here we describe a protocol using a well-defined, serum-free media for the robust de novo generation of epithelial iPSC-derived HIOs devoid of mesenchyme. In addition, we report the generation of a hiPSC CDX2-GFP reporter line that highlights the role of CDX2 as a specific marker for the emergence of iPSC-derived intestinal progenitors. This platform enables the study of both normal development as well as disease states of the gut (exemplified by cystic fibrosis), supporting the generation of patient-specific iPSC-derived organoids for interrogation, genetic manipulation, and large-scale drug screening applications. Results Generation of intestinal progenitors from iPSCs We and others have previously shown that dual-smad inhibition of the BMP/TGFβ signaling pathways (with dorsomorphin and SB431542) in definitive endoderm derived from iPSCs and ESCs promotes the development of endoderm competent to form anterior foregut derivatives, such as NKX2-1 positive lung or thyroid lineages 10 , 11 , 12 , 13 , 23 , 24 . Indeed, we performed fluorescence activated cell sorting (FACS) of cells expressing the anterior foregut endodermal transcription factor NKX2-1 or a combination of cell surface markers CD47 hi /CD26 lo (NKX2-1 + ) to enrich for a population of progenitors which can then be differentiated into proximal and distal lung lineages from human iPSCs 11 , 12 , 13 . In this protocol, prior single-cell sequencing of day 15 progenitors revealed the presence of cells expressing non-lung endodermal markers, including CDX2, and these non-lung lineages were enriched in the NKX2-1 negative fraction of cells (refs. 25 , 26 and Supplementary Fig. 1 ). Thus, we sought to investigate the potential of this differentiation approach to obtain intestinal organoids in defined, mesenchyme-free (MF) and serum-free culture conditions, in comparison to the previously described mesenchyme-containing (MC) protocol 15 (Fig. 1a ). Fig. 1: Emergence of intestinal-competent progenitors from iPSCs. a Schematic of comparison between mesenchyme-containing (MC) HIO vs mesenchyme-free (MF) directed differentiation protocols. b Mean Average (MA) Plots of significantly differentially expressed genes that were either upregulated (red dots) or downregulated (blue dots) in digital gene expression analysis from day 42 (D42) organoids sorted for CD47 on day 15, comparing the CD47 hi (Alveolospheres, left) and CD47 lo (HIOs, right) cultured in CK-DCI, as compared", "role": "user" }, { "content": "Boston researchers have developed a new way to generate groups of intestinal cells that can be used, among others, to make disease models in the lab to test treatments for diseases affecting the gastrointestinal system. Using human induced pluripotent stem cells, this novel approach combined a variety of techniques that enabled the development of three-dimensional groups of intestinal cells called organoids in vitro, which can expand disease treatment testing in the lab using human cells. Published online in Nature Communications, this process provides a novel platform to improve drug screenings and uncover novel therapies to treat a variety of diseases impacting the intestine, such as inflammatory bowel disease, colon cancer and Cystic Fibrosis. Researchers at the Center for Regenerative Medicine (CReM) of Boston University and Boston Medical Center used donated human induced pluripotent stem cells (hiPSCs), which are created by reprogramming adult cells into a primitive state. For this study, these cells were pushed to differentiate into intestinal cells using specific growth factors in order to create organoids in a gel. This new protocol allowed the cells to develop without mesenchyme, which typically in other protocols, provides support for the intestinal epithelial cells to grow. By taking out the mesenchyme, the researchers could study exclusively epithelial cells, which make up the intestinal tract. In addition, using CRISPR technology, the researchers were able to modify and create a novel iPSC stem cell line that glowed green when differentiated into intestinal cells. This allowed the researchers to follow the process of how intestinal cells differentiate in vitro. \"Generating organoids in our lab allows us to create more accurate disease models, which are used to test treatments and therapies targeted to a specific genetic defect or tissue—and it's all possible without harming the patient,\" said Gustavo Mostoslavsky, MD, Ph.D., co-director of CReM and faculty in the gastroenterology section at Boston Medical Center. \"This approach allows us to determine what treatments could be most effective, and which are ineffective, against a disease.\" Using this new protocol, the researchers generated intestinal organoids from iPSCs containing a mutation that causes Cystic Fibrosis, which typically affects several organs, including the gastrointestinal tract. Using CRISPR technology, the researchers corrected the mutation in the intestinal organoids. The intestinal organoids with the mutation did not respond to a drug while the genetically corrected cells did respond, demonstrating their future potential for disease modeling and therapeutic screening applications. The protocol developed in this study provides strong evidence to continue using human iPSCs to study development at the cellular level, tissue engineering and disease modeling in order to advance the understanding—and possibilities—of regenerative medicine. \"I hope that this study helps move forward our collective understanding about how diseases impact the gastrointestinal tract at the cellular level,\" said Mostoslavsky, who also is associate professor of medicine and microbiology at Boston University School of Medicine. \"The continual development of novel techniques in creating highly differentiated cells that can be used to develop disease models in a lab setting will pave the way for the development of more targeted approaches to treat many different diseases.\" ", "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 Efficient generation of human induced pluripotent stem cell (hiPSC)-derived human intestinal organoids (HIOs) would facilitate the development of in vitro models for a variety of diseases that affect the gastrointestinal tract, such as inflammatory bowel disease or Cystic Fibrosis. Here, we report a directed differentiation protocol for the generation of mesenchyme-free HIOs that can be primed towards more colonic or proximal intestinal lineages in serum-free defined conditions. Using a CDX2 eGFP iPSC knock-in reporter line to track the emergence of hindgut progenitors, we follow the kinetics of CDX2 expression throughout directed differentiation, enabling the purification of intestinal progenitors and robust generation of mesenchyme-free organoids expressing characteristic markers of small intestinal or colonic epithelium. We employ HIOs generated in this way to measure CFTR function using cystic fibrosis patient-derived iPSC lines before and after correction of the CFTR mutation, demonstrating their future potential for disease modeling and therapeutic screening applications. Introduction Three-dimensional tissue-specific organoids represent a powerful tool to study both normal development and disease. Organoids have been generated from a variety of primary tissue samples, including small intestine 1 , 2 , stomach 3 , colon 4 , and pancreas 5 . Since the discovery of the Wnt-activated LGR5 + stem cell niche at the base of small intestinal and colonic crypts 1 , previous studies have reported the generation of 3D intestinal organoids containing crypt-like structures from murine and human LGR5 + intestinal stem cells in the presence of Wnt stimulation, epidermal growth factor (EGF) signaling, and Noggin 2 . However, the invasive procedures to obtain intestinal and colonic biopsy samples present a major challenge for larger scale applications of human intestinal organoids. The discovery of induced pluripotent stem cells (iPSCs) 6 has led to the development of multiple directed differentiation protocols, resulting in the in vitro generation of various endoderm-derived tissue types of interest, including liver 7 , stomach 8 , pancreas 9 , proximal 10 , 11 , 12 and distal 13 lung, kidney 14 , as well as intestine 15 . Moreover, the three-dimensional culture systems that generate organoids allow cells to self-organize, promoting further maturation and differentiation into target cell types that more closely resemble their in vivo counterparts 16 , 17 . The efficient generation of iPSC-derived human intestinal organoids (HIOs) serves not only as a relevant tool to study development, but has great potential for patient-specific in vitro disease modeling and high-throughput drug screening applications. HIOs positive for intestinal markers such as the intestinal homeobox transcription factor Cdx2 18 , 19 and intestinal epithelium marker Cdh17 have been generated from iPSCs using activin A to derive SOX17 + /FOXA2 + endoderm, followed by Wnt3A and FGF4 (with serum) to specify CDX2 + hindgut (Hindgut Medium), and R-spondin, EGF, and the BMP inhibitor, noggin (Intestinal Medium or IM) to promote intestinal specification and crypt-like formation 15 . More recently, distal patterning of iPSC-derived HIOs to generate SATB2 + colonic organoids was achieved through BMP2 stimulation 20 . These factors have all been shown to play a role in intestinal specification and epithelial proliferation during embryonic development 21 . Interestingly, this protocol often generates HIOs containing both epithelial and mesenchymal stromal cells 15 , 20 , necessitating a FACS-based approach to isolate epithelial cell adhesion molecule positive (EpCAM + ) cells in order to interrogate epithelial-specific populations 22 , complicating their use in disease modeling or drug screening applications to isolate epithelial-specific factors. The derivation of HIOs from intestinal crypts using the LGR5 + adult stem cell population can generate organoids in the absence of mesenchyme 2 , raising questions as to whether intestinal progenitors derived from iPSCs are comparable to native crypts in generating HIOs. Moreover, a directed differentiation protocol using fully defined culture conditions is still lacking, as current protocols rely on the addition of exogenous serum. Here we describe a protocol using a well-defined, serum-free media for the robust de novo generation of epithelial iPSC-derived HIOs devoid of mesenchyme. In addition, we report the generation of a hiPSC CDX2-GFP reporter line that highlights the role of CDX2 as a specific marker for the emergence of iPSC-derived intestinal progenitors. This platform enables the study of both normal development as well as disease states of the gut (exemplified by cystic fibrosis), supporting the generation of patient-specific iPSC-derived organoids for interrogation, genetic manipulation, and large-scale drug screening applications. Results Generation of intestinal progenitors from iPSCs We and others have previously shown that dual-smad inhibition of the BMP/TGFβ signaling pathways (with dorsomorphin and SB431542) in definitive endoderm derived from iPSCs and ESCs promotes the development of endoderm competent to form anterior foregut derivatives, such as NKX2-1 positive lung or thyroid lineages 10 , 11 , 12 , 13 , 23 , 24 . Indeed, we performed fluorescence activated cell sorting (FACS) of cells expressing the anterior foregut endodermal transcription factor NKX2-1 or a combination of cell surface markers CD47 hi /CD26 lo (NKX2-1 + ) to enrich for a population of progenitors which can then be differentiated into proximal and distal lung lineages from human iPSCs 11 , 12 , 13 . In this protocol, prior single-cell sequencing of day 15 progenitors revealed the presence of cells expressing non-lung endodermal markers, including CDX2, and these non-lung lineages were enriched in the NKX2-1 negative fraction of cells (refs. 25 , 26 and Supplementary Fig. 1 ). Thus, we sought to investigate the potential of this differentiation approach to obtain intestinal organoids in defined, mesenchyme-free (MF) and serum-free culture conditions, in comparison to the previously described mesenchyme-containing (MC) protocol 15 (Fig. 1a ). Fig. 1: Emergence of intestinal-competent progenitors from iPSCs. a Schematic of comparison between mesenchyme-containing (MC) HIO vs mesenchyme-free (MF) directed differentiation protocols. b Mean Average (MA) Plots of significantly differentially expressed genes that were either upregulated (red dots) or downregulated (blue dots) in digital gene expression analysis from day 42 (D42) organoids sorted for CD47 on day 15, comparing the CD47 hi (Alveolospheres, left) and CD47 lo (HIOs, right) cultured in CK-DCI, as compared<|im_end|> <|im_start|>assistant Boston researchers have developed a new way to generate groups of intestinal cells that can be used, among others, to make disease models in the lab to test treatments for diseases affecting the gastrointestinal system. Using human induced pluripotent stem cells, this novel approach combined a variety of techniques that enabled the development of three-dimensional groups of intestinal cells called organoids in vitro, which can expand disease treatment testing in the lab using human cells. Published online in Nature Communications, this process provides a novel platform to improve drug screenings and uncover novel therapies to treat a variety of diseases impacting the intestine, such as inflammatory bowel disease, colon cancer and Cystic Fibrosis. Researchers at the Center for Regenerative Medicine (CReM) of Boston University and Boston Medical Center used donated human induced pluripotent stem cells (hiPSCs), which are created by reprogramming adult cells into a primitive state. For this study, these cells were pushed to differentiate into intestinal cells using specific growth factors in order to create organoids in a gel. This new protocol allowed the cells to develop without mesenchyme, which typically in other protocols, provides support for the intestinal epithelial cells to grow. By taking out the mesenchyme, the researchers could study exclusively epithelial cells, which make up the intestinal tract. In addition, using CRISPR technology, the researchers were able to modify and create a novel iPSC stem cell line that glowed green when differentiated into intestinal cells. This allowed the researchers to follow the process of how intestinal cells differentiate in vitro. "Generating organoids in our lab allows us to create more accurate disease models, which are used to test treatments and therapies targeted to a specific genetic defect or tissue—and it's all possible without harming the patient," said Gustavo Mostoslavsky, MD, Ph.D., co-director of CReM and faculty in the gastroenterology section at Boston Medical Center. "This approach allows us to determine what treatments could be most effective, and which are ineffective, against a disease." Using this new protocol, the researchers generated intestinal organoids from iPSCs containing a mutation that causes Cystic Fibrosis, which typically affects several organs, including the gastrointestinal tract. Using CRISPR technology, the researchers corrected the mutation in the intestinal organoids. The intestinal organoids with the mutation did not respond to a drug while the genetically corrected cells did respond, demonstrating their future potential for disease modeling and therapeutic screening applications. The protocol developed in this study provides strong evidence to continue using human iPSCs to study development at the cellular level, tissue engineering and disease modeling in order to advance the understanding—and possibilities—of regenerative medicine. "I hope that this study helps move forward our collective understanding about how diseases impact the gastrointestinal tract at the cellular level," said Mostoslavsky, who also is associate professor of medicine and microbiology at Boston University School of Medicine. "The continual development of novel techniques in creating highly differentiated cells that can be used to develop disease models in a lab setting will pave the way for the development of more targeted approaches to treat many different diseases." <|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 Ecosystems face both local hazards, such as over-exploitation, and global hazards, such as climate change. Since the impact of local hazards attenuates with distance from humans, local extinction risk should decrease with remoteness, making faraway areas safe havens for biodiversity. However, isolation and reduced anthropogenic disturbance may increase ecological specialization in remote communities, and hence their vulnerability to secondary effects of diversity loss propagating through networks of interacting species. We show this to be true for reef fish communities across the globe. An increase in fish-coral dependency with the distance of coral reefs from human settlements, paired with the far-reaching impacts of global hazards, increases the risk of fish species loss, counteracting the benefits of remoteness. Hotspots of fish risk from fish-coral dependency are distinct from those caused by direct human impacts, increasing the number of risk hotspots by ~30% globally. These findings might apply to other ecosystems on Earth and depict a world where no place, no matter how remote, is safe for biodiversity, calling for a reconsideration of global conservation priorities. Introduction The effects of human activities on our planet are so pervasive 1 that many denote the current epoch as the Anthropocene 2 . In these challenging times for biodiversity, species face extinction 3 , 4 , and ecosystems deteriorate under the synergic influence of global hazards (such as climate change) and local human stressors (such as overexploitation) 5 , 6 . Since global hazards act indeed globally, while local ones are associated with proximity to human activities, their combined effect is expected to decrease with the remoteness of the local ecosystem (Fig. 1a ). Therefore, pristine and isolated ecosystems—sometimes referred to as “wilderness areas”—are considered sanctuaries that have the potential to preserve nature during the current and future biodiversity crises 7 . Fig. 1: Theoretical and empirical relationships between remoteness vs local/global hazards and ecosystem vulnerability from ecological dependencies. a Theoretical expectation of a decrease in local and local + global hazards with remoteness, and a counteracting increase in ecosystem vulnerability due to ecological dependencies. b Comparison between reef remoteness, measured as travel time (in log e transformed hours) from a reef locality to the closest major city 21 , and local hazards (cumulative local impacts on reef localities for 2013, consisting of six impacts related to fishing activities, light pollution, shipping, nutrient pollution, organic chemical pollution, and direct human interactions on coastal and near-coastal habitats 19 ). c Comparison between reef remoteness and global hazards (cumulative global impacts on reef localities for 2013, consisting of warming, acidification, and sea level rise 19 ). d Comparison between reef remoteness and cumulative local + global impacts. e Comparison between reef remoteness and bleaching susceptibility quantified, for each reef locality, as the average bleaching alert level from 1985 to 2019. f Comparison between reef remoteness and fish-coral dependency (quantified as the fraction of fish diversity directly or indirectly connected to corals through a coral → fish → fish network path at 1761 reef localities at a resolution of 1° × 1°). For each relationship, we report the Spearman’s rank correlation coefficient (r s ). Full size image However, local anthropogenic disturbances can favour generalist species over specialized ones 8 , 9 , 10 , as corroborated by previous work showing a positive relationship between the degree of ecological specialization and time with no disturbances in in-silico ecological networks 11 . In addition, due to the reduced in-flow of individuals into communities, we might also expect a higher specialization of ecological interactions in isolated habitats 12 . Specialized consumers can be more efficient in using their (few) resources when these are available but have, in principle, a higher co-extinction risk than generalist species 13 , 14 . Thus, while specialization increases ecological networks’ robustness to species loss under stable environmental conditions, it also makes them more fragile towards potential cascading effects of primary extinctions (triggered, for example, by warming) 11 . Therefore, undisturbed and isolated communities should have many specialized interactions increasing their vulnerability to global change (Fig. 1a ). Such an ecological mechanism depicts a component of risk which is distinct and adds up to that stemming from the increased chances of local extinction that species are experiencing in isolated habitats 15 . Here we test whether a positive relationship between ecological specialization/vulnerability and remoteness exists in natural systems, and whether the resulting increased risk of species loss in remote areas can question the common reliance on remote areas as biodiversity strongholds. For these goals, we focused on one of the most biologically diverse and socio-economically significant ecosystems on the planet, coral reefs, which, despite international attention and global protection programmes, continue to deteriorate under the influence of local human impacts (such as physical destruction and pollution) and the increasing effects of climate change (such as coral bleaching) 16 , 17 , 18 , 19 . By assessing the local dependency of fish assemblages on corals across the world’s oceans, we show that the increase in the frequency and strength of fish-coral associations with distance from human settlements, combined with the global reach of coral bleaching, obliterate the benefits of remoteness on reef fish local extinction risk. Results and discussion Exploring the risk-remoteness relationship in reef fish We quantified remoteness as travel time to major cities 20 , 21 (Fig. 2a ). This measure captures both the local impact of direct anthropogenic disturbances (Fig. 1b ) and geographical isolation (Supplementary Fig. 1 ), being therefore well suited to test our hypotheses. Using a global dataset providing standardized measures of anthropogenic impacts on oceans 19 , we quantified the cumulative risk of species loss for reef fish assemblages from local and global hazards. Local hazards stem from direct human activities (six impacts related to fishing activities plus light pollution, shipping, nutrient pollution, organic chemical pollution, and direct human impacts on coastal and near-coastal habitats). They decline with increasing remoteness from human settlements (Figs. 1 b, 2b ). Global hazards are related to global processes such as ocean warming,", "role": "user" }, { "content": "An international research team led by Associate Professor Giovanni Strona from the University of Helsinki has identified a general macroecological mechanism that calls for a reconsideration of global conservation strategies. \"To truly understand how global change is affecting natural communities and to identify effective strategies to mitigate the ongoing dramatic biodiversity loss, it is fundamental to account for the overarching complexity emerging from biotic interactions. As we show in our new research, doing this might reveal important counterintuitive mechanisms,\" Giovanni Strona says. The researchers combined a massive dataset of fish distribution and ecological traits for more than 9,000 fish species. Using artificial intelligence techniques, they generated thousands of networks mapping the interactions between corals and fish and those between fish prey and fish predators in all reef localities worldwide. They quantified, for each locality, the degree of fish dependency on corals. This analysis confirmed what Strona and colleagues showed in another paper published earlier this year: coral loss might detrimentally affect, on average, around 40 per cent of fish species in each coral reef area. The researchers also found that the dependency between fish and corals becomes stronger the further away they are from humans. This means that fish communities in remote reefs might be the most vulnerable to the cascading effects of coral mortality. Areas of critical vulnerability Next, the researchers asked whether the increased risk that stems from the potential cascading effects of coral mortality might counteract the benefits that remote fish communities experience because they are far away from direct impacts of human activities. \"For this, we devised a novel risk assessment framework that is applicable to any ecosystem. It combines local anthropogenic impacts such as overfishing and pollution and global impacts like climate and environmental change with the risk deriving from ecological interactions,\" explains Mar Cabeza, head of the Global Change and Conservation Lab at the University of Helsinki. The framework revealed that taking into account ecological dependencies flattens the expected negative relationship between extinction risk for fish communities and remoteness. \"For example, the hotspots of risks for fish communities from local human-derived impacts and global change are almost perfectly the same as the hotspots of risk from fish coral dependencies. This produces a global map of risk for fish communities where no place is safe, regardless of distance from humans,\" Giovanni Strona says. \"The validity and relevance of these findings might extend far beyond reef fish, depicting a world where remote localities, rather than safe havens for biodiversity, might be, instead, areas of critical vulnerability,\" Mar Cabeza concludes. The research was published in Nature Communications. ", "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 Ecosystems face both local hazards, such as over-exploitation, and global hazards, such as climate change. Since the impact of local hazards attenuates with distance from humans, local extinction risk should decrease with remoteness, making faraway areas safe havens for biodiversity. However, isolation and reduced anthropogenic disturbance may increase ecological specialization in remote communities, and hence their vulnerability to secondary effects of diversity loss propagating through networks of interacting species. We show this to be true for reef fish communities across the globe. An increase in fish-coral dependency with the distance of coral reefs from human settlements, paired with the far-reaching impacts of global hazards, increases the risk of fish species loss, counteracting the benefits of remoteness. Hotspots of fish risk from fish-coral dependency are distinct from those caused by direct human impacts, increasing the number of risk hotspots by ~30% globally. These findings might apply to other ecosystems on Earth and depict a world where no place, no matter how remote, is safe for biodiversity, calling for a reconsideration of global conservation priorities. Introduction The effects of human activities on our planet are so pervasive 1 that many denote the current epoch as the Anthropocene 2 . In these challenging times for biodiversity, species face extinction 3 , 4 , and ecosystems deteriorate under the synergic influence of global hazards (such as climate change) and local human stressors (such as overexploitation) 5 , 6 . Since global hazards act indeed globally, while local ones are associated with proximity to human activities, their combined effect is expected to decrease with the remoteness of the local ecosystem (Fig. 1a ). Therefore, pristine and isolated ecosystems—sometimes referred to as “wilderness areas”—are considered sanctuaries that have the potential to preserve nature during the current and future biodiversity crises 7 . Fig. 1: Theoretical and empirical relationships between remoteness vs local/global hazards and ecosystem vulnerability from ecological dependencies. a Theoretical expectation of a decrease in local and local + global hazards with remoteness, and a counteracting increase in ecosystem vulnerability due to ecological dependencies. b Comparison between reef remoteness, measured as travel time (in log e transformed hours) from a reef locality to the closest major city 21 , and local hazards (cumulative local impacts on reef localities for 2013, consisting of six impacts related to fishing activities, light pollution, shipping, nutrient pollution, organic chemical pollution, and direct human interactions on coastal and near-coastal habitats 19 ). c Comparison between reef remoteness and global hazards (cumulative global impacts on reef localities for 2013, consisting of warming, acidification, and sea level rise 19 ). d Comparison between reef remoteness and cumulative local + global impacts. e Comparison between reef remoteness and bleaching susceptibility quantified, for each reef locality, as the average bleaching alert level from 1985 to 2019. f Comparison between reef remoteness and fish-coral dependency (quantified as the fraction of fish diversity directly or indirectly connected to corals through a coral → fish → fish network path at 1761 reef localities at a resolution of 1° × 1°). For each relationship, we report the Spearman’s rank correlation coefficient (r s ). Full size image However, local anthropogenic disturbances can favour generalist species over specialized ones 8 , 9 , 10 , as corroborated by previous work showing a positive relationship between the degree of ecological specialization and time with no disturbances in in-silico ecological networks 11 . In addition, due to the reduced in-flow of individuals into communities, we might also expect a higher specialization of ecological interactions in isolated habitats 12 . Specialized consumers can be more efficient in using their (few) resources when these are available but have, in principle, a higher co-extinction risk than generalist species 13 , 14 . Thus, while specialization increases ecological networks’ robustness to species loss under stable environmental conditions, it also makes them more fragile towards potential cascading effects of primary extinctions (triggered, for example, by warming) 11 . Therefore, undisturbed and isolated communities should have many specialized interactions increasing their vulnerability to global change (Fig. 1a ). Such an ecological mechanism depicts a component of risk which is distinct and adds up to that stemming from the increased chances of local extinction that species are experiencing in isolated habitats 15 . Here we test whether a positive relationship between ecological specialization/vulnerability and remoteness exists in natural systems, and whether the resulting increased risk of species loss in remote areas can question the common reliance on remote areas as biodiversity strongholds. For these goals, we focused on one of the most biologically diverse and socio-economically significant ecosystems on the planet, coral reefs, which, despite international attention and global protection programmes, continue to deteriorate under the influence of local human impacts (such as physical destruction and pollution) and the increasing effects of climate change (such as coral bleaching) 16 , 17 , 18 , 19 . By assessing the local dependency of fish assemblages on corals across the world’s oceans, we show that the increase in the frequency and strength of fish-coral associations with distance from human settlements, combined with the global reach of coral bleaching, obliterate the benefits of remoteness on reef fish local extinction risk. Results and discussion Exploring the risk-remoteness relationship in reef fish We quantified remoteness as travel time to major cities 20 , 21 (Fig. 2a ). This measure captures both the local impact of direct anthropogenic disturbances (Fig. 1b ) and geographical isolation (Supplementary Fig. 1 ), being therefore well suited to test our hypotheses. Using a global dataset providing standardized measures of anthropogenic impacts on oceans 19 , we quantified the cumulative risk of species loss for reef fish assemblages from local and global hazards. Local hazards stem from direct human activities (six impacts related to fishing activities plus light pollution, shipping, nutrient pollution, organic chemical pollution, and direct human impacts on coastal and near-coastal habitats). They decline with increasing remoteness from human settlements (Figs. 1 b, 2b ). Global hazards are related to global processes such as ocean warming,<|im_end|> <|im_start|>assistant An international research team led by Associate Professor Giovanni Strona from the University of Helsinki has identified a general macroecological mechanism that calls for a reconsideration of global conservation strategies. "To truly understand how global change is affecting natural communities and to identify effective strategies to mitigate the ongoing dramatic biodiversity loss, it is fundamental to account for the overarching complexity emerging from biotic interactions. As we show in our new research, doing this might reveal important counterintuitive mechanisms," Giovanni Strona says. The researchers combined a massive dataset of fish distribution and ecological traits for more than 9,000 fish species. Using artificial intelligence techniques, they generated thousands of networks mapping the interactions between corals and fish and those between fish prey and fish predators in all reef localities worldwide. They quantified, for each locality, the degree of fish dependency on corals. This analysis confirmed what Strona and colleagues showed in another paper published earlier this year: coral loss might detrimentally affect, on average, around 40 per cent of fish species in each coral reef area. The researchers also found that the dependency between fish and corals becomes stronger the further away they are from humans. This means that fish communities in remote reefs might be the most vulnerable to the cascading effects of coral mortality. Areas of critical vulnerability Next, the researchers asked whether the increased risk that stems from the potential cascading effects of coral mortality might counteract the benefits that remote fish communities experience because they are far away from direct impacts of human activities. "For this, we devised a novel risk assessment framework that is applicable to any ecosystem. It combines local anthropogenic impacts such as overfishing and pollution and global impacts like climate and environmental change with the risk deriving from ecological interactions," explains Mar Cabeza, head of the Global Change and Conservation Lab at the University of Helsinki. The framework revealed that taking into account ecological dependencies flattens the expected negative relationship between extinction risk for fish communities and remoteness. "For example, the hotspots of risks for fish communities from local human-derived impacts and global change are almost perfectly the same as the hotspots of risk from fish coral dependencies. This produces a global map of risk for fish communities where no place is safe, regardless of distance from humans," Giovanni Strona says. "The validity and relevance of these findings might extend far beyond reef fish, depicting a world where remote localities, rather than safe havens for biodiversity, might be, instead, areas of critical vulnerability," Mar Cabeza concludes. The research was published in Nature Communications. <|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 Natural D-serine (D-Ser) has been detected in animals more than two decades ago, but little is known about the physiological functions of D-Ser. Here we reveal sleep regulation by endogenous D-Ser. Sleep was decreased in mutants defective in D-Ser synthesis or its receptor the N-methyl-D-aspartic receptor 1 (NMDAR1), but increased in mutants defective in D-Ser degradation. D-Ser but not L-Ser rescued the phenotype of mutants lacking serine racemase (SR), the key enzyme for D-Ser synthesis. Pharmacological and triple gene knockout experiments indicate that D-Ser functions upstream of NMDAR1. Expression of SR was detected in both the nervous system and the intestines. Strikingly, reintroduction of SR into specific intestinal epithelial cells rescued the sleep phenotype of sr mutants. Our results have established a novel physiological function for endogenous D-Ser and a surprising role for intestinal cells. Introduction Amino acids exist in stereoisomers, with all common amino acids except glycine having L- and D-enantiomers depending on the relative spatial arrangement surrounding the α-carbon. Though L-amino acids were traditionally thought to be the only natural form, D-amino acids have been found in biological organisms. Free D-serine (D-Ser) has been found in species ranging from bacteria to mammals 1 , 2 , 3 , 4 . D-Ser is an effective co-agonist of the N-methyl-D-aspartate subtype of glutamate receptor (NMDAR) 5 , 6 . D-Ser is synthesized from L-Ser by serine racemase (SR) 7 and degraded by D-amino acid oxidase (DAAO) 4 and SR 8 . Distribution of D-Ser and NMDAR as determined by chemical measurement 9 and immunohistochemistry 10 supports D-Ser as an endogenous coagonist acting on the glycine modulatory site of the NR1 subunits of the NMDAR 11 , 12 . A role for endogenous D-Ser in synaptic transmission was confirmed by selective degradation of D-Ser with DAAO which attenuated NMDAR function and its rescue by D-Ser 13 . It was proposed that the synaptic NMDAR is activated by D-Ser, whereas the extrasynaptic NMDAR is gated by glycine 14 . Sleep is important for animals and is regulated by both circadian and homeostatic processes 15 . While significant progress has been made in the molecular understanding of circadian rhythm, much less is known about homeostatic regulation of sleep. For more than a decade, Drosophila has been used as a model for genetic studies of sleep 16 , 17 . Genes and brain regions regulating sleep have been identified 18 , 19 , 20 , 21 . Recently, NMDAR and D-Ser have been indicated to participate in sleep regulation in both flies and mammals 22 , 23 , 24 . However, whether D-Ser regulates sleep remains unclear. Here, through a genetic screen followed by a thorough investigation of the synthases, the oxidases, and the receptor of D-Ser, combined with pharmacological genetic epistasis experiments, we report evidence that sleep is regulated by D-Ser through NMDAR1. Furthermore, the synthases, the oxidases, and the receptor of D-Ser have all been found to be expressed in the central nervous system and in the intestine. Strikingly, the intestinal but not neuronal expression has been proved to be important for sleep regulation, indicating a novel role of the intestine in sleep regulation. Taken together, these results suggest that D-Ser made by intestinal SR promotes sleep through NMDAR1 in Drosophila . Results Decreased sleep in shmt mutants and rescue by L-Ser or D-Ser In a screen of homozygous P-element insertion lines for mutations affecting sleep, we found that sleep duration was decreased when a P element was inserted into the CG3011 gene. Analysis of its sequence (Fig. 1a and Supplementary Fig. 1 ) indicates that CG3011 encodes the serine hydroxymethyltransferase (SHMT), which participates in the synthesis of L-Ser 25 , 26 (Fig. 1b ). There are three isoforms of shmt in fly, the original mutant uncovered by our screen contained a P element insertion in the 5′ non-coding region of isoform A (Fig. 1a ). To investigate the function of Drosophila SHMT, we generated mutations in the shmt gene by using CRISPR-Cas9. Deletion of all three isoforms caused lethality, whereas frameshift mutations introducing a STOP codon in the first coding exon of shmt affecting only isoform A resulted in viable shmt mutants ( shmt-es in Fig. 1a ). The mRNA level of isoform A shmt in shmt-es was significantly decreased compared with wild type ( wt ) flies detected by quantitative polymerase chain reaction (qPCR) analyses (Fig. 1c ). The shmt-es mutants were backcrossed into an isogenic Canton-S (CS) line in our lab 27 , and used in further analysis. Fig. 1 Sleep phenotypes of shmt mutants. a A schematic representation of a point mutation leading to a premature stop codon in shmt (thus shmt-early stop or shmt-es ). Also shown is the amino acid sequences of the shmt-es mutant line used here. Single gRNA generated insertion and/or deletion (indel) in the shmt gene, introducing a frameshift and a stop codon (asterisk). b A diagram of D-Ser synthesis pathway. c mRNA level of isoform A shmt in shmt-es was significantly reduced. d Sleep profiles of shmt-es (red) ( n = 57) and wt (black) ( n = 236) flies, plotted in 30 min bins. White background indicates the light phase (ZT 0–12); shaded background indicates the dark phase (ZT 12–24). e Statistical analyses. Daytime and nighttime sleep durations were significantly reduced in shmt-es flies. In this and other figures, open bars denote daytime sleep and filled bars nighttime sleep. f Drug treatment of both L- and D-Ser rescued the nighttime sleep duration of shmt-es flies to the wt level. The number of flies used in the experiment was denoted under each bar. *** P < 0.001, n.s. P > 0.05, Mann–Whitney test was used in ( c , e ), two-way ANOVA test with Bonferroni posttests was used in ( f ) to compare the sleep durations between wt and shmt-es , Kruskal–Wallis test with Dunn’s posttest was used in ( f ) to compare the sleep durations of shmt-es under different drug treatments. Error bars represent s.e.m. Male flies", "role": "user" }, { "content": "A team of researchers affiliated with several institutions in China has found that an amino acid made in fruit fly intestines plays a key role in regulating their sleep. In their paper published in the journal Nature Communications, the group describes their study of D-serine in Drosophila melanogaster and what they found. Scientists have known about D-serine for many years, but thought that it only existed in bacteria. Recently, however, researchers found that humans also produce the amino acid, as do fruit flies. But until now, it was not known what function it served. In this new effort, the researchers found that, at least in fruit flies, it helps regulate sleep. To learn more about the amino acid, the researchers edited the genes of fly specimens to halt its production and found that doing so resulted in the flies sleeping only half as much as normal flies. But they also found something else. Fruit flies actually produce D-serine in two places—in their intestines and their brains. Logic would suggest that the acid produced in the brain would be the one associated with sleep, but the researchers found that the opposite was true. When they turned off the genes that controlled production of the enzyme, serine racemase, which syntheses D-serine in the intestines, the flies slept less, but when they did the same for those made in the brain, they saw no change in sleep habits. The researchers report that they have no idea how an amino acid produced in the intestines can impact sleep patterns, noting that sleep regulation is probably carried out by the central nervous system. Prior research has shown that sleep is a very old evolutionary development, which suggests its control is likely similar across species. They suggest that more research is needed to find the answers to other questions surrounding D-serine—for instance, is it produced in other parts of the body? Does it play a role in regulating sleep in humans, and if so, how? ", "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 Natural D-serine (D-Ser) has been detected in animals more than two decades ago, but little is known about the physiological functions of D-Ser. Here we reveal sleep regulation by endogenous D-Ser. Sleep was decreased in mutants defective in D-Ser synthesis or its receptor the N-methyl-D-aspartic receptor 1 (NMDAR1), but increased in mutants defective in D-Ser degradation. D-Ser but not L-Ser rescued the phenotype of mutants lacking serine racemase (SR), the key enzyme for D-Ser synthesis. Pharmacological and triple gene knockout experiments indicate that D-Ser functions upstream of NMDAR1. Expression of SR was detected in both the nervous system and the intestines. Strikingly, reintroduction of SR into specific intestinal epithelial cells rescued the sleep phenotype of sr mutants. Our results have established a novel physiological function for endogenous D-Ser and a surprising role for intestinal cells. Introduction Amino acids exist in stereoisomers, with all common amino acids except glycine having L- and D-enantiomers depending on the relative spatial arrangement surrounding the α-carbon. Though L-amino acids were traditionally thought to be the only natural form, D-amino acids have been found in biological organisms. Free D-serine (D-Ser) has been found in species ranging from bacteria to mammals 1 , 2 , 3 , 4 . D-Ser is an effective co-agonist of the N-methyl-D-aspartate subtype of glutamate receptor (NMDAR) 5 , 6 . D-Ser is synthesized from L-Ser by serine racemase (SR) 7 and degraded by D-amino acid oxidase (DAAO) 4 and SR 8 . Distribution of D-Ser and NMDAR as determined by chemical measurement 9 and immunohistochemistry 10 supports D-Ser as an endogenous coagonist acting on the glycine modulatory site of the NR1 subunits of the NMDAR 11 , 12 . A role for endogenous D-Ser in synaptic transmission was confirmed by selective degradation of D-Ser with DAAO which attenuated NMDAR function and its rescue by D-Ser 13 . It was proposed that the synaptic NMDAR is activated by D-Ser, whereas the extrasynaptic NMDAR is gated by glycine 14 . Sleep is important for animals and is regulated by both circadian and homeostatic processes 15 . While significant progress has been made in the molecular understanding of circadian rhythm, much less is known about homeostatic regulation of sleep. For more than a decade, Drosophila has been used as a model for genetic studies of sleep 16 , 17 . Genes and brain regions regulating sleep have been identified 18 , 19 , 20 , 21 . Recently, NMDAR and D-Ser have been indicated to participate in sleep regulation in both flies and mammals 22 , 23 , 24 . However, whether D-Ser regulates sleep remains unclear. Here, through a genetic screen followed by a thorough investigation of the synthases, the oxidases, and the receptor of D-Ser, combined with pharmacological genetic epistasis experiments, we report evidence that sleep is regulated by D-Ser through NMDAR1. Furthermore, the synthases, the oxidases, and the receptor of D-Ser have all been found to be expressed in the central nervous system and in the intestine. Strikingly, the intestinal but not neuronal expression has been proved to be important for sleep regulation, indicating a novel role of the intestine in sleep regulation. Taken together, these results suggest that D-Ser made by intestinal SR promotes sleep through NMDAR1 in Drosophila . Results Decreased sleep in shmt mutants and rescue by L-Ser or D-Ser In a screen of homozygous P-element insertion lines for mutations affecting sleep, we found that sleep duration was decreased when a P element was inserted into the CG3011 gene. Analysis of its sequence (Fig. 1a and Supplementary Fig. 1 ) indicates that CG3011 encodes the serine hydroxymethyltransferase (SHMT), which participates in the synthesis of L-Ser 25 , 26 (Fig. 1b ). There are three isoforms of shmt in fly, the original mutant uncovered by our screen contained a P element insertion in the 5′ non-coding region of isoform A (Fig. 1a ). To investigate the function of Drosophila SHMT, we generated mutations in the shmt gene by using CRISPR-Cas9. Deletion of all three isoforms caused lethality, whereas frameshift mutations introducing a STOP codon in the first coding exon of shmt affecting only isoform A resulted in viable shmt mutants ( shmt-es in Fig. 1a ). The mRNA level of isoform A shmt in shmt-es was significantly decreased compared with wild type ( wt ) flies detected by quantitative polymerase chain reaction (qPCR) analyses (Fig. 1c ). The shmt-es mutants were backcrossed into an isogenic Canton-S (CS) line in our lab 27 , and used in further analysis. Fig. 1 Sleep phenotypes of shmt mutants. a A schematic representation of a point mutation leading to a premature stop codon in shmt (thus shmt-early stop or shmt-es ). Also shown is the amino acid sequences of the shmt-es mutant line used here. Single gRNA generated insertion and/or deletion (indel) in the shmt gene, introducing a frameshift and a stop codon (asterisk). b A diagram of D-Ser synthesis pathway. c mRNA level of isoform A shmt in shmt-es was significantly reduced. d Sleep profiles of shmt-es (red) ( n = 57) and wt (black) ( n = 236) flies, plotted in 30 min bins. White background indicates the light phase (ZT 0–12); shaded background indicates the dark phase (ZT 12–24). e Statistical analyses. Daytime and nighttime sleep durations were significantly reduced in shmt-es flies. In this and other figures, open bars denote daytime sleep and filled bars nighttime sleep. f Drug treatment of both L- and D-Ser rescued the nighttime sleep duration of shmt-es flies to the wt level. The number of flies used in the experiment was denoted under each bar. *** P < 0.001, n.s. P > 0.05, Mann–Whitney test was used in ( c , e ), two-way ANOVA test with Bonferroni posttests was used in ( f ) to compare the sleep durations between wt and shmt-es , Kruskal–Wallis test with Dunn’s posttest was used in ( f ) to compare the sleep durations of shmt-es under different drug treatments. Error bars represent s.e.m. Male flies<|im_end|> <|im_start|>assistant A team of researchers affiliated with several institutions in China has found that an amino acid made in fruit fly intestines plays a key role in regulating their sleep. In their paper published in the journal Nature Communications, the group describes their study of D-serine in Drosophila melanogaster and what they found. Scientists have known about D-serine for many years, but thought that it only existed in bacteria. Recently, however, researchers found that humans also produce the amino acid, as do fruit flies. But until now, it was not known what function it served. In this new effort, the researchers found that, at least in fruit flies, it helps regulate sleep. To learn more about the amino acid, the researchers edited the genes of fly specimens to halt its production and found that doing so resulted in the flies sleeping only half as much as normal flies. But they also found something else. Fruit flies actually produce D-serine in two places—in their intestines and their brains. Logic would suggest that the acid produced in the brain would be the one associated with sleep, but the researchers found that the opposite was true. When they turned off the genes that controlled production of the enzyme, serine racemase, which syntheses D-serine in the intestines, the flies slept less, but when they did the same for those made in the brain, they saw no change in sleep habits. The researchers report that they have no idea how an amino acid produced in the intestines can impact sleep patterns, noting that sleep regulation is probably carried out by the central nervous system. Prior research has shown that sleep is a very old evolutionary development, which suggests its control is likely similar across species. They suggest that more research is needed to find the answers to other questions surrounding D-serine—for instance, is it produced in other parts of the body? Does it play a role in regulating sleep in humans, and if so, how? <|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 Tumour-specific CD8 T cell dysfunction is a differentiation state that is distinct from the functional effector or memory T cell states 1 , 2 , 3 , 4 , 5 , 6 . Here we identify the nuclear factor TOX as a crucial regulator of the differentiation of tumour-specific T (TST) cells. We show that TOX is highly expressed in dysfunctional TST cells from tumours and in exhausted T cells during chronic viral infection. Expression of TOX is driven by chronic T cell receptor stimulation and NFAT activation. Ectopic expression of TOX in effector T cells in vitro induced a transcriptional program associated with T cell exhaustion. Conversely, deletion of Tox in TST cells in tumours abrogated the exhaustion program: Tox -deleted TST cells did not upregulate genes for inhibitory receptors (such as Pdcd1 , Entpd1 , Havcr2 , Cd244 and Tigit ), the chromatin of which remained largely inaccessible, and retained high expression of transcription factors such as TCF-1. Despite their normal, ‘non-exhausted’ immunophenotype, Tox -deleted TST cells remained dysfunctional, which suggests that the regulation of expression of inhibitory receptors is uncoupled from the loss of effector function. Notably, although Tox -deleted CD8 T cells differentiated normally to effector and memory states in response to acute infection, Tox -deleted TST cells failed to persist in tumours. We hypothesize that the TOX-induced exhaustion program serves to prevent the overstimulation of T cells and activation-induced cell death in settings of chronic antigen stimulation such as cancer. Main Using an inducible model of autochthonous liver cancer in which SV40 large T antigen (TAG) is the oncogenic driver and tumour-specific antigen 7 (Fig. 1a and Extended Data Fig. 1a ), we recently showed that CD8 + T cells expressing a restricted T cell receptor (TCR) specific for TAG (hereafter referred to as TCR TAG cells) differentiate to an epigenetically encoded dysfunctional state, exhibiting hallmarks of TST cell dysfunction including the expression of inhibitory receptors and loss of effector cytokines 3 , 5 . Numerous transcription factors were dysregulated in dysfunctional TCR TAG cells (such as NFAT, TCF-1, LEF1, IRF4 and BLIMP1) compared with functional effector or memory TCR TAG cells generated during acute infection with Listeria (using a recombinant Listeria monocytogenes strain that expressed TAG epitope I ( Lm TAG)) 5 . However, many of these transcription factors are also crucial for the development of normal effector and memory T cells 8 ; thus, we set out to identify transcription factors that were specifically expressed in dysfunctional TCR TAG cells. We analysed our RNA sequencing (RNA-seq) data 5 and found that the gene encoding the nuclear factor TOX was highly expressed in dysfunctional TCR TAG cells, but low in functional naive, effector and memory TCR TAG cells (Fig. 1b ). TOX is a nuclear DNA-binding factor and a member of the high-motility group box superfamily that is thought to bind DNA in a sequence-independent but structure-dependent manner 9 . Although TOX is required during thymic development of CD4 + T lineage cells, natural killer and innate lymphoid cells 10 , 11 , 12 , and in regulating CD8 T cell-mediated autoimmunity 13 , its role in tumour-induced T cell dysfunction is unknown. To assess TOX expression during CD8 T cell differentiation in acute infection and tumorigenesis, congenically marked naive TCR TAG cells were transferred into (i) wild-type C57BL/6 (B6) mice immunized with Lm TAG, or (ii) tamoxifen-inducible liver cancer mice (AST×Cre-ER T2 ; AST denotes albumin-floxStop-SV40 large T antigen) treated with tamoxifen (Fig. 1a and Extended Data Fig. 1a, b ). TOX was expressed at low levels early after Listeria infection but declined to baseline levels (by day 5 after infection) and remained low in memory T cells (Fig. 1c and Extended Data Figs. 1c , 2 ). By contrast, during tumour progression, TOX expression increased in TCR TAG cells and remained high (Fig. 1c and Extended Data Figs. 1c , 2 ). High expression of TOX correlated with high expression of several inhibitory receptors and low expression of TCF-1 (Fig. 1d and Extended Data Figs. 1d , 2b, c ). Moreover, TOX-expressing TCR TAG cells failed to produce the effector cytokines IFNγ and TNF after stimulation ex vivo with cognate peptide or phorbol myristate acetate (PMA) and ionomycin (Fig. 1e and Extended Data Fig. 1e–g ). Fig. 1: TOX is highly expressed in tumour-infiltrating CD8 T cells of mouse and human tumours. a , Experimental scheme for acute infection (green) and tumorigenesis (red). E 3 and E 7 , effector cells isolated 3 and 7 days after immunization, respectively; M, memory cells; T 7 and T 14–60 , T cells isolated from liver tumours at 7 and 14–60 days after transfer. b , Reads per kilobase of transcript per million mapped read (RPKM) values of Tox . n = 3 (naive (N), memory); n = 6 (E 5– 7 ); n = 14 (T 14–60 ) TCR TAG cells isolated from liver tumour lesions of AST×Cre-ER T2 mice at 14, 21, 28, 35 and more than 60 days after transfer 5 . c , Expression levels of TOX protein in TCR TAG cells during Listeria infection (green) or tumorigenesis (red), assessed by flow cytometry at indicated time points with n = 2–3 mice. MFI, mean fluorescent intensity; Tam, tamoxifen. d , Expression of TOX, TCF-1 and PD-1 in TCR TAG cells isolated from liver tumour lesions 35 days after transfer (T 35 ; red, n = 5); memory TCR TAG cells are shown as control (M; green). e , IFNγ and TNF production of memory TCR TAG cells (M; green, n = 2) and liver tumour-infiltrating TCR TAG cells (T; red, n = 3). Data are representative of more than five independent experiments. f – h , TOX expression in human tumour-infiltrating CD8 + T cells isolated from patients with melanoma ( n = 4) ( f ), breast cancer ( n = 4) ( g ), and lung cancer ( n = 6) ( h ). Each symbol represents an", "role": "user" }, { "content": "Immune checkpoint therapy has revolutionized cancer therapy, leading to long-term remission for patients with advanced cancer. However, most cancer patients either do not respond or have only short-term responses to checkpoint therapy, which targets inhibitory receptors on T cells. A study published June 17 in Nature offers clues as to why blocking inhibitory receptors on tumor-infiltrating T cells may not always work. Mary Philip, MD, Ph.D., assistant professor of Medicine in the Division of Hematology and Oncology and a senior author on the story, together with Andrea Schietinger, Ph.D., of the Sloan Kettering Institute, found that the thymocyte selection-associated high-mobility group box protein, TOX, is expressed at high levels in dysfunctional tumor-infiltrating T cells in mice and humans. The investigators found that TOX controls the high expression of inhibitory receptors such as PD1 on dysfunctional tumor-infiltrating T cells. These inhibitory receptors act like brakes on T cells. The team deleted TOX from tumor-infiltrating T cells to see if that would restore their function. To their surprise, though the tumor-infiltrating T cells no longer expressed PD1 and other inhibitory receptors, the T cells were still dysfunctional and unable to eliminate cancers. Even more surprising, the T cells without TOX were unable to survive long term. The study demonstrates that control of the killing machinery in T cells is uncoupled from regulation of inhibitory receptors. \"Taking off the brakes is not enough to restore the killing capacity of anti-tumor cells. In fact, T cells need the brakes to avoid getting over-activated and dying,\" Philip said. The study follows a previous investigation published in Nature on May 25, 2018, by Philip and colleagues on T cell dysfunction in liver cancer using mouse models. Philip was the lead author of that study. The overarching goal of Philip's research group is to decipher the mechanisms regulating T cell dysfunction in cancers and to design new strategies to override these mechanisms to improve cancer immunotherapy. ", "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 Tumour-specific CD8 T cell dysfunction is a differentiation state that is distinct from the functional effector or memory T cell states 1 , 2 , 3 , 4 , 5 , 6 . Here we identify the nuclear factor TOX as a crucial regulator of the differentiation of tumour-specific T (TST) cells. We show that TOX is highly expressed in dysfunctional TST cells from tumours and in exhausted T cells during chronic viral infection. Expression of TOX is driven by chronic T cell receptor stimulation and NFAT activation. Ectopic expression of TOX in effector T cells in vitro induced a transcriptional program associated with T cell exhaustion. Conversely, deletion of Tox in TST cells in tumours abrogated the exhaustion program: Tox -deleted TST cells did not upregulate genes for inhibitory receptors (such as Pdcd1 , Entpd1 , Havcr2 , Cd244 and Tigit ), the chromatin of which remained largely inaccessible, and retained high expression of transcription factors such as TCF-1. Despite their normal, ‘non-exhausted’ immunophenotype, Tox -deleted TST cells remained dysfunctional, which suggests that the regulation of expression of inhibitory receptors is uncoupled from the loss of effector function. Notably, although Tox -deleted CD8 T cells differentiated normally to effector and memory states in response to acute infection, Tox -deleted TST cells failed to persist in tumours. We hypothesize that the TOX-induced exhaustion program serves to prevent the overstimulation of T cells and activation-induced cell death in settings of chronic antigen stimulation such as cancer. Main Using an inducible model of autochthonous liver cancer in which SV40 large T antigen (TAG) is the oncogenic driver and tumour-specific antigen 7 (Fig. 1a and Extended Data Fig. 1a ), we recently showed that CD8 + T cells expressing a restricted T cell receptor (TCR) specific for TAG (hereafter referred to as TCR TAG cells) differentiate to an epigenetically encoded dysfunctional state, exhibiting hallmarks of TST cell dysfunction including the expression of inhibitory receptors and loss of effector cytokines 3 , 5 . Numerous transcription factors were dysregulated in dysfunctional TCR TAG cells (such as NFAT, TCF-1, LEF1, IRF4 and BLIMP1) compared with functional effector or memory TCR TAG cells generated during acute infection with Listeria (using a recombinant Listeria monocytogenes strain that expressed TAG epitope I ( Lm TAG)) 5 . However, many of these transcription factors are also crucial for the development of normal effector and memory T cells 8 ; thus, we set out to identify transcription factors that were specifically expressed in dysfunctional TCR TAG cells. We analysed our RNA sequencing (RNA-seq) data 5 and found that the gene encoding the nuclear factor TOX was highly expressed in dysfunctional TCR TAG cells, but low in functional naive, effector and memory TCR TAG cells (Fig. 1b ). TOX is a nuclear DNA-binding factor and a member of the high-motility group box superfamily that is thought to bind DNA in a sequence-independent but structure-dependent manner 9 . Although TOX is required during thymic development of CD4 + T lineage cells, natural killer and innate lymphoid cells 10 , 11 , 12 , and in regulating CD8 T cell-mediated autoimmunity 13 , its role in tumour-induced T cell dysfunction is unknown. To assess TOX expression during CD8 T cell differentiation in acute infection and tumorigenesis, congenically marked naive TCR TAG cells were transferred into (i) wild-type C57BL/6 (B6) mice immunized with Lm TAG, or (ii) tamoxifen-inducible liver cancer mice (AST×Cre-ER T2 ; AST denotes albumin-floxStop-SV40 large T antigen) treated with tamoxifen (Fig. 1a and Extended Data Fig. 1a, b ). TOX was expressed at low levels early after Listeria infection but declined to baseline levels (by day 5 after infection) and remained low in memory T cells (Fig. 1c and Extended Data Figs. 1c , 2 ). By contrast, during tumour progression, TOX expression increased in TCR TAG cells and remained high (Fig. 1c and Extended Data Figs. 1c , 2 ). High expression of TOX correlated with high expression of several inhibitory receptors and low expression of TCF-1 (Fig. 1d and Extended Data Figs. 1d , 2b, c ). Moreover, TOX-expressing TCR TAG cells failed to produce the effector cytokines IFNγ and TNF after stimulation ex vivo with cognate peptide or phorbol myristate acetate (PMA) and ionomycin (Fig. 1e and Extended Data Fig. 1e–g ). Fig. 1: TOX is highly expressed in tumour-infiltrating CD8 T cells of mouse and human tumours. a , Experimental scheme for acute infection (green) and tumorigenesis (red). E 3 and E 7 , effector cells isolated 3 and 7 days after immunization, respectively; M, memory cells; T 7 and T 14–60 , T cells isolated from liver tumours at 7 and 14–60 days after transfer. b , Reads per kilobase of transcript per million mapped read (RPKM) values of Tox . n = 3 (naive (N), memory); n = 6 (E 5– 7 ); n = 14 (T 14–60 ) TCR TAG cells isolated from liver tumour lesions of AST×Cre-ER T2 mice at 14, 21, 28, 35 and more than 60 days after transfer 5 . c , Expression levels of TOX protein in TCR TAG cells during Listeria infection (green) or tumorigenesis (red), assessed by flow cytometry at indicated time points with n = 2–3 mice. MFI, mean fluorescent intensity; Tam, tamoxifen. d , Expression of TOX, TCF-1 and PD-1 in TCR TAG cells isolated from liver tumour lesions 35 days after transfer (T 35 ; red, n = 5); memory TCR TAG cells are shown as control (M; green). e , IFNγ and TNF production of memory TCR TAG cells (M; green, n = 2) and liver tumour-infiltrating TCR TAG cells (T; red, n = 3). Data are representative of more than five independent experiments. f – h , TOX expression in human tumour-infiltrating CD8 + T cells isolated from patients with melanoma ( n = 4) ( f ), breast cancer ( n = 4) ( g ), and lung cancer ( n = 6) ( h ). Each symbol represents an<|im_end|> <|im_start|>assistant Immune checkpoint therapy has revolutionized cancer therapy, leading to long-term remission for patients with advanced cancer. However, most cancer patients either do not respond or have only short-term responses to checkpoint therapy, which targets inhibitory receptors on T cells. A study published June 17 in Nature offers clues as to why blocking inhibitory receptors on tumor-infiltrating T cells may not always work. Mary Philip, MD, Ph.D., assistant professor of Medicine in the Division of Hematology and Oncology and a senior author on the story, together with Andrea Schietinger, Ph.D., of the Sloan Kettering Institute, found that the thymocyte selection-associated high-mobility group box protein, TOX, is expressed at high levels in dysfunctional tumor-infiltrating T cells in mice and humans. The investigators found that TOX controls the high expression of inhibitory receptors such as PD1 on dysfunctional tumor-infiltrating T cells. These inhibitory receptors act like brakes on T cells. The team deleted TOX from tumor-infiltrating T cells to see if that would restore their function. To their surprise, though the tumor-infiltrating T cells no longer expressed PD1 and other inhibitory receptors, the T cells were still dysfunctional and unable to eliminate cancers. Even more surprising, the T cells without TOX were unable to survive long term. The study demonstrates that control of the killing machinery in T cells is uncoupled from regulation of inhibitory receptors. "Taking off the brakes is not enough to restore the killing capacity of anti-tumor cells. In fact, T cells need the brakes to avoid getting over-activated and dying," Philip said. The study follows a previous investigation published in Nature on May 25, 2018, by Philip and colleagues on T cell dysfunction in liver cancer using mouse models. Philip was the lead author of that study. The overarching goal of Philip's research group is to decipher the mechanisms regulating T cell dysfunction in cancers and to design new strategies to override these mechanisms to improve cancer immunotherapy. <|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 mammalian cells, chromosomes are partitioned into megabase-sized topologically associating domains (TADs). TADs can be in either A (active) or B (inactive) subnuclear compartments, which exhibit early and late replication timing (RT), respectively. Here, we show that A/B compartments change coordinately with RT changes genome wide during mouse embryonic stem cell (mESC) differentiation. While A to B compartment changes and early to late RT changes were temporally inseparable, B to A changes clearly preceded late to early RT changes and transcriptional activation. Compartments changed primarily by boundary shifting, altering the compartmentalization of TADs facing the A/B compartment interface, which was conserved during reprogramming and confirmed in individual cells by single-cell Repli-seq. Differentiating mESCs altered single-cell Repli-seq profiles gradually but uniformly, transiently resembling RT profiles of epiblast-derived stem cells (EpiSCs), suggesting that A/B compartments might also change gradually but uniformly toward a primed pluripotent state. These results provide insights into how megabase-scale chromosome organization changes in individual cells during differentiation. Main DNA replication has served as an excellent forum in which to investigate the principles of megabase (Mb)-scale organization of the genome 1 , 2 , 3 . Early- and late-replicating chromosomal bands correspond to Giemsa R- and G-bands, respectively 1 . 5-Bromodeoxyuridine (BrdU) pulse-labeling of mammalian cells has identified ~1 Mb units of DNA replication called the replication foci 1 . Each focus completes replication within ~1 h and remains stable as a unit after multiple cell cycles 3 . RT-profiling technologies have mapped Mb-sized replication domains genome wide 4 , 5 , 6 . If we define replication domains as stretches of DNA that show uniform RT separated by timing transition regions (TTRs) 4 , replication-domain boundaries of a given cell type constitute approximately half of all potential boundaries and replication-domain organization changes dynamically during differentiation 4 , 5 , 6 , 7 . Aside from various chromosomal banding studies, evidence for Mb-scale structural units of chromosomes other than replication domains, replication foci and lamina-associated domains (LADs) were virtually nonexistent 1 , 8 . This situation changed with the advent of Hi-C, a genome-wide chromosome conformation capture (3C) technology 9 . Hi-C has shown that mammalian chromosomes can be subdivided into stable Mb-sized self-associating units called TADs 10 , 11 , which are separated into A and B subnuclear compartments 9 . Unlike TADs, A/B compartments change dynamically during differentiation 11 , 12 but their boundaries coincide with a subset of TAD boundaries 7 , 12 . Interestingly, A and B compartments align remarkably well with early- and late-replicating domains, respectively 6 , suggesting that Hi-C and RT analyses probe similar aspects of genome organization at the Mb scale. However, we still do not know how TADs, A/B compartments and replication domains relate to each other 3 . How and when do RT and A/B compartments change during differentiation? Are the changes coordinated to maintain the tight relationship observed in cultured cells? To address these questions and gain insights into the regulatory principles of three-dimensional (3D) genome organization, we performed Hi-C and RT analyses at one-day intervals during mESC differentiation and analyzed their relationship extensively. Moreover, we took advantage of our latest single-cell RT-profiling technology, scRepli-seq 13 , to infer how they change at the single-cell level. Results A mESC neural differentiation system in a defined medium We modified a differentiation protocol developed by Hayashi et al. 14 and combined it with the SFEBq neural differentiation protocol 15 . In this protocol (Fig. 1a ), naïve mESCs grown in MEK and GSK3 inhibitors (2i) and leukemia inhibitory factor (LIF) (see Methods ) are first differentiated to epiblast-like cells (EpiLCs). On day 2, the monolayer EpiLCs are detached, aggregated as embryoid bodies (EBs) in Lipidure-coated 96-well plates and cultured until day 7. The only difference from the SFEBq method 15 is the use of EpiLCs instead of mESCs as the starting materials for EB formation. Fig. 1: An mESC neural differentiation system in a defined medium. a , Neural differentiation of mESCs via EpiLCs. EB photographs were taken after transfer from 96-well plates to single plates. b , Immunofluorescence staining of representative cell colonies (days 0 and 2) and EB sections (days 3–7) during mESC differentiation with antibodies against Oct4, Nanog, Sox1 and Eomes (two independent experiments showed similar results). Nuclei were counterstained with DAPI. c , Comparison of genome-wide RT profiles from differentiation intermediates derived from CBMS1 mESCs (this study) and D3 mESCs, as well as ES-Gsc gfp Sox17 huCD25 mESCs (mesoderm and endoderm cells) 5 by hierarchical clustering. d , Comparison of fold changes in gene expression values between the two mESC differentiation protocols described in c , by RNA-seq (CBMS1) or expression microarrays (D3). Pearson’s R values are shown. See also Supplementary Fig. 3b . e , Percentage of outlier cells as assayed by the scRepli-seq technology. See also Fig. 4e . N , number of cells analyzed. f , A comparison of RT and A/B compartments (Hi-C PC1) during differentiation of CBMS1 mESCs at one-day intervals. The ∆RT and ∆PC1 plots present RT and Hi-C PC1 differentials, respectively, from day 0 to day 7. Regions 1 and 2 are representative early to late/A to B and late to early/B to A switching regions, respectively. Full size image By RNA-seq, naïve CBMS1 mESCs 16 correctly adopted an EpiLC fate on day 2, sharply downregulating early inner cell mass markers ( Prdm14 , Zfp42 , Tbx3 , Tcl1 , Esrrb , Nanog , Klf2 , Klf4 , Klf5 ), upregulating epiblast markers ( Fgf5 , Wnt3 , Dnmt3b ) and either maintaining ( Pou5f1/Oct4 , Fgf4 ) or downregulating ( Sox2 ) pluripotency markers, as expected 14 (Supplementary Fig. 1a and Supplementary Table 1 ). By day 7, ectodermal and pluripotency markers were up- and downregulated, respectively (Supplementary Fig. 1a,b ), while many mesoderm and endoderm markers were expressed at low levels (Supplementary Fig. 1b ). During day 4–5 transition, Pou5f1/Oct4 showed sharp downregulation, while ectodermal markers showed sharp upregulation (Supplementary Fig. 1c ). As expected, activation", "role": "user" }, { "content": "The human genome is made up of 46 chromosomes, each of which has a length of about 100 to 200 million base pairs, the building blocks of the DNA double helix. Even during interphase, the period in between the cell division phases, chromosomes are still tightly packed inside the cell nucleus. On each chromosome, a regular structural unit called the nucleosome corresponds to a 146-base-pair-long strand of DNA wrapped around eight histone protein molecules. Until recently, no other regular structures beyond the nucleosomes were known. Thanks to the emerging genomics-based technology Hi-C (high-throughput chromosome conformation capture), researchers now know that there are regular structural units at the megabase scale, referring to millions of base pairs. It is now generally accepted that mammalian chromosomes are composed of megabase-sized globular units called topologically associating domains (TADs), which are separated by boundaries, presumably in a beads-on-a-string manner. Further, multiple TADs assemble to form what are called A and B subnuclear compartments. TADs containing many active genes form A compartments, while TADs with few or no active genes form B compartments. It is generally believed that TADs are stable units of the chromosomes and that their boundary positions do not change between cell types. By contrast, the organization of A/B compartments differs between cell types, meaning that the boundaries between them change during differentiation. However, nobody has ever observed changes in A/B compartments as they occurred. Scientists from the RIKEN Center for Biosystems Dynamics Research have now observed A/B compartment changes in detail during the differentiation of mouse embryonic stem cells (mESCs). They discovered many genomic regions that switched compartments, either from A to B or vice versa, which, interestingly, correlated well with the genomic regions that switched their replication timing (the temporal order of genomic DNA replication) from early to late or vice versa, respectively. A to B compartment changes were accompanied by movements from the nuclear interior to the periphery and by gene repression, while B to A compartment changes were accompanied by movements from the nuclear periphery to the interior and by gene activation. These results strongly suggest that A/B compartment changes represent physical movements of portions of chromosomes within the 3-D nuclear space, accompanied by changes in gene expression and replication timing. Regarding the temporal relationship between the physical movements of chromosomes and changes in gene expression and replication timing, the research team found that genomic regions that switched from B to A compartment clearly did so one to two days prior to gene activation, and that the changes in replication timing were from late to early. This raised an intriguing possibility that compartment changes might be a prerequisite for gene activation and replication timing changes. The team went on to characterize the features of genomic regions that changed A/B compartments. Compartments were found to change primarily by the shifting of A/B compartment boundaries, while the emergence of new compartments—for example the emergence of an A compartment within a stretch of B compartment or vice versa—was rare. Because compartment boundaries corresponded to a subset of TAD boundaries, they looked at how many TADs changed compartments and discovered that the majority of the changes affected single TADs. Importantly, this single-TAD-level switching of compartments was confirmed in single cells by a method, called single-cell Repli-seq, which was recently developed by the research team to analyze DNA replication regulation genome-wide in single cells (note that replication timing correlates very well with A/B compartments). The team also found that A/B compartment profiles changed gradually but uniformly within a differentiating cell population, with the cells transiently resembling the epiblast-derived stem cell (EpiSC) state, an advanced form of stem cells compared to ESCs. Taken together, the team's finding suggests that A/B compartments change primarily by the relocation of single TADs facing the A/B compartment interface to the opposite compartment. \"It is possible,\" says Ichiro Hiratani, the leader of the group, \"that the accumulation of these compartment switching events may reflect or represent changes in differentiation states such as from ESCs to EpiSCs.\" In this way, this study, published in Nature Genetics, explains how chromosomes undergo structural changes during cell differentiation. According to Hiratani, \"Our study was the first to clearly demonstrate that changes in chromosome conformation preceded changes in DNA-based transactions such as gene expression and DNA replication timing. Intriguingly, chromosome conformation changes were regulated at the level of single TADs. We are eager to explore the basis of such single-TAD-level regulation of chromosomes and entertain the possibility of predicting DNA transactions based on preceding changes in chromosome 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 In mammalian cells, chromosomes are partitioned into megabase-sized topologically associating domains (TADs). TADs can be in either A (active) or B (inactive) subnuclear compartments, which exhibit early and late replication timing (RT), respectively. Here, we show that A/B compartments change coordinately with RT changes genome wide during mouse embryonic stem cell (mESC) differentiation. While A to B compartment changes and early to late RT changes were temporally inseparable, B to A changes clearly preceded late to early RT changes and transcriptional activation. Compartments changed primarily by boundary shifting, altering the compartmentalization of TADs facing the A/B compartment interface, which was conserved during reprogramming and confirmed in individual cells by single-cell Repli-seq. Differentiating mESCs altered single-cell Repli-seq profiles gradually but uniformly, transiently resembling RT profiles of epiblast-derived stem cells (EpiSCs), suggesting that A/B compartments might also change gradually but uniformly toward a primed pluripotent state. These results provide insights into how megabase-scale chromosome organization changes in individual cells during differentiation. Main DNA replication has served as an excellent forum in which to investigate the principles of megabase (Mb)-scale organization of the genome 1 , 2 , 3 . Early- and late-replicating chromosomal bands correspond to Giemsa R- and G-bands, respectively 1 . 5-Bromodeoxyuridine (BrdU) pulse-labeling of mammalian cells has identified ~1 Mb units of DNA replication called the replication foci 1 . Each focus completes replication within ~1 h and remains stable as a unit after multiple cell cycles 3 . RT-profiling technologies have mapped Mb-sized replication domains genome wide 4 , 5 , 6 . If we define replication domains as stretches of DNA that show uniform RT separated by timing transition regions (TTRs) 4 , replication-domain boundaries of a given cell type constitute approximately half of all potential boundaries and replication-domain organization changes dynamically during differentiation 4 , 5 , 6 , 7 . Aside from various chromosomal banding studies, evidence for Mb-scale structural units of chromosomes other than replication domains, replication foci and lamina-associated domains (LADs) were virtually nonexistent 1 , 8 . This situation changed with the advent of Hi-C, a genome-wide chromosome conformation capture (3C) technology 9 . Hi-C has shown that mammalian chromosomes can be subdivided into stable Mb-sized self-associating units called TADs 10 , 11 , which are separated into A and B subnuclear compartments 9 . Unlike TADs, A/B compartments change dynamically during differentiation 11 , 12 but their boundaries coincide with a subset of TAD boundaries 7 , 12 . Interestingly, A and B compartments align remarkably well with early- and late-replicating domains, respectively 6 , suggesting that Hi-C and RT analyses probe similar aspects of genome organization at the Mb scale. However, we still do not know how TADs, A/B compartments and replication domains relate to each other 3 . How and when do RT and A/B compartments change during differentiation? Are the changes coordinated to maintain the tight relationship observed in cultured cells? To address these questions and gain insights into the regulatory principles of three-dimensional (3D) genome organization, we performed Hi-C and RT analyses at one-day intervals during mESC differentiation and analyzed their relationship extensively. Moreover, we took advantage of our latest single-cell RT-profiling technology, scRepli-seq 13 , to infer how they change at the single-cell level. Results A mESC neural differentiation system in a defined medium We modified a differentiation protocol developed by Hayashi et al. 14 and combined it with the SFEBq neural differentiation protocol 15 . In this protocol (Fig. 1a ), naïve mESCs grown in MEK and GSK3 inhibitors (2i) and leukemia inhibitory factor (LIF) (see Methods ) are first differentiated to epiblast-like cells (EpiLCs). On day 2, the monolayer EpiLCs are detached, aggregated as embryoid bodies (EBs) in Lipidure-coated 96-well plates and cultured until day 7. The only difference from the SFEBq method 15 is the use of EpiLCs instead of mESCs as the starting materials for EB formation. Fig. 1: An mESC neural differentiation system in a defined medium. a , Neural differentiation of mESCs via EpiLCs. EB photographs were taken after transfer from 96-well plates to single plates. b , Immunofluorescence staining of representative cell colonies (days 0 and 2) and EB sections (days 3–7) during mESC differentiation with antibodies against Oct4, Nanog, Sox1 and Eomes (two independent experiments showed similar results). Nuclei were counterstained with DAPI. c , Comparison of genome-wide RT profiles from differentiation intermediates derived from CBMS1 mESCs (this study) and D3 mESCs, as well as ES-Gsc gfp Sox17 huCD25 mESCs (mesoderm and endoderm cells) 5 by hierarchical clustering. d , Comparison of fold changes in gene expression values between the two mESC differentiation protocols described in c , by RNA-seq (CBMS1) or expression microarrays (D3). Pearson’s R values are shown. See also Supplementary Fig. 3b . e , Percentage of outlier cells as assayed by the scRepli-seq technology. See also Fig. 4e . N , number of cells analyzed. f , A comparison of RT and A/B compartments (Hi-C PC1) during differentiation of CBMS1 mESCs at one-day intervals. The ∆RT and ∆PC1 plots present RT and Hi-C PC1 differentials, respectively, from day 0 to day 7. Regions 1 and 2 are representative early to late/A to B and late to early/B to A switching regions, respectively. Full size image By RNA-seq, naïve CBMS1 mESCs 16 correctly adopted an EpiLC fate on day 2, sharply downregulating early inner cell mass markers ( Prdm14 , Zfp42 , Tbx3 , Tcl1 , Esrrb , Nanog , Klf2 , Klf4 , Klf5 ), upregulating epiblast markers ( Fgf5 , Wnt3 , Dnmt3b ) and either maintaining ( Pou5f1/Oct4 , Fgf4 ) or downregulating ( Sox2 ) pluripotency markers, as expected 14 (Supplementary Fig. 1a and Supplementary Table 1 ). By day 7, ectodermal and pluripotency markers were up- and downregulated, respectively (Supplementary Fig. 1a,b ), while many mesoderm and endoderm markers were expressed at low levels (Supplementary Fig. 1b ). During day 4–5 transition, Pou5f1/Oct4 showed sharp downregulation, while ectodermal markers showed sharp upregulation (Supplementary Fig. 1c ). As expected, activation<|im_end|> <|im_start|>assistant The human genome is made up of 46 chromosomes, each of which has a length of about 100 to 200 million base pairs, the building blocks of the DNA double helix. Even during interphase, the period in between the cell division phases, chromosomes are still tightly packed inside the cell nucleus. On each chromosome, a regular structural unit called the nucleosome corresponds to a 146-base-pair-long strand of DNA wrapped around eight histone protein molecules. Until recently, no other regular structures beyond the nucleosomes were known. Thanks to the emerging genomics-based technology Hi-C (high-throughput chromosome conformation capture), researchers now know that there are regular structural units at the megabase scale, referring to millions of base pairs. It is now generally accepted that mammalian chromosomes are composed of megabase-sized globular units called topologically associating domains (TADs), which are separated by boundaries, presumably in a beads-on-a-string manner. Further, multiple TADs assemble to form what are called A and B subnuclear compartments. TADs containing many active genes form A compartments, while TADs with few or no active genes form B compartments. It is generally believed that TADs are stable units of the chromosomes and that their boundary positions do not change between cell types. By contrast, the organization of A/B compartments differs between cell types, meaning that the boundaries between them change during differentiation. However, nobody has ever observed changes in A/B compartments as they occurred. Scientists from the RIKEN Center for Biosystems Dynamics Research have now observed A/B compartment changes in detail during the differentiation of mouse embryonic stem cells (mESCs). They discovered many genomic regions that switched compartments, either from A to B or vice versa, which, interestingly, correlated well with the genomic regions that switched their replication timing (the temporal order of genomic DNA replication) from early to late or vice versa, respectively. A to B compartment changes were accompanied by movements from the nuclear interior to the periphery and by gene repression, while B to A compartment changes were accompanied by movements from the nuclear periphery to the interior and by gene activation. These results strongly suggest that A/B compartment changes represent physical movements of portions of chromosomes within the 3-D nuclear space, accompanied by changes in gene expression and replication timing. Regarding the temporal relationship between the physical movements of chromosomes and changes in gene expression and replication timing, the research team found that genomic regions that switched from B to A compartment clearly did so one to two days prior to gene activation, and that the changes in replication timing were from late to early. This raised an intriguing possibility that compartment changes might be a prerequisite for gene activation and replication timing changes. The team went on to characterize the features of genomic regions that changed A/B compartments. Compartments were found to change primarily by the shifting of A/B compartment boundaries, while the emergence of new compartments—for example the emergence of an A compartment within a stretch of B compartment or vice versa—was rare. Because compartment boundaries corresponded to a subset of TAD boundaries, they looked at how many TADs changed compartments and discovered that the majority of the changes affected single TADs. Importantly, this single-TAD-level switching of compartments was confirmed in single cells by a method, called single-cell Repli-seq, which was recently developed by the research team to analyze DNA replication regulation genome-wide in single cells (note that replication timing correlates very well with A/B compartments). The team also found that A/B compartment profiles changed gradually but uniformly within a differentiating cell population, with the cells transiently resembling the epiblast-derived stem cell (EpiSC) state, an advanced form of stem cells compared to ESCs. Taken together, the team's finding suggests that A/B compartments change primarily by the relocation of single TADs facing the A/B compartment interface to the opposite compartment. "It is possible," says Ichiro Hiratani, the leader of the group, "that the accumulation of these compartment switching events may reflect or represent changes in differentiation states such as from ESCs to EpiSCs." In this way, this study, published in Nature Genetics, explains how chromosomes undergo structural changes during cell differentiation. According to Hiratani, "Our study was the first to clearly demonstrate that changes in chromosome conformation preceded changes in DNA-based transactions such as gene expression and DNA replication timing. Intriguingly, chromosome conformation changes were regulated at the level of single TADs. We are eager to explore the basis of such single-TAD-level regulation of chromosomes and entertain the possibility of predicting DNA transactions based on preceding changes in chromosome structures." <|im_end|>
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883, 323, 3060, 20958, 320, 90123, 20, 69, 16, 17991, 302, 19, 1174, 435, 46224, 19, 883, 477, 1523, 1610, 15853, 320, 39645, 17, 883, 60217, 575, 354, 2301, 24915, 11, 439, 3685, 220, 975, 320, 10254, 67082, 23966, 13, 220, 16, 64, 323, 99371, 6771, 220, 16, 7609, 3296, 1938, 220, 22, 11, 77594, 347, 18558, 323, 60217, 575, 354, 2301, 24915, 1051, 709, 12, 323, 1523, 81722, 11, 15947, 320, 10254, 67082, 23966, 13, 220, 16, 64, 8568, 7026, 1418, 1690, 11083, 347, 4289, 323, 842, 347, 4289, 24915, 1051, 13605, 520, 3428, 5990, 320, 10254, 67082, 23966, 13, 220, 16, 65, 7609, 12220, 1938, 220, 19, 4235, 20, 9320, 11, 90123, 20, 69, 16, 17991, 302, 19, 8710, 17676, 1523, 1610, 2987, 11, 1418, 77594, 347, 18558, 24915, 8710, 17676, 709, 1610, 2987, 320, 10254, 67082, 23966, 13, 220, 16, 66, 7609, 1666, 3685, 11, 15449, 128257, 198, 128256, 78191, 198, 791, 3823, 33869, 374, 1903, 709, 315, 220, 2790, 83181, 11, 1855, 315, 902, 706, 264, 3160, 315, 922, 220, 1041, 311, 220, 1049, 3610, 2385, 13840, 11, 279, 4857, 10215, 315, 279, 15922, 2033, 11591, 953, 13, 7570, 2391, 958, 26199, 11, 279, 4261, 304, 1990, 279, 2849, 13096, 35530, 11, 83181, 527, 2103, 40069, 19937, 4871, 279, 2849, 62607, 13, 1952, 1855, 51815, 11, 264, 5912, 24693, 5089, 2663, 279, 31484, 32554, 34310, 311, 264, 220, 10465, 31113, 2320, 1334, 24725, 42589, 315, 15922, 20037, 2212, 8223, 13034, 606, 13128, 35715, 13, 30070, 6051, 11, 912, 1023, 5912, 14726, 7953, 279, 31484, 58375, 1051, 3967, 13, 11361, 311, 279, 24084, 4173, 24203, 6108, 5557, 21694, 7813, 320, 12156, 43847, 631, 51815, 390, 1659, 12602, 705, 12074, 1457, 1440, 430, 1070, 527, 5912, 24693, 8316, 520, 279, 19262, 115218, 5569, 11, 22797, 311, 11990, 315, 2385, 13840, 13, 1102, 374, 1457, 8965, 11928, 430, 36041, 10700, 83181, 527, 24306, 315, 19262, 115218, 28935, 13509, 1299, 8316, 2663, 1948, 30450, 4189, 1113, 31576, 320, 51, 1846, 82, 705, 902, 527, 19180, 555, 23546, 11, 36548, 304, 264, 55308, 10539, 7561, 31981, 11827, 13, 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30975, 872, 48891, 18912, 320, 1820, 37015, 2015, 315, 81064, 15922, 48891, 8, 505, 4216, 311, 3389, 477, 17192, 46391, 11, 15947, 13, 362, 311, 426, 44598, 4442, 1051, 24895, 555, 19567, 505, 279, 11499, 15135, 311, 279, 824, 94648, 323, 555, 15207, 72498, 11, 1418, 426, 311, 362, 44598, 4442, 1051, 24895, 555, 19567, 505, 279, 11499, 824, 94648, 311, 279, 15135, 323, 555, 15207, 15449, 13, 4314, 3135, 16917, 4284, 430, 362, 16675, 44598, 4442, 4097, 7106, 19567, 315, 19885, 315, 83181, 2949, 279, 220, 18, 9607, 11499, 3634, 11, 24895, 555, 4442, 304, 15207, 7645, 323, 48891, 18912, 13, 73773, 279, 37015, 5133, 1990, 279, 7106, 19567, 315, 83181, 323, 4442, 304, 15207, 7645, 323, 48891, 18912, 11, 279, 3495, 2128, 1766, 430, 81064, 13918, 430, 30975, 505, 426, 311, 362, 44598, 9539, 1550, 779, 832, 311, 1403, 2919, 4972, 311, 15207, 15449, 11, 323, 430, 279, 4442, 304, 48891, 18912, 1051, 505, 3389, 311, 4216, 13, 1115, 9408, 459, 41765, 13336, 430, 44598, 4442, 2643, 387, 264, 80884, 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2,512
[ { "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 Biologists have long been fascinated by the striking diversity of complex color patterns in tropical reef fishes. However, the origins and evolution of this diversity are still poorly understood. Disentangling the evolution of simple color patterns offers the opportunity to dissect both ultimate and proximate causes underlying color diversity. Results Here, we study clownfishes, a tribe of 30 species within the Pomacentridae that displays a relatively simple color pattern made of zero to three vertical white stripes on a dark body background. Mapping the number of white stripes on the evolutionary tree of clownfishes reveals that their color pattern diversification results from successive caudal to rostral losses of stripes. Moreover, we demonstrate that stripes always appear with a rostral to caudal stereotyped sequence during larval to juvenile transition. Drug treatments (TAE 684) during this period leads to a dose-dependent loss of stripes, demonstrating that white stripes are made of iridophores and that these cells initiate the stripe formation. Surprisingly, juveniles of several species (e.g., Amphiprion frenatus ) have supplementary stripes when compared to their respective adults. These stripes disappear caudo-rostrally during the juvenile phase leading to the definitive color pattern. Remarkably, the reduction of stripe number over ontogeny matches the sequences of stripe losses during evolution, showing that color pattern diversification among clownfish lineages results from changes in developmental processes. Finally, we reveal that the diversity of striped patterns plays a key role for species recognition. Conclusions Overall, our findings illustrate how developmental, ecological, and social processes have shaped the diversification of color patterns during the radiation of an emblematic coral reef fish lineage. Background Understanding the diversification of phenotypes requires to integrate developmental and evolutionary analysis in an ecological context [ 1 ]. Having a well-defined phylogenetic context is essential to recognize the pattern of trait evolution as well as to detect events of parallel or convergent evolution. In addition, studying how phenotypic traits differ across natural environments as well as their adaptive value allows to reveal the factors shaping the emergence of diversity. Lastly, the study of trait development helps to identify the molecular mechanisms behind phenotypic diversification as well as constraints that bias their evolutionary trajectories. Pigmentation, in particular color patterns, provides an incredible number of cases that allow the exploration of the interplay between ecology, evolution, and development that are at the basis of trait diversification [ 2 , 3 , 4 , 5 , 6 ]. Among vertebrates, coral reef fishes provide classical examples of complex color patterns exhibiting a huge variety, and therefore, they offer a unique opportunity to better understand, in an integrated manner, the origin of those traits [ 7 ]. Most of coral reef fish species display spots, stripes, repeated lines, eyespots, grids, etc. This diversity in color patterns serves for species recognition [ 8 , 9 ], camouflage [ 10 , 11 ], mimicry [ 12 ], and/or warning [ 13 ]. For example, the eyespots of the damselfish Pomacentrus amboinensis have been suggested to serve as a subordinate signal directed to dominant males [ 14 ]. To date, work on coral reef fishes has mainly been focused on the link between color patterns, ecology, and behavior, that is, the ultimate role of these patterns [ 15 ]. However, the underlying development controlling these patterns and their evolution, that is, their proximal mechanism, is still largely unknown [ 15 , 16 ]. It is now well known that phenotypic diversification between lineages may be achieved by changes in developmental processes [ 1 , 17 ]. There are a number of possible developmental mechanisms that explain how specific changes in signaling pathways can induce phenotypic changes between lineages, and a main goal of Evo/Devo is to better understand these processes. Within this framework, various studies devoted to the pigmentation of zebrafish allowed to pinpoint changes in developmental mechanisms leading to color variation among related fish species [ 18 , 19 , 20 ]. However, the incredibly diverse color patterns of coral reef fishes have never been explored with such an Evo/Devo perspective. Despite this, there are some evidences that developmental processes may indeed sustain the diversification of color patterns in some species. For example, the polymorphic damselfish Chrysiptera leucopoma may retain its juvenile color (a bright yellow body with a dorsal blue line) or shift to the adult phenotype (a dark brown body) depending on habitat type and/or population densities [ 21 ]. However, in this example, no study of the underlying developmental mechanisms has been performed. Clownfishes ( Amphiprion and the monotypic Premnas ) are iconic coral reef fishes [ 22 ]. This tribe (Amphiprionini; [ 23 ]) within Pomacentridae is composed of 30 species that display a relatively simple color pattern made of zero to three white vertical stripes that are well visible on a yellow to red, brown, or even black body background [ 22 ]. Their life cycle includes a relatively short dispersive planktonic larval phase in the open ocean [ 24 ], followed by the settlement of juveniles into sea anemones where they live in a social group composed of a dominant breeding pair and a varying number of sexually immature subalterns [ 22 ]. The functional role of striped patterns in clownfishes is still unknown but could be associated with predator defense, foraging mode, macro-habitat type, species recognition, etc. as observed in various teleosts [ 15 , 25 ]. The relatively simple color pattern of Amphiprion offers a good opportunity to better delineate the patterns and processes allowing the diversification of such ornamental diversity. The clownfish evolutionary radiation has recently received much attention, providing a suitable phylogenetic framework for testing new evolutionary hypotheses on the rise of color diversity in coral reef fishes [ 26 ]. In this study, we focus on the vertical white stripes present in most species of Amphiprion . We first map their occurrence and pattern on the clownfish evolutionary tree and reconstruct the ancestral state in terms of white stripe presence/absence. Our results provide evidences that the diversification", "role": "user" }, { "content": "Coral reef fishes, including clownfish, display a wide variety of colors but it remains unclear how these colors evolved or how they develop throughout a fish's life. Research published in BMC Biology sheds new light on the evolution of different stripe patterns in clownfish and on how these patterns change as individuals from different species grow from larvae into adults. Dr. Vincent Laudet, the corresponding author at Sorbonne University, France said: \"We show that the ancestor of today's clownfish possessed three white stripes. Then, as some species evolved they lost stripes and we reveal a surprising similarity between this loss of stripes during species evolution and the development of different stripe patterns in individuals from different species today. \" Studying two species of clownfish - Amphiprion ocellaris and Amphiprion frenatus - that have three stripes or a single head stripe, respectively, the authors found that shortly after hatching, the larvae of neither species had any stripes. Subsequently, both species acquired stripes on head and trunk at the same time, with A. oscellaris acquiring a third stripe near the tail and A. frenatus losing the trunk stripe before reaching adulthood. Examining development information for 26 additional species of clownfish, the authors observed that at least nine species have more stripes as juveniles than they do as adults, which prompted the authors to investigating the development of stripes across the evolution of clownfish. Dr. Laudet said: \"Interestingly, every clownfish species existing today gains stripes from front to back after they are born, before individuals of some species lose stripes again from back to front as they grow into adults, which is similar to the loss of stripes observed during clownfish evolution; while all clownfish started out with three stripes—that is their last common ancestor had three stripes—as they diversified into what are now 30 different species, some clownfish lost stripes in a pattern that is similar to how today's clownfish lose stripes as they grow up.\" Fifteen-day-old juvenile clown fish (A. ocellaris). It already fully displays two anterior stripes, on the head and trunk, while a third is forming on the tail. Credit: © Natacha Roux Dr. Laudet added: \"It is also interesting that while clownfish species vary in their number of stripes from zero to three, there is limited variation in how these stripes are organised. In all two-striped species, the stripe nearest the tail has been lost, while the head and the trunk stripes are retained. All one-striped species have retained the head stripe and have lost the trunk and tailfin stripes. So, some fish have no stripes at all, while others have one stripe near the head, one stripe each near the head and on the trunk, or three stripes near the head, on the trunk, and near the tail, but you will never find a clownfish with just one stripe near the tail, or one stripe near the tail and one near the head.\" In order to investigate the molecular mechanisms that underlie stripe formation and loss, the authors treated clownfish larvae with a substance known to suppress stripe development in zebrafish. The substance works by targeting certain receptors in iridophores; the cells that produce a reflective/ iridescent color. The authors found that larvae treated with the substance did not fully develop stripes or developed no stripes at all in a dose-dependent manner. The findings suggest that the white stripes in clownfish are produced by iridophores and that a decrease in the number of these cells will inhibit stripe formation. Dr. Laudet said: \"Because coral reef fishes provide examples of complex color patterns, they offer a unique opportunity to better understand the origin of these traits. Unraveling the mysteries of why pigmentation patterns from coral reef fish are so diverse, how they evolved and where their diversity originated will help us to understand the formation of very complex phenotypes.\" The authors also suggest a possible purpose for the different stripe patterns; they may allow clownfish to recognize individuals belonging to the same species, including potential partners for reproduction. ", "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 Biologists have long been fascinated by the striking diversity of complex color patterns in tropical reef fishes. However, the origins and evolution of this diversity are still poorly understood. Disentangling the evolution of simple color patterns offers the opportunity to dissect both ultimate and proximate causes underlying color diversity. Results Here, we study clownfishes, a tribe of 30 species within the Pomacentridae that displays a relatively simple color pattern made of zero to three vertical white stripes on a dark body background. Mapping the number of white stripes on the evolutionary tree of clownfishes reveals that their color pattern diversification results from successive caudal to rostral losses of stripes. Moreover, we demonstrate that stripes always appear with a rostral to caudal stereotyped sequence during larval to juvenile transition. Drug treatments (TAE 684) during this period leads to a dose-dependent loss of stripes, demonstrating that white stripes are made of iridophores and that these cells initiate the stripe formation. Surprisingly, juveniles of several species (e.g., Amphiprion frenatus ) have supplementary stripes when compared to their respective adults. These stripes disappear caudo-rostrally during the juvenile phase leading to the definitive color pattern. Remarkably, the reduction of stripe number over ontogeny matches the sequences of stripe losses during evolution, showing that color pattern diversification among clownfish lineages results from changes in developmental processes. Finally, we reveal that the diversity of striped patterns plays a key role for species recognition. Conclusions Overall, our findings illustrate how developmental, ecological, and social processes have shaped the diversification of color patterns during the radiation of an emblematic coral reef fish lineage. Background Understanding the diversification of phenotypes requires to integrate developmental and evolutionary analysis in an ecological context [ 1 ]. Having a well-defined phylogenetic context is essential to recognize the pattern of trait evolution as well as to detect events of parallel or convergent evolution. In addition, studying how phenotypic traits differ across natural environments as well as their adaptive value allows to reveal the factors shaping the emergence of diversity. Lastly, the study of trait development helps to identify the molecular mechanisms behind phenotypic diversification as well as constraints that bias their evolutionary trajectories. Pigmentation, in particular color patterns, provides an incredible number of cases that allow the exploration of the interplay between ecology, evolution, and development that are at the basis of trait diversification [ 2 , 3 , 4 , 5 , 6 ]. Among vertebrates, coral reef fishes provide classical examples of complex color patterns exhibiting a huge variety, and therefore, they offer a unique opportunity to better understand, in an integrated manner, the origin of those traits [ 7 ]. Most of coral reef fish species display spots, stripes, repeated lines, eyespots, grids, etc. This diversity in color patterns serves for species recognition [ 8 , 9 ], camouflage [ 10 , 11 ], mimicry [ 12 ], and/or warning [ 13 ]. For example, the eyespots of the damselfish Pomacentrus amboinensis have been suggested to serve as a subordinate signal directed to dominant males [ 14 ]. To date, work on coral reef fishes has mainly been focused on the link between color patterns, ecology, and behavior, that is, the ultimate role of these patterns [ 15 ]. However, the underlying development controlling these patterns and their evolution, that is, their proximal mechanism, is still largely unknown [ 15 , 16 ]. It is now well known that phenotypic diversification between lineages may be achieved by changes in developmental processes [ 1 , 17 ]. There are a number of possible developmental mechanisms that explain how specific changes in signaling pathways can induce phenotypic changes between lineages, and a main goal of Evo/Devo is to better understand these processes. Within this framework, various studies devoted to the pigmentation of zebrafish allowed to pinpoint changes in developmental mechanisms leading to color variation among related fish species [ 18 , 19 , 20 ]. However, the incredibly diverse color patterns of coral reef fishes have never been explored with such an Evo/Devo perspective. Despite this, there are some evidences that developmental processes may indeed sustain the diversification of color patterns in some species. For example, the polymorphic damselfish Chrysiptera leucopoma may retain its juvenile color (a bright yellow body with a dorsal blue line) or shift to the adult phenotype (a dark brown body) depending on habitat type and/or population densities [ 21 ]. However, in this example, no study of the underlying developmental mechanisms has been performed. Clownfishes ( Amphiprion and the monotypic Premnas ) are iconic coral reef fishes [ 22 ]. This tribe (Amphiprionini; [ 23 ]) within Pomacentridae is composed of 30 species that display a relatively simple color pattern made of zero to three white vertical stripes that are well visible on a yellow to red, brown, or even black body background [ 22 ]. Their life cycle includes a relatively short dispersive planktonic larval phase in the open ocean [ 24 ], followed by the settlement of juveniles into sea anemones where they live in a social group composed of a dominant breeding pair and a varying number of sexually immature subalterns [ 22 ]. The functional role of striped patterns in clownfishes is still unknown but could be associated with predator defense, foraging mode, macro-habitat type, species recognition, etc. as observed in various teleosts [ 15 , 25 ]. The relatively simple color pattern of Amphiprion offers a good opportunity to better delineate the patterns and processes allowing the diversification of such ornamental diversity. The clownfish evolutionary radiation has recently received much attention, providing a suitable phylogenetic framework for testing new evolutionary hypotheses on the rise of color diversity in coral reef fishes [ 26 ]. In this study, we focus on the vertical white stripes present in most species of Amphiprion . We first map their occurrence and pattern on the clownfish evolutionary tree and reconstruct the ancestral state in terms of white stripe presence/absence. Our results provide evidences that the diversification<|im_end|> <|im_start|>assistant Coral reef fishes, including clownfish, display a wide variety of colors but it remains unclear how these colors evolved or how they develop throughout a fish's life. Research published in BMC Biology sheds new light on the evolution of different stripe patterns in clownfish and on how these patterns change as individuals from different species grow from larvae into adults. Dr. Vincent Laudet, the corresponding author at Sorbonne University, France said: "We show that the ancestor of today's clownfish possessed three white stripes. Then, as some species evolved they lost stripes and we reveal a surprising similarity between this loss of stripes during species evolution and the development of different stripe patterns in individuals from different species today. " Studying two species of clownfish - Amphiprion ocellaris and Amphiprion frenatus - that have three stripes or a single head stripe, respectively, the authors found that shortly after hatching, the larvae of neither species had any stripes. Subsequently, both species acquired stripes on head and trunk at the same time, with A. oscellaris acquiring a third stripe near the tail and A. frenatus losing the trunk stripe before reaching adulthood. Examining development information for 26 additional species of clownfish, the authors observed that at least nine species have more stripes as juveniles than they do as adults, which prompted the authors to investigating the development of stripes across the evolution of clownfish. Dr. Laudet said: "Interestingly, every clownfish species existing today gains stripes from front to back after they are born, before individuals of some species lose stripes again from back to front as they grow into adults, which is similar to the loss of stripes observed during clownfish evolution; while all clownfish started out with three stripes—that is their last common ancestor had three stripes—as they diversified into what are now 30 different species, some clownfish lost stripes in a pattern that is similar to how today's clownfish lose stripes as they grow up." Fifteen-day-old juvenile clown fish (A. ocellaris). It already fully displays two anterior stripes, on the head and trunk, while a third is forming on the tail. Credit: © Natacha Roux Dr. Laudet added: "It is also interesting that while clownfish species vary in their number of stripes from zero to three, there is limited variation in how these stripes are organised. In all two-striped species, the stripe nearest the tail has been lost, while the head and the trunk stripes are retained. All one-striped species have retained the head stripe and have lost the trunk and tailfin stripes. So, some fish have no stripes at all, while others have one stripe near the head, one stripe each near the head and on the trunk, or three stripes near the head, on the trunk, and near the tail, but you will never find a clownfish with just one stripe near the tail, or one stripe near the tail and one near the head." In order to investigate the molecular mechanisms that underlie stripe formation and loss, the authors treated clownfish larvae with a substance known to suppress stripe development in zebrafish. The substance works by targeting certain receptors in iridophores; the cells that produce a reflective/ iridescent color. The authors found that larvae treated with the substance did not fully develop stripes or developed no stripes at all in a dose-dependent manner. The findings suggest that the white stripes in clownfish are produced by iridophores and that a decrease in the number of these cells will inhibit stripe formation. Dr. Laudet said: "Because coral reef fishes provide examples of complex color patterns, they offer a unique opportunity to better understand the origin of these traits. Unraveling the mysteries of why pigmentation patterns from coral reef fish are so diverse, how they evolved and where their diversity originated will help us to understand the formation of very complex phenotypes." The authors also suggest a possible purpose for the different stripe patterns; they may allow clownfish to recognize individuals belonging to the same species, including potential partners for reproduction. <|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 Eukaryotic phytoplankton are responsible for at least 20% of annual global carbon fixation. Their diversity and activity are shaped by interactions with prokaryotes as part of complex microbiomes. Although differences in their local species diversity have been estimated, we still have a limited understanding of environmental conditions responsible for compositional differences between local species communities on a large scale from pole to pole. Here, we show, based on pole-to-pole phytoplankton metatranscriptomes and microbial rDNA sequencing, that environmental differences between polar and non-polar upper oceans most strongly impact the large-scale spatial pattern of biodiversity and gene activity in algal microbiomes. The geographic differentiation of co-occurring microbes in algal microbiomes can be well explained by the latitudinal temperature gradient and associated break points in their beta diversity, with an average breakpoint at 14 °C ± 4.3, separating cold and warm upper oceans. As global warming impacts upper ocean temperatures, we project that break points of beta diversity move markedly pole-wards. Hence, abrupt regime shifts in algal microbiomes could be caused by anthropogenic climate change. Introduction Phytoplankton are a diverse group of largely photoautotrophic microorganisms encompassing algae and cyanobacteria 1 , 2 , contributing approximately half of the annual global carbon fixation 3 . Although the interconnected oceans generally do not limit their global dispersal 4 , 5 , 6 many studies have shown that their local diversity is correlated with geographical partitioning based on either oceanographic fronts that separate populations or larger-scale ecosystem gradients such as the latitude gradient in local species diversity 7 , 8 , 9 , 10 . However, there is also evidence that environmental and ecological selection in geographically well-defined and seemingly unstructured marine ecosystems likely plays a role in generating and maintaining microbial diversity 11 . Regardless as to whether inter or intra-specific variations are being considered to explain microbial diversity patterns in the global ocean, two variables usually explain most of the relatedness between species and populations, respectively: temperature and whole-community chlorophyll a 9 , 11 . Temperature is known to be a strong selecting agent evidenced by thermal tolerance limits according to the geographic origin of species 9 , 12 , 13 . Furthermore, temperature together with salinity and the flow of currents creates ecological boundaries in the upper ocean such as oceanographic fronts, which might impact the structure and evolution of inter and intra-specific diversity across spatio-temporal scales 10 , 14 . Chlorophyll a on the other hand, which is a proxy for the biomass of phytoplankton, suggests that ecological selection is at play via interactions with organisms that benefit from phytoplankton and vice versa 11 . Besides herbivores such as copepods and krill, heterotrophic microbes such as bacteria and archaea are among those groups with significant interactions with phytoplankton 15 . Some of them even form intimate relationships including mutualism and symbiosis 16 , 17 . The space where most of the interactions between phytoplankton and heterotrophic prokaryotes take place is the phycosphere, a microscale mucus region that is rich in organic matter surrounding a phytoplankton cell analogous to the rhizosphere in plants 18 , 19 . Thus, organic matter released by phytoplankton are used as substrates for prokaryotes, which sometimes provide essential bioactive compounds in return, such as vitamin B12. About 60% of examined heterokont microalgae (e.g. diatoms) require vitamin B12 that is synthesized by bacteria and archaea 20 . Thus, those bacteria have formed a mutualistic relationship with phytoplankton that potentially help to sustain primary productivity in many parts of the global ocean 16 . There is also evidence for species-specific diversity of algal microbiomes. Often, it is the phytoplankton partner that recruits heterotrophic microbes via the secretion of infochemicals, which elicits a response from the other microbes 19 . As these signalling processes can be species-specific and likely have co-evolved in association with responding partners, algal microbiomes are complex and dynamic and their diversity might be either driven by ecological or environmental selection, generating and maintaining these intimate relationships over space and evolutionary time. As algal microbiomes underpin some of the largest food webs on Earth and drive global biogeochemical cycles, significant international efforts, especially over the last decade have provided insights into what drives their diversity and global biogeography in the global ocean. For instance, large-scale ocean omics studies in the epipelagic realm as part of the Tara Oceans project 21 , 22 showed that associations among microbes were non-randomly distributed in co-occurrence networks and that their structure was driven by both local and global patterns 15 . Microbial networks that included a significant amount of prokaryotic phytoplankton (cyanobacteria) even appear to be responsible for the majority of carbon exported in the oligotrophic ocean 23 . Interestingly, some of the co-occurrence networks that contained eukaryotic phytoplankton groups were not taxon-specific and dominated by mutual exclusions, which suggests that their biogeography may be influenced by predator-prey dynamics 24 . These studies have provided a step change in our understanding of how ecological interactions in the context of changing environmental conditions likely influence the diversity of the photoautotrophic microbial interactome in the global ocean. However, to assess how environmental conditions such as temperature and variable nutrient concentrations impact the diversity of algal microbiomes, it is instrumental to include polar oceans. With their inclusion, the complete spectrum of environmental parameters that co-vary can be used to assess how these parameters on a truly global scale from pole-to-pole impact differences in the variation of species identities and abundances between local assemblages across larger regions (beta diversity) 25 , 26 of interacting algal microbiomes, which, to the best of our knowledge, has not been addressed in previous studies. The application of beta diversity enables us to understand the degree of differentiation among biological communities, which across the complete latitudinal scale from pole to pole will provide insights into how marine microbes are latitudinally distributed. As the Arctic and Southern Oceans and specifically their eukaryotic phytoplankton and associated prokaryotes are often not included in global biodiversity surveys, our understanding of how environmental variables including", "role": "user" }, { "content": "Global warming is likely to cause abrupt changes to important algal communities because of shifting biodiversity 'break point' boundaries in the oceans—according to research from the University of East Anglia and the Earlham Institute. A new study, published today in the journal Nature Communications, finds that as climate change extends the warm hemisphere, these boundaries are predicted to shift pole-wards over the next 100 years. Instead of a gradual change in microbial diversity due to warming, the researchers suggest it will happen more abruptly at what they call 'break points' - wherever the upper ocean temperature is around 15 degrees on an annual average, separating cold and warm waters. The UK is one of the areas most likely to be severely affected, and more suddenly than previously thought. But the team say that the changes could be stopped if we act swiftly to halt climate change. Prof Thomas Mock, from UEA's School of Environmental Sciences, said: \"Algae are essential in maintaining a healthy ecosystem to balance ocean life. By absorbing energy from sunlight, carbon dioxide and water, they produce organic compounds for marine life to live off. \"These organisms underpin some of the largest food webs on Earth and drive global biogeochemical cycles. \"Accountable for at least 20 percent of annual global carbon fixation, temperature changes could have a significant impact upon the algae that our marine systems, fisheries and ocean biodiversity depend on. As average sea surface temperatures increase due to climate change, Thomas Mock has seen shifting aquatic life — for example, this European sea bass — off England’s southeast coast. European sea bass have a temperature optimum range of around 50 to 77 degrees Fahrenheit, while cod, iconic for its popularity at UK fish-and-chip shops, prefer to live between about 34 to 59 degrees Fahrenheit. Credit: Thomas Mock \"We wanted to better-understand how the climate crisis is impacting algae worldwide from the Arctic to the Antarctic.\" The research was led by scientists at UEA in collaboration with the US Department of Energy (DOE) Joint Genome Institute (JGI, U.S.) and the Earlham Institute (UK). The major study was conducted over more than 10 years by an international team of 32 researchers, from institutions including the University of Exeter in the UK and the Alfred Wegener Institute for Polar and Marine Research in Germany. It involved the first pole-to-pole analysis of how algae (Eukaryotic phytoplankton) and their expressed genes are geographically distributed in the oceans. Thus, the team studied how their gene activity is changing due to environmental conditions in the upper ocean from pole to pole. As the upper ocean is already experiencing significant warming due to rising CO2 levels, the researchers estimated how the distribution of these algal communities might change based on a model from the Intergovernmental Panel on Climate Change (IPCC) 5th Assessment Report. The algal communities' diversity and gene activity are shaped by interactions with microscopic single-celled organisms, or prokaryotes, as part of complex microbiomes. The researchers found that these global communities can be split into two main clusters—organisms that mainly live in cold polar and warm non-polar waters. Scientists sampling under-ice phytoplankton communities utilising a ‘mummy chair.’ Under-ice communities are vital for, for example, krill and other under-ice feeding organisms. Credit: Katrin Schmidt The geographic patterns are best explained by the differences in the water's physical structure (for example, seasonally mixed cold versus permanently stratified warm water) of the upper ocean caused by latitudinal gradients of temperature. The organisms were analyzed through nucleic acids extraction and DNA and mRNA sequencing of samples collected during four research cruises in the Arctic Ocean, North Atlantic Ocean, South Atlantic Ocean and Southern Ocean. Prof Mock said: \"Significant international efforts have provided insights into what drives the diversity of these organisms and their global biogeography in the global ocean, however, there is still limited understanding of environmental conditions responsible for differences between local species communities on a large scale from pole to pole. \"Our results provide new insights into how changing environmental conditions correlate with biodiversity changes subject to large-scale environmental fluctuation and disturbances. This knowledge is essential for predicting the consequences of global warming and therefore may guide environmental management. \"We can expect the marine systems around the UK and other countries on this latitude to be severely affected, and more suddenly than previously thought. \"The largest ecosystem change will occur when marine microalgal communities and their associated bacteria around the UK will be replaced by their warm-water counterparts. \"This is expected to be caused by the pole-ward shifting ecosystem boundary or 'biodiversity break point' separating both communities. For this to take place, the annual average upper ocean temperature needs to become warmer than 15C. Colouring the water, the algae Phaeocystis blooms off the side of the sampling vessel, Polarstern, in the temperate region of the North Atlantic. Credit: Katrin Schmidt \"It's not irreversible though, if we can stop global warming,\" he added. Co-author Dr. Richard Leggett at the Earlham Institute, added: \"This study also shows what an important role advances in DNA sequencing technologies have played in understanding ocean-based ecosystems and, in doing so, helping researchers shed light on and grapple with some of the biggest environmental challenges facing the planet.\" The work was led by two former Ph.D. students from UEA's Schools of Environmental Sciences and Computing Sciences, Dr. Kara Martin (also based at the Earlham Institute) and Dr. Katrin Schmidt. Dr. Martin said: \"These results suggest that the most important ecological boundary in the upper ocean separates polar from non-polar algal microbiomes at both hemispheres, which not only alters the spatial scaling of algal microbiomes but also shifts pole-wards due to global warming. \"We predict that 'break points' of microbial diversity will move markedly pole-wards due to warming—particularly around the British Isles—with abrupt shifts in algal microbiomes caused by human-induced climate change. \"This has been a wonderful experience and an incredible opportunity to work with a magnificent team. Together, we analyzed an amazing dataset which expands the latitude of our microbial ocean research, enabling us to gain insights to our changing ocean from pole to pole.\" Dr. Schmidt said: \"During our research cruises we already noticed quite different algal communities from warm to cold waters. This initial finding was supported by our results suggesting that the most important ecological boundary in the upper ocean separates polar from non-polar algal microbiomes at both hemispheres. And more importantly, this boundary not only alters the spatial scaling of algal microbiomes but also shifts pole-wards due to global warming.\" A curious polar bear near Greenland checks out the icebreaker Polarstern. Polar bears, which feed on seals, are part of the arctic ocean food web that climate change threatens. Credit: Katrin Schmidt Prof Tim Lenton, from the University of Exeter said: \"As the ocean warms up with climate change this century we predict that the 'break point' between cold, polar microalgal communities and warm, non-polar microalgal communities will move northwards through the seas around the British Isles. \"As microalgae are key to the base of the food chain we can expect major changes in the rest of the marine ecosystem, with implications for fisheries, as well as marine conservation. \"The 'biological carbon pump' whereby the ocean takes up carbon dioxide from the atmosphere will change with this shift in microalgal communities—most likely becoming less effective—which could in turn feedback to amplify global warming.\" Sequencing was done at the JGI as part of the Community Science Program project Sea of Change: Eukaryotic Phytoplankton Communities in the Arctic Ocean. \"The biogeographic differentiation of algal microbiomes in the upper ocean from pole to pole\" is published in Nature Communications on September 16, 2021. 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<|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 Eukaryotic phytoplankton are responsible for at least 20% of annual global carbon fixation. Their diversity and activity are shaped by interactions with prokaryotes as part of complex microbiomes. Although differences in their local species diversity have been estimated, we still have a limited understanding of environmental conditions responsible for compositional differences between local species communities on a large scale from pole to pole. Here, we show, based on pole-to-pole phytoplankton metatranscriptomes and microbial rDNA sequencing, that environmental differences between polar and non-polar upper oceans most strongly impact the large-scale spatial pattern of biodiversity and gene activity in algal microbiomes. The geographic differentiation of co-occurring microbes in algal microbiomes can be well explained by the latitudinal temperature gradient and associated break points in their beta diversity, with an average breakpoint at 14 °C ± 4.3, separating cold and warm upper oceans. As global warming impacts upper ocean temperatures, we project that break points of beta diversity move markedly pole-wards. Hence, abrupt regime shifts in algal microbiomes could be caused by anthropogenic climate change. Introduction Phytoplankton are a diverse group of largely photoautotrophic microorganisms encompassing algae and cyanobacteria 1 , 2 , contributing approximately half of the annual global carbon fixation 3 . Although the interconnected oceans generally do not limit their global dispersal 4 , 5 , 6 many studies have shown that their local diversity is correlated with geographical partitioning based on either oceanographic fronts that separate populations or larger-scale ecosystem gradients such as the latitude gradient in local species diversity 7 , 8 , 9 , 10 . However, there is also evidence that environmental and ecological selection in geographically well-defined and seemingly unstructured marine ecosystems likely plays a role in generating and maintaining microbial diversity 11 . Regardless as to whether inter or intra-specific variations are being considered to explain microbial diversity patterns in the global ocean, two variables usually explain most of the relatedness between species and populations, respectively: temperature and whole-community chlorophyll a 9 , 11 . Temperature is known to be a strong selecting agent evidenced by thermal tolerance limits according to the geographic origin of species 9 , 12 , 13 . Furthermore, temperature together with salinity and the flow of currents creates ecological boundaries in the upper ocean such as oceanographic fronts, which might impact the structure and evolution of inter and intra-specific diversity across spatio-temporal scales 10 , 14 . Chlorophyll a on the other hand, which is a proxy for the biomass of phytoplankton, suggests that ecological selection is at play via interactions with organisms that benefit from phytoplankton and vice versa 11 . Besides herbivores such as copepods and krill, heterotrophic microbes such as bacteria and archaea are among those groups with significant interactions with phytoplankton 15 . Some of them even form intimate relationships including mutualism and symbiosis 16 , 17 . The space where most of the interactions between phytoplankton and heterotrophic prokaryotes take place is the phycosphere, a microscale mucus region that is rich in organic matter surrounding a phytoplankton cell analogous to the rhizosphere in plants 18 , 19 . Thus, organic matter released by phytoplankton are used as substrates for prokaryotes, which sometimes provide essential bioactive compounds in return, such as vitamin B12. About 60% of examined heterokont microalgae (e.g. diatoms) require vitamin B12 that is synthesized by bacteria and archaea 20 . Thus, those bacteria have formed a mutualistic relationship with phytoplankton that potentially help to sustain primary productivity in many parts of the global ocean 16 . There is also evidence for species-specific diversity of algal microbiomes. Often, it is the phytoplankton partner that recruits heterotrophic microbes via the secretion of infochemicals, which elicits a response from the other microbes 19 . As these signalling processes can be species-specific and likely have co-evolved in association with responding partners, algal microbiomes are complex and dynamic and their diversity might be either driven by ecological or environmental selection, generating and maintaining these intimate relationships over space and evolutionary time. As algal microbiomes underpin some of the largest food webs on Earth and drive global biogeochemical cycles, significant international efforts, especially over the last decade have provided insights into what drives their diversity and global biogeography in the global ocean. For instance, large-scale ocean omics studies in the epipelagic realm as part of the Tara Oceans project 21 , 22 showed that associations among microbes were non-randomly distributed in co-occurrence networks and that their structure was driven by both local and global patterns 15 . Microbial networks that included a significant amount of prokaryotic phytoplankton (cyanobacteria) even appear to be responsible for the majority of carbon exported in the oligotrophic ocean 23 . Interestingly, some of the co-occurrence networks that contained eukaryotic phytoplankton groups were not taxon-specific and dominated by mutual exclusions, which suggests that their biogeography may be influenced by predator-prey dynamics 24 . These studies have provided a step change in our understanding of how ecological interactions in the context of changing environmental conditions likely influence the diversity of the photoautotrophic microbial interactome in the global ocean. However, to assess how environmental conditions such as temperature and variable nutrient concentrations impact the diversity of algal microbiomes, it is instrumental to include polar oceans. With their inclusion, the complete spectrum of environmental parameters that co-vary can be used to assess how these parameters on a truly global scale from pole-to-pole impact differences in the variation of species identities and abundances between local assemblages across larger regions (beta diversity) 25 , 26 of interacting algal microbiomes, which, to the best of our knowledge, has not been addressed in previous studies. The application of beta diversity enables us to understand the degree of differentiation among biological communities, which across the complete latitudinal scale from pole to pole will provide insights into how marine microbes are latitudinally distributed. As the Arctic and Southern Oceans and specifically their eukaryotic phytoplankton and associated prokaryotes are often not included in global biodiversity surveys, our understanding of how environmental variables including<|im_end|> <|im_start|>assistant Global warming is likely to cause abrupt changes to important algal communities because of shifting biodiversity 'break point' boundaries in the oceans—according to research from the University of East Anglia and the Earlham Institute. A new study, published today in the journal Nature Communications, finds that as climate change extends the warm hemisphere, these boundaries are predicted to shift pole-wards over the next 100 years. Instead of a gradual change in microbial diversity due to warming, the researchers suggest it will happen more abruptly at what they call 'break points' - wherever the upper ocean temperature is around 15 degrees on an annual average, separating cold and warm waters. The UK is one of the areas most likely to be severely affected, and more suddenly than previously thought. But the team say that the changes could be stopped if we act swiftly to halt climate change. Prof Thomas Mock, from UEA's School of Environmental Sciences, said: "Algae are essential in maintaining a healthy ecosystem to balance ocean life. By absorbing energy from sunlight, carbon dioxide and water, they produce organic compounds for marine life to live off. "These organisms underpin some of the largest food webs on Earth and drive global biogeochemical cycles. "Accountable for at least 20 percent of annual global carbon fixation, temperature changes could have a significant impact upon the algae that our marine systems, fisheries and ocean biodiversity depend on. As average sea surface temperatures increase due to climate change, Thomas Mock has seen shifting aquatic life — for example, this European sea bass — off England’s southeast coast. European sea bass have a temperature optimum range of around 50 to 77 degrees Fahrenheit, while cod, iconic for its popularity at UK fish-and-chip shops, prefer to live between about 34 to 59 degrees Fahrenheit. Credit: Thomas Mock "We wanted to better-understand how the climate crisis is impacting algae worldwide from the Arctic to the Antarctic." The research was led by scientists at UEA in collaboration with the US Department of Energy (DOE) Joint Genome Institute (JGI, U.S.) and the Earlham Institute (UK). The major study was conducted over more than 10 years by an international team of 32 researchers, from institutions including the University of Exeter in the UK and the Alfred Wegener Institute for Polar and Marine Research in Germany. It involved the first pole-to-pole analysis of how algae (Eukaryotic phytoplankton) and their expressed genes are geographically distributed in the oceans. Thus, the team studied how their gene activity is changing due to environmental conditions in the upper ocean from pole to pole. As the upper ocean is already experiencing significant warming due to rising CO2 levels, the researchers estimated how the distribution of these algal communities might change based on a model from the Intergovernmental Panel on Climate Change (IPCC) 5th Assessment Report. The algal communities' diversity and gene activity are shaped by interactions with microscopic single-celled organisms, or prokaryotes, as part of complex microbiomes. The researchers found that these global communities can be split into two main clusters—organisms that mainly live in cold polar and warm non-polar waters. Scientists sampling under-ice phytoplankton communities utilising a ‘mummy chair.’ Under-ice communities are vital for, for example, krill and other under-ice feeding organisms. Credit: Katrin Schmidt The geographic patterns are best explained by the differences in the water's physical structure (for example, seasonally mixed cold versus permanently stratified warm water) of the upper ocean caused by latitudinal gradients of temperature. The organisms were analyzed through nucleic acids extraction and DNA and mRNA sequencing of samples collected during four research cruises in the Arctic Ocean, North Atlantic Ocean, South Atlantic Ocean and Southern Ocean. Prof Mock said: "Significant international efforts have provided insights into what drives the diversity of these organisms and their global biogeography in the global ocean, however, there is still limited understanding of environmental conditions responsible for differences between local species communities on a large scale from pole to pole. "Our results provide new insights into how changing environmental conditions correlate with biodiversity changes subject to large-scale environmental fluctuation and disturbances. This knowledge is essential for predicting the consequences of global warming and therefore may guide environmental management. "We can expect the marine systems around the UK and other countries on this latitude to be severely affected, and more suddenly than previously thought. "The largest ecosystem change will occur when marine microalgal communities and their associated bacteria around the UK will be replaced by their warm-water counterparts. "This is expected to be caused by the pole-ward shifting ecosystem boundary or 'biodiversity break point' separating both communities. For this to take place, the annual average upper ocean temperature needs to become warmer than 15C. Colouring the water, the algae Phaeocystis blooms off the side of the sampling vessel, Polarstern, in the temperate region of the North Atlantic. Credit: Katrin Schmidt "It's not irreversible though, if we can stop global warming," he added. Co-author Dr. Richard Leggett at the Earlham Institute, added: "This study also shows what an important role advances in DNA sequencing technologies have played in understanding ocean-based ecosystems and, in doing so, helping researchers shed light on and grapple with some of the biggest environmental challenges facing the planet." The work was led by two former Ph.D. students from UEA's Schools of Environmental Sciences and Computing Sciences, Dr. Kara Martin (also based at the Earlham Institute) and Dr. Katrin Schmidt. Dr. Martin said: "These results suggest that the most important ecological boundary in the upper ocean separates polar from non-polar algal microbiomes at both hemispheres, which not only alters the spatial scaling of algal microbiomes but also shifts pole-wards due to global warming. "We predict that 'break points' of microbial diversity will move markedly pole-wards due to warming—particularly around the British Isles—with abrupt shifts in algal microbiomes caused by human-induced climate change. "This has been a wonderful experience and an incredible opportunity to work with a magnificent team. Together, we analyzed an amazing dataset which expands the latitude of our microbial ocean research, enabling us to gain insights to our changing ocean from pole to pole." Dr. Schmidt said: "During our research cruises we already noticed quite different algal communities from warm to cold waters. This initial finding was supported by our results suggesting that the most important ecological boundary in the upper ocean separates polar from non-polar algal microbiomes at both hemispheres. And more importantly, this boundary not only alters the spatial scaling of algal microbiomes but also shifts pole-wards due to global warming." A curious polar bear near Greenland checks out the icebreaker Polarstern. Polar bears, which feed on seals, are part of the arctic ocean food web that climate change threatens. Credit: Katrin Schmidt Prof Tim Lenton, from the University of Exeter said: "As the ocean warms up with climate change this century we predict that the 'break point' between cold, polar microalgal communities and warm, non-polar microalgal communities will move northwards through the seas around the British Isles. "As microalgae are key to the base of the food chain we can expect major changes in the rest of the marine ecosystem, with implications for fisheries, as well as marine conservation. "The 'biological carbon pump' whereby the ocean takes up carbon dioxide from the atmosphere will change with this shift in microalgal communities—most likely becoming less effective—which could in turn feedback to amplify global warming." Sequencing was done at the JGI as part of the Community Science Program project Sea of Change: Eukaryotic Phytoplankton Communities in the Arctic Ocean. "The biogeographic differentiation of algal microbiomes in the upper ocean from pole to pole" is published in Nature Communications on September 16, 2021. <|im_end|>
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2,987
[ { "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 Invasive alien species are widely recognized as one of the main threats to global biodiversity. Rapid flow of information on the occurrence of invasive alien species is critical to underpin effective action. Citizen science, i.e. the involvement of volunteers in science, provides an opportunity to improve the information available on invasive alien species. Here we describe the dataset created via a citizen science approach to track the spread of a well-studied invasive alien species, the harlequin ladybird Harmonia axyridis (Coleoptera: Coccinellidae) in Britain and Ireland. This dataset comprises 48 510 verified and validated spatio-temporal records of the occurrence of H. axyridis in Britain and Ireland, from first arrival in 2003, to the end of 2016. A clear and rapid spread of the species within Britain and Ireland is evident. A major reuse value of the dataset is in modelling the spread of an invasive species and applying this to other potential invasive alien species in order to predict and prevent their further spread. Design Type(s) database creation objective • citizen science design • biodiversity assessment objective Measurement Type(s) population data Technology Type(s) longitudinal data collection method Factor Type(s) temporal_interval • body marking • developmental stage Sample Characteristic(s) Harmonia axyridis • British Isles • habitat Machine-accessible metadata file describing the reported data (ISA-Tab format) Background & Summary The invasion process for an alien species involves various stages, notably introduction, establishment, increase in abundance and geographic spread 1 . An alien species that spreads and has negative effects (which may be ecological, economic or social) is termed invasive 2 , 3 . Invasive alien species are widely recognized as one of the main threats to global biodiversity 4 – 6 . There are a number of international agreements which recognize the threat posed by invasive alien species, which are designated as a priority within the Convention on Biological Diversity Aichi biodiversity target 9 ( ) and are relevant to many of the Sustainable Development Goals ( ). An EU Regulation on invasive alien species came into force on 1 January 2015 ( ) and subsequently a list of invasive alien species of EU concern was adopted for which member states are required to take action to eradicate, manage or prevent entry. Rapid flow of information on the occurrence of invasive alien species is critical to underpin effective action. There have been few attempts to monitor the spread of invasive alien species systematically from the onset of the invasion process. Citizen science, i.e. the involvement of volunteers in science, provides an opportunity to improve the information available on invasive alien species 7 . Here we describe the dataset created via a citizen science approach to track the spread of a well-studied invasive alien species, the harlequin ladybird Harmonia axyridis (Coleoptera: Coccinellidae) in Britain and Ireland. This species was detected very early in the invasion process and a citizen science project was initiated and widely promoted to maximize the opportunity to gather data from the public across Britain and Ireland. Harmonia axyridis was introduced between approximately 1982 and 2003 to at least 13 European countries 8 as a biological control agent. It was mainly introduced to control aphids that are pests to a range of field and glasshouse crops. From the early 2000s it subsequently spread to many other European countries, including Britain and Ireland. It is native to Asia (including China, Japan, Mongolia and Russia) 9 and was also introduced in North and South America and Africa 10 . Harmonia axyridis was introduced unintentionally to Britain from mainland Europe by a number of pathways: some were transported with produce such as cut flowers, fruit and vegetables; others arrived through natural dispersal (flight) from other invaded regions 11 . To a lesser extent H. axyridis also arrived from North America 12 . The major pathways of spread to Ireland were probably natural dispersal (from Britain) and arrival with produce. Harmonia axyridis is a eurytopic (generalist) species and may be found on deciduous or coniferous trees, arable and horticultural crops and herbaceous vegetation in a wide range of habitats. It is particularly prevalent in urban and suburban localities (e.g. parks, gardens, and in or on buildings) 13 . Citizen science approaches to collecting species data are becoming increasingly popular and respected 14 . Advances in communication and digital technologies (e.g. online recording via websites and smartphone applications; digital photography) have increasingly enabled scientists to collect and verify large datasets of species information 15 . For a few species groups, including ladybirds, verification to species is possible if a reasonably good photograph of the animal is available. In late 2004, shortly after the first H. axyridis ladybird record was reported, funding was acquired from Defra and the National Biodiversity Network (NBN) to set up and trial an online recording scheme for ladybirds, and H. axyridis in particular. Thus, the online Harlequin Ladybird Survey and UK Ladybird Survey were launched in March 2005. The surveys have been very successful in gaining records from the public since 2005. Innovations such as the launch of a free smartphone application (iRecord Ladybirds) in 2013 helped to maintain the supply of records. The dataset here comprises species records of H. axyridis in various life stages (larva, pupa or adult) from Britain and Ireland over the period 2003 to 2016. A major reuse value of the dataset is in modelling the spread of an invasive species and applying this to other potential invasive alien species in order to predict and prevent their further spread. The time period of the study captures the initial fast spread of H. axyridis (principally from 2004 to 2009) plus a further substantial period (2010 to 2016) in which the distribution of the species altered relatively little, despite many further records being received. Methods This dataset ( Data Citation 1 ) comprises 48 510 spatio-temporal records of the occurrence of H. axyridis in Britain and Ireland, from first arrival in 2003, to the end of 2016. For its type it is thus an unusually substantial dataset. Whilst", "role": "user" }, { "content": "New research published in the Nature journal Scientific Data shows how the public can play a vital role in helping to track invasive species. The journal has published data from the UK Ladybird Survey which shows how the harlequin ladybird, which is a species native to Asia, has spread across the country. The harlequin ladybird was introduced to mainland Europe in the 1980s to control aphids. It was first reported in the UK in 2003 and is now outcompeting a number of smaller native ladybird species. The new open access study maps 48,510 observations of the harlequin ladybird, submitted by the general public, spanning over a decade. Spreading at over 60 miles per year during the early stage of invasion, the observations show that harlequins are now widespread through England and Wales and increasingly being reported in the south of Scotland. There have been few attempts to monitor the spread of invasive alien species systematically from the onset of the invasion process but the model used by the online UK Ladybird Survey, led by academics from Anglia Ruskin University and the Centre for Ecology & Hydrology, shows the important role that citizen science can play. Rapid flow of information about the occurrence of invasive species is critical in order to take any effective action, and the citizen science approach developed through the UK Ladybird Survey is already being used for surveillance of other invasive non-native species, including the Asian hornet. Lead author Dr. Peter Brown, Senior Lecturer in Zoology at Anglia Ruskin University, said: \"All these observations have made major contributions to our understanding of the ecology of the harlequin ladybird in the UK. We are now excited to see how others might use the model and the patterns of data to explore invasions by other species.\" Co-lead Professor Helen Roy, from the Centre for Ecology & Hydrology, said: \"It has been incredible to see the way in which so many people have got involved in tracking this invasion—it is a truly collaborative project. We have been able to answer many important ecological questions using this vast dataset. This would not have been possible without these inspiring citizen science contributions.\" ", "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 Invasive alien species are widely recognized as one of the main threats to global biodiversity. Rapid flow of information on the occurrence of invasive alien species is critical to underpin effective action. Citizen science, i.e. the involvement of volunteers in science, provides an opportunity to improve the information available on invasive alien species. Here we describe the dataset created via a citizen science approach to track the spread of a well-studied invasive alien species, the harlequin ladybird Harmonia axyridis (Coleoptera: Coccinellidae) in Britain and Ireland. This dataset comprises 48 510 verified and validated spatio-temporal records of the occurrence of H. axyridis in Britain and Ireland, from first arrival in 2003, to the end of 2016. A clear and rapid spread of the species within Britain and Ireland is evident. A major reuse value of the dataset is in modelling the spread of an invasive species and applying this to other potential invasive alien species in order to predict and prevent their further spread. Design Type(s) database creation objective • citizen science design • biodiversity assessment objective Measurement Type(s) population data Technology Type(s) longitudinal data collection method Factor Type(s) temporal_interval • body marking • developmental stage Sample Characteristic(s) Harmonia axyridis • British Isles • habitat Machine-accessible metadata file describing the reported data (ISA-Tab format) Background & Summary The invasion process for an alien species involves various stages, notably introduction, establishment, increase in abundance and geographic spread 1 . An alien species that spreads and has negative effects (which may be ecological, economic or social) is termed invasive 2 , 3 . Invasive alien species are widely recognized as one of the main threats to global biodiversity 4 – 6 . There are a number of international agreements which recognize the threat posed by invasive alien species, which are designated as a priority within the Convention on Biological Diversity Aichi biodiversity target 9 ( ) and are relevant to many of the Sustainable Development Goals ( ). An EU Regulation on invasive alien species came into force on 1 January 2015 ( ) and subsequently a list of invasive alien species of EU concern was adopted for which member states are required to take action to eradicate, manage or prevent entry. Rapid flow of information on the occurrence of invasive alien species is critical to underpin effective action. There have been few attempts to monitor the spread of invasive alien species systematically from the onset of the invasion process. Citizen science, i.e. the involvement of volunteers in science, provides an opportunity to improve the information available on invasive alien species 7 . Here we describe the dataset created via a citizen science approach to track the spread of a well-studied invasive alien species, the harlequin ladybird Harmonia axyridis (Coleoptera: Coccinellidae) in Britain and Ireland. This species was detected very early in the invasion process and a citizen science project was initiated and widely promoted to maximize the opportunity to gather data from the public across Britain and Ireland. Harmonia axyridis was introduced between approximately 1982 and 2003 to at least 13 European countries 8 as a biological control agent. It was mainly introduced to control aphids that are pests to a range of field and glasshouse crops. From the early 2000s it subsequently spread to many other European countries, including Britain and Ireland. It is native to Asia (including China, Japan, Mongolia and Russia) 9 and was also introduced in North and South America and Africa 10 . Harmonia axyridis was introduced unintentionally to Britain from mainland Europe by a number of pathways: some were transported with produce such as cut flowers, fruit and vegetables; others arrived through natural dispersal (flight) from other invaded regions 11 . To a lesser extent H. axyridis also arrived from North America 12 . The major pathways of spread to Ireland were probably natural dispersal (from Britain) and arrival with produce. Harmonia axyridis is a eurytopic (generalist) species and may be found on deciduous or coniferous trees, arable and horticultural crops and herbaceous vegetation in a wide range of habitats. It is particularly prevalent in urban and suburban localities (e.g. parks, gardens, and in or on buildings) 13 . Citizen science approaches to collecting species data are becoming increasingly popular and respected 14 . Advances in communication and digital technologies (e.g. online recording via websites and smartphone applications; digital photography) have increasingly enabled scientists to collect and verify large datasets of species information 15 . For a few species groups, including ladybirds, verification to species is possible if a reasonably good photograph of the animal is available. In late 2004, shortly after the first H. axyridis ladybird record was reported, funding was acquired from Defra and the National Biodiversity Network (NBN) to set up and trial an online recording scheme for ladybirds, and H. axyridis in particular. Thus, the online Harlequin Ladybird Survey and UK Ladybird Survey were launched in March 2005. The surveys have been very successful in gaining records from the public since 2005. Innovations such as the launch of a free smartphone application (iRecord Ladybirds) in 2013 helped to maintain the supply of records. The dataset here comprises species records of H. axyridis in various life stages (larva, pupa or adult) from Britain and Ireland over the period 2003 to 2016. A major reuse value of the dataset is in modelling the spread of an invasive species and applying this to other potential invasive alien species in order to predict and prevent their further spread. The time period of the study captures the initial fast spread of H. axyridis (principally from 2004 to 2009) plus a further substantial period (2010 to 2016) in which the distribution of the species altered relatively little, despite many further records being received. Methods This dataset ( Data Citation 1 ) comprises 48 510 spatio-temporal records of the occurrence of H. axyridis in Britain and Ireland, from first arrival in 2003, to the end of 2016. For its type it is thus an unusually substantial dataset. Whilst<|im_end|> <|im_start|>assistant New research published in the Nature journal Scientific Data shows how the public can play a vital role in helping to track invasive species. The journal has published data from the UK Ladybird Survey which shows how the harlequin ladybird, which is a species native to Asia, has spread across the country. The harlequin ladybird was introduced to mainland Europe in the 1980s to control aphids. It was first reported in the UK in 2003 and is now outcompeting a number of smaller native ladybird species. The new open access study maps 48,510 observations of the harlequin ladybird, submitted by the general public, spanning over a decade. Spreading at over 60 miles per year during the early stage of invasion, the observations show that harlequins are now widespread through England and Wales and increasingly being reported in the south of Scotland. There have been few attempts to monitor the spread of invasive alien species systematically from the onset of the invasion process but the model used by the online UK Ladybird Survey, led by academics from Anglia Ruskin University and the Centre for Ecology & Hydrology, shows the important role that citizen science can play. Rapid flow of information about the occurrence of invasive species is critical in order to take any effective action, and the citizen science approach developed through the UK Ladybird Survey is already being used for surveillance of other invasive non-native species, including the Asian hornet. Lead author Dr. Peter Brown, Senior Lecturer in Zoology at Anglia Ruskin University, said: "All these observations have made major contributions to our understanding of the ecology of the harlequin ladybird in the UK. We are now excited to see how others might use the model and the patterns of data to explore invasions by other species." Co-lead Professor Helen Roy, from the Centre for Ecology & Hydrology, said: "It has been incredible to see the way in which so many people have got involved in tracking this invasion—it is a truly collaborative project. We have been able to answer many important ecological questions using this vast dataset. This would not have been possible without these inspiring citizen science contributions." <|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 glucocorticoid receptor (GR) binds as a homodimer to genomic response elements, which have particular sequence and shape characteristics. Here we show that the nucleotides directly flanking the core-binding site, differ depending on the strength of GR-dependent activation of nearby genes. Our study indicates that these flanking nucleotides change the three-dimensional structure of the DNA-binding site, the DNA-binding domain of GR and the quaternary structure of the dimeric complex. Functional studies in a defined genomic context show that sequence-induced changes in GR activity cannot be explained by differences in GR occupancy. Rather, mutating the dimerization interface mitigates DNA-induced changes in both activity and structure, arguing for a role of DNA-induced structural changes in modulating GR activity. Together, our study shows that DNA sequence identity of genomic binding sites modulates GR activity downstream of binding, which may play a role in achieving regulatory specificity towards individual target genes. Introduction Cells can exploit a variety of strategies to ensure that genes are expressed at a specific and well-defined level, including the tight control of the production process of transcripts. The transcription of genes is controlled by the coordinated action of transcriptional factors (TFs), which bind to cis-regulatory elements to integrate a combination of inputs to specify where and when a gene is expressed and how much gene product is synthesized 1 . Signals influencing the level of transcriptional output include the sequence composition of cis-regulatory elements that can, for example, direct the assembly of distinct regulatory complexes (reviewed in refs 2 , 3 ). Other mechanisms that influence the transcriptional output of individual genes include the distance of regulatory elements to the transcriptional start site (TSS) of genes 4 , the chromatin context in which regulatory elements are embedded 5 , DNA methylation 6 , 7 and post-translational modifications of proteins 1 . For the glucocorticoid receptor (GR), a member of the steroid hormone receptor family, the sequence of its DNA-binding site is known to modulate the receptor’s activity. Some studies suggests that depending on the sequence of the GR-binding sequence (GBS), the direction of regulation might be influenced, that is, whether GR will activate or repress transcription 8 , 9 , 10 , 11 . Furthermore, the magnitude of transcriptional activation by GR depends on the exact sequence composition of the GBS, which consists of inverted repeats of two half-sites of 6 base pairs (bp) separated by a 3-bp spacer 11 . Affinity for specific GBSs can explain some, but not all, of the modulation of GR activity by the sequence composition of the GBSs 12 . GR activity can also be modulated by DNA shape, which can serve as an allosteric ligand that fine-tunes the structure and activity of GR without apparent changes in DNA binding affinity 13 . GR can ‘read’ the shape of DNA through non-specific DNA contacts with the phosphate backbone in the spacer region and at other positions within each half-site 11 , 13 . In addition, GR contacts the minor groove just outside the core 15-bp GBS 11 . How the DNA-induced structural changes in the associated protein result in different transcriptional outputs is largely unknown, but requires an intact dimerization interface and may involve sequence-specific cooperation with GR cofactors 11 , 13 . Here we further investigated this question and uncovered that the 2 bp flanking the GBS, which are involved in modifying the shape of the DNA target, influence transcriptional output levels. We first studied if GBS variants can modulate GR activity in a chromosomal context and found that GBS variants can indeed modulate GR activity when integrated at a defined genomic locus. Interestingly, this modulation appears to occur downstream of GR binding as the differences in transcriptional responses cannot be explained by differences in occupancy levels based on chromatin immunoprecipitation (ChIP) experiments. Furthermore, we analysed genome-wide data on GR binding and gene regulation and identified differences in the sequence composition between GBSs associated with genes with strong and those with weak transcriptional responses to GR activation. Using a combination of experiments with atomic resolution and functional studies, we found that the base pairs directly flanking the core 15-bp GBS modulate GR activity and induce structural changes in both DNA and the associated DNA-binding domain of GR. Together, our studies suggest that modulation of GR activity and structure by GBS variation at positions directly adjacent to the core recognition sequence plays a role in fine-tuning the expression of endogenous target genes. Results Genomic GR-binding site sequence affects GR activity Previous studies relied on transiently transfected reporters to show that GBS composition can modulate GR activity 11 , 13 . To determine if GBS variants can also influence GR activity in a chromosomal context, we used zinc finger nucleases (ZFN) to generate isogenic cell lines with integrated GBS reporters 14 . The GBS reporters consist of a GBS variant upstream of a minimal promoter driving expression of a luciferase reporter gene ( Fig. 1a ). Single-cell-derived clonal cell lines with integrated reporters were isolated by flow-activated cell sorting (FACS) and genotyped for correct integration at the AAVS1 locus ( Supplementary Fig. 1A ). Consistent with our expectation, no induction by dexamethasone, a synthetic glucocorticoid hormone, was observed for the reporter lacking a GBS ( Fig. 1b ). For reporters with a single GBS, transcriptional activation was observed with sequence-specific activities ranging from ∼ 17-fold for the Cgt, to ∼ 9-fold for the GILZ and ∼ 2-fold for the SGK2 GBS ( Fig. 1b ). Notably, activation of the endogenous GR target gene TSC22D3 was comparable for all clonal lines ( Supplementary Fig. 1B ), arguing that the GBS-specific activities are not a simple consequence of clonal variation in GR activity. Figure 1: GBS activity and binding in a genomic context. ( a ) Cartoon depicting donor design, GBS sequence and the genotype at the AAVS1 locus after integration of the GBS-reporters. Nucleotides that diverge from the Gilz sequence are highlighted in red for the Cgt and Sgk2 GBSs, respectively. ( b ) Top:", "role": "user" }, { "content": "Substances known as transcription factors often determine how a cell develops as well as which proteins it produces and in what quantities. Transcription factors bind to a section of DNA and control how strongly a gene in that section is activated. Scientists had previously assumed that gene activity is controlled by the binding strength and the proximity of the binding site to the gene. Researchers at the Max Planck Institute for Molecular Genetics in Berlin have now discovered that the DNA segment to which a transcription factor binds can assume various spatial arrangements. As a result, it alters the structure of the transcription factor itself and controls its activity. Neighbouring DNA segments have a significant impact on transcription factor shape, thus modulating the activity of the gene. For a car to move, it is not enough for a person to sit in the driver's seat: the driver has to start the engine, press on the accelerator and engage the transmission. Things work similarly in the cells of our body. Until recently, scientists had suspected that certain proteins only bind to specific sites on the DNA strand, directing the cell's fate in the process. The closer and more tightly they bind to a gene on the DNA, the more active the gene was thought to be. These proteins, known as transcription factors, control the activity of genes. A team of scientists headed by Sebastiaan Meijsing at the Max Planck Institute for Molecular Genetics have now come to a different conclusion: The researchers discovered that transcription factors can assume various shapes depending on which DNA segment they bind to. \"The shape of the bond, in turn, influences whether and how strongly a gene is activated,\" Meijsing explains. Consequently, transcription factors can bind to DNA segments without affecting a nearby gene. As in our car analogy, the mere presence of a \"driver\" is evidently not sufficient to set the mechanism in train. Other factors must also be involved in determining how strongly a transcription factor activates a gene. Glucocorticoid receptor is also a transcription factor One example is glucose production in the liver. If the blood contains too little glucose, the adrenal glands release glucocorticoids, which act as chemical messengers. These hormones circulate through the body and bind to glucocorticoid receptors on liver cells. The receptors simultaneously act as transcription factors and regulate gene activity in the cells. In this way, the liver is able to produce more glucose, and the blood sugar level rises again. \"Sometimes glucocorticoid receptor binding results in strong activation of neighbouring genes, whereas at other times little if anything changes,\" Meijsing reports. The scientists found that the composition of DNA segments to which the receptors bind help determine how strongly a gene is activated. However, these segments are not in direct contact with the receptors acting as transcription factors; they only flank the binding sites. Yet, that is evidently enough to have a significant influence on the interaction. \"The structure of the interface between the transcription factor and genome segments must therefore play a key role in determining gene activity. In addition, adjacent DNA segments influence the activity of the bound transcription factors. These mechanisms ultimately ensure that liver cells produce the right substances in the right amounts,\" Meijsing says. Medical applications The findings could also have medical applications. Many DNA variants associated with diseases belong to sequences that evidently control the activity of transcription factors. \"Scientists had previously assumed that these segments exert an effect by inhibiting the binding of transcription factors, thus impeding the activity of neighbouring genes,\" Meijsing says. \"Our findings have now shown that some of these segments may not influence the contact directly but nevertheless reduce the activation state of the associated transcription factor.\" ", "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 glucocorticoid receptor (GR) binds as a homodimer to genomic response elements, which have particular sequence and shape characteristics. Here we show that the nucleotides directly flanking the core-binding site, differ depending on the strength of GR-dependent activation of nearby genes. Our study indicates that these flanking nucleotides change the three-dimensional structure of the DNA-binding site, the DNA-binding domain of GR and the quaternary structure of the dimeric complex. Functional studies in a defined genomic context show that sequence-induced changes in GR activity cannot be explained by differences in GR occupancy. Rather, mutating the dimerization interface mitigates DNA-induced changes in both activity and structure, arguing for a role of DNA-induced structural changes in modulating GR activity. Together, our study shows that DNA sequence identity of genomic binding sites modulates GR activity downstream of binding, which may play a role in achieving regulatory specificity towards individual target genes. Introduction Cells can exploit a variety of strategies to ensure that genes are expressed at a specific and well-defined level, including the tight control of the production process of transcripts. The transcription of genes is controlled by the coordinated action of transcriptional factors (TFs), which bind to cis-regulatory elements to integrate a combination of inputs to specify where and when a gene is expressed and how much gene product is synthesized 1 . Signals influencing the level of transcriptional output include the sequence composition of cis-regulatory elements that can, for example, direct the assembly of distinct regulatory complexes (reviewed in refs 2 , 3 ). Other mechanisms that influence the transcriptional output of individual genes include the distance of regulatory elements to the transcriptional start site (TSS) of genes 4 , the chromatin context in which regulatory elements are embedded 5 , DNA methylation 6 , 7 and post-translational modifications of proteins 1 . For the glucocorticoid receptor (GR), a member of the steroid hormone receptor family, the sequence of its DNA-binding site is known to modulate the receptor’s activity. Some studies suggests that depending on the sequence of the GR-binding sequence (GBS), the direction of regulation might be influenced, that is, whether GR will activate or repress transcription 8 , 9 , 10 , 11 . Furthermore, the magnitude of transcriptional activation by GR depends on the exact sequence composition of the GBS, which consists of inverted repeats of two half-sites of 6 base pairs (bp) separated by a 3-bp spacer 11 . Affinity for specific GBSs can explain some, but not all, of the modulation of GR activity by the sequence composition of the GBSs 12 . GR activity can also be modulated by DNA shape, which can serve as an allosteric ligand that fine-tunes the structure and activity of GR without apparent changes in DNA binding affinity 13 . GR can ‘read’ the shape of DNA through non-specific DNA contacts with the phosphate backbone in the spacer region and at other positions within each half-site 11 , 13 . In addition, GR contacts the minor groove just outside the core 15-bp GBS 11 . How the DNA-induced structural changes in the associated protein result in different transcriptional outputs is largely unknown, but requires an intact dimerization interface and may involve sequence-specific cooperation with GR cofactors 11 , 13 . Here we further investigated this question and uncovered that the 2 bp flanking the GBS, which are involved in modifying the shape of the DNA target, influence transcriptional output levels. We first studied if GBS variants can modulate GR activity in a chromosomal context and found that GBS variants can indeed modulate GR activity when integrated at a defined genomic locus. Interestingly, this modulation appears to occur downstream of GR binding as the differences in transcriptional responses cannot be explained by differences in occupancy levels based on chromatin immunoprecipitation (ChIP) experiments. Furthermore, we analysed genome-wide data on GR binding and gene regulation and identified differences in the sequence composition between GBSs associated with genes with strong and those with weak transcriptional responses to GR activation. Using a combination of experiments with atomic resolution and functional studies, we found that the base pairs directly flanking the core 15-bp GBS modulate GR activity and induce structural changes in both DNA and the associated DNA-binding domain of GR. Together, our studies suggest that modulation of GR activity and structure by GBS variation at positions directly adjacent to the core recognition sequence plays a role in fine-tuning the expression of endogenous target genes. Results Genomic GR-binding site sequence affects GR activity Previous studies relied on transiently transfected reporters to show that GBS composition can modulate GR activity 11 , 13 . To determine if GBS variants can also influence GR activity in a chromosomal context, we used zinc finger nucleases (ZFN) to generate isogenic cell lines with integrated GBS reporters 14 . The GBS reporters consist of a GBS variant upstream of a minimal promoter driving expression of a luciferase reporter gene ( Fig. 1a ). Single-cell-derived clonal cell lines with integrated reporters were isolated by flow-activated cell sorting (FACS) and genotyped for correct integration at the AAVS1 locus ( Supplementary Fig. 1A ). Consistent with our expectation, no induction by dexamethasone, a synthetic glucocorticoid hormone, was observed for the reporter lacking a GBS ( Fig. 1b ). For reporters with a single GBS, transcriptional activation was observed with sequence-specific activities ranging from ∼ 17-fold for the Cgt, to ∼ 9-fold for the GILZ and ∼ 2-fold for the SGK2 GBS ( Fig. 1b ). Notably, activation of the endogenous GR target gene TSC22D3 was comparable for all clonal lines ( Supplementary Fig. 1B ), arguing that the GBS-specific activities are not a simple consequence of clonal variation in GR activity. Figure 1: GBS activity and binding in a genomic context. ( a ) Cartoon depicting donor design, GBS sequence and the genotype at the AAVS1 locus after integration of the GBS-reporters. Nucleotides that diverge from the Gilz sequence are highlighted in red for the Cgt and Sgk2 GBSs, respectively. ( b ) Top:<|im_end|> <|im_start|>assistant Substances known as transcription factors often determine how a cell develops as well as which proteins it produces and in what quantities. Transcription factors bind to a section of DNA and control how strongly a gene in that section is activated. Scientists had previously assumed that gene activity is controlled by the binding strength and the proximity of the binding site to the gene. Researchers at the Max Planck Institute for Molecular Genetics in Berlin have now discovered that the DNA segment to which a transcription factor binds can assume various spatial arrangements. As a result, it alters the structure of the transcription factor itself and controls its activity. Neighbouring DNA segments have a significant impact on transcription factor shape, thus modulating the activity of the gene. For a car to move, it is not enough for a person to sit in the driver's seat: the driver has to start the engine, press on the accelerator and engage the transmission. Things work similarly in the cells of our body. Until recently, scientists had suspected that certain proteins only bind to specific sites on the DNA strand, directing the cell's fate in the process. The closer and more tightly they bind to a gene on the DNA, the more active the gene was thought to be. These proteins, known as transcription factors, control the activity of genes. A team of scientists headed by Sebastiaan Meijsing at the Max Planck Institute for Molecular Genetics have now come to a different conclusion: The researchers discovered that transcription factors can assume various shapes depending on which DNA segment they bind to. "The shape of the bond, in turn, influences whether and how strongly a gene is activated," Meijsing explains. Consequently, transcription factors can bind to DNA segments without affecting a nearby gene. As in our car analogy, the mere presence of a "driver" is evidently not sufficient to set the mechanism in train. Other factors must also be involved in determining how strongly a transcription factor activates a gene. Glucocorticoid receptor is also a transcription factor One example is glucose production in the liver. If the blood contains too little glucose, the adrenal glands release glucocorticoids, which act as chemical messengers. These hormones circulate through the body and bind to glucocorticoid receptors on liver cells. The receptors simultaneously act as transcription factors and regulate gene activity in the cells. In this way, the liver is able to produce more glucose, and the blood sugar level rises again. "Sometimes glucocorticoid receptor binding results in strong activation of neighbouring genes, whereas at other times little if anything changes," Meijsing reports. The scientists found that the composition of DNA segments to which the receptors bind help determine how strongly a gene is activated. However, these segments are not in direct contact with the receptors acting as transcription factors; they only flank the binding sites. Yet, that is evidently enough to have a significant influence on the interaction. "The structure of the interface between the transcription factor and genome segments must therefore play a key role in determining gene activity. In addition, adjacent DNA segments influence the activity of the bound transcription factors. These mechanisms ultimately ensure that liver cells produce the right substances in the right amounts," Meijsing says. Medical applications The findings could also have medical applications. Many DNA variants associated with diseases belong to sequences that evidently control the activity of transcription factors. "Scientists had previously assumed that these segments exert an effect by inhibiting the binding of transcription factors, thus impeding the activity of neighbouring genes," Meijsing says. "Our findings have now shown that some of these segments may not influence the contact directly but nevertheless reduce the activation state of the associated transcription factor." <|im_end|>
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2,082
[ { "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 Are gender differences in face recognition influenced by familiarity and socio-cultural factors? Previous studies have reported gender differences in processing unfamiliar faces, consistently finding a female advantage and a female own-gender bias. However, researchers have recently highlighted that unfamiliar faces are processed less efficiently than familiar faces, which have more robust, invariant representations. To-date, no study has examined whether gender differences exist for familiar face recognition. The current study addressed this by using a famous faces task in a large, web-based sample of > 2000 participants across different countries. We also sought to examine if differences varied by socio-cultural gender equality within countries. When examining raw accuracy as well when controlling for fame, the results demonstrated that there were no participant gender differences in overall famous face accuracy, in contrast to studies of unfamiliar faces. There was also a consistent own-gender bias in male but not female participants. In countries with low gender equality, including the USA, females showed significantly better recognition of famous female faces compared to male participants, whereas this difference was abolished in high gender equality countries. Together, this suggests that gender differences in recognizing unfamiliar faces can be attenuated when there is enough face learning and that sociocultural gender equality can drive gender differences in familiar face recognition. Introduction Gender differences in cognitive performance and its origins have important implications for models of cognitive abilities as well as society. Consistent gender differences have been reported in visuospatial tasks such as mental rotation 1 , visual working memory 2 , visual motion processing 3 , sustained attention 4 , emotion recognition 5 , face recognition 6 , and episodic memory recollection 7 , with females showing superior performance over males in most of the tasks except for visuospatial attention tasks where males perform better than females. Though it is debated whether these differences are driven by biological or socio-cultural factors 8 , 9 , many studies emphasize the impact of the latter 10 , 11 , 12 , 13 , 14 . The aims of the current study were twofold; first, we sought to understand gender differences in face recognition beyond “unfamiliar” face recognition (the rapid learning of previously unfamiliar faces) to “familiar” face recognition (recognizing faces that one has semantic knowledge about and previous exposure). Second, we used a large, multi-country sample to probe for any modulation of gender differences by socio-cultural gender equality. Previous studies on gender differences in face processing have focused on the perception and recognition of unfamiliar faces. These differences were observed specifically in within-task learning and recognition paradigms 15 , 16 , 17 or simultaneous perceptual matching paradigms 6 , 18 , 19 , with females showing better performance than males. Further, superior recognition of unfamiliar faces in females has shown to be highly robust and invariant to face view 20 , gaze direction 21 , face-race 22 , 23 as well as duration of presentation 15 , 24 . Studies have also reported own-gender biases, with females being consistently better at recognizing female than male faces 6 , 24 , 25 and less consistently reported a male own-gender bias 26 , 27 . These effects were also supported by multiple eye movement 28 and electrophysiological studies 26 , 29 , 30 . Notably, two recent studies suggest that female superiority in face recognition can be reduced when there is sufficient face learning 31 or prior experience 32 with faces or face categories used. For example, Heisz et al . 31 , conducted a four-day face recognition study for unfamiliar faces, where faces were repeated each day, and showed that the female advantage in response accuracies on the first day was eliminated on the fourth day with repeated face learning. Despite the extensive literature on gender differences in learning and recognizing unfamiliar faces, no study to date has closely examined gender differences in recognizing familiar faces. Though unfamiliar face stimuli are easier to manipulate and control in laboratory settings, in real-world situations we are typically required to identify familiar faces that are learned over many instances and for whom detailed semantic knowledge is available. Because of this enhanced learning, familiar faces have shown to be processed more efficiently than unfamiliar faces, reflected by faster, and more accurate recognition 33 , 34 , 35 . For example, severe image degradation and image distortion has very little effect on the ability to recognize familiar faces, whereas this severely disrupts recognizing unfamiliar faces 36 , 37 . To study the role of familiarity in face recognition, a common approach has been to recall the identity of famous faces. The recollection of semantic (e.g., name, profession) and/or episodic information required by these tasks is quite different from typical matching and recognition tasks used for unfamiliar faces. In particular, most unfamiliar face recognition tasks do not present semantic information along with the face (though see Sperling et al . 38 ) and recognition judgments may rely more on ‘familiarity’, i.e., feeling of knowing, rather than recollecting specific contextual and semantic details 39 , 40 , 41 . Further, the extent or degree of familiarity is also dependent on frequency of prior exposure and subsequent learning. Previous famous faces recognition studies 42 , 43 , 44 have not reported or examined gender differences. Famous face recognition has shown to involve distinct processing from unfamiliar faces 34 , 45 , including extended face learning through repeated exposure, acquiring semantic and episodic knowledge associated with the face, and more reliance on recollection than familiarity 39 , 46 . Given these processing differences between unfamiliar and familiar faces, it is essential to understand to what extent previous theories supporting female superiority in unfamiliar face recognition are generalizable and influenced by face learning and familiarity. Socio-cultural factors such as ethnicity and in-group/out-group effects have also shown to influence face processing, but there have been limited investigations on how they contribute to gender differences in face recognition performance 47 . Previous studies have examined how socio-cultural gender equality affects gender differences", "role": "user" }, { "content": "Our ability to recognize faces is a complex interplay of neurobiology, environment and contextual cues. Now a study from Harvard Medical School suggests that country-to-country variations in sociocultural dynamics—notably the degree of gender equality—can yield marked differences in men's and women's ability to recognize famous faces. The findings, published Nov. 29 in Scientific Reports, reveal that men living in countries with high gender equality—Scandinavian and certain Northern European nations—perform nearly as well as women in accurately identifying the faces of female celebrities. Men living in countries with lower gender equality, such as India or Pakistan for example, fare worse than both their Scandinavian peers and women in their own country in recognizing female celebrities. U.S. males, the study found, fall somewhere in between, a finding that aligns closely with United States' mid-range score on international metrics of gender equality. The results are based on scores from web-based facial recognition tests of nearly 3,000 participants from the United States and eight other countries and suggest that sociocultural factors can shape the ability to discern individual characteristics over broad categories. They suggest that men living in countries with low gender equality are prone to cognitive \"lumping\" that obscures individual differences when it comes to recognizing female faces. \"Our study suggests that whom we pay attention to appears to be, at least in part, fueled by our culture, and how and whom we choose to categorize varies by the sociocultural context we live in.\" said study senior investigator Joseph DeGutis, Harvard Medical School assistant professor of psychiatry and a researcher at VA Boston Healthcare System. \"Our findings underscore how important social and cultural factors are in shaping our cognition and in influencing whom we recognize and whom we do not,\" said study first author Maruti Mishra, Harvard Medical School research fellow in psychiatry in DeGutis's lab. \"Culture and society have the power to shape how we see the world.\" The team's findings showed that men living in the United States—a country that ranks midrange on the United Nations' Gender Inequality Index—performed better when asked to identify famous male politicians, actors or athletes than when they were asked to identify famous female politicians, actors or athletes. And they fared worse than women in identifying famous female celebrities. Men from Scandinavian countries, such as Norway, Denmark and Finland—all places with a high level of gender equality—performed equally well in recognizing famous male faces and famous female faces. On the other hand, men living in countries with low gender equality—India, Brazil and Pakistan, among others—performed worse than U.S. men and worse still than Scandinavian men in identifying famous women. The Gender Inequality Index measures the level of a country's gender inequality by taking into account things like the status of women's reproductive health, education, economic status, and participation and attainment of high-level positions in the workforce. The algorithm scored the United States in the mid-range in 2014-2015 with a score of 0.21—a higher score denotes greater degree of gender inequality—compared with 0.05 for Scandinavian countries, and 0.49 for countries such as India, Pakistan or Egypt. Famous faces For the study, the researchers asked nearly 2,773 adults, ages 18 to 50, to look at a series of famous faces online and identify them. Participants included 2,295 U.S. men and women; 203 men and women from Denmark, the Netherlands, Finland and Norway; and 275 men and women from India, Egypt, Brazil, Pakistan and Indonesia. The celebrity faces were almost exclusively those of U.S. politicians, actors, athletes and performers. The researchers point out that the faces shown were exclusively those of U.S. celebrities. To ensure that U.S. participants didn't have unfair advantage in facial familiarity over their foreign peers, the researchers only analyzed results from international participants who had indicated they were familiar with or had seen the celebrities' faces before. Overall, male celebrity faces were better recognized than female celebrity faces by both men and women, regardless of where they lived. On average, male faces were recognized with 8 percent greater accuracy than female faces. The one notable exception were women from countries with lower gender equality, who performed better at identifying female celebrities than at identifying male celebrities. But the truly intriguing differences emerged when researchers analyzed the accuracy of recognizing famous female celebrities by participant gender. In the U.S. sample, female participants had, on average, 7 percent more accurate scores than their male counterparts in recognizing the faces of famous women. Gender differences were also pronounced among participants from Pakistan, India, Brazil and Egypt. In those countries, women scored, on average 10 percent higher on female celebrity recognition than men. In contrast, test score differences in recognizing famous women's faces were minuscule (less than 2 percent difference) among participants from the Netherlands, Norway, Finland and Denmark. The researchers say the pronounced own-gender bias among males—the tendency to recognize more accurately famous male over famous female faces —is a variation of other forms of perceptual bias that have been documented in past research. For example, research shows that people tend to overlook interpersonal variations in the faces of people from races that differ from their own—the so-called \"other race\" effect. Another manifestation of this tendency is the bias toward noticing the interpersonal variations in individuals who are higher on the workplace hierarchy but obscuring interpersonal differences among those who rank lower on work totem pole. The classic example would be forgetting the name or other individual characteristics of a lower-rung coworker or an intern but remembering the name or distinguishing characteristics of someone higher up. \"All these biases stem from a tendency to categorize rather than individualize,\" DeGutis said. Self-awareness is the first step to combating own-gender bias, the researchers said. For example, previous research into the other-race effect suggests that practicing to individualize members of other racial groups rather than lump them into categories can seriously mitigate the other-race effect. \"Own-gender bias is a form of unconscious bias,\" DeGutis said. \"But by becoming aware of it, we can overcome it or at least minimize it.\" The researchers acknowledge the study has a few limitations, including the use of binary gender designations rather than a continuous gender spectrum. ", "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 Are gender differences in face recognition influenced by familiarity and socio-cultural factors? Previous studies have reported gender differences in processing unfamiliar faces, consistently finding a female advantage and a female own-gender bias. However, researchers have recently highlighted that unfamiliar faces are processed less efficiently than familiar faces, which have more robust, invariant representations. To-date, no study has examined whether gender differences exist for familiar face recognition. The current study addressed this by using a famous faces task in a large, web-based sample of > 2000 participants across different countries. We also sought to examine if differences varied by socio-cultural gender equality within countries. When examining raw accuracy as well when controlling for fame, the results demonstrated that there were no participant gender differences in overall famous face accuracy, in contrast to studies of unfamiliar faces. There was also a consistent own-gender bias in male but not female participants. In countries with low gender equality, including the USA, females showed significantly better recognition of famous female faces compared to male participants, whereas this difference was abolished in high gender equality countries. Together, this suggests that gender differences in recognizing unfamiliar faces can be attenuated when there is enough face learning and that sociocultural gender equality can drive gender differences in familiar face recognition. Introduction Gender differences in cognitive performance and its origins have important implications for models of cognitive abilities as well as society. Consistent gender differences have been reported in visuospatial tasks such as mental rotation 1 , visual working memory 2 , visual motion processing 3 , sustained attention 4 , emotion recognition 5 , face recognition 6 , and episodic memory recollection 7 , with females showing superior performance over males in most of the tasks except for visuospatial attention tasks where males perform better than females. Though it is debated whether these differences are driven by biological or socio-cultural factors 8 , 9 , many studies emphasize the impact of the latter 10 , 11 , 12 , 13 , 14 . The aims of the current study were twofold; first, we sought to understand gender differences in face recognition beyond “unfamiliar” face recognition (the rapid learning of previously unfamiliar faces) to “familiar” face recognition (recognizing faces that one has semantic knowledge about and previous exposure). Second, we used a large, multi-country sample to probe for any modulation of gender differences by socio-cultural gender equality. Previous studies on gender differences in face processing have focused on the perception and recognition of unfamiliar faces. These differences were observed specifically in within-task learning and recognition paradigms 15 , 16 , 17 or simultaneous perceptual matching paradigms 6 , 18 , 19 , with females showing better performance than males. Further, superior recognition of unfamiliar faces in females has shown to be highly robust and invariant to face view 20 , gaze direction 21 , face-race 22 , 23 as well as duration of presentation 15 , 24 . Studies have also reported own-gender biases, with females being consistently better at recognizing female than male faces 6 , 24 , 25 and less consistently reported a male own-gender bias 26 , 27 . These effects were also supported by multiple eye movement 28 and electrophysiological studies 26 , 29 , 30 . Notably, two recent studies suggest that female superiority in face recognition can be reduced when there is sufficient face learning 31 or prior experience 32 with faces or face categories used. For example, Heisz et al . 31 , conducted a four-day face recognition study for unfamiliar faces, where faces were repeated each day, and showed that the female advantage in response accuracies on the first day was eliminated on the fourth day with repeated face learning. Despite the extensive literature on gender differences in learning and recognizing unfamiliar faces, no study to date has closely examined gender differences in recognizing familiar faces. Though unfamiliar face stimuli are easier to manipulate and control in laboratory settings, in real-world situations we are typically required to identify familiar faces that are learned over many instances and for whom detailed semantic knowledge is available. Because of this enhanced learning, familiar faces have shown to be processed more efficiently than unfamiliar faces, reflected by faster, and more accurate recognition 33 , 34 , 35 . For example, severe image degradation and image distortion has very little effect on the ability to recognize familiar faces, whereas this severely disrupts recognizing unfamiliar faces 36 , 37 . To study the role of familiarity in face recognition, a common approach has been to recall the identity of famous faces. The recollection of semantic (e.g., name, profession) and/or episodic information required by these tasks is quite different from typical matching and recognition tasks used for unfamiliar faces. In particular, most unfamiliar face recognition tasks do not present semantic information along with the face (though see Sperling et al . 38 ) and recognition judgments may rely more on ‘familiarity’, i.e., feeling of knowing, rather than recollecting specific contextual and semantic details 39 , 40 , 41 . Further, the extent or degree of familiarity is also dependent on frequency of prior exposure and subsequent learning. Previous famous faces recognition studies 42 , 43 , 44 have not reported or examined gender differences. Famous face recognition has shown to involve distinct processing from unfamiliar faces 34 , 45 , including extended face learning through repeated exposure, acquiring semantic and episodic knowledge associated with the face, and more reliance on recollection than familiarity 39 , 46 . Given these processing differences between unfamiliar and familiar faces, it is essential to understand to what extent previous theories supporting female superiority in unfamiliar face recognition are generalizable and influenced by face learning and familiarity. Socio-cultural factors such as ethnicity and in-group/out-group effects have also shown to influence face processing, but there have been limited investigations on how they contribute to gender differences in face recognition performance 47 . Previous studies have examined how socio-cultural gender equality affects gender differences<|im_end|> <|im_start|>assistant Our ability to recognize faces is a complex interplay of neurobiology, environment and contextual cues. Now a study from Harvard Medical School suggests that country-to-country variations in sociocultural dynamics—notably the degree of gender equality—can yield marked differences in men's and women's ability to recognize famous faces. The findings, published Nov. 29 in Scientific Reports, reveal that men living in countries with high gender equality—Scandinavian and certain Northern European nations—perform nearly as well as women in accurately identifying the faces of female celebrities. Men living in countries with lower gender equality, such as India or Pakistan for example, fare worse than both their Scandinavian peers and women in their own country in recognizing female celebrities. U.S. males, the study found, fall somewhere in between, a finding that aligns closely with United States' mid-range score on international metrics of gender equality. The results are based on scores from web-based facial recognition tests of nearly 3,000 participants from the United States and eight other countries and suggest that sociocultural factors can shape the ability to discern individual characteristics over broad categories. They suggest that men living in countries with low gender equality are prone to cognitive "lumping" that obscures individual differences when it comes to recognizing female faces. "Our study suggests that whom we pay attention to appears to be, at least in part, fueled by our culture, and how and whom we choose to categorize varies by the sociocultural context we live in." said study senior investigator Joseph DeGutis, Harvard Medical School assistant professor of psychiatry and a researcher at VA Boston Healthcare System. "Our findings underscore how important social and cultural factors are in shaping our cognition and in influencing whom we recognize and whom we do not," said study first author Maruti Mishra, Harvard Medical School research fellow in psychiatry in DeGutis's lab. "Culture and society have the power to shape how we see the world." The team's findings showed that men living in the United States—a country that ranks midrange on the United Nations' Gender Inequality Index—performed better when asked to identify famous male politicians, actors or athletes than when they were asked to identify famous female politicians, actors or athletes. And they fared worse than women in identifying famous female celebrities. Men from Scandinavian countries, such as Norway, Denmark and Finland—all places with a high level of gender equality—performed equally well in recognizing famous male faces and famous female faces. On the other hand, men living in countries with low gender equality—India, Brazil and Pakistan, among others—performed worse than U.S. men and worse still than Scandinavian men in identifying famous women. The Gender Inequality Index measures the level of a country's gender inequality by taking into account things like the status of women's reproductive health, education, economic status, and participation and attainment of high-level positions in the workforce. The algorithm scored the United States in the mid-range in 2014-2015 with a score of 0.21—a higher score denotes greater degree of gender inequality—compared with 0.05 for Scandinavian countries, and 0.49 for countries such as India, Pakistan or Egypt. Famous faces For the study, the researchers asked nearly 2,773 adults, ages 18 to 50, to look at a series of famous faces online and identify them. Participants included 2,295 U.S. men and women; 203 men and women from Denmark, the Netherlands, Finland and Norway; and 275 men and women from India, Egypt, Brazil, Pakistan and Indonesia. The celebrity faces were almost exclusively those of U.S. politicians, actors, athletes and performers. The researchers point out that the faces shown were exclusively those of U.S. celebrities. To ensure that U.S. participants didn't have unfair advantage in facial familiarity over their foreign peers, the researchers only analyzed results from international participants who had indicated they were familiar with or had seen the celebrities' faces before. Overall, male celebrity faces were better recognized than female celebrity faces by both men and women, regardless of where they lived. On average, male faces were recognized with 8 percent greater accuracy than female faces. The one notable exception were women from countries with lower gender equality, who performed better at identifying female celebrities than at identifying male celebrities. But the truly intriguing differences emerged when researchers analyzed the accuracy of recognizing famous female celebrities by participant gender. In the U.S. sample, female participants had, on average, 7 percent more accurate scores than their male counterparts in recognizing the faces of famous women. Gender differences were also pronounced among participants from Pakistan, India, Brazil and Egypt. In those countries, women scored, on average 10 percent higher on female celebrity recognition than men. In contrast, test score differences in recognizing famous women's faces were minuscule (less than 2 percent difference) among participants from the Netherlands, Norway, Finland and Denmark. The researchers say the pronounced own-gender bias among males—the tendency to recognize more accurately famous male over famous female faces —is a variation of other forms of perceptual bias that have been documented in past research. For example, research shows that people tend to overlook interpersonal variations in the faces of people from races that differ from their own—the so-called "other race" effect. Another manifestation of this tendency is the bias toward noticing the interpersonal variations in individuals who are higher on the workplace hierarchy but obscuring interpersonal differences among those who rank lower on work totem pole. The classic example would be forgetting the name or other individual characteristics of a lower-rung coworker or an intern but remembering the name or distinguishing characteristics of someone higher up. "All these biases stem from a tendency to categorize rather than individualize," DeGutis said. Self-awareness is the first step to combating own-gender bias, the researchers said. For example, previous research into the other-race effect suggests that practicing to individualize members of other racial groups rather than lump them into categories can seriously mitigate the other-race effect. "Own-gender bias is a form of unconscious bias," DeGutis said. "But by becoming aware of it, we can overcome it or at least minimize it." The researchers acknowledge the study has a few limitations, including the use of binary gender designations rather than a continuous gender spectrum. <|im_end|>
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1101, 6982, 311, 10383, 3663, 8863, 11, 719, 1070, 617, 1027, 7347, 26969, 389, 1268, 814, 17210, 311, 10026, 12062, 304, 3663, 18324, 5178, 220, 2618, 662, 30013, 7978, 617, 25078, 1268, 41589, 94526, 10026, 22526, 22223, 10026, 12062, 128257, 198, 128256, 78191, 198, 8140, 5845, 311, 15641, 12580, 374, 264, 6485, 958, 1387, 315, 18247, 81162, 11, 4676, 323, 66251, 57016, 13, 4800, 264, 4007, 505, 25996, 13235, 6150, 13533, 430, 3224, 4791, 56971, 27339, 304, 15983, 511, 44547, 30295, 63938, 2915, 279, 8547, 315, 10026, 22526, 2345, 4919, 7692, 13160, 12062, 304, 3026, 596, 323, 3278, 596, 5845, 311, 15641, 11495, 12580, 13, 578, 14955, 11, 4756, 4723, 13, 220, 1682, 304, 38130, 29140, 11, 16805, 430, 3026, 5496, 304, 5961, 449, 1579, 10026, 22526, 2345, 3407, 51701, 60278, 323, 3738, 17355, 7665, 17089, 2345, 29588, 7154, 439, 1664, 439, 3278, 304, 30357, 25607, 279, 12580, 315, 8954, 40501, 13, 11258, 5496, 304, 5961, 449, 4827, 10026, 22526, 11, 1778, 439, 6890, 477, 17076, 369, 3187, 11, 21057, 11201, 1109, 2225, 872, 85674, 26081, 323, 3278, 304, 872, 1866, 3224, 304, 49183, 8954, 40501, 13, 549, 815, 13, 25000, 11, 279, 4007, 1766, 11, 4498, 15038, 304, 1990, 11, 264, 9455, 430, 5398, 82, 15499, 449, 3723, 4273, 6, 5209, 31608, 5573, 389, 6625, 17150, 315, 10026, 22526, 13, 578, 3135, 527, 3196, 389, 12483, 505, 3566, 6108, 28900, 18324, 7177, 315, 7154, 220, 18, 11, 931, 13324, 505, 279, 3723, 4273, 323, 8223, 1023, 5961, 323, 4284, 430, 15983, 511, 44547, 9547, 649, 6211, 279, 5845, 311, 42645, 3927, 17910, 927, 7353, 11306, 13, 2435, 4284, 430, 3026, 5496, 304, 5961, 449, 3428, 10026, 22526, 527, 38097, 311, 25702, 330, 75, 55432, 1, 430, 26730, 1439, 3927, 12062, 994, 433, 4131, 311, 49183, 8954, 12580, 13, 330, 8140, 4007, 13533, 430, 8884, 584, 2343, 6666, 311, 8111, 311, 387, 11, 520, 3325, 304, 961, 11, 59461, 555, 1057, 7829, 11, 323, 1268, 323, 8884, 584, 5268, 311, 22824, 553, 35327, 555, 279, 15983, 511, 44547, 2317, 584, 3974, 304, 1210, 1071, 4007, 10195, 49581, 15466, 1611, 38, 332, 285, 11, 25996, 13235, 6150, 18328, 14561, 315, 46876, 894, 323, 264, 32185, 520, 21571, 10406, 39435, 744, 13, 330, 8140, 14955, 53209, 1268, 3062, 3674, 323, 13042, 9547, 527, 304, 46620, 1057, 75310, 323, 304, 66700, 8884, 584, 15641, 323, 8884, 584, 656, 539, 1359, 1071, 4007, 1176, 3229, 2947, 32973, 78576, 969, 11, 25996, 13235, 6150, 3495, 12637, 304, 46876, 894, 304, 1611, 38, 332, 285, 596, 10278, 13, 330, 26896, 323, 8396, 617, 279, 2410, 311, 6211, 1268, 584, 1518, 279, 1917, 1210, 578, 2128, 596, 14955, 8710, 430, 3026, 5496, 304, 279, 3723, 4273, 29096, 3224, 430, 21467, 5209, 9866, 389, 279, 3723, 19687, 6, 29317, 763, 82738, 8167, 2345, 716, 10365, 2731, 994, 4691, 311, 10765, 11495, 8762, 19287, 11, 20142, 477, 23579, 1109, 994, 814, 1051, 4691, 311, 10765, 11495, 8954, 19287, 11, 20142, 477, 23579, 13, 1628, 814, 282, 1636, 11201, 1109, 3278, 304, 25607, 11495, 8954, 40501, 13, 11258, 505, 85674, 5961, 11, 1778, 439, 32603, 11, 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2,527
[ { "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 Specific cell populations may have unique contributions to schizophrenia but may be missed in studies of homogenate tissue. Here laser capture microdissection followed by RNA sequencing (LCM-seq) was used to transcriptomically profile the granule cell layer of the dentate gyrus (DG-GCL) in human hippocampus and contrast these data to those obtained from bulk hippocampal homogenate. We identified widespread cell-type-enriched aging and genetic effects in the DG-GCL that were either absent or directionally discordant in bulk hippocampus data. Of the ~9 million expression quantitative trait loci identified in the DG-GCL, 15% were not detected in bulk hippocampus, including 15 schizophrenia risk variants. We created transcriptome-wide association study genetic weights from the DG-GCL, which identified many schizophrenia-associated genetic signals not found in transcriptome-wide association studies from bulk hippocampus, including GRM3 and CACNA1C . These results highlight the improved biological resolution provided by targeted sampling strategies like LCM and complement homogenate and single-nucleus approaches in human brain. Main Extensive effort has been spent over the past 10 years to more fully characterize the human brain transcriptome within and across cell types and to better understand changes in RNA expression associated with brain development and aging, developmental or psychiatric brain disorders, and local genetic variation. Large consortia have primarily focused on molecular profiling of RNA extracted from homogenate or bulk tissue from different brain regions across tens or hundreds of individuals 1 , 2 , 3 , 4 , although single-cell expression approaches are increasingly available. We have previously identified extensive gene expression associations in human brain with schizophrenia and its genetic risk 5 , development and aging, and local genetic variation in the dorsolateral prefrontal cortex (DLPFC) 6 and, more recently, the hippocampal formation 7 . While expression quantitative trait loci (eQTLs) in these two brain regions were highly overlapping, in line with previous work across many tissues in the body 4 , there were distinct, region-specific expression profiles associated with brain development that were subsequently dysregulated in schizophrenia. We further identified stronger effects of schizophrenia diagnosis in the DLPFC than in the hippocampal formation, with an order of magnitude more genes differentially expressed. While these differences in signatures across brain regions are likely related to the unique cell types underlying each region, particularly for changes across development 7 , the specific cell types in which these signals act within and across brain regions are largely unknown. To better understand expression within and across individual cell types, there has been a dramatic shift to RNA-seq approaches that profile tens or hundreds of thousands of cells or nuclei from a few individuals. While these single-cell (scRNA-seq) or single-nucleus (snRNA-seq) approaches have cataloged dozens of transcriptionally distinct cell classes in the human brain 8 , 9 , 10 , 11 , 12 , the limited number of individuals and the high cost have largely prevented use of these approaches for association with genetic variation and human traits. Furthermore, rarer cell populations have lower probabilities of ascertainment and subsequent characterization in these analyses. An alternative strategy for cell type enrichment expression involves isolating specific cell populations with nuclear-specific antibodies followed by flow cytometry or LCM of cell bodies for cells clearly defined by morphology. While previous research has used LCM for expression profiling of precise anatomical regions in the human and primate brains 13 , 14 or layer-specific analysis of human cortex using microarray technologies 15 , there have been few efforts to transcriptionally profile individual cell populations with this technique. We therefore sought to evaluate LCM followed by RNA-seq (LCM-seq) as a tool for cell-type-enriched expression analysis in human brain tissue. Here we profiled the granule cell layer of the dentate gyrus subfield (DG-GCL) in the hippocampal formation, which has a critical role in neurogenesis 16 and a neuromodulatory role controlling information flow from the entorhinal cortex to CA3, and downstream targets including CA1 and the prefrontal cortex. This layer primarily contains the cell bodies of granule neurons, the primary excitatory neuronal cell type in the dentate gyrus. Single-nucleus sequencing studies of human hippocampus estimated that these cells constitute ~5–10% of the hippocampus 17 . The dentate gyrus has a role in pattern separation and its downstream target CA3 has a role in pattern completion in both rodent and human systems 18 , 19 . Deficits in activity in these granule neurons have previously been associated with bipolar disorder and schizophrenia, but many of the previous findings linking this important cell type to these debilitating disorders have been based on animal models 20 , induced pluripotent stem cell (iPSC)-based approaches 21 or low-resolution functional imaging 22 , 23 , 24 . We additionally selected this cell population to permit direct comparisons to bulk hippocampus RNA-seq data from a largely overlapping set of individuals 7 . Results LCM-seq strongly enriches for target cell populations We performed LCM to extract the DG-GCL in postmortem human hippocampal tissue from 263 individuals, including 75 donors with schizophrenia, 66 donors with bipolar disorder, 29 donors with major depression and 93 neurotypical controls, all with genome-wide genotype data and between the ages of 16 and 84 years ( Methods , Extended Data Fig. 1 and Supplementary Table 1 ). Furthermore, 112 individuals also had bulk hippocampus RNA-seq data available (from 333 total hippocampal samples 7 ), which were obtained from the contralateral hemisphere. We first demonstrated that the LCM-seq procedure generates high-quality RNA-seq data, finding that the LCM-seq data and bulk hippocampus RNA-seq data generated with the same Illumina RiboZero Gold library types had similar mitochondrial chromosome (Extended Data Fig. 2a ) and genome (Extended Data Fig. 2b ) mapping rates, albeit with slightly lower exonic mapping rates (Extended Data Fig. 2c ) and correspondingly lower RNA integrity numbers (RINs) (Extended Data Fig. 2d ) for the LCM-seq data. We then used the paired DG-GCL and hippocampus RNA-seq data on 112 individuals to confirm that the LCM-seq sample was enriched for neuronal cells as compared to bulk tissue (Extended Data Fig. 3a and Methods ). We identified 1,899 genes differentially", "role": "user" }, { "content": "Past research in the field of neuroscience suggests that specific types of cells can contribute to the development of psychiatric disorders, including schizophrenia. However, identifying the types of cells that may play a role in schizophrenia can be quite challenging, particularly when using some of the most conventional techniques for the analysis of human tissue. Researchers at the Lieber Institute for Brain Development and the Astellas Research Institute of America have recently carried out new study aimed at investigating gene expression in an important type of neuron that could be associated with schizophrenia. In their paper, published in Nature Neuroscience, they profiled gene expression in a region of the brain that has been found to be linked to schizophrenia, namely the dentate gyrus of the hippocampus. Over the past few years, the same team of researchers conducted several studies with the goal of better understanding molecular correlates of schizophrenia by analyzing human brain tissue collected post-mortem. These experiments were carried out on homogenate brain tissue, which contains a complex mixture of a variety of cell types. While they gathered important insight, the use of homogenate brain tissue seemed far from ideal, as it made it harder to focus investigations on specific cell types hypothetically associated with gene expression signals in schizophrenia. \"Previous research had implicated the dentate gyrus in psychiatric illness and this subregion of hippocampus plays an important role in memory,\" Daniel Hoeppner, one of the researchers who carried out the study, told Medical Xpress. \"In our study, we leveraged the distinct morphological appearance of the granule cell layer, using laser capture microdissection to cut this layer out of the surrounding hippocampus tissue.\" The experimental design that the researchers used in their recent work has several important advantages. One of its key strengths is that it involves the use of RNA sequencing (RNA-seq) data from both hemispheres of the same brains; the bulk hippocampus region from one hemisphere and the dentate gyrus granule cell layer from the other. By analyzing this data, the researchers were able to identify gene expression signatures specific to the granule cell layer of the dentate gyrus (DG-GCL) and others that appeared to be shared with other parts of the hippocampus. These contrasts in the cellular specificity of different parts of the hippocampus were the primary focus of the researchers' analyses. \"From a methodological standpoint, many researchers have moved from homogenate brain tissue directly to individual nuclei using so-called single nucleus RNA sequencing (snRNA-seq),\" Thomas Hyde, another researcher involved in the study, told Medical Xpress. \"However, these evolving methods still shallowly profile gene expression, particularly from less abundant cell populations. The use of laser capture microdissection allowed us to focus on morphologically—or spatially—defined cell populations and use existing well-established sequencing technologies to deeply profile their transcriptomes.\" Using laser capture microdissection combined with RNA sequencing, the researchers were able to identify far more cellular specificity for genes found in genome-wide association study (GWAS) risk loci than those characterized in previous studies. In other words, they identified cell types and genetic effects in the DG-GCL brain region that could be associated with the risk of developing schizophrenia. The researchers identified approximately 9 million gene expression features in the DG-GCL, 15% of which were unique to this brain region and absent in other parts of the bulk hippocampus. This 15% included 15 expression loci that were previously highlighted as potential schizophrenia risk variants. By analyzing these findings, the researchers were able to unveil genetic signals associated with schizophrenia that were never identified before, including a decreased expression of genes GRM3 and CACNA1C. \"Identifying novel risk gene associations specifically in the dentate gyrus could ultimately motivate functional experiments to generate hippocampal granule cell neurons from induced pluripotent stem cells (iPSCs) and alter the expression of these risk genes to better understand biological mechanisms of risk,\" Mitsuyuki Matsumoto, another researcher who carried out the study, told MedicalXpress. This recent report highlights the vast potential of using targeted sampling strategies, such as laser capture microdissection, to investigate specific cellular patterns in the human brain. The findings gathered by Hoeppner, Hyde, Matsumoto and their colleagues also provide new valuable insight about gene expression patterns that may be associated with the risk of developing schizophrenia. \"Our work suggests that diving deeper into specific cell types of the human brain might be more fruitful for risk gene discovery than additional brain regions of homogenate tissue,\" Andrew Jaffe said. \"The Lieber Institute for Brain Development will thus continue developing laser capture microdissection strategies to profile additional specific cell populations in human postmortem brain tissue. In parallel, we have developed strategies for spatial transcriptomics analyses of human postmortem brain tissue and are now adapting these approaches to study the human hippocampus.\" ", "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 Specific cell populations may have unique contributions to schizophrenia but may be missed in studies of homogenate tissue. Here laser capture microdissection followed by RNA sequencing (LCM-seq) was used to transcriptomically profile the granule cell layer of the dentate gyrus (DG-GCL) in human hippocampus and contrast these data to those obtained from bulk hippocampal homogenate. We identified widespread cell-type-enriched aging and genetic effects in the DG-GCL that were either absent or directionally discordant in bulk hippocampus data. Of the ~9 million expression quantitative trait loci identified in the DG-GCL, 15% were not detected in bulk hippocampus, including 15 schizophrenia risk variants. We created transcriptome-wide association study genetic weights from the DG-GCL, which identified many schizophrenia-associated genetic signals not found in transcriptome-wide association studies from bulk hippocampus, including GRM3 and CACNA1C . These results highlight the improved biological resolution provided by targeted sampling strategies like LCM and complement homogenate and single-nucleus approaches in human brain. Main Extensive effort has been spent over the past 10 years to more fully characterize the human brain transcriptome within and across cell types and to better understand changes in RNA expression associated with brain development and aging, developmental or psychiatric brain disorders, and local genetic variation. Large consortia have primarily focused on molecular profiling of RNA extracted from homogenate or bulk tissue from different brain regions across tens or hundreds of individuals 1 , 2 , 3 , 4 , although single-cell expression approaches are increasingly available. We have previously identified extensive gene expression associations in human brain with schizophrenia and its genetic risk 5 , development and aging, and local genetic variation in the dorsolateral prefrontal cortex (DLPFC) 6 and, more recently, the hippocampal formation 7 . While expression quantitative trait loci (eQTLs) in these two brain regions were highly overlapping, in line with previous work across many tissues in the body 4 , there were distinct, region-specific expression profiles associated with brain development that were subsequently dysregulated in schizophrenia. We further identified stronger effects of schizophrenia diagnosis in the DLPFC than in the hippocampal formation, with an order of magnitude more genes differentially expressed. While these differences in signatures across brain regions are likely related to the unique cell types underlying each region, particularly for changes across development 7 , the specific cell types in which these signals act within and across brain regions are largely unknown. To better understand expression within and across individual cell types, there has been a dramatic shift to RNA-seq approaches that profile tens or hundreds of thousands of cells or nuclei from a few individuals. While these single-cell (scRNA-seq) or single-nucleus (snRNA-seq) approaches have cataloged dozens of transcriptionally distinct cell classes in the human brain 8 , 9 , 10 , 11 , 12 , the limited number of individuals and the high cost have largely prevented use of these approaches for association with genetic variation and human traits. Furthermore, rarer cell populations have lower probabilities of ascertainment and subsequent characterization in these analyses. An alternative strategy for cell type enrichment expression involves isolating specific cell populations with nuclear-specific antibodies followed by flow cytometry or LCM of cell bodies for cells clearly defined by morphology. While previous research has used LCM for expression profiling of precise anatomical regions in the human and primate brains 13 , 14 or layer-specific analysis of human cortex using microarray technologies 15 , there have been few efforts to transcriptionally profile individual cell populations with this technique. We therefore sought to evaluate LCM followed by RNA-seq (LCM-seq) as a tool for cell-type-enriched expression analysis in human brain tissue. Here we profiled the granule cell layer of the dentate gyrus subfield (DG-GCL) in the hippocampal formation, which has a critical role in neurogenesis 16 and a neuromodulatory role controlling information flow from the entorhinal cortex to CA3, and downstream targets including CA1 and the prefrontal cortex. This layer primarily contains the cell bodies of granule neurons, the primary excitatory neuronal cell type in the dentate gyrus. Single-nucleus sequencing studies of human hippocampus estimated that these cells constitute ~5–10% of the hippocampus 17 . The dentate gyrus has a role in pattern separation and its downstream target CA3 has a role in pattern completion in both rodent and human systems 18 , 19 . Deficits in activity in these granule neurons have previously been associated with bipolar disorder and schizophrenia, but many of the previous findings linking this important cell type to these debilitating disorders have been based on animal models 20 , induced pluripotent stem cell (iPSC)-based approaches 21 or low-resolution functional imaging 22 , 23 , 24 . We additionally selected this cell population to permit direct comparisons to bulk hippocampus RNA-seq data from a largely overlapping set of individuals 7 . Results LCM-seq strongly enriches for target cell populations We performed LCM to extract the DG-GCL in postmortem human hippocampal tissue from 263 individuals, including 75 donors with schizophrenia, 66 donors with bipolar disorder, 29 donors with major depression and 93 neurotypical controls, all with genome-wide genotype data and between the ages of 16 and 84 years ( Methods , Extended Data Fig. 1 and Supplementary Table 1 ). Furthermore, 112 individuals also had bulk hippocampus RNA-seq data available (from 333 total hippocampal samples 7 ), which were obtained from the contralateral hemisphere. We first demonstrated that the LCM-seq procedure generates high-quality RNA-seq data, finding that the LCM-seq data and bulk hippocampus RNA-seq data generated with the same Illumina RiboZero Gold library types had similar mitochondrial chromosome (Extended Data Fig. 2a ) and genome (Extended Data Fig. 2b ) mapping rates, albeit with slightly lower exonic mapping rates (Extended Data Fig. 2c ) and correspondingly lower RNA integrity numbers (RINs) (Extended Data Fig. 2d ) for the LCM-seq data. We then used the paired DG-GCL and hippocampus RNA-seq data on 112 individuals to confirm that the LCM-seq sample was enriched for neuronal cells as compared to bulk tissue (Extended Data Fig. 3a and Methods ). We identified 1,899 genes differentially<|im_end|> <|im_start|>assistant Past research in the field of neuroscience suggests that specific types of cells can contribute to the development of psychiatric disorders, including schizophrenia. However, identifying the types of cells that may play a role in schizophrenia can be quite challenging, particularly when using some of the most conventional techniques for the analysis of human tissue. Researchers at the Lieber Institute for Brain Development and the Astellas Research Institute of America have recently carried out new study aimed at investigating gene expression in an important type of neuron that could be associated with schizophrenia. In their paper, published in Nature Neuroscience, they profiled gene expression in a region of the brain that has been found to be linked to schizophrenia, namely the dentate gyrus of the hippocampus. Over the past few years, the same team of researchers conducted several studies with the goal of better understanding molecular correlates of schizophrenia by analyzing human brain tissue collected post-mortem. These experiments were carried out on homogenate brain tissue, which contains a complex mixture of a variety of cell types. While they gathered important insight, the use of homogenate brain tissue seemed far from ideal, as it made it harder to focus investigations on specific cell types hypothetically associated with gene expression signals in schizophrenia. "Previous research had implicated the dentate gyrus in psychiatric illness and this subregion of hippocampus plays an important role in memory," Daniel Hoeppner, one of the researchers who carried out the study, told Medical Xpress. "In our study, we leveraged the distinct morphological appearance of the granule cell layer, using laser capture microdissection to cut this layer out of the surrounding hippocampus tissue." The experimental design that the researchers used in their recent work has several important advantages. One of its key strengths is that it involves the use of RNA sequencing (RNA-seq) data from both hemispheres of the same brains; the bulk hippocampus region from one hemisphere and the dentate gyrus granule cell layer from the other. By analyzing this data, the researchers were able to identify gene expression signatures specific to the granule cell layer of the dentate gyrus (DG-GCL) and others that appeared to be shared with other parts of the hippocampus. These contrasts in the cellular specificity of different parts of the hippocampus were the primary focus of the researchers' analyses. "From a methodological standpoint, many researchers have moved from homogenate brain tissue directly to individual nuclei using so-called single nucleus RNA sequencing (snRNA-seq)," Thomas Hyde, another researcher involved in the study, told Medical Xpress. "However, these evolving methods still shallowly profile gene expression, particularly from less abundant cell populations. The use of laser capture microdissection allowed us to focus on morphologically—or spatially—defined cell populations and use existing well-established sequencing technologies to deeply profile their transcriptomes." Using laser capture microdissection combined with RNA sequencing, the researchers were able to identify far more cellular specificity for genes found in genome-wide association study (GWAS) risk loci than those characterized in previous studies. In other words, they identified cell types and genetic effects in the DG-GCL brain region that could be associated with the risk of developing schizophrenia. The researchers identified approximately 9 million gene expression features in the DG-GCL, 15% of which were unique to this brain region and absent in other parts of the bulk hippocampus. This 15% included 15 expression loci that were previously highlighted as potential schizophrenia risk variants. By analyzing these findings, the researchers were able to unveil genetic signals associated with schizophrenia that were never identified before, including a decreased expression of genes GRM3 and CACNA1C. "Identifying novel risk gene associations specifically in the dentate gyrus could ultimately motivate functional experiments to generate hippocampal granule cell neurons from induced pluripotent stem cells (iPSCs) and alter the expression of these risk genes to better understand biological mechanisms of risk," Mitsuyuki Matsumoto, another researcher who carried out the study, told MedicalXpress. This recent report highlights the vast potential of using targeted sampling strategies, such as laser capture microdissection, to investigate specific cellular patterns in the human brain. The findings gathered by Hoeppner, Hyde, Matsumoto and their colleagues also provide new valuable insight about gene expression patterns that may be associated with the risk of developing schizophrenia. "Our work suggests that diving deeper into specific cell types of the human brain might be more fruitful for risk gene discovery than additional brain regions of homogenate tissue," Andrew Jaffe said. "The Lieber Institute for Brain Development will thus continue developing laser capture microdissection strategies to profile additional specific cell populations in human postmortem brain tissue. In parallel, we have developed strategies for spatial transcriptomics analyses of human postmortem brain tissue and are now adapting these approaches to study the human hippocampus." <|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 Because of the extreme persistence of per- and polyfluoroalkyl substances (PFASs) and their associated risks, the Madrid Statement argues for stopping their use where they are deemed not essential or when safer alternatives exist. To determine when uses of PFASs have an essential function in modern society, and when they do not, is not an easy task. Here, we: (1) develop the concept of “essential use” based on an existing approach described in the Montreal Protocol, (2) apply the concept to various uses of PFASs to determine the feasibility of elimination or substitution of PFASs in each use category, and (3) outline the challenges for phasing out uses of PFASs in society. In brief, we developed three distinct categories to describe the different levels of essentiality of individual uses. A phase-out of many uses of PFASs can be implemented because they are not necessary for the betterment of society in terms of health and safety, or because functional alternatives are currently available that can be substituted into these products or applications. Some specific uses of PFASs would be considered essential because they provide for vital functions and are currently without established alternatives. However, this essentiality should not be considered as permanent; rather, constant efforts are needed to search for alternatives. We provide a description of several ongoing uses of PFASs and discuss whether these uses are essential or non-essential according to the three essentiality categories. It is not possible to describe each use case of PFASs in detail in this single article. For follow-up work, we suggest further refining the assessment of the use cases of PFASs covered here, where necessary, and expanding the application of this concept to all other uses of PFASs. The concept of essential use can also be applied in the management of other chemicals, or groups of chemicals, of concern. This article is part of the themed collections: PFAS and Best Papers 2019 – Environmental Science: Processes & Impacts Environmental significance PFASs are manmade organic contaminants that can be found everywhere in the global environment, largely as a result of their high persistence and wide use. Based on concerns regarding their high persistence and other hazardous properties, it has been argued that the production and use of PFASs should be limited to essential uses only. In this paper, we translate the concept of “essential uses” or “essentiality” into three criteria to determine when uses of PFASs are essential, or not, and demonstrate how the criteria can be applied to different use cases of PFASs. This approach can inform and encourage manufacturers, retailers and end users to consider phasing out and substituting uses of PFASs. Thus, the uses and related emissions of PFASs can be systematically limited and the long-term harm to human health and the environment can be avoided. Introduction Per- and polyfluoroalkyl substances (PFASs) are a group of more than 4700 substances 1 that have been produced since the 1940s and used in a broad range of consumer products and industrial applications. 2 The multiple uses of PFASs have been well-illustrated by the FluoroCouncil. 3 PFASs can be broadly divided into low molecular weight and high molecular weight (polymeric) substances. The polymeric PFASs can be further subdivided into side-chain fluorinated polymers, fluoropolymers and perfluoropolyethers. 2 The review of Buck et al. 2 and the FluoroCouncil website 3 should be consulted for a detailed description of the structures, classes and uses of low and high molecular weight PFASs as that background will not be provided here. Since 2000 there have been a number of voluntary industry phase-outs and regulatory actions to cease the manufacture and use of long-chain perfluoroalkyl acids (PFAAs; defined as including perfluoroalkane sulfonic acids (PFSAs) with perfluoroalkyl chains containing 6 carbons or more, and perfluoroalkyl carboxylic acids (PFCAs) with perfluoroalkyl chains containing 7 carbons or more) and their precursors, which can transform in the environment or within organisms to long-chain PFAAs. The most common replacements for the above defined long-chain PFAS chemistries are shorter-chain PFASs, e.g. PFAAs with fewer fluorinated carbons than long-chain PFAAs, and perfluoroether-based substances (PFASs with perfluoroalkyl segments joined by ether linkages). 4 Although some of these replacement PFASs are less bioaccumulative, they are all similarly highly persistent in the environment as their predecessors. 5,6 PFAAs which are considered short-chain and non-bioaccumulative may also lead to high internal concentrations if people are continuously exposed to high levels. Moreover, short-chain PFAAs, such as perfluorobutanoic acid (PFBA) and PFHxA, tend to be highly mobile and to move readily into ground and surface waters once released to the environment where they can reside for decades to centuries. 7–10 As a result of their high environmental persistence, widespread use and release of any PFAS, even polymeric PFASs, 11 will lead to irreversible global contamination and exposure of wildlife and humans, with currently unknown consequences. 12–14 Based on concerns regarding the high persistence of PFASs and the lack of knowledge on chemical structures, properties, uses, and toxicological profiles of most PFASs currently in use, it has been argued by more than 200 scientists in the Madrid Statement that the production and use of PFASs should be limited. 12 Indeed, in the textile sector, some brand names and retailers have recognized the problems associated with PFASs and have already taken significant steps to phase out all uses of PFASs in their consumer products. 15–18 It is neither practical nor reasonable to ban all uses of PFASs in one step. Some specific applications may serve a critical role for which alternatives currently do not exist. However, if some uses of PFASs are found not to be essential to health, safety or the functioning of today's society, they could be eliminated without having to first find functional alternatives providing an adequate function and performance. Elimination of non-essential uses of PFASs could form a starting point for a process that leads to a global phase-out ( e.g. through the Stockholm Convention on Persistent Organic Pollutants). To critically evaluate the idea that PFASs are essential in modern society,", "role": "user" }, { "content": "Human exposure to unnecessary and potentially harmful chemicals could be greatly reduced if manufacturers add chemicals only when they are truly essential in terms of health, safety and functioning of society. That's the conclusion of a study published today in Environmental Science: Processes & Impacts, a peer-reviewed journal published by the Royal Society of Chemistry. In this study, the researchers proposed a framework based on the concept of \"essential use\" to determine whether a chemical is really needed in a particular application. They demonstrate the concept on a class of synthetic chemicals known as PFAS (per- and polyfluoroalkyl substances). PFAS are used in many consumer goods because of their unique properties, including water and stain repellency. However, a growing number of scientists and health professionals are expressing concern about these chemicals since they persist for a very long time, seep into the water and soil, and may adversely impact humans and wildlife. Human health problems linked to certain PFAS exposure include kidney and testicular cancer, liver malfunction, hypothyroidism, high cholesterol, ulcerative colitis, lower birth weight and size, obesity, and decreased immune response to vaccines. The study classifies many uses of PFAS as \"non-essential.\" For example, the study points out that it may be nice to have water-repelling surfer shorts, but in this instance, water repellency is not essential. Other products analyzed with the Essential Use Framework include personal care products and cosmetics, durable water repellency and stain resistance in textiles, food contact materials, medical devices, pharmaceuticals, laboratory supplies and ski waxes. Some uses may be regarded as essential in terms of health and safety, e.g., fire-fighting foams, but functional alternatives have been developed that can be substituted for PFASs. \"Our hope is the approach can inform and encourage manufacturers, retailers and end users to consider phasing out and substituting uses of PFASs.\" said Ian Cousins of Stockholm University, lead author of the study and a world-leading researcher specializing in understanding the sources and exposure pathways of highly fluorinated chemicals. \"A starting point would be the phase-out of the multiple non-essential uses of PFASs, which are driven primarily by market opportunity.\" The article notes that some retailers and manufacturers are already taking voluntary measures to phase out the use of PFAS in their products. It suggests that the Essential Use Framework can be applied to other chemicals of concern. ", "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 Because of the extreme persistence of per- and polyfluoroalkyl substances (PFASs) and their associated risks, the Madrid Statement argues for stopping their use where they are deemed not essential or when safer alternatives exist. To determine when uses of PFASs have an essential function in modern society, and when they do not, is not an easy task. Here, we: (1) develop the concept of “essential use” based on an existing approach described in the Montreal Protocol, (2) apply the concept to various uses of PFASs to determine the feasibility of elimination or substitution of PFASs in each use category, and (3) outline the challenges for phasing out uses of PFASs in society. In brief, we developed three distinct categories to describe the different levels of essentiality of individual uses. A phase-out of many uses of PFASs can be implemented because they are not necessary for the betterment of society in terms of health and safety, or because functional alternatives are currently available that can be substituted into these products or applications. Some specific uses of PFASs would be considered essential because they provide for vital functions and are currently without established alternatives. However, this essentiality should not be considered as permanent; rather, constant efforts are needed to search for alternatives. We provide a description of several ongoing uses of PFASs and discuss whether these uses are essential or non-essential according to the three essentiality categories. It is not possible to describe each use case of PFASs in detail in this single article. For follow-up work, we suggest further refining the assessment of the use cases of PFASs covered here, where necessary, and expanding the application of this concept to all other uses of PFASs. The concept of essential use can also be applied in the management of other chemicals, or groups of chemicals, of concern. This article is part of the themed collections: PFAS and Best Papers 2019 – Environmental Science: Processes & Impacts Environmental significance PFASs are manmade organic contaminants that can be found everywhere in the global environment, largely as a result of their high persistence and wide use. Based on concerns regarding their high persistence and other hazardous properties, it has been argued that the production and use of PFASs should be limited to essential uses only. In this paper, we translate the concept of “essential uses” or “essentiality” into three criteria to determine when uses of PFASs are essential, or not, and demonstrate how the criteria can be applied to different use cases of PFASs. This approach can inform and encourage manufacturers, retailers and end users to consider phasing out and substituting uses of PFASs. Thus, the uses and related emissions of PFASs can be systematically limited and the long-term harm to human health and the environment can be avoided. Introduction Per- and polyfluoroalkyl substances (PFASs) are a group of more than 4700 substances 1 that have been produced since the 1940s and used in a broad range of consumer products and industrial applications. 2 The multiple uses of PFASs have been well-illustrated by the FluoroCouncil. 3 PFASs can be broadly divided into low molecular weight and high molecular weight (polymeric) substances. The polymeric PFASs can be further subdivided into side-chain fluorinated polymers, fluoropolymers and perfluoropolyethers. 2 The review of Buck et al. 2 and the FluoroCouncil website 3 should be consulted for a detailed description of the structures, classes and uses of low and high molecular weight PFASs as that background will not be provided here. Since 2000 there have been a number of voluntary industry phase-outs and regulatory actions to cease the manufacture and use of long-chain perfluoroalkyl acids (PFAAs; defined as including perfluoroalkane sulfonic acids (PFSAs) with perfluoroalkyl chains containing 6 carbons or more, and perfluoroalkyl carboxylic acids (PFCAs) with perfluoroalkyl chains containing 7 carbons or more) and their precursors, which can transform in the environment or within organisms to long-chain PFAAs. The most common replacements for the above defined long-chain PFAS chemistries are shorter-chain PFASs, e.g. PFAAs with fewer fluorinated carbons than long-chain PFAAs, and perfluoroether-based substances (PFASs with perfluoroalkyl segments joined by ether linkages). 4 Although some of these replacement PFASs are less bioaccumulative, they are all similarly highly persistent in the environment as their predecessors. 5,6 PFAAs which are considered short-chain and non-bioaccumulative may also lead to high internal concentrations if people are continuously exposed to high levels. Moreover, short-chain PFAAs, such as perfluorobutanoic acid (PFBA) and PFHxA, tend to be highly mobile and to move readily into ground and surface waters once released to the environment where they can reside for decades to centuries. 7–10 As a result of their high environmental persistence, widespread use and release of any PFAS, even polymeric PFASs, 11 will lead to irreversible global contamination and exposure of wildlife and humans, with currently unknown consequences. 12–14 Based on concerns regarding the high persistence of PFASs and the lack of knowledge on chemical structures, properties, uses, and toxicological profiles of most PFASs currently in use, it has been argued by more than 200 scientists in the Madrid Statement that the production and use of PFASs should be limited. 12 Indeed, in the textile sector, some brand names and retailers have recognized the problems associated with PFASs and have already taken significant steps to phase out all uses of PFASs in their consumer products. 15–18 It is neither practical nor reasonable to ban all uses of PFASs in one step. Some specific applications may serve a critical role for which alternatives currently do not exist. However, if some uses of PFASs are found not to be essential to health, safety or the functioning of today's society, they could be eliminated without having to first find functional alternatives providing an adequate function and performance. Elimination of non-essential uses of PFASs could form a starting point for a process that leads to a global phase-out ( e.g. through the Stockholm Convention on Persistent Organic Pollutants). To critically evaluate the idea that PFASs are essential in modern society,<|im_end|> <|im_start|>assistant Human exposure to unnecessary and potentially harmful chemicals could be greatly reduced if manufacturers add chemicals only when they are truly essential in terms of health, safety and functioning of society. That's the conclusion of a study published today in Environmental Science: Processes & Impacts, a peer-reviewed journal published by the Royal Society of Chemistry. In this study, the researchers proposed a framework based on the concept of "essential use" to determine whether a chemical is really needed in a particular application. They demonstrate the concept on a class of synthetic chemicals known as PFAS (per- and polyfluoroalkyl substances). PFAS are used in many consumer goods because of their unique properties, including water and stain repellency. However, a growing number of scientists and health professionals are expressing concern about these chemicals since they persist for a very long time, seep into the water and soil, and may adversely impact humans and wildlife. Human health problems linked to certain PFAS exposure include kidney and testicular cancer, liver malfunction, hypothyroidism, high cholesterol, ulcerative colitis, lower birth weight and size, obesity, and decreased immune response to vaccines. The study classifies many uses of PFAS as "non-essential." For example, the study points out that it may be nice to have water-repelling surfer shorts, but in this instance, water repellency is not essential. Other products analyzed with the Essential Use Framework include personal care products and cosmetics, durable water repellency and stain resistance in textiles, food contact materials, medical devices, pharmaceuticals, laboratory supplies and ski waxes. Some uses may be regarded as essential in terms of health and safety, e.g., fire-fighting foams, but functional alternatives have been developed that can be substituted for PFASs. "Our hope is the approach can inform and encourage manufacturers, retailers and end users to consider phasing out and substituting uses of PFASs." said Ian Cousins of Stockholm University, lead author of the study and a world-leading researcher specializing in understanding the sources and exposure pathways of highly fluorinated chemicals. "A starting point would be the phase-out of the multiple non-essential uses of PFASs, which are driven primarily by market opportunity." The article notes that some retailers and manufacturers are already taking voluntary measures to phase out the use of PFAS in their products. It suggests that the Essential Use Framework can be applied to other chemicals of concern. <|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 Without a protective atmosphere, space-exposed surfaces of airless Solar System bodies gradually experience an alteration in composition, structure and optical properties through a collective process called space weathering. The return of samples from near-Earth asteroid (162173) Ryugu by Hayabusa2 provides the first opportunity for laboratory study of space-weathering signatures on the most abundant type of inner solar system body: a C-type asteroid, composed of materials largely unchanged since the formation of the Solar System. Weathered Ryugu grains show areas of surface amorphization and partial melting of phyllosilicates, in which reduction from Fe 3+ to Fe 2+ and dehydration developed. Space weathering probably contributed to dehydration by dehydroxylation of Ryugu surface phyllosilicates that had already lost interlayer water molecules and to weakening of the 2.7 µm hydroxyl (–OH) band in reflectance spectra. For C-type asteroids in general, this indicates that a weak 2.7 µm band can signify space-weathering-induced surface dehydration, rather than bulk volatile loss. Main Solar wind irradiation and high-velocity micrometeoroid bombardment dominate space weathering 1 , 2 for all airless bodies. However, the effects of these processes vary substantially, depending on the specific class of body. The solar wind is a plasma composed mainly of low-energy protons and electrons streaming from our Sun 1 , 2 , 3 , which induces radiation damage, including amorphization of silicates and formation of nanophase metallic iron particles (npFe 0 ). In contrast, micrometeoroids are interplanetary dust particles that impact airless surfaces at hypervelocities 4 , resulting in cratering, melting and vapour deposits, and sometimes also amorphous silicates and npFe 0 . Space-weathering products of two anhydrous bodies, the Moon and the S-type asteroid Itokawa, have been investigated extensively 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 . These studies revealed that nanometre-sized metallic Fe particles (npFe 0 ), formed via space weathering, resulted in weakened absorption features in visible to near-infrared reflectance. In contrast, it has been unclear what role npFe 0 plays in the reflectance properties of dark (C- and D-type) asteroids 1 , 2 . Space-weathering modification of reflectance spectra features from airless bodies makes identifying a direct link between asteroids and specific meteorite classes based on composition and mineralogy difficult. The Hayabusa mission of the Japan Aerospace Exploration Agency (JAXA) revealed the connection between visible to near-infrared reflectance spectra from S-type asteroids and ordinary chondrite meteorites 5 , with the difference largely attributable to the role of nanophase particles. However, laboratory experiments that mimic solar wind irradiation and micrometeoroid impact on C-type asteroids show a lack of detectable production of npFe 0 , with some spectra reddening (a positive change in spectral slope) and others bluing (just the opposite) 15 , 16 , 17 , 18 , 19 , 20 . Thus, the observed change of spectral slope and absorption band in reflectance spectra of C-type asteroids compared with carbonaceous chondrites meteorites is difficult to interpret 15 , 16 , 17 , 18 , 19 , 20 . JAXA’s Hayabusa2 spacecraft observed spectral variation on asteroid Ryugu 21 , 22 , 23 , 24 thought to be related to space weathering. Our studies of Ryugu samples offer the first opportunity to directly link the spectral variation to the space-weathering-induced physical and chemical alteration of regolith on C-type asteroids. Results Surface modifications found on Ryugu grains The mineralogy of most Ryugu grains investigated by (scanning) transmission electron microscopy is similar to that of CI chondrites 25 , which are the most chemically primitive materials in the Solar System 26 , consistent with other recent studies 27 , 28 , 29 , 30 , 31 . Therefore, to understand the space weathering of Ryugu grains is to understand the weathering of the most chemically primitive Solar System material. More than 500 grains (average diameter ~71 µm) collected at the first touchdown (landing) site (TD1) and >300 grains (average diameter ~57 µm) collected at the second touchdown site (TD2) were investigated for surface modifications potentially related to space weathering. Recognizable surface modifications of the phyllosilicate-rich matrix were found in ~6% of the observed grains from TD1 and ~7% from TD2 (Extended Data Fig. 1 ). The surface modifications of grains differ considerably from those from the Moon and Itokawa because the most abundant phases in Ryugu grains are hydrated sheet silicates (phyllosilicates), not anhydrous silicates (for example, olivine). Several distinct surface modifications are observed, including smooth layers, frothy layers, melt splashes and their combinations (Fig. 1 and Extended Figs. 2 and 3 ). We also examined three millimetre-sized grains (A0067, A0094 and A0058) that have surface modifications related to space weathering. Fig. 1: Secondary electron images of Ryugu grains showing surface modifications related to space weathering. a , The grain C0105–03004800 was collected at the second touchdown site. It is composed of two parts showing different types of space weathering: a frothy layer and a smooth layer. Enlarged images of the two boxed areas on this grain are shown in the insets at the upper right (frothy layer) and the lower left (smooth layer) corners of a . b , The grain A0104–02203700 was collected at the first touchdown site. The frothy layer partially covers the smooth layer on the left-hand side of the image. The boundary between two types of layers is indicated by a dashed curve. The frothy layer has many burst vesicles. A melt splash, located at the lower centre of the image, is attached to the surface of the frothy layer. Source data Full size image Smooth layers on Ryugu grains Approximately 5% of the observed grains from TD1 and ~3% from TD2 have a smooth layer, evident as a thin (<100 nm) continuous smooth sheet covering the surface. Some of these layers contain vesciles of <50 nm diameter that intersect the surface (Fig. 2a and Extended Data Fig. 2a ). Partial detachment of the smooth layers is observed in some grains (Extended Data Fig. 4 ). Electron diffraction reveals that smooth layers are almost completely", "role": "user" }, { "content": "The U.K.'s national synchrotron facility, Diamond Light Source, was used by a large, international collaboration to study grains collected from a near-Earth asteroid to further our understanding of the evolution of our solar system. Researchers from the University of Leicester brought a fragment of the Ryugu asteroid to Diamond's Nanoprobe beamline I14 where a special technique called X-ray Absorption Near Edge Spectroscopy (XANES) was used to map out the chemical states of the elements within the asteroid material, to examine its composition in fine detail. The team also studied the asteroid grains using an electron microscope at Diamond's electron Physical Science Imaging Center (ePSIC). Julia Parker is the principal beamline scientist for I14 at Diamond. She said, \"The X-ray Nanoprobe allows scientists to examine the chemical structure of their samples at micron- to nano-length scales, which is complemented by the nano to atomic resolution of the imaging at ePSIC. It's very exciting to be able to contribute to the understanding of these unique samples, and to work with the team at Leicester to demonstrate how the techniques at the beamline, and correlatively at ePSIC, can benefit future sample return missions.\" The data collected at Diamond contributed to a wider study of the space weathering signatures on the asteroid. The pristine asteroid samples enabled the collaborators to explore how space weathering can alter the physical and chemical composition of the surface of carbonaceous asteroids like Ryugu. Image taken at E01 ePSIC of Ryugu serpentine and Fe oxide minerals. Credit: ePSIC/University of Leicester. The researchers discovered that the surface of Ryugu is dehydrated and that it is likely that space weathering is responsible. The findings of the study, published today in Nature Astronomy, have led the authors to conclude that asteroids that appear dry on the surface may be water-rich, potentially requiring revision of our understanding of the abundances of asteroid types and the formation history of the asteroid belt. Ryugu is a near-Earth asteroid, around 900 meters in diameter, first discovered in 1999 within the asteroid belt between Mars and Jupiter. It is named after the undersea palace of the Dragon God in Japanese mythology. In 2014, the Japanese state space agency JAXA launched Hayabusa2, an asteroid sample-return mission, to rendezvous with the Ryugu asteroid and collect material samples from its surface and sub-surface. The spacecraft returned to Earth in 2020, releasing a capsule containing precious fragments of the asteroid. These small samples were distributed to labs around the world for scientific study, including the University of Leicester's School of Physics & Astronomy and Space Park where John Bridges, one of the authors on the paper, is a Professor of Planetary Science. John said, \"This unique mission to gather samples from the most primitive, carbonaceous, building blocks of the solar system needs the world's most detailed microscopy, and that's why JAXA and the Fine Grained Mineralogy team wanted us to analyze samples at Diamond's X-ray nanoprobe beamline. We helped reveal the nature of space weathering on this asteroid with micrometeorite impacts and the solar wind creating dehydrated serpentine minerals, and an associated reduction from oxidized Fe3+ to more reduced Fe2+. \"It's important to build up experience in studying samples returned from asteroids, as in the Hayabusa2 mission, because soon there will be new samples from other asteroid types, the Moon and within the next 10 years Mars, returned to Earth. The U.K. community will be able to perform some of the critical analyses due to our facilities at Diamond and the electron microscopes at ePSIC.\" The building blocks of Ryugu are remnants of interactions between water, minerals and organics in the early solar system prior to the formation of Earth. Understanding the composition of asteroids can help explain how the early solar system developed, and subsequently how the Earth formed. They may even help explain how life on Earth came about, with asteroids believed to have delivered much of the planet's water as well as organic compounds such as amino acids, which provide the fundamental building blocks from which all human life is constructed. The information that is being gleaned from these tiny asteroid samples will help us to better understand the origin not only of the planets and stars but also of life itself. Whether it's fragments of asteroids, ancient paintings or unknown virus structures, at the synchrotron, scientists can study their samples using a machine that is 10,000 times more powerful than a traditional microscope. ", "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 Without a protective atmosphere, space-exposed surfaces of airless Solar System bodies gradually experience an alteration in composition, structure and optical properties through a collective process called space weathering. The return of samples from near-Earth asteroid (162173) Ryugu by Hayabusa2 provides the first opportunity for laboratory study of space-weathering signatures on the most abundant type of inner solar system body: a C-type asteroid, composed of materials largely unchanged since the formation of the Solar System. Weathered Ryugu grains show areas of surface amorphization and partial melting of phyllosilicates, in which reduction from Fe 3+ to Fe 2+ and dehydration developed. Space weathering probably contributed to dehydration by dehydroxylation of Ryugu surface phyllosilicates that had already lost interlayer water molecules and to weakening of the 2.7 µm hydroxyl (–OH) band in reflectance spectra. For C-type asteroids in general, this indicates that a weak 2.7 µm band can signify space-weathering-induced surface dehydration, rather than bulk volatile loss. Main Solar wind irradiation and high-velocity micrometeoroid bombardment dominate space weathering 1 , 2 for all airless bodies. However, the effects of these processes vary substantially, depending on the specific class of body. The solar wind is a plasma composed mainly of low-energy protons and electrons streaming from our Sun 1 , 2 , 3 , which induces radiation damage, including amorphization of silicates and formation of nanophase metallic iron particles (npFe 0 ). In contrast, micrometeoroids are interplanetary dust particles that impact airless surfaces at hypervelocities 4 , resulting in cratering, melting and vapour deposits, and sometimes also amorphous silicates and npFe 0 . Space-weathering products of two anhydrous bodies, the Moon and the S-type asteroid Itokawa, have been investigated extensively 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 . These studies revealed that nanometre-sized metallic Fe particles (npFe 0 ), formed via space weathering, resulted in weakened absorption features in visible to near-infrared reflectance. In contrast, it has been unclear what role npFe 0 plays in the reflectance properties of dark (C- and D-type) asteroids 1 , 2 . Space-weathering modification of reflectance spectra features from airless bodies makes identifying a direct link between asteroids and specific meteorite classes based on composition and mineralogy difficult. The Hayabusa mission of the Japan Aerospace Exploration Agency (JAXA) revealed the connection between visible to near-infrared reflectance spectra from S-type asteroids and ordinary chondrite meteorites 5 , with the difference largely attributable to the role of nanophase particles. However, laboratory experiments that mimic solar wind irradiation and micrometeoroid impact on C-type asteroids show a lack of detectable production of npFe 0 , with some spectra reddening (a positive change in spectral slope) and others bluing (just the opposite) 15 , 16 , 17 , 18 , 19 , 20 . Thus, the observed change of spectral slope and absorption band in reflectance spectra of C-type asteroids compared with carbonaceous chondrites meteorites is difficult to interpret 15 , 16 , 17 , 18 , 19 , 20 . JAXA’s Hayabusa2 spacecraft observed spectral variation on asteroid Ryugu 21 , 22 , 23 , 24 thought to be related to space weathering. Our studies of Ryugu samples offer the first opportunity to directly link the spectral variation to the space-weathering-induced physical and chemical alteration of regolith on C-type asteroids. Results Surface modifications found on Ryugu grains The mineralogy of most Ryugu grains investigated by (scanning) transmission electron microscopy is similar to that of CI chondrites 25 , which are the most chemically primitive materials in the Solar System 26 , consistent with other recent studies 27 , 28 , 29 , 30 , 31 . Therefore, to understand the space weathering of Ryugu grains is to understand the weathering of the most chemically primitive Solar System material. More than 500 grains (average diameter ~71 µm) collected at the first touchdown (landing) site (TD1) and >300 grains (average diameter ~57 µm) collected at the second touchdown site (TD2) were investigated for surface modifications potentially related to space weathering. Recognizable surface modifications of the phyllosilicate-rich matrix were found in ~6% of the observed grains from TD1 and ~7% from TD2 (Extended Data Fig. 1 ). The surface modifications of grains differ considerably from those from the Moon and Itokawa because the most abundant phases in Ryugu grains are hydrated sheet silicates (phyllosilicates), not anhydrous silicates (for example, olivine). Several distinct surface modifications are observed, including smooth layers, frothy layers, melt splashes and their combinations (Fig. 1 and Extended Figs. 2 and 3 ). We also examined three millimetre-sized grains (A0067, A0094 and A0058) that have surface modifications related to space weathering. Fig. 1: Secondary electron images of Ryugu grains showing surface modifications related to space weathering. a , The grain C0105–03004800 was collected at the second touchdown site. It is composed of two parts showing different types of space weathering: a frothy layer and a smooth layer. Enlarged images of the two boxed areas on this grain are shown in the insets at the upper right (frothy layer) and the lower left (smooth layer) corners of a . b , The grain A0104–02203700 was collected at the first touchdown site. The frothy layer partially covers the smooth layer on the left-hand side of the image. The boundary between two types of layers is indicated by a dashed curve. The frothy layer has many burst vesicles. A melt splash, located at the lower centre of the image, is attached to the surface of the frothy layer. Source data Full size image Smooth layers on Ryugu grains Approximately 5% of the observed grains from TD1 and ~3% from TD2 have a smooth layer, evident as a thin (<100 nm) continuous smooth sheet covering the surface. Some of these layers contain vesciles of <50 nm diameter that intersect the surface (Fig. 2a and Extended Data Fig. 2a ). Partial detachment of the smooth layers is observed in some grains (Extended Data Fig. 4 ). Electron diffraction reveals that smooth layers are almost completely<|im_end|> <|im_start|>assistant The U.K.'s national synchrotron facility, Diamond Light Source, was used by a large, international collaboration to study grains collected from a near-Earth asteroid to further our understanding of the evolution of our solar system. Researchers from the University of Leicester brought a fragment of the Ryugu asteroid to Diamond's Nanoprobe beamline I14 where a special technique called X-ray Absorption Near Edge Spectroscopy (XANES) was used to map out the chemical states of the elements within the asteroid material, to examine its composition in fine detail. The team also studied the asteroid grains using an electron microscope at Diamond's electron Physical Science Imaging Center (ePSIC). Julia Parker is the principal beamline scientist for I14 at Diamond. She said, "The X-ray Nanoprobe allows scientists to examine the chemical structure of their samples at micron- to nano-length scales, which is complemented by the nano to atomic resolution of the imaging at ePSIC. It's very exciting to be able to contribute to the understanding of these unique samples, and to work with the team at Leicester to demonstrate how the techniques at the beamline, and correlatively at ePSIC, can benefit future sample return missions." The data collected at Diamond contributed to a wider study of the space weathering signatures on the asteroid. The pristine asteroid samples enabled the collaborators to explore how space weathering can alter the physical and chemical composition of the surface of carbonaceous asteroids like Ryugu. Image taken at E01 ePSIC of Ryugu serpentine and Fe oxide minerals. Credit: ePSIC/University of Leicester. The researchers discovered that the surface of Ryugu is dehydrated and that it is likely that space weathering is responsible. The findings of the study, published today in Nature Astronomy, have led the authors to conclude that asteroids that appear dry on the surface may be water-rich, potentially requiring revision of our understanding of the abundances of asteroid types and the formation history of the asteroid belt. Ryugu is a near-Earth asteroid, around 900 meters in diameter, first discovered in 1999 within the asteroid belt between Mars and Jupiter. It is named after the undersea palace of the Dragon God in Japanese mythology. In 2014, the Japanese state space agency JAXA launched Hayabusa2, an asteroid sample-return mission, to rendezvous with the Ryugu asteroid and collect material samples from its surface and sub-surface. The spacecraft returned to Earth in 2020, releasing a capsule containing precious fragments of the asteroid. These small samples were distributed to labs around the world for scientific study, including the University of Leicester's School of Physics & Astronomy and Space Park where John Bridges, one of the authors on the paper, is a Professor of Planetary Science. John said, "This unique mission to gather samples from the most primitive, carbonaceous, building blocks of the solar system needs the world's most detailed microscopy, and that's why JAXA and the Fine Grained Mineralogy team wanted us to analyze samples at Diamond's X-ray nanoprobe beamline. We helped reveal the nature of space weathering on this asteroid with micrometeorite impacts and the solar wind creating dehydrated serpentine minerals, and an associated reduction from oxidized Fe3+ to more reduced Fe2+. "It's important to build up experience in studying samples returned from asteroids, as in the Hayabusa2 mission, because soon there will be new samples from other asteroid types, the Moon and within the next 10 years Mars, returned to Earth. The U.K. community will be able to perform some of the critical analyses due to our facilities at Diamond and the electron microscopes at ePSIC." The building blocks of Ryugu are remnants of interactions between water, minerals and organics in the early solar system prior to the formation of Earth. Understanding the composition of asteroids can help explain how the early solar system developed, and subsequently how the Earth formed. They may even help explain how life on Earth came about, with asteroids believed to have delivered much of the planet's water as well as organic compounds such as amino acids, which provide the fundamental building blocks from which all human life is constructed. The information that is being gleaned from these tiny asteroid samples will help us to better understand the origin not only of the planets and stars but also of life itself. Whether it's fragments of asteroids, ancient paintings or unknown virus structures, at the synchrotron, scientists can study their samples using a machine that is 10,000 times more powerful than a traditional microscope. <|im_end|>
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685, 6012, 315, 6453, 320, 34, 12, 323, 423, 10827, 8, 85322, 220, 16, 1174, 220, 17, 662, 11746, 12, 15561, 287, 17466, 315, 8881, 685, 63697, 4519, 505, 3805, 1752, 13162, 3727, 25607, 264, 2167, 2723, 1990, 85322, 323, 3230, 42142, 635, 6989, 3196, 389, 18528, 323, 25107, 16035, 5107, 13, 578, 18276, 370, 31853, 9131, 315, 279, 6457, 81965, 76022, 16784, 320, 41, 3027, 32, 8, 10675, 279, 3717, 1990, 9621, 311, 3221, 3502, 82482, 8881, 685, 63697, 505, 328, 10827, 85322, 323, 19664, 523, 2159, 1269, 42142, 3695, 220, 20, 1174, 449, 279, 6811, 14090, 71526, 311, 279, 3560, 315, 20622, 5237, 521, 19252, 13, 4452, 11, 27692, 21896, 430, 56459, 13238, 10160, 76327, 367, 323, 19748, 442, 60566, 590, 5536, 389, 356, 10827, 85322, 1501, 264, 6996, 315, 11388, 481, 5788, 315, 2660, 6251, 220, 15, 1174, 449, 1063, 63697, 63244, 6147, 320, 64, 6928, 2349, 304, 57077, 31332, 8, 323, 3885, 1529, 7623, 320, 4345, 279, 14329, 8, 220, 868, 1174, 220, 845, 1174, 220, 1114, 1174, 220, 972, 1174, 220, 777, 1174, 220, 508, 662, 14636, 11, 279, 13468, 2349, 315, 57077, 31332, 323, 44225, 7200, 304, 8881, 685, 63697, 315, 356, 10827, 85322, 7863, 449, 12782, 77140, 523, 2159, 24143, 42142, 3695, 374, 5107, 311, 14532, 220, 868, 1174, 220, 845, 1174, 220, 1114, 1174, 220, 972, 1174, 220, 777, 1174, 220, 508, 662, 622, 3027, 32, 753, 18276, 370, 31853, 17, 42640, 13468, 57077, 23851, 389, 55479, 26775, 30885, 220, 1691, 1174, 220, 1313, 1174, 220, 1419, 1174, 220, 1187, 3463, 311, 387, 5552, 311, 3634, 9282, 287, 13, 5751, 7978, 315, 26775, 30885, 10688, 3085, 279, 1176, 6776, 311, 6089, 2723, 279, 57077, 23851, 311, 279, 3634, 12, 15561, 287, 38973, 7106, 323, 11742, 73681, 315, 1239, 48218, 389, 356, 10827, 85322, 13, 18591, 28061, 29882, 1766, 389, 26775, 30885, 41936, 578, 25107, 16035, 315, 1455, 26775, 30885, 41936, 27313, 555, 320, 2445, 6073, 8, 18874, 17130, 92914, 374, 4528, 311, 430, 315, 21351, 523, 2159, 24143, 220, 914, 1174, 902, 527, 279, 1455, 8590, 2740, 28694, 7384, 304, 279, 25450, 744, 220, 1627, 1174, 13263, 449, 1023, 3293, 7978, 220, 1544, 1174, 220, 1591, 1174, 220, 1682, 1174, 220, 966, 1174, 220, 2148, 662, 15636, 11, 311, 3619, 279, 3634, 9282, 287, 315, 26775, 30885, 41936, 374, 311, 3619, 279, 9282, 287, 315, 279, 1455, 8590, 2740, 28694, 25450, 744, 3769, 13, 4497, 1109, 220, 2636, 41936, 320, 17645, 23899, 4056, 6028, 64012, 76, 8, 14890, 520, 279, 1176, 26079, 320, 49441, 8, 2816, 320, 17417, 16, 8, 323, 871, 3101, 41936, 320, 17645, 23899, 4056, 3226, 64012, 76, 8, 14890, 520, 279, 2132, 26079, 2816, 320, 17417, 17, 8, 1051, 27313, 369, 7479, 29882, 13893, 5552, 311, 3634, 9282, 287, 13, 67975, 8499, 7479, 29882, 315, 279, 1343, 4010, 2353, 321, 8630, 41947, 6303, 1051, 1766, 304, 4056, 21, 4, 315, 279, 13468, 41936, 505, 28816, 16, 323, 4056, 22, 4, 505, 28816, 17, 320, 54290, 2956, 23966, 13, 220, 16, 7609, 578, 7479, 29882, 315, 41936, 1782, 33452, 505, 1884, 505, 279, 17781, 323, 1102, 564, 14406, 1606, 279, 1455, 44611, 35530, 304, 26775, 30885, 41936, 527, 95831, 11071, 5554, 25858, 320, 110231, 2353, 321, 25858, 705, 539, 459, 8671, 67, 27620, 5554, 25858, 320, 2000, 3187, 11, 8492, 344, 483, 570, 26778, 12742, 7479, 29882, 527, 13468, 11, 2737, 11113, 13931, 11, 13091, 27520, 13931, 11, 30099, 12786, 14380, 323, 872, 28559, 320, 30035, 13, 220, 16, 323, 41665, 435, 14801, 13, 220, 17, 323, 220, 18, 7609, 1226, 1101, 25078, 2380, 2606, 318, 47987, 28935, 41936, 320, 32, 11030, 22, 11, 362, 13858, 19, 323, 362, 8504, 23, 8, 430, 617, 7479, 29882, 5552, 311, 3634, 9282, 287, 13, 23966, 13, 220, 16, 25, 44634, 17130, 5448, 315, 26775, 30885, 41936, 9204, 7479, 29882, 5552, 311, 3634, 9282, 287, 13, 264, 1174, 578, 24875, 356, 7755, 20, 4235, 14649, 23904, 410, 574, 14890, 520, 279, 2132, 26079, 2816, 13, 1102, 374, 24306, 315, 1403, 5596, 9204, 2204, 4595, 315, 3634, 9282, 287, 25, 264, 13091, 27520, 6324, 323, 264, 11113, 6324, 13, 2998, 27995, 291, 5448, 315, 279, 1403, 74764, 5789, 389, 420, 24875, 527, 6982, 304, 279, 99169, 520, 279, 8582, 1314, 320, 69, 299, 27520, 6324, 8, 323, 279, 4827, 2163, 320, 57966, 6324, 8, 24359, 315, 264, 662, 293, 1174, 578, 24875, 362, 7755, 19, 4235, 18642, 23587, 410, 574, 14890, 520, 279, 1176, 26079, 2816, 13, 578, 13091, 27520, 6324, 26310, 14861, 279, 11113, 6324, 389, 279, 2163, 25417, 3185, 315, 279, 2217, 13, 578, 19254, 1990, 1403, 4595, 315, 13931, 374, 16717, 555, 264, 67822, 16029, 13, 578, 13091, 27520, 6324, 706, 1690, 21165, 65635, 4440, 13, 362, 30099, 35732, 11, 7559, 520, 279, 4827, 12541, 315, 279, 2217, 11, 374, 12673, 311, 279, 7479, 315, 279, 13091, 27520, 6324, 13, 8922, 828, 8797, 1404, 2217, 51825, 13931, 389, 26775, 30885, 41936, 79904, 220, 20, 4, 315, 279, 13468, 41936, 505, 28816, 16, 323, 4056, 18, 4, 505, 28816, 17, 617, 264, 11113, 6324, 11, 30576, 439, 264, 15792, 23246, 1041, 26807, 8, 19815, 11113, 11071, 18702, 279, 7479, 13, 4427, 315, 1521, 13931, 6782, 348, 3380, 3742, 315, 366, 1135, 26807, 23899, 430, 32896, 279, 7479, 320, 30035, 13, 220, 17, 64, 323, 41665, 2956, 23966, 13, 220, 17, 64, 7609, 25570, 100177, 315, 279, 11113, 13931, 374, 13468, 304, 1063, 41936, 320, 54290, 2956, 23966, 13, 220, 19, 7609, 77976, 3722, 16597, 21667, 430, 11113, 13931, 527, 4661, 6724, 128257, 198, 128256, 78191, 198, 791, 549, 11606, 3238, 82, 5426, 6925, 331, 299, 35785, 12764, 11, 25328, 8828, 8922, 11, 574, 1511, 555, 264, 3544, 11, 6625, 20632, 311, 4007, 41936, 14890, 505, 264, 3221, 13737, 47601, 55479, 311, 4726, 1057, 8830, 315, 279, 15740, 315, 1057, 13238, 1887, 13, 59250, 505, 279, 3907, 315, 58849, 7263, 264, 12569, 315, 279, 26775, 30885, 55479, 311, 25328, 596, 33242, 454, 33936, 24310, 1074, 358, 975, 1405, 264, 3361, 15105, 2663, 1630, 30630, 22855, 66181, 31494, 10564, 27726, 299, 51856, 320, 55, 1111, 1600, 8, 574, 1511, 311, 2472, 704, 279, 11742, 5415, 315, 279, 5540, 2949, 279, 55479, 3769, 11, 311, 21635, 1202, 18528, 304, 7060, 7872, 13, 578, 2128, 1101, 20041, 279, 55479, 41936, 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85322, 1093, 26775, 30885, 13, 4758, 4529, 520, 469, 1721, 384, 5119, 1341, 315, 26775, 30885, 1446, 79, 27970, 323, 3926, 51180, 34072, 13, 16666, 25, 384, 5119, 1341, 14, 31272, 315, 58849, 13, 578, 12074, 11352, 430, 279, 7479, 315, 26775, 30885, 374, 409, 26233, 660, 323, 430, 433, 374, 4461, 430, 3634, 9282, 287, 374, 8647, 13, 578, 14955, 315, 279, 4007, 11, 4756, 3432, 304, 22037, 95803, 11, 617, 6197, 279, 12283, 311, 32194, 430, 85322, 430, 5101, 9235, 389, 279, 7479, 1253, 387, 3090, 41947, 11, 13893, 23537, 24493, 315, 1057, 8830, 315, 279, 23325, 3095, 315, 55479, 4595, 323, 279, 18488, 3925, 315, 279, 55479, 19671, 13, 26775, 30885, 374, 264, 3221, 13737, 47601, 55479, 11, 2212, 220, 7467, 20645, 304, 23899, 11, 1176, 11352, 304, 220, 2550, 24, 2949, 279, 55479, 19671, 1990, 21725, 323, 50789, 13, 1102, 374, 7086, 1306, 279, 1234, 37541, 44439, 315, 279, 16537, 4359, 304, 11002, 59492, 13, 763, 220, 679, 19, 11, 279, 11002, 1614, 3634, 9266, 622, 3027, 32, 11887, 18276, 370, 31853, 17, 11, 459, 55479, 6205, 81123, 9131, 11, 311, 66651, 58545, 449, 279, 26775, 30885, 55479, 323, 6667, 3769, 10688, 505, 1202, 7479, 323, 1207, 1355, 10730, 13, 578, 42640, 6052, 311, 9420, 304, 220, 2366, 15, 11, 28965, 264, 48739, 8649, 27498, 35603, 315, 279, 55479, 13, 4314, 2678, 10688, 1051, 4332, 311, 51048, 2212, 279, 1917, 369, 12624, 4007, 11, 2737, 279, 3907, 315, 58849, 596, 6150, 315, 28415, 612, 95803, 323, 11746, 5657, 1405, 3842, 77339, 11, 832, 315, 279, 12283, 389, 279, 5684, 11, 374, 264, 17054, 315, 9878, 16238, 10170, 13, 3842, 1071, 11, 330, 2028, 5016, 9131, 311, 9762, 10688, 505, 279, 1455, 28694, 11, 12782, 77140, 11, 4857, 10215, 315, 279, 13238, 1887, 3966, 279, 1917, 596, 1455, 11944, 92914, 11, 323, 430, 596, 3249, 622, 3027, 32, 323, 279, 31253, 2895, 2692, 50416, 16035, 2128, 4934, 603, 311, 24564, 10688, 520, 25328, 596, 1630, 30630, 76307, 33936, 24310, 1074, 13, 1226, 9087, 16805, 279, 7138, 315, 3634, 9282, 287, 389, 420, 55479, 449, 19748, 442, 60566, 635, 25949, 323, 279, 13238, 10160, 6968, 409, 26233, 660, 1446, 79, 27970, 34072, 11, 323, 459, 5938, 14278, 505, 36172, 1534, 3926, 18, 10, 311, 810, 11293, 3926, 17, 50020, 330, 2181, 596, 3062, 311, 1977, 709, 3217, 304, 21630, 10688, 6052, 505, 85322, 11, 439, 304, 279, 18276, 370, 31853, 17, 9131, 11, 1606, 5246, 1070, 690, 387, 502, 10688, 505, 1023, 55479, 4595, 11, 279, 17781, 323, 2949, 279, 1828, 220, 605, 1667, 21725, 11, 6052, 311, 9420, 13, 578, 549, 11606, 13, 4029, 690, 387, 3025, 311, 2804, 1063, 315, 279, 9200, 29060, 4245, 311, 1057, 13077, 520, 25328, 323, 279, 17130, 8162, 82025, 520, 384, 5119, 1341, 1210, 578, 4857, 10215, 315, 26775, 30885, 527, 73440, 315, 22639, 1990, 3090, 11, 34072, 323, 2942, 1233, 304, 279, 4216, 13238, 1887, 4972, 311, 279, 18488, 315, 9420, 13, 46551, 279, 18528, 315, 85322, 649, 1520, 10552, 1268, 279, 4216, 13238, 1887, 8040, 11, 323, 28520, 1268, 279, 9420, 14454, 13, 2435, 1253, 1524, 1520, 10552, 1268, 2324, 389, 9420, 3782, 922, 11, 449, 85322, 11846, 311, 617, 12886, 1790, 315, 279, 11841, 596, 3090, 439, 1664, 439, 17808, 32246, 1778, 439, 42500, 33969, 11, 902, 3493, 279, 16188, 4857, 10215, 505, 902, 682, 3823, 2324, 374, 20968, 13, 578, 2038, 430, 374, 1694, 95116, 291, 505, 1521, 13987, 55479, 10688, 690, 1520, 603, 311, 2731, 3619, 279, 6371, 539, 1193, 315, 279, 33975, 323, 9958, 719, 1101, 315, 2324, 5196, 13, 13440, 433, 596, 35603, 315, 85322, 11, 14154, 36692, 477, 9987, 17188, 14726, 11, 520, 279, 6925, 331, 299, 35785, 11, 14248, 649, 4007, 872, 10688, 1701, 264, 5780, 430, 374, 220, 605, 11, 931, 3115, 810, 8147, 1109, 264, 8776, 73757, 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 Extracellular deposition of amyloid-β as neuritic plaques and intracellular accumulation of hyperphosphorylated, aggregated tau as neurofibrillary tangles are two of the characteristic hallmarks of Alzheimer’s disease 1 , 2 . The regional progression of brain atrophy in Alzheimer’s disease highly correlates with tau accumulation but not amyloid deposition 3 , 4 , 5 , and the mechanisms of tau-mediated neurodegeneration remain elusive. Innate immune responses represent a common pathway for the initiation and progression of some neurodegenerative diseases. So far, little is known about the extent or role of the adaptive immune response and its interaction with the innate immune response in the presence of amyloid-β or tau pathology 6 . Here we systematically compared the immunological milieux in the brain of mice with amyloid deposition or tau aggregation and neurodegeneration. We found that mice with tauopathy but not those with amyloid deposition developed a unique innate and adaptive immune response and that depletion of microglia or T cells blocked tau-mediated neurodegeneration. Numbers of T cells, especially those of cytotoxic T cells, were markedly increased in areas with tau pathology in mice with tauopathy and in the Alzheimer’s disease brain. T cell numbers correlated with the extent of neuronal loss, and the cells dynamically transformed their cellular characteristics from activated to exhausted states along with unique TCR clonal expansion. Inhibition of interferon-γ and PDCD1 signalling both significantly ameliorated brain atrophy. Our results thus reveal a tauopathy- and neurodegeneration-related immune hub involving activated microglia and T cell responses, which could serve as therapeutic targets for preventing neurodegeneration in Alzheimer’s disease and primary tauopathies. Main To explore the disease microenvironment in the presence of amyloid-β or tau deposition, we systematically compared the immunological milieux in the brains of the amyloid-β-depositing mice APP/PS1-21 (A/PE4) and 5xFAD (5xE4) 7 , 8 , 9 , 10 , and tauopathy (TE4) mice 11 that express human APOE4 (E4). The pathologies in these models mirror amyloid deposition and tau aggregation with neurodegeneration, respectively 12 . We observed significant brain regional atrophy by 9.5 months but not at 6 months of age in TE4 mice (Fig. 1a ). In addition, brain atrophy was not present in A/PE4 or 5xE4 mice by 9.5 months of age despite high levels of amyloid-β deposition in the brain (Fig. 1a and Extended Data Fig. 1a ). The atrophy in the TE4 mice at 9.5 months primarily occurred in regions that developed the most tauopathy (that is, the hippocampus, piriform–entorhinal cortex and amygdala) and was accompanied by significant lateral ventricular enlargement (Fig. 1a–d and Extended Data Fig. 1b–d ). The thickness of the granule cell layer in the dentate gyrus as assessed by NeuN staining was noticeably decreased in TE4 mice, and the thickness correlated highly with hippocampal volume (Extended Data Fig. 1e–g ). Consistent with the neuronal loss, positive staining for myelin basic protein, which is present around intact axons, was altered in TE4 mice at 9.5 months (Extended Data Fig. 1h,i ). Both TE4 and TE3 (expressing human APOE3) mice developed prominent brain atrophy with greater atrophy in the TE4 mice (Extended Data Fig. 1j–l ). Additionally, male mice tended to have higher levels of brain atrophy than that of females (Extended Data Fig. 1m–o ). For further exploration of mechanisms of brain atrophy and neurodegeneration, we focused on male mice for the remainder of the experiments. Fig. 1: Immune scRNA-seq reveals increased proportion of T cells in the context of tau-mediated neurodegeneration. a , Representative images of 6-month-old E4 and TE4, and 9.5-month-old E4, TE4, A/PE4 and 5xE4 mouse brain sections stained with Sudan black. Scale bar, 1 mm. b – d , Volumes of hippocampus ( b ), piriform–entorhinal cortex (piri–ent ctx) ( c ) and posterior lateral ventricle ( d ) in 6-month-old E4 and TE4, and 9.5-month-old E4, TE4, A/PE4, 5xE4 and WT mice (6-month E4: n = 3; 6-month TE4: n = 7; 9.5-month E4: n = 15; 9.5-month TE4: n = 13; 9.5-month A/PE4: n = 7; 9.5-month 5xE4: n = 6; 9.5-month WT: n = 6). Data are mean ± s.e.m.; *** P < 0.0001 for 9.5-month TE4 versus A/PE4; TE4 versus 5xE4; TE4 versus E4; and TE4 versus WT (one-way analysis of variance (ANOVA) with Tukey’s post hoc test). e , Fluorescence-activated cell sorting of CD45 total and/or CD45 hi cells from brain parenchyma and meninges from E4, A/PE4 and TE4 mice for immune scRNA-seq. f , CD45 total immune cells from brain parenchyma assigned into 12 cell types as visualized by uniform manifold approximation and projection (UMAP) plots. DCs, dendritic cells; ILCs, innate lymphocyte cells. g , Bar plot showing the proportions of the 12 cell types of immune cells in the brain parenchyma. Data are mean ± s.e.m.; two biologically independent samples were used, and samples were sequenced in n = 2 batches from the E4 and TE4 groups. Prolif., proliferating. h , CD45 total immune cells from meninges assigned into 12 cell types as visualized by UMAP plots. i , Bar plot showing the proportions of the 12 cell types of immune cell in the meninges. Data are mean ± s.e.m.; two biologically independent samples were used, and samples were sequenced in n = 2 batches from the E4 and TE4 groups. Full size image Dysregulated innate and adaptive immune responses contribute to some neurodegenerative diseases 13 , 14 . Neuroinflammation is present in the brain of individuals with Alzheimer’s disease, and many studies focus on the cellular and molecular changes and the role of microglia, a key component of the innate immune response in the brain during the development and progression of Alzheimer’s disease 15 . Microglia are brain-resident cells, which may lead to a pro- or anti-inflammatory milieu within the brain together with monocytes, monocyte-derived macrophages and dendritic cells 16 , 17 , 18 . T cells and natural killer (NK) cells, if present, are more directly linked with cytotoxicity, and could potentially contribute to neuronal loss in a pro-inflammatory environment 19 , 20 , 21 ,", "role": "user" }, { "content": "Nearly two dozen experimental therapies targeting the immune system are in clinical trials for Alzheimer's disease, a reflection of the growing recognition that immune processes play a key role in driving the brain damage that leads to confusion, memory loss and other debilitating symptoms. Many of the immunity-focused Alzheimer's drugs under development are aimed at microglia, the brain's resident immune cells, which can injure brain tissue if they're activated at the wrong time or in the wrong way. A new study from researchers at Washington University School of Medicine in St. Louis indicates that microglia partner with another type of immune cell—T cells—to cause neurodegeneration. Studying mice with Alzheimer's-like damage in their brains due to the protein tau, the researchers discovered that microglia attract powerful cell-killing T cells into the brain, and that most of the neurodegeneration could be avoided by blocking the T cells' entry or activation. The findings, published March 8 in the journal Nature, suggest that targeting T cells is an alternative route to preventing neurodegeneration and treating Alzheimer's disease and related diseases involving tau, collectively known as tauopathies. \"This could really change the way we think about developing treatments for Alzheimer's disease and related conditions,\" said senior author David M. Holtzman, MD, the Barbara Burton and Reuben M. Morriss III Distinguished Professor of Neurology. \"Before this study, we knew that T cells were increased in the brains of people with Alzheimer's disease and other tauopathies, but we didn't know for sure that they caused neurodegeneration. These findings open up exciting new therapeutic approaches. Some widely used drugs target T cells.\" CD3 and IBA1 staining in hippocampus of TE4 mice. IBA1 (red) and CD3 (green) staining in 9.5-month-old TE4 mice with tau pathology in DG. Scale bar, 10 μm. Credit: Nature (2023). DOI: 10.1038/s41586-023-05788-0 \"Fingolomid, for example, is commonly used to treat multiple sclerosis, which is an autoimmune disease of the brain and spinal cord. It's likely that some drugs that act on T cells could be moved into clinical trials for Alzheimer's disease and other tauopathies if these drugs are protective in animal models.\" Alzheimer's develops in two main phases. First, plaques of the protein amyloid beta start to form. The plaques can build up for decades without obvious effects on brain health. But eventually, tau also begins to aggregate, signaling the start of the second phase. From there, the disease quickly worsens: The brain shrinks, nerve cells die, neurodegeneration spreads, and people start having difficulty thinking and remembering. Microglia and their role in Alzheimer's have been intensely studied. The cells become activated and dysfunctional as amyloid plaques build up, and even more so once tau begins to aggregate. Microglial dysfunction worsens neurodegeneration and accelerates the course of the disease. First author Xiaoying Chen, Ph.D., an instructor in neurology, wondered about the role of other, less studied immune cells in neurodegeneration. She analyzed immune cells in the brains of mice genetically engineered to mimic different aspects of Alzheimer's disease in people, looking for changes to the immune cell population that occur over the course of the disease. Mirroring the early phase of the disease in people, two of the mouse strains build up extensive amyloid deposits but do not develop brain atrophy. A third strain, representative of the later phase, develops tau tangles, brain atrophy, neurodegeneration and behavioral deficits by 9½ months of age. A fourth mouse strain does not develop amyloid plaques, tau tangles or cognitive impairments; it was studied for comparison. Along with Chen and Holtzman, the research team included Maxim N. Artyomov, Ph.D., the Alumni Endowed Professor of Pathology & Immunology, and Jason D. Ulrich, Ph.D., an associate professor of neurology, among others. The researchers found many more T cells in the brains of tau mice than the brains of amyloid or comparison mice. Notably, T cells were most plentiful in the parts of the brain with the most degeneration and the highest concentration of microglia. T cells were similarly abundant at sites of tau aggregation and neurodegeneration in the brains of people who had died with Alzheimer's disease. Additional mouse studies indicated that the two kinds of immune cells work together to create an inflammatory environment primed for neuronal damage. Microglia release molecular compounds that draw T cells into the brain from the blood and activate them; T cells release compounds that push microglia toward a more pro-inflammatory mode. Eliminating either microglia or T cells broke the toxic connection between the two and dramatically reduced damage to the brain. For example, when tau mice were given an antibody to deplete their T cells, they had fewer inflammatory microglia in their brains, less neurodegeneration and atrophy, and an improved ability to perform tasks such as building a nest and remembering recent things. \"What got me very excited was the fact that if you prevent T cells from getting into the brain, it blocks the majority of the neurodegeneration,\" Holtzman said. \"Scientists have put a lot of effort into finding therapies that prevent neurodegeneration by affecting tau or microglia. As a community, we haven't looked at what we can do to T cells to prevent neurodegeneration. This highlights a new area to better understand and therapeutically explore.\" ", "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 Extracellular deposition of amyloid-β as neuritic plaques and intracellular accumulation of hyperphosphorylated, aggregated tau as neurofibrillary tangles are two of the characteristic hallmarks of Alzheimer’s disease 1 , 2 . The regional progression of brain atrophy in Alzheimer’s disease highly correlates with tau accumulation but not amyloid deposition 3 , 4 , 5 , and the mechanisms of tau-mediated neurodegeneration remain elusive. Innate immune responses represent a common pathway for the initiation and progression of some neurodegenerative diseases. So far, little is known about the extent or role of the adaptive immune response and its interaction with the innate immune response in the presence of amyloid-β or tau pathology 6 . Here we systematically compared the immunological milieux in the brain of mice with amyloid deposition or tau aggregation and neurodegeneration. We found that mice with tauopathy but not those with amyloid deposition developed a unique innate and adaptive immune response and that depletion of microglia or T cells blocked tau-mediated neurodegeneration. Numbers of T cells, especially those of cytotoxic T cells, were markedly increased in areas with tau pathology in mice with tauopathy and in the Alzheimer’s disease brain. T cell numbers correlated with the extent of neuronal loss, and the cells dynamically transformed their cellular characteristics from activated to exhausted states along with unique TCR clonal expansion. Inhibition of interferon-γ and PDCD1 signalling both significantly ameliorated brain atrophy. Our results thus reveal a tauopathy- and neurodegeneration-related immune hub involving activated microglia and T cell responses, which could serve as therapeutic targets for preventing neurodegeneration in Alzheimer’s disease and primary tauopathies. Main To explore the disease microenvironment in the presence of amyloid-β or tau deposition, we systematically compared the immunological milieux in the brains of the amyloid-β-depositing mice APP/PS1-21 (A/PE4) and 5xFAD (5xE4) 7 , 8 , 9 , 10 , and tauopathy (TE4) mice 11 that express human APOE4 (E4). The pathologies in these models mirror amyloid deposition and tau aggregation with neurodegeneration, respectively 12 . We observed significant brain regional atrophy by 9.5 months but not at 6 months of age in TE4 mice (Fig. 1a ). In addition, brain atrophy was not present in A/PE4 or 5xE4 mice by 9.5 months of age despite high levels of amyloid-β deposition in the brain (Fig. 1a and Extended Data Fig. 1a ). The atrophy in the TE4 mice at 9.5 months primarily occurred in regions that developed the most tauopathy (that is, the hippocampus, piriform–entorhinal cortex and amygdala) and was accompanied by significant lateral ventricular enlargement (Fig. 1a–d and Extended Data Fig. 1b–d ). The thickness of the granule cell layer in the dentate gyrus as assessed by NeuN staining was noticeably decreased in TE4 mice, and the thickness correlated highly with hippocampal volume (Extended Data Fig. 1e–g ). Consistent with the neuronal loss, positive staining for myelin basic protein, which is present around intact axons, was altered in TE4 mice at 9.5 months (Extended Data Fig. 1h,i ). Both TE4 and TE3 (expressing human APOE3) mice developed prominent brain atrophy with greater atrophy in the TE4 mice (Extended Data Fig. 1j–l ). Additionally, male mice tended to have higher levels of brain atrophy than that of females (Extended Data Fig. 1m–o ). For further exploration of mechanisms of brain atrophy and neurodegeneration, we focused on male mice for the remainder of the experiments. Fig. 1: Immune scRNA-seq reveals increased proportion of T cells in the context of tau-mediated neurodegeneration. a , Representative images of 6-month-old E4 and TE4, and 9.5-month-old E4, TE4, A/PE4 and 5xE4 mouse brain sections stained with Sudan black. Scale bar, 1 mm. b – d , Volumes of hippocampus ( b ), piriform–entorhinal cortex (piri–ent ctx) ( c ) and posterior lateral ventricle ( d ) in 6-month-old E4 and TE4, and 9.5-month-old E4, TE4, A/PE4, 5xE4 and WT mice (6-month E4: n = 3; 6-month TE4: n = 7; 9.5-month E4: n = 15; 9.5-month TE4: n = 13; 9.5-month A/PE4: n = 7; 9.5-month 5xE4: n = 6; 9.5-month WT: n = 6). Data are mean ± s.e.m.; *** P < 0.0001 for 9.5-month TE4 versus A/PE4; TE4 versus 5xE4; TE4 versus E4; and TE4 versus WT (one-way analysis of variance (ANOVA) with Tukey’s post hoc test). e , Fluorescence-activated cell sorting of CD45 total and/or CD45 hi cells from brain parenchyma and meninges from E4, A/PE4 and TE4 mice for immune scRNA-seq. f , CD45 total immune cells from brain parenchyma assigned into 12 cell types as visualized by uniform manifold approximation and projection (UMAP) plots. DCs, dendritic cells; ILCs, innate lymphocyte cells. g , Bar plot showing the proportions of the 12 cell types of immune cells in the brain parenchyma. Data are mean ± s.e.m.; two biologically independent samples were used, and samples were sequenced in n = 2 batches from the E4 and TE4 groups. Prolif., proliferating. h , CD45 total immune cells from meninges assigned into 12 cell types as visualized by UMAP plots. i , Bar plot showing the proportions of the 12 cell types of immune cell in the meninges. Data are mean ± s.e.m.; two biologically independent samples were used, and samples were sequenced in n = 2 batches from the E4 and TE4 groups. Full size image Dysregulated innate and adaptive immune responses contribute to some neurodegenerative diseases 13 , 14 . Neuroinflammation is present in the brain of individuals with Alzheimer’s disease, and many studies focus on the cellular and molecular changes and the role of microglia, a key component of the innate immune response in the brain during the development and progression of Alzheimer’s disease 15 . Microglia are brain-resident cells, which may lead to a pro- or anti-inflammatory milieu within the brain together with monocytes, monocyte-derived macrophages and dendritic cells 16 , 17 , 18 . T cells and natural killer (NK) cells, if present, are more directly linked with cytotoxicity, and could potentially contribute to neuronal loss in a pro-inflammatory environment 19 , 20 , 21 ,<|im_end|> <|im_start|>assistant Nearly two dozen experimental therapies targeting the immune system are in clinical trials for Alzheimer's disease, a reflection of the growing recognition that immune processes play a key role in driving the brain damage that leads to confusion, memory loss and other debilitating symptoms. Many of the immunity-focused Alzheimer's drugs under development are aimed at microglia, the brain's resident immune cells, which can injure brain tissue if they're activated at the wrong time or in the wrong way. A new study from researchers at Washington University School of Medicine in St. Louis indicates that microglia partner with another type of immune cell—T cells—to cause neurodegeneration. Studying mice with Alzheimer's-like damage in their brains due to the protein tau, the researchers discovered that microglia attract powerful cell-killing T cells into the brain, and that most of the neurodegeneration could be avoided by blocking the T cells' entry or activation. The findings, published March 8 in the journal Nature, suggest that targeting T cells is an alternative route to preventing neurodegeneration and treating Alzheimer's disease and related diseases involving tau, collectively known as tauopathies. "This could really change the way we think about developing treatments for Alzheimer's disease and related conditions," said senior author David M. Holtzman, MD, the Barbara Burton and Reuben M. Morriss III Distinguished Professor of Neurology. "Before this study, we knew that T cells were increased in the brains of people with Alzheimer's disease and other tauopathies, but we didn't know for sure that they caused neurodegeneration. These findings open up exciting new therapeutic approaches. Some widely used drugs target T cells." CD3 and IBA1 staining in hippocampus of TE4 mice. IBA1 (red) and CD3 (green) staining in 9.5-month-old TE4 mice with tau pathology in DG. Scale bar, 10 μm. Credit: Nature (2023). DOI: 10.1038/s41586-023-05788-0 "Fingolomid, for example, is commonly used to treat multiple sclerosis, which is an autoimmune disease of the brain and spinal cord. It's likely that some drugs that act on T cells could be moved into clinical trials for Alzheimer's disease and other tauopathies if these drugs are protective in animal models." Alzheimer's develops in two main phases. First, plaques of the protein amyloid beta start to form. The plaques can build up for decades without obvious effects on brain health. But eventually, tau also begins to aggregate, signaling the start of the second phase. From there, the disease quickly worsens: The brain shrinks, nerve cells die, neurodegeneration spreads, and people start having difficulty thinking and remembering. Microglia and their role in Alzheimer's have been intensely studied. The cells become activated and dysfunctional as amyloid plaques build up, and even more so once tau begins to aggregate. Microglial dysfunction worsens neurodegeneration and accelerates the course of the disease. First author Xiaoying Chen, Ph.D., an instructor in neurology, wondered about the role of other, less studied immune cells in neurodegeneration. She analyzed immune cells in the brains of mice genetically engineered to mimic different aspects of Alzheimer's disease in people, looking for changes to the immune cell population that occur over the course of the disease. Mirroring the early phase of the disease in people, two of the mouse strains build up extensive amyloid deposits but do not develop brain atrophy. A third strain, representative of the later phase, develops tau tangles, brain atrophy, neurodegeneration and behavioral deficits by 9½ months of age. A fourth mouse strain does not develop amyloid plaques, tau tangles or cognitive impairments; it was studied for comparison. Along with Chen and Holtzman, the research team included Maxim N. Artyomov, Ph.D., the Alumni Endowed Professor of Pathology & Immunology, and Jason D. Ulrich, Ph.D., an associate professor of neurology, among others. The researchers found many more T cells in the brains of tau mice than the brains of amyloid or comparison mice. Notably, T cells were most plentiful in the parts of the brain with the most degeneration and the highest concentration of microglia. T cells were similarly abundant at sites of tau aggregation and neurodegeneration in the brains of people who had died with Alzheimer's disease. Additional mouse studies indicated that the two kinds of immune cells work together to create an inflammatory environment primed for neuronal damage. Microglia release molecular compounds that draw T cells into the brain from the blood and activate them; T cells release compounds that push microglia toward a more pro-inflammatory mode. Eliminating either microglia or T cells broke the toxic connection between the two and dramatically reduced damage to the brain. For example, when tau mice were given an antibody to deplete their T cells, they had fewer inflammatory microglia in their brains, less neurodegeneration and atrophy, and an improved ability to perform tasks such as building a nest and remembering recent things. "What got me very excited was the fact that if you prevent T cells from getting into the brain, it blocks the majority of the neurodegeneration," Holtzman said. "Scientists have put a lot of effort into finding therapies that prevent neurodegeneration by affecting tau or microglia. As a community, we haven't looked at what we can do to T cells to prevent neurodegeneration. This highlights a new area to better understand and therapeutically explore." <|im_end|>
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7917, 374, 459, 10778, 6149, 311, 27252, 18247, 451, 81157, 323, 27723, 44531, 596, 8624, 323, 5552, 19338, 16239, 32923, 11, 45925, 3967, 439, 32923, 36211, 552, 13, 330, 2028, 1436, 2216, 2349, 279, 1648, 584, 1781, 922, 11469, 22972, 369, 44531, 596, 8624, 323, 5552, 4787, 1359, 1071, 10195, 3229, 6941, 386, 13, 60006, 82016, 11, 14306, 11, 279, 32207, 54755, 323, 1050, 77067, 386, 13, 45957, 1056, 14767, 423, 80382, 17054, 315, 32359, 36781, 13, 330, 10438, 420, 4007, 11, 584, 7020, 430, 350, 7917, 1051, 7319, 304, 279, 35202, 315, 1274, 449, 44531, 596, 8624, 323, 1023, 32923, 36211, 552, 11, 719, 584, 3287, 956, 1440, 369, 2771, 430, 814, 9057, 18247, 451, 81157, 13, 4314, 14955, 1825, 709, 13548, 502, 37471, 20414, 13, 4427, 13882, 1511, 11217, 2218, 350, 7917, 1210, 11325, 18, 323, 358, 7209, 16, 88896, 304, 71206, 44651, 315, 18793, 19, 24548, 13, 358, 7209, 16, 320, 1171, 8, 323, 11325, 18, 320, 13553, 8, 88896, 304, 220, 24, 13, 20, 23086, 6418, 18793, 19, 24548, 449, 32923, 77041, 304, 51375, 13, 25635, 3703, 11, 220, 605, 33983, 76, 13, 16666, 25, 22037, 320, 2366, 18, 570, 59670, 25, 220, 605, 13, 6889, 23, 2754, 18136, 4218, 12, 20063, 12, 26866, 2421, 12, 15, 330, 37, 287, 337, 44119, 11, 369, 3187, 11, 374, 17037, 1511, 311, 4322, 5361, 91357, 11, 902, 374, 459, 88191, 8624, 315, 279, 8271, 323, 50112, 23125, 13, 1102, 596, 4461, 430, 1063, 11217, 430, 1180, 389, 350, 7917, 1436, 387, 7882, 1139, 14830, 19622, 369, 44531, 596, 8624, 323, 1023, 32923, 36211, 552, 422, 1521, 11217, 527, 29219, 304, 10065, 4211, 1210, 44531, 596, 39671, 304, 1403, 1925, 35530, 13, 5629, 11, 40852, 14295, 315, 279, 13128, 64383, 52196, 13746, 1212, 311, 1376, 13, 578, 40852, 14295, 649, 1977, 709, 369, 11026, 2085, 8196, 6372, 389, 8271, 2890, 13, 2030, 9778, 11, 32923, 1101, 12302, 311, 24069, 11, 43080, 279, 1212, 315, 279, 2132, 10474, 13, 5659, 1070, 11, 279, 8624, 6288, 47293, 729, 25, 578, 8271, 14362, 15872, 11, 32015, 7917, 2815, 11, 18247, 451, 81157, 43653, 11, 323, 1274, 1212, 3515, 17250, 7422, 323, 48384, 13, 18654, 6200, 689, 323, 872, 3560, 304, 44531, 596, 617, 1027, 70733, 20041, 13, 578, 7917, 3719, 22756, 323, 88804, 439, 64383, 52196, 40852, 14295, 1977, 709, 11, 323, 1524, 810, 779, 3131, 32923, 12302, 311, 24069, 13, 18654, 6200, 532, 32403, 47293, 729, 18247, 451, 81157, 323, 14511, 988, 279, 3388, 315, 279, 8624, 13, 5629, 3229, 41235, 2303, 287, 25507, 11, 2405, 920, 2637, 459, 33315, 304, 18247, 36781, 11, 31156, 922, 279, 3560, 315, 1023, 11, 2753, 20041, 22852, 7917, 304, 18247, 451, 81157, 13, 3005, 30239, 22852, 7917, 304, 279, 35202, 315, 24548, 52033, 46036, 311, 56459, 2204, 13878, 315, 44531, 596, 8624, 304, 1274, 11, 3411, 369, 4442, 311, 279, 22852, 2849, 7187, 430, 12446, 927, 279, 3388, 315, 279, 8624, 13, 14603, 90679, 279, 4216, 10474, 315, 279, 8624, 304, 1274, 11, 1403, 315, 279, 8814, 42400, 1977, 709, 16781, 64383, 52196, 34751, 719, 656, 539, 2274, 8271, 520, 58175, 13, 362, 4948, 26800, 11, 18740, 315, 279, 3010, 10474, 11, 39671, 32923, 259, 17694, 11, 8271, 520, 58175, 11, 18247, 451, 81157, 323, 36695, 57096, 555, 220, 24, 27154, 4038, 315, 4325, 13, 362, 11999, 8814, 26800, 1587, 539, 2274, 64383, 52196, 40852, 14295, 11, 32923, 259, 17694, 477, 25702, 38974, 1392, 26, 433, 574, 20041, 369, 12593, 13, 32944, 449, 25507, 323, 60006, 82016, 11, 279, 3495, 2128, 5343, 56625, 452, 13, 1676, 1919, 316, 869, 11, 2405, 920, 2637, 279, 76526, 4060, 13111, 17054, 315, 8092, 2508, 612, 67335, 2508, 11, 323, 18984, 423, 13, 16991, 14172, 11, 2405, 920, 2637, 459, 22712, 14561, 315, 18247, 36781, 11, 4315, 3885, 13, 578, 12074, 1766, 1690, 810, 350, 7917, 304, 279, 35202, 315, 32923, 24548, 1109, 279, 35202, 315, 64383, 52196, 477, 12593, 24548, 13, 2876, 2915, 11, 350, 7917, 1051, 1455, 81826, 304, 279, 5596, 315, 279, 8271, 449, 279, 1455, 5367, 17699, 323, 279, 8592, 20545, 315, 8162, 6200, 689, 13, 350, 7917, 1051, 30293, 44611, 520, 6732, 315, 32923, 52729, 323, 18247, 451, 81157, 304, 279, 35202, 315, 1274, 889, 1047, 8636, 449, 44531, 596, 8624, 13, 24086, 8814, 7978, 16717, 430, 279, 1403, 13124, 315, 22852, 7917, 990, 3871, 311, 1893, 459, 47288, 4676, 9036, 291, 369, 79402, 5674, 13, 18654, 6200, 689, 4984, 31206, 32246, 430, 4128, 350, 7917, 1139, 279, 8271, 505, 279, 6680, 323, 20891, 1124, 26, 350, 7917, 4984, 32246, 430, 4585, 8162, 6200, 689, 9017, 264, 810, 463, 67595, 3941, 13, 43420, 16252, 3060, 8162, 6200, 689, 477, 350, 7917, 14760, 279, 21503, 3717, 1990, 279, 1403, 323, 29057, 11293, 5674, 311, 279, 8271, 13, 1789, 3187, 11, 994, 32923, 24548, 1051, 2728, 459, 63052, 311, 409, 5282, 872, 350, 7917, 11, 814, 1047, 17162, 47288, 8162, 6200, 689, 304, 872, 35202, 11, 2753, 18247, 451, 81157, 323, 520, 58175, 11, 323, 459, 13241, 5845, 311, 2804, 9256, 1778, 439, 4857, 264, 23634, 323, 48384, 3293, 2574, 13, 330, 3923, 2751, 757, 1633, 12304, 574, 279, 2144, 430, 422, 499, 5471, 350, 7917, 505, 3794, 1139, 279, 8271, 11, 433, 10215, 279, 8857, 315, 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 Although the existence of coral-reef habitats at depths to 165 m in tropical regions has been known for decades, the richness, diversity, and ecological importance of mesophotic coral ecosystems (MCEs) has only recently become widely acknowledged. During an interdisciplinary effort spanning more than two decades, we characterized the most expansive MCEs ever recorded, with vast macroalgal communities and areas of 100% coral cover between depths of 50–90 m extending for tens of km 2 in the Hawaiian Archipelago. We used a variety of sensors and techniques to establish geophysical characteristics. Biodiversity patterns were established from visual and video observations and collected specimens obtained from submersible, remotely operated vehicles and mixed-gas SCUBA and rebreather dives. Population dynamics based on age, growth and fecundity estimates of selected fish species were obtained from laser-videogrammetry, specimens, and otolith preparations. Trophic dynamics were determined using carbon and nitrogen stable isotopic analyses on more than 750 reef fishes. MCEs are associated with clear water and suitable substrate. In comparison to shallow reefs in the Hawaiian Archipelago, inhabitants of MCEs have lower total diversity, harbor new and unique species, and have higher rates of endemism in fishes. Fish species present in shallow and mesophotic depths have similar population and trophic (except benthic invertivores) structures and high genetic connectivity with lower fecundity at mesophotic depths. MCEs in Hawai‘i are widespread but associated with specific geophysical characteristics. High genetic, ecological and trophic connectivity establish the potential for MCEs to serve as refugia for some species, but our results question the premise that MCEs are more resilient than shallow reefs. We found that endemism within MCEs increases with depth, and our results do not support suggestions of a global faunal break at 60 m. Our findings enhance the scientific foundations for conservation and management of MCEs, and provide a template for future interdisciplinary research on MCEs worldwide. Cite this as Pyle RL, Boland R, Bolick H, Bowen BW, Bradley CJ, Kane C, Kosaki RK, Langston R, Longenecker K, Montgomery A, Parrish FA, Popp BN, Rooney J, Smith CM, Wagner D, Spalding HL. 2016 . A comprehensive investigation of mesophotic coral ecosystems in the Hawaiian Archipelago . PeerJ 4 : e2475 Main article text Introduction Tropical coral reefs are compelling subjects for a wide range of scientific investigations because they provide an optimal combination of high diversity, extensive existing data, robust information infrastructure, large potential for the discovery of new taxa, and opportunities to gain new insights into fundamental ecological dynamics ( Reaka-Kudla, 1997 ). They are also among the most severely threatened ecosystems on Earth ( Pandolfi et al., 2003 ; Knowlton et al., 2010 ). It has become increasingly evident in recent years that anthropogenic impacts, such as overharvesting, pollution, coastal development, invasive species, ocean acidification, and global climate change, imperil the health of coral-reef ecosystems worldwide ( Bruno & Selig, 2007 ; Burke et al., 2011 ). Although the vast majority of known hermatypic coral reefs occur at depths of less than 40 m, there is longstanding evidence for photosynthetic corals and associated reef communities at greater depths. Zooxanthellate hermatypic corals have been found at 98 m in the tropical Atlantic ( Hartman, 1973 ; Fricke & Meischne, 1985 ; Reed, 1985 ), below 100 m in the Caribbean ( Locker et al., 2010 ; Bongaerts et al., 2015 ; Garcia-Sais et al., 2014 ; Smith et al., 2014 ), 112 m at Enewetak ( Colin et al., 1986 ), 125 m on the Great Barrier Reef ( Englebert et al., 2014 ), 145 m in the Red Sea ( Fricke & Schuhmacher, 1983 ), 153 m in Hawai‘i, and 165 m at Johnston Atoll ( Strasburg, Jones & Iversen, 1968 ; Maragos & Jokiel, 1985 ; Kahng & Maragos, 2006 ). Hopley (1991) reported 100% coral cover at 70 m on the Great Barrier Reef, and Jarrett et al. (2005) reported up to 60% coral cover at 60–75 m at Pulley Ridge in the Gulf of Mexico. Photosynthetic algae have been observed at similar or deeper depths ( Porter, 1973 ; Littler et al., 1985 ; Colin et al., 1986 ; Hills-Colinvaux, 1986 ), and fish species at such depths belong almost exclusively to families typical of shallower coral-reef environments ( Pyle, 1996b ; Pyle, 1999a ). Despite these scattered reports, coral-reef environments at depths greater than 30 m are poorly characterized, largely because of the logistical difficulties associated with accessing such depths ( Pyle, 1996c ; Pyle, 1998 ; Pyle, 1999b ; Pyle, 2000 ; Parrish & Pyle, 2001 ). There are potentially thousands of species that have yet to be discovered and scientifically described from deeper coral reef habitats ( Pyle, 1996d ; Pyle, 2000 ; Rowley, 2014 ) and the basic ecology and population dynamics of these communities, as well as their connectivity with shallow reefs, are just beginning to be explored. Most coral-reef monitoring programs are designed to target shallow reefs ( Jokiel et al., 2001 ; Brown et al., 2004 ; Preskitt, Vroom & Smith, 2004 ; Kenyon et al., 2006 ). In recent years, there has been a greater effort to document coral-reef ecosystems at depths of 30 to over 150 m, now referred to as “Mesophotic Coral Ecosystems” (MCEs) ( Hinderstein et al., 2010 ; Baker, Puglise & Harris, 2016 ). These research efforts have primarily focused on aspects of MCEs that are relevant to management policies, such as their distribution, ecology and biodiversity, as MCEs have been identified as a conservation priority ( Blyth-Skyrme et al., 2013 ; Sadovy de Mitcheson et al., 2013 ). However, despite the growing body of research targeting MCEs, they are often not included in reef assessment and monitoring programs, management-related reports on the status and health of coral reefs ( Brainard et al., 2003 ), or general overviews of coral-reef science ( Trenhaile, 1997 ). Most studies of coral-reef development (and the models derived from them) ( Dollar, 1982 ; Grigg, 1998 ; Braithwaite et al., 2000 ; Rooney et al., 2004", "role": "user" }, { "content": "A team of sixteen researchers has completed a comprehensive investigation of deep coral-reef environments, known as mesophotic coral ecosystems, throughout the Hawaiian Archipelago. The study, published in the open-access journal PeerJ, spanned more than two decades and involved a combination of submersibles, remotely operated vehicles, drop-cameras, data recorders, and advanced mixed-gas diving to study these difficult-to-reach environments. The researchers documented vast areas of 100% coral-cover and extensive algal communities at depths of 50-90 meters (165-300 feet) extending for tens of square kilometers, and found that the deep-reef habitats are home to many unique and distinct species not found on shallow reefs. The findings of the study have important implications for the protection and management of coral reefs in Hawaii and elsewhere. \"This is one of the largest and most comprehensive studies of its kind,\" said Richard Pyle, Bishop Museum researcher and lead author of the publication. \"It involved scientists in many different disciplines and from multiple federal, state, and private organizations working together with a range of different technologies across the entire Hawaiian Archipelago.\" The primary objective of the study was to characterize deep coral reef habitat, known as \"mesophotic coral ecosystems\" or the coral-reef \"Twilight Zone\". Coral reefs at depths of 30 to 150 meters (100 to 500 feet) are among the most poorly explored of all marine ecosystems on Earth. Deeper than conventional scuba divers can safely venture, and shallower than most submersible-based exploration, these reefs represent a new frontier for coral-reef research. To document these elusive deep coral reefs, the team used a wide range of advanced technology, including multibeam bathymetry mapping, mixed-gas closed-circuit rebreather diving, towed and remotely operated camera systems, a variety of environmental sensors for recording light, temperature, water movement and other parameters, and two research submersibles operated by the Hawai'i Undersea Research Laboratory. One of the novel approaches taken during the project was to combine rebreather divers and submersibles together on coordinated dives. \"Free-swimming divers and submersibles don't often work side-by-side on scientific research projects,\" said Pyle. \"Submersibles can go much deeper and stay much longer, but divers can perform more complex tasks to conduct experiments and collect specimens. Combining both together on the same dives allowed us to achieve tasks that could not have been performed by either technology alone.\" A major focus of the study was to document extensive areas of 100% coral cover at depths of 90 meters (300 feet) or more off the islands of Maui and Kaua'i. In particular, vast expanses of continuous coral cover, extending for tens of square kilometers, exist in many sites in the 'Au'au channel off the southwest side of Maui. The reefs are dominated by stony, reef-building corals in the genus Leptoseris, a plate-like coral specialized for deep-reef environments. \"These are some of the most extensive and densely populated coral reefs in Hawai'i,\" said Anthony Montgomery, a U.S. Fish and Wildlife biologist and co-author of the study who previously represented the Hawai'i State Department of Land and Natural Resources during most of the project. \"It's amazing to find such rich coral communities down so deep.\" In addition to the corals, the area is also home to extensive algae meadows that support unique communities of fishes and invertebrates. More than seventy species of macroalgae inhabiting the deep reefs were identified during the study, and several more new species have not yet been assigned formal scientific names. Both corals and algae depend on sunlight to drive photosynthesis, and the study attributed the existence of many of the deep reef habitats to exceptionally clear water. Macroalgae beds such as this Microdictyon setchellianum at a depth of 64 meters (210 feet) off Pearl and Hermes Atoll play a critical role in the ecology of deep coral-reef ecosystems. Nearly every fish in this image is a species endemic to the Hawaiian Islands. Credit: Greg McFall \"We found that the diversity of macroalgal species actually peaked at around 90 meters [300 feet] deep,\" said Heather Spalding of the Department of Botany at the University of Hawai'i at Mānoa and a co-author of the study. \"These extensive algae meadows represent a major component of the deep-reef communities, and play a fundamentally important role in the overall ecology.\" Another interesting finding of the study is that the rate of endemism - species found nowhere else on Earth - increases substantially on the deep reefs. Whereas only 17% of the fishes surveyed at depths less than 30 meters (100 meters) are species endemic to the Hawaiian Islands, more than half of the species below 70 meters (230 feet) are Hawaiian endemics. The rate of endemism increases even more in the Northwestern Hawaiian Islands, where 100% of the fishes inhabiting some of the deep reefs are found only in Hawai'i. \"The extent of fish endemism on these deep coral reefs, particularly in the Northwestern Hawaiian Islands, is astonishing,\" said Randall Kosaki, NOAA's Deputy Superintendent of the Papahānaumokuākea Marine National Monument and a co-author of the study. \"We were able to document the highest rates of endemism of any marine environment on Earth.\" The food web supporting the fishes on deep reefs was studied using advanced stable isotope methods, which revealed small but important differences in the ecology of fish living on deep and shallow reefs. \"We used these methods because more traditional approaches require large numbers of specimens,\" said Brian N. Popp, University of Hawai'i at Mānoa Professor of Geology and Geophysics in the School of Ocean and Earth Science and Technology. \"Our results are helping us better understand the relationship between the ecology of deep and shallow coral reef fish communities.\" The results of the study have important implications for conservation management. In addition to the rich and unique biodiversity inhabiting these environments, deep coral reefs may serve as a refuge for certain species that are more heavily impacted on shallow coral reefs. \"With coral reefs facing a myriad of threats,\" said Kimberly Puglise, an oceanographer with NOAA's National Centers for Coastal Ocean Science, \"the finding of extensive reefs off Maui provides managers with a unique opportunity to ensure that future activities in the region, such as cable laying, dredging dump sites, and deep sewer outfalls, do not irreparably damage these reefs.\" The research, which spanned more than two decades and encompassed the entire 2,590-kilometer (1,600-mile) extend of the Hawaiian Archipelago, was primarily supported by NOAA's National Centers for Coastal Ocean Science, Papahānaumokuākea Marine National Monument, Coral Reef Conservation Program, Office of Ocean Exploration and Research, and the Pacific Islands Fisheries Science Center, as well as, the Hawai'i Undersea Research Laboratory and the State of Hawai'i. ", "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 the existence of coral-reef habitats at depths to 165 m in tropical regions has been known for decades, the richness, diversity, and ecological importance of mesophotic coral ecosystems (MCEs) has only recently become widely acknowledged. During an interdisciplinary effort spanning more than two decades, we characterized the most expansive MCEs ever recorded, with vast macroalgal communities and areas of 100% coral cover between depths of 50–90 m extending for tens of km 2 in the Hawaiian Archipelago. We used a variety of sensors and techniques to establish geophysical characteristics. Biodiversity patterns were established from visual and video observations and collected specimens obtained from submersible, remotely operated vehicles and mixed-gas SCUBA and rebreather dives. Population dynamics based on age, growth and fecundity estimates of selected fish species were obtained from laser-videogrammetry, specimens, and otolith preparations. Trophic dynamics were determined using carbon and nitrogen stable isotopic analyses on more than 750 reef fishes. MCEs are associated with clear water and suitable substrate. In comparison to shallow reefs in the Hawaiian Archipelago, inhabitants of MCEs have lower total diversity, harbor new and unique species, and have higher rates of endemism in fishes. Fish species present in shallow and mesophotic depths have similar population and trophic (except benthic invertivores) structures and high genetic connectivity with lower fecundity at mesophotic depths. MCEs in Hawai‘i are widespread but associated with specific geophysical characteristics. High genetic, ecological and trophic connectivity establish the potential for MCEs to serve as refugia for some species, but our results question the premise that MCEs are more resilient than shallow reefs. We found that endemism within MCEs increases with depth, and our results do not support suggestions of a global faunal break at 60 m. Our findings enhance the scientific foundations for conservation and management of MCEs, and provide a template for future interdisciplinary research on MCEs worldwide. Cite this as Pyle RL, Boland R, Bolick H, Bowen BW, Bradley CJ, Kane C, Kosaki RK, Langston R, Longenecker K, Montgomery A, Parrish FA, Popp BN, Rooney J, Smith CM, Wagner D, Spalding HL. 2016 . A comprehensive investigation of mesophotic coral ecosystems in the Hawaiian Archipelago . PeerJ 4 : e2475 Main article text Introduction Tropical coral reefs are compelling subjects for a wide range of scientific investigations because they provide an optimal combination of high diversity, extensive existing data, robust information infrastructure, large potential for the discovery of new taxa, and opportunities to gain new insights into fundamental ecological dynamics ( Reaka-Kudla, 1997 ). They are also among the most severely threatened ecosystems on Earth ( Pandolfi et al., 2003 ; Knowlton et al., 2010 ). It has become increasingly evident in recent years that anthropogenic impacts, such as overharvesting, pollution, coastal development, invasive species, ocean acidification, and global climate change, imperil the health of coral-reef ecosystems worldwide ( Bruno & Selig, 2007 ; Burke et al., 2011 ). Although the vast majority of known hermatypic coral reefs occur at depths of less than 40 m, there is longstanding evidence for photosynthetic corals and associated reef communities at greater depths. Zooxanthellate hermatypic corals have been found at 98 m in the tropical Atlantic ( Hartman, 1973 ; Fricke & Meischne, 1985 ; Reed, 1985 ), below 100 m in the Caribbean ( Locker et al., 2010 ; Bongaerts et al., 2015 ; Garcia-Sais et al., 2014 ; Smith et al., 2014 ), 112 m at Enewetak ( Colin et al., 1986 ), 125 m on the Great Barrier Reef ( Englebert et al., 2014 ), 145 m in the Red Sea ( Fricke & Schuhmacher, 1983 ), 153 m in Hawai‘i, and 165 m at Johnston Atoll ( Strasburg, Jones & Iversen, 1968 ; Maragos & Jokiel, 1985 ; Kahng & Maragos, 2006 ). Hopley (1991) reported 100% coral cover at 70 m on the Great Barrier Reef, and Jarrett et al. (2005) reported up to 60% coral cover at 60–75 m at Pulley Ridge in the Gulf of Mexico. Photosynthetic algae have been observed at similar or deeper depths ( Porter, 1973 ; Littler et al., 1985 ; Colin et al., 1986 ; Hills-Colinvaux, 1986 ), and fish species at such depths belong almost exclusively to families typical of shallower coral-reef environments ( Pyle, 1996b ; Pyle, 1999a ). Despite these scattered reports, coral-reef environments at depths greater than 30 m are poorly characterized, largely because of the logistical difficulties associated with accessing such depths ( Pyle, 1996c ; Pyle, 1998 ; Pyle, 1999b ; Pyle, 2000 ; Parrish & Pyle, 2001 ). There are potentially thousands of species that have yet to be discovered and scientifically described from deeper coral reef habitats ( Pyle, 1996d ; Pyle, 2000 ; Rowley, 2014 ) and the basic ecology and population dynamics of these communities, as well as their connectivity with shallow reefs, are just beginning to be explored. Most coral-reef monitoring programs are designed to target shallow reefs ( Jokiel et al., 2001 ; Brown et al., 2004 ; Preskitt, Vroom & Smith, 2004 ; Kenyon et al., 2006 ). In recent years, there has been a greater effort to document coral-reef ecosystems at depths of 30 to over 150 m, now referred to as “Mesophotic Coral Ecosystems” (MCEs) ( Hinderstein et al., 2010 ; Baker, Puglise & Harris, 2016 ). These research efforts have primarily focused on aspects of MCEs that are relevant to management policies, such as their distribution, ecology and biodiversity, as MCEs have been identified as a conservation priority ( Blyth-Skyrme et al., 2013 ; Sadovy de Mitcheson et al., 2013 ). However, despite the growing body of research targeting MCEs, they are often not included in reef assessment and monitoring programs, management-related reports on the status and health of coral reefs ( Brainard et al., 2003 ), or general overviews of coral-reef science ( Trenhaile, 1997 ). Most studies of coral-reef development (and the models derived from them) ( Dollar, 1982 ; Grigg, 1998 ; Braithwaite et al., 2000 ; Rooney et al., 2004<|im_end|> <|im_start|>assistant A team of sixteen researchers has completed a comprehensive investigation of deep coral-reef environments, known as mesophotic coral ecosystems, throughout the Hawaiian Archipelago. The study, published in the open-access journal PeerJ, spanned more than two decades and involved a combination of submersibles, remotely operated vehicles, drop-cameras, data recorders, and advanced mixed-gas diving to study these difficult-to-reach environments. The researchers documented vast areas of 100% coral-cover and extensive algal communities at depths of 50-90 meters (165-300 feet) extending for tens of square kilometers, and found that the deep-reef habitats are home to many unique and distinct species not found on shallow reefs. The findings of the study have important implications for the protection and management of coral reefs in Hawaii and elsewhere. "This is one of the largest and most comprehensive studies of its kind," said Richard Pyle, Bishop Museum researcher and lead author of the publication. "It involved scientists in many different disciplines and from multiple federal, state, and private organizations working together with a range of different technologies across the entire Hawaiian Archipelago." The primary objective of the study was to characterize deep coral reef habitat, known as "mesophotic coral ecosystems" or the coral-reef "Twilight Zone". Coral reefs at depths of 30 to 150 meters (100 to 500 feet) are among the most poorly explored of all marine ecosystems on Earth. Deeper than conventional scuba divers can safely venture, and shallower than most submersible-based exploration, these reefs represent a new frontier for coral-reef research. To document these elusive deep coral reefs, the team used a wide range of advanced technology, including multibeam bathymetry mapping, mixed-gas closed-circuit rebreather diving, towed and remotely operated camera systems, a variety of environmental sensors for recording light, temperature, water movement and other parameters, and two research submersibles operated by the Hawai'i Undersea Research Laboratory. One of the novel approaches taken during the project was to combine rebreather divers and submersibles together on coordinated dives. "Free-swimming divers and submersibles don't often work side-by-side on scientific research projects," said Pyle. "Submersibles can go much deeper and stay much longer, but divers can perform more complex tasks to conduct experiments and collect specimens. Combining both together on the same dives allowed us to achieve tasks that could not have been performed by either technology alone." A major focus of the study was to document extensive areas of 100% coral cover at depths of 90 meters (300 feet) or more off the islands of Maui and Kaua'i. In particular, vast expanses of continuous coral cover, extending for tens of square kilometers, exist in many sites in the 'Au'au channel off the southwest side of Maui. The reefs are dominated by stony, reef-building corals in the genus Leptoseris, a plate-like coral specialized for deep-reef environments. "These are some of the most extensive and densely populated coral reefs in Hawai'i," said Anthony Montgomery, a U.S. Fish and Wildlife biologist and co-author of the study who previously represented the Hawai'i State Department of Land and Natural Resources during most of the project. "It's amazing to find such rich coral communities down so deep." In addition to the corals, the area is also home to extensive algae meadows that support unique communities of fishes and invertebrates. More than seventy species of macroalgae inhabiting the deep reefs were identified during the study, and several more new species have not yet been assigned formal scientific names. Both corals and algae depend on sunlight to drive photosynthesis, and the study attributed the existence of many of the deep reef habitats to exceptionally clear water. Macroalgae beds such as this Microdictyon setchellianum at a depth of 64 meters (210 feet) off Pearl and Hermes Atoll play a critical role in the ecology of deep coral-reef ecosystems. Nearly every fish in this image is a species endemic to the Hawaiian Islands. Credit: Greg McFall "We found that the diversity of macroalgal species actually peaked at around 90 meters [300 feet] deep," said Heather Spalding of the Department of Botany at the University of Hawai'i at Mānoa and a co-author of the study. "These extensive algae meadows represent a major component of the deep-reef communities, and play a fundamentally important role in the overall ecology." Another interesting finding of the study is that the rate of endemism - species found nowhere else on Earth - increases substantially on the deep reefs. Whereas only 17% of the fishes surveyed at depths less than 30 meters (100 meters) are species endemic to the Hawaiian Islands, more than half of the species below 70 meters (230 feet) are Hawaiian endemics. The rate of endemism increases even more in the Northwestern Hawaiian Islands, where 100% of the fishes inhabiting some of the deep reefs are found only in Hawai'i. "The extent of fish endemism on these deep coral reefs, particularly in the Northwestern Hawaiian Islands, is astonishing," said Randall Kosaki, NOAA's Deputy Superintendent of the Papahānaumokuākea Marine National Monument and a co-author of the study. "We were able to document the highest rates of endemism of any marine environment on Earth." The food web supporting the fishes on deep reefs was studied using advanced stable isotope methods, which revealed small but important differences in the ecology of fish living on deep and shallow reefs. "We used these methods because more traditional approaches require large numbers of specimens," said Brian N. Popp, University of Hawai'i at Mānoa Professor of Geology and Geophysics in the School of Ocean and Earth Science and Technology. "Our results are helping us better understand the relationship between the ecology of deep and shallow coral reef fish communities." The results of the study have important implications for conservation management. In addition to the rich and unique biodiversity inhabiting these environments, deep coral reefs may serve as a refuge for certain species that are more heavily impacted on shallow coral reefs. "With coral reefs facing a myriad of threats," said Kimberly Puglise, an oceanographer with NOAA's National Centers for Coastal Ocean Science, "the finding of extensive reefs off Maui provides managers with a unique opportunity to ensure that future activities in the region, such as cable laying, dredging dump sites, and deep sewer outfalls, do not irreparably damage these reefs." The research, which spanned more than two decades and encompassed the entire 2,590-kilometer (1,600-mile) extend of the Hawaiian Archipelago, was primarily supported by NOAA's National Centers for Coastal Ocean Science, Papahānaumokuākea Marine National Monument, Coral Reef Conservation Program, Office of Ocean Exploration and Research, and the Pacific Islands Fisheries Science Center, as well as, the Hawai'i Undersea Research Laboratory and the State of Hawai'i. <|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 Investigation of neural circuit dynamics is crucial for deciphering the functional connections among regions of the brain and understanding the mechanism of brain dysfunction. Despite the advancements of neural circuit models in vitro, technologies for both precisely monitoring and modulating neural activities within three-dimensional (3D) neural circuit models have yet to be developed. Specifically, no existing 3D microelectrode arrays (MEAs) have integrated capabilities to stimulate surrounding neurons and to monitor the temporal evolution of the formation of a neural network in real time. Herein, we present a 3D high-density multifunctional MEA with optical stimulation and drug delivery for investigating neural circuit dynamics within engineered 3D neural tissues. We demonstrate precise measurements of synaptic latencies in 3D neural networks. We expect our 3D multifunctional MEA to open up opportunities for studies of neural circuits through precise, in vitro investigations of neural circuit dynamics with 3D brain models. Introduction Neural circuit dynamics is known as spatiotemporally varying activity patterns of synaptically-wired neurons that become active or silent. The investigation of neural circuit dynamics is essential for deciphering the functional connectivities among the regions of the brain for identifying the mechanisms of circuit dysfunctions related to brain diseases. While microphysiological systems (MPS; tissues/organs-on-chips) have emerged as increasingly promising tools in vitro for augmenting drug developments and for elaborating physiological and pathological states of the body 1 , such efforts for the brain have focused on reconstructions of neural networks or circuits on chips. The needs of these models in vitro continue growing because the models become complementary to animal experiments and can accomplish what in vivo tests cannot. Recently, the developments of in vitro platforms have provided controllable environments for measuring inter-neuronal dynamics 2 . For example, the comparisons of neural dynamics between healthy and diseased model cells via two-dimensional (2D) cultures demonstrated the potential mechanisms associated with brain disorder-induced circuit dysfunctions 3 , 4 , 5 . However, 2D cell cultures, which are still used extensively, inherently cannot recapitulate the structure and functions of three-dimensional (3D) living tissues 6 . Especially for brain or neural tissues, a surge of interest in 3D cultures has occurred with the hope of developing both physiological and pathological models in vitro with the utilization of brain organoids, microphysiological systems (i.e., brain-on-chips), or 3D-printed, engineered tissues 7 , 8 , 9 , 10 , 11 . Specifically, the assembly of silk-based modular scaffolds seeded with cortical neurons allowed the building of multi-layered, 3D cortical tissue 12 . In addition, the directional alignment of the collagen microfibrils enabled the reconstruction of a functional hippocampal neural circuit in vitro at a 3D tissue scale 13 . Despite the emerging advancements of engineered 3D neural circuit models, technologies for both precisely monitoring and modulating neural activities within the neural circuit models in vitro have not been developed yet. Calcium imaging or planar extracellular electrophysiology with a 2D microelectrode array (MEA), which are the tools that are commonly used in 2D cultures of neurons in vitro, remain the mainstream methodologies for monitoring neural activities in 3D in vitro models 14 , 15 , 16 , 17 , 18 , 19 , 20 . A significant disadvantage of these measurement techniques is the difficulty of analyzing the neuronal connections and the dynamics of the neural network in a 3D microenvironment. Similarly, the investigation of neural circuits in vivo remains limited due to the nature of 3D connectivity 21 . As an excellent alternative, 3D MEAs have provided an opportunity to study neural networks in 3D brain models in vitro 22 , 23 . However, the 3D MEAs that have been reported to date have limitations in monitoring the neural circuit dynamics due to both low density 23 and the randomly arranged 22 recording sites. The previous 3D MEAs were also only capable of stimulating the surrounding neurons electrically; thus, stimulating specific cell types has been challenging 24 , 25 . However, the MEA with localized optical stimulation and drug delivery capabilities would help map functional connectivity in neural circuits in vitro by cell-type-specific stimulation and neurochemical modulation 26 . In addition, in 3D MEAs, the compact system is required to monitor the growth phases of developing neural networks in a temporally-resolved manner, for instance, by daily recordings 27 , 28 , 29 , 30 . This feature has been an advantage of the analyses of developing neuronal connections on a 2D MEA 27 , 28 , 29 , 30 , 31 , 32 that can be accommodated in an incubator. Therefore, an ideal 3D MEA that can be used to investigate the neural circuit dynamics in vitro must satisfy the following requirements: spatial coverage across the total volume of an engineered 3D in vitro model, design flexibility according to types and sizes of 3D in vitro models (e.g., engineered neural tissues, organoids), high spatial resolution to analyze the functional connectivity among neurons in 3D in vitro models, localized optical and chemical stimulation capabilities for accurate modulations, and compact integration for temporally-resolved measurements in an incubator. To address the challenges listed above, we present a 3D multifunctional MEA system integrated with a 3D high-density microelectrode array, a thin optical fiber coupled with a small light-emitting diode (LED) and microfluidic channels, both of which are embedded in a shank for precise modulation of neural networks, and a miniaturized incubating and recording system for daily recordings of the developing neural networks (Fig. 1 ). The high-density array of electrodes integrated on the multi-shank structure of the 3D MEA allows the dynamics of the neural network to be measured from a compartmentalized neural tissue. The thin optical fiber and microfluidic channels integrated on our 3D MEA enable precise investigation of the functional connectivity between different neuronal groups through locally optical stimulation and drug delivery. Due to its miniaturized packaging, the incubating and recording system provides a suitable environment for the investigation of temporal evolutions in the dynamics of developing neural networks. Consequently, our 3D multifunctional MEA offers pivotal functions for the precise analysis of 3D", "role": "user" }, { "content": "The human brain is less accessible than other organs because it is covered by a thick, hard skull. As a result, researchers have been limited to low-resolution imaging or analysis of brain signals measured outside the skull. This has proved to be a major hindrance in brain research, including research on developmental stages, causes of diseases, and their treatments. Recently, studies have been performed using primary neurons from rats or human-derived induced pluripotent stem cells (iPSCs) to create artificial brain models that have been applied to investigate brain developmental processes and the causes of brain diseases. These studies are expected to play a key role to unlocking the mysteries of the brain. In the past, artificial brain models were created and studied in 2D; however, in 2017, a research team from KIST developed a 3D artificial brain model that more closely resembled the real brain. Unfortunately, due to the absence of an analytical framework for studying signals in a 3D brain model, studies were limited to analyses of surface signals or had to reform the 3D structure to a flat shape. As such, tracking neural signals in a complex, interconnected artificial network remained a challenge. The Korea Institute of Science and Technology (KIST) announced that the research teams of Doctors Il-Joo Cho and Nakwon Choi have developed a analysis system that can apply precise non-destructive stimuli to a 3D artificial neural circuit and measure neural signals in real-time from multiple locations inside the model at the cellular level. The 3D multifunctional system for measuring neural signals is in the form of a 50μm-wide needel shaped silicon probe array (about half the width of a human hair) integrated with 63 microelectrodes. When this system is inserted in the artificial brain model, it is capable of simultaneously measuring signals from multiple locations inside the neural circuit. The probe contains an optical fiber and drug-delivery channels, enabling precise stimulation of neurons using light or drugs. By measuring functional changes in the brain model in response to these stimuli, the model can be used to study brain function and brain diseases. A researcher of KIST is looking at a three-dimensional multifunctional electrode chip developed by Dr. Il-Joo Cho and Dr. Nakwon Choi Credit: Korea Institute of Science and Technology(KIST) Using this system to stimulate neural circuits in the artificial brain model optically and simultaneously measure the spread of the response signal in multiple locations, the research team demonstrated that the propagation speed of neural signals were different according to directions inside the 3D brain modeln. In addition to structural brain maps, which can be constructed using electron microscopy, this study demonstrated the possibility of constructing 3D functional brain maps that show how different circuits are functionally connected within complex artificial brain networks. Dr. Choi, from KIST, stated that, \"The newly developed system allows us to study various developmental brain disorders and the causes of and treatments for brain diseases.\" Co-PI Dr. Cho added, \"This system enables functional measurements from 3D artificial brain models, which was previously impossible. We expect that the development of this system will help to radically reduce the time required to develop drug or treatments for various brain diseases.\" ", "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 Investigation of neural circuit dynamics is crucial for deciphering the functional connections among regions of the brain and understanding the mechanism of brain dysfunction. Despite the advancements of neural circuit models in vitro, technologies for both precisely monitoring and modulating neural activities within three-dimensional (3D) neural circuit models have yet to be developed. Specifically, no existing 3D microelectrode arrays (MEAs) have integrated capabilities to stimulate surrounding neurons and to monitor the temporal evolution of the formation of a neural network in real time. Herein, we present a 3D high-density multifunctional MEA with optical stimulation and drug delivery for investigating neural circuit dynamics within engineered 3D neural tissues. We demonstrate precise measurements of synaptic latencies in 3D neural networks. We expect our 3D multifunctional MEA to open up opportunities for studies of neural circuits through precise, in vitro investigations of neural circuit dynamics with 3D brain models. Introduction Neural circuit dynamics is known as spatiotemporally varying activity patterns of synaptically-wired neurons that become active or silent. The investigation of neural circuit dynamics is essential for deciphering the functional connectivities among the regions of the brain for identifying the mechanisms of circuit dysfunctions related to brain diseases. While microphysiological systems (MPS; tissues/organs-on-chips) have emerged as increasingly promising tools in vitro for augmenting drug developments and for elaborating physiological and pathological states of the body 1 , such efforts for the brain have focused on reconstructions of neural networks or circuits on chips. The needs of these models in vitro continue growing because the models become complementary to animal experiments and can accomplish what in vivo tests cannot. Recently, the developments of in vitro platforms have provided controllable environments for measuring inter-neuronal dynamics 2 . For example, the comparisons of neural dynamics between healthy and diseased model cells via two-dimensional (2D) cultures demonstrated the potential mechanisms associated with brain disorder-induced circuit dysfunctions 3 , 4 , 5 . However, 2D cell cultures, which are still used extensively, inherently cannot recapitulate the structure and functions of three-dimensional (3D) living tissues 6 . Especially for brain or neural tissues, a surge of interest in 3D cultures has occurred with the hope of developing both physiological and pathological models in vitro with the utilization of brain organoids, microphysiological systems (i.e., brain-on-chips), or 3D-printed, engineered tissues 7 , 8 , 9 , 10 , 11 . Specifically, the assembly of silk-based modular scaffolds seeded with cortical neurons allowed the building of multi-layered, 3D cortical tissue 12 . In addition, the directional alignment of the collagen microfibrils enabled the reconstruction of a functional hippocampal neural circuit in vitro at a 3D tissue scale 13 . Despite the emerging advancements of engineered 3D neural circuit models, technologies for both precisely monitoring and modulating neural activities within the neural circuit models in vitro have not been developed yet. Calcium imaging or planar extracellular electrophysiology with a 2D microelectrode array (MEA), which are the tools that are commonly used in 2D cultures of neurons in vitro, remain the mainstream methodologies for monitoring neural activities in 3D in vitro models 14 , 15 , 16 , 17 , 18 , 19 , 20 . A significant disadvantage of these measurement techniques is the difficulty of analyzing the neuronal connections and the dynamics of the neural network in a 3D microenvironment. Similarly, the investigation of neural circuits in vivo remains limited due to the nature of 3D connectivity 21 . As an excellent alternative, 3D MEAs have provided an opportunity to study neural networks in 3D brain models in vitro 22 , 23 . However, the 3D MEAs that have been reported to date have limitations in monitoring the neural circuit dynamics due to both low density 23 and the randomly arranged 22 recording sites. The previous 3D MEAs were also only capable of stimulating the surrounding neurons electrically; thus, stimulating specific cell types has been challenging 24 , 25 . However, the MEA with localized optical stimulation and drug delivery capabilities would help map functional connectivity in neural circuits in vitro by cell-type-specific stimulation and neurochemical modulation 26 . In addition, in 3D MEAs, the compact system is required to monitor the growth phases of developing neural networks in a temporally-resolved manner, for instance, by daily recordings 27 , 28 , 29 , 30 . This feature has been an advantage of the analyses of developing neuronal connections on a 2D MEA 27 , 28 , 29 , 30 , 31 , 32 that can be accommodated in an incubator. Therefore, an ideal 3D MEA that can be used to investigate the neural circuit dynamics in vitro must satisfy the following requirements: spatial coverage across the total volume of an engineered 3D in vitro model, design flexibility according to types and sizes of 3D in vitro models (e.g., engineered neural tissues, organoids), high spatial resolution to analyze the functional connectivity among neurons in 3D in vitro models, localized optical and chemical stimulation capabilities for accurate modulations, and compact integration for temporally-resolved measurements in an incubator. To address the challenges listed above, we present a 3D multifunctional MEA system integrated with a 3D high-density microelectrode array, a thin optical fiber coupled with a small light-emitting diode (LED) and microfluidic channels, both of which are embedded in a shank for precise modulation of neural networks, and a miniaturized incubating and recording system for daily recordings of the developing neural networks (Fig. 1 ). The high-density array of electrodes integrated on the multi-shank structure of the 3D MEA allows the dynamics of the neural network to be measured from a compartmentalized neural tissue. The thin optical fiber and microfluidic channels integrated on our 3D MEA enable precise investigation of the functional connectivity between different neuronal groups through locally optical stimulation and drug delivery. Due to its miniaturized packaging, the incubating and recording system provides a suitable environment for the investigation of temporal evolutions in the dynamics of developing neural networks. Consequently, our 3D multifunctional MEA offers pivotal functions for the precise analysis of 3D<|im_end|> <|im_start|>assistant The human brain is less accessible than other organs because it is covered by a thick, hard skull. As a result, researchers have been limited to low-resolution imaging or analysis of brain signals measured outside the skull. This has proved to be a major hindrance in brain research, including research on developmental stages, causes of diseases, and their treatments. Recently, studies have been performed using primary neurons from rats or human-derived induced pluripotent stem cells (iPSCs) to create artificial brain models that have been applied to investigate brain developmental processes and the causes of brain diseases. These studies are expected to play a key role to unlocking the mysteries of the brain. In the past, artificial brain models were created and studied in 2D; however, in 2017, a research team from KIST developed a 3D artificial brain model that more closely resembled the real brain. Unfortunately, due to the absence of an analytical framework for studying signals in a 3D brain model, studies were limited to analyses of surface signals or had to reform the 3D structure to a flat shape. As such, tracking neural signals in a complex, interconnected artificial network remained a challenge. The Korea Institute of Science and Technology (KIST) announced that the research teams of Doctors Il-Joo Cho and Nakwon Choi have developed a analysis system that can apply precise non-destructive stimuli to a 3D artificial neural circuit and measure neural signals in real-time from multiple locations inside the model at the cellular level. The 3D multifunctional system for measuring neural signals is in the form of a 50μm-wide needel shaped silicon probe array (about half the width of a human hair) integrated with 63 microelectrodes. When this system is inserted in the artificial brain model, it is capable of simultaneously measuring signals from multiple locations inside the neural circuit. The probe contains an optical fiber and drug-delivery channels, enabling precise stimulation of neurons using light or drugs. By measuring functional changes in the brain model in response to these stimuli, the model can be used to study brain function and brain diseases. A researcher of KIST is looking at a three-dimensional multifunctional electrode chip developed by Dr. Il-Joo Cho and Dr. Nakwon Choi Credit: Korea Institute of Science and Technology(KIST) Using this system to stimulate neural circuits in the artificial brain model optically and simultaneously measure the spread of the response signal in multiple locations, the research team demonstrated that the propagation speed of neural signals were different according to directions inside the 3D brain modeln. In addition to structural brain maps, which can be constructed using electron microscopy, this study demonstrated the possibility of constructing 3D functional brain maps that show how different circuits are functionally connected within complex artificial brain networks. Dr. Choi, from KIST, stated that, "The newly developed system allows us to study various developmental brain disorders and the causes of and treatments for brain diseases." Co-PI Dr. Cho added, "This system enables functional measurements from 3D artificial brain models, which was previously impossible. We expect that the development of this system will help to radically reduce the time required to develop drug or treatments for various brain diseases." <|im_end|>
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2,010
[ { "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 existence of massive (10 11 solar masses) elliptical galaxies by redshift z ≈ 4 (refs 1 , 2 , 3 ; when the Universe was 1.5 billion years old) necessitates the presence of galaxies with star-formation rates exceeding 100 solar masses per year at z > 6 (corresponding to an age of the Universe of less than 1 billion years). Surveys have discovered hundreds of galaxies at these early cosmic epochs, but their star-formation rates are more than an order of magnitude lower 4 . The only known galaxies with very high star-formation rates at z > 6 are, with one exception 5 , the host galaxies of quasars 6 , 7 , 8 , 9 , but these galaxies also host accreting supermassive (more than 10 9 solar masses) black holes, which probably affect the properties of the galaxies. Here we report observations of an emission line of singly ionized carbon ([C ii ] at a wavelength of 158 micrometres) in four galaxies at z > 6 that are companions of quasars, with velocity offsets of less than 600 kilometres per second and linear offsets of less than 100 kiloparsecs. The discovery of these four galaxies was serendipitous; they are close to their companion quasars and appear bright in the far-infrared. On the basis of the [C ii ] measurements, we estimate star-formation rates in the companions of more than 100 solar masses per year. These sources are similar to the host galaxies of the quasars in [C ii ] brightness, linewidth and implied dynamical mass, but do not show evidence for accreting supermassive black holes. Similar systems have previously been found at lower redshift 10 , 11 , 12 . We find such close companions in four out of the twenty-five z > 6 quasars surveyed, a fraction that needs to be accounted for in simulations 13 , 14 . If they are representative of the bright end of the [C ii ] luminosity function, then they can account for the population of massive elliptical galaxies at z ≈ 4 in terms of the density of cosmic space. Main We used the Atacama Large Millimeter Array (ALMA) to survey the fine-structure line of singly ionized carbon ([C ii ] at 158 μm) and its underlying continuum emission in high-redshift quasars in the southern sky (declination of less than 15°). The [C ii ] line, a strong coolant of the interstellar medium, is the brightest far-infrared emission line at these frequencies 9 , 15 , 16 . It arises ubiquitously in galaxies and is therefore an ideal tracer of gas morphology and dynamics in quasar hosts. The far-infrared continuum emission is associated with the light from young stars that has been reprocessed by dust and is therefore a measure of the dust mass and puts constraints on the star-formation rate of the host galaxies. The parent sample includes 35 luminous (rest-frame 1,450-Å absolute magnitude of less than −25.25 mag) quasars at z > 5.95 (for which the redshifted [C ii ] line would fall in ALMA band 6), most of which were selected from the Pan-STARRS1 survey 17 ; of these, 25 targets were observed with ALMA, all in single pointings with similar depth (0.6–0.9 mJy per beam per 30 km s −1 channel). The survey resulted in a very high detection rate (>90%) in both the continuum and the line emission from the host galaxies of the quasars. We searched the data cubes (in projected sky position and frequency or redshift) for additional sources in the quasar fields. The field of view of ALMA at these frequencies is about 25″, or 140 physical kiloparsecs at the mean redshift of the quasars (assuming a Lambda cold dark matter cosmology with Hubble constant H 0 = 70 km s −1 Mpc −1 , mass density Ω m = 0.3 and vacuum density Ω Λ = 0.7). The detection algorithm and strategy follows previous work with ALMA data 18 . We imposed a conservative significance threshold of 7 σ (corresponding to a [C ii ] luminosity of L [C ii ] ≈ 10 9 L ⊙ , where L ⊙ is the luminosity of the Sun), which excludes any contamination from noise peaks. This search resulted in the discovery of four bright line-emitting sources around four of the targeted quasars ( Fig. 1 ). The modest frequency differences with respect to the nearby quasars, the brightness of the lines compared to the underlying continua, and the lack of optical and near-infrared counterparts (which suggests that the companion sources reside at high redshift; see Fig. 1 ) imply that the detected lines are also [C ii ]. Furthermore, chance alignments of low-redshift CO emitters are expected to be more than 20 times rarer at these fluxes 18 . These newly detected galaxies are also seen (at various degrees of significance) in their dust continuum emission. The line and continuum fluxes are comparable to, and in some cases even brighter than, those of the quasars (see Table 1 ), although the companion sources are not detected in near-infrared images (which sample the rest-frame ultraviolet emission). Any potential accreting supermassive black holes in these companions would therefore be at least one order of magnitude fainter than the quasars, or strongly obscured (see Fig. 1 ). Figure 1: Images and spectra of the quasars and their companion galaxies discovered in this study. a , The dust continuum at 1.2 mm from ALMA is shown by red contours, which mark the ±2 σ , ±4 σ , ±6 σ , … isophotes, with σ = (81, 86, 65, 63) μJy per beam (left to right). The images were obtained with natural weighting, yielding beams of 1.20″ × 1.06″, 0.74″ × 0.63″, 1.24″ × 0.89″ and 0.85″ × 0.65″ (left to right), shown as black ellipses. The grey scale shows the near-infrared images of the Y- + J- (left) or J-band (otherwise) flux of the fields, obtained with (left to right) the WFC3 instrument on", "role": "user" }, { "content": "A team of astronomers including Carnegie's Eduardo Bañados and led by Roberto Decarli of the Max Planck Institute for Astronomy has discovered a new kind of galaxy which, although extremely old—formed less than a billion years after the Big Bang—creates stars more than a hundred times faster than our own Milky Way. Their findings are published by Nature. The team's discovery could help solve a cosmic puzzle—a mysterious population of surprisingly massive galaxies from when the universe was only about 10 percent of its current age. After first observing these galaxies a few years ago, astronomers proposed that they must have been created from hyper-productive precursor galaxies, which is the only way so many stars could have formed so quickly. But astronomers had never seen anything that fit the bill for these precursors until now. This newly discovered population could solve the mystery of how these extremely large galaxies came to have hundreds of billions of stars in them when they formed only 1.5 billion years after the Big Bang, requiring very rapid star formation. The team made this discovery by accident when investigating quasars, which are supermassive black holes that sit at the center of enormous galaxies, accreting matter. They were trying to study star formation in the galaxies that host these quasars. \"But what we found, in four separate cases, were neighboring galaxies that were forming stars at a furious pace, producing a hundred solar masses' worth of new stars per year,\" Decarli explained. \"Very likely it is not a coincidence to find these productive galaxies close to bright quasars. Quasars are thought to form in regions of the universe where the large-scale density of matter is much higher than average. Those same conditions should also be conducive to galaxies forming new stars at a greatly increased rate,\" added Fabian Walter, also of Max Planck. \"Whether or not the fast-growing galaxies we discovered are indeed precursors of the massive galaxies first seen a few years back will require more work to see how common they actually are,\" Bañados explained. Decarli's team already has follow-up investigations planned to explore this question. The team also found what appears to be the earliest known example of two galaxies undergoing a merger, which is another major mechanism of galaxy growth. The new observations provide the first direct evidence that such mergers have been taking place even at the earliest stages of galaxy evolution, less than a billion years after the Big Bang. ", "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 existence of massive (10 11 solar masses) elliptical galaxies by redshift z ≈ 4 (refs 1 , 2 , 3 ; when the Universe was 1.5 billion years old) necessitates the presence of galaxies with star-formation rates exceeding 100 solar masses per year at z > 6 (corresponding to an age of the Universe of less than 1 billion years). Surveys have discovered hundreds of galaxies at these early cosmic epochs, but their star-formation rates are more than an order of magnitude lower 4 . The only known galaxies with very high star-formation rates at z > 6 are, with one exception 5 , the host galaxies of quasars 6 , 7 , 8 , 9 , but these galaxies also host accreting supermassive (more than 10 9 solar masses) black holes, which probably affect the properties of the galaxies. Here we report observations of an emission line of singly ionized carbon ([C ii ] at a wavelength of 158 micrometres) in four galaxies at z > 6 that are companions of quasars, with velocity offsets of less than 600 kilometres per second and linear offsets of less than 100 kiloparsecs. The discovery of these four galaxies was serendipitous; they are close to their companion quasars and appear bright in the far-infrared. On the basis of the [C ii ] measurements, we estimate star-formation rates in the companions of more than 100 solar masses per year. These sources are similar to the host galaxies of the quasars in [C ii ] brightness, linewidth and implied dynamical mass, but do not show evidence for accreting supermassive black holes. Similar systems have previously been found at lower redshift 10 , 11 , 12 . We find such close companions in four out of the twenty-five z > 6 quasars surveyed, a fraction that needs to be accounted for in simulations 13 , 14 . If they are representative of the bright end of the [C ii ] luminosity function, then they can account for the population of massive elliptical galaxies at z ≈ 4 in terms of the density of cosmic space. Main We used the Atacama Large Millimeter Array (ALMA) to survey the fine-structure line of singly ionized carbon ([C ii ] at 158 μm) and its underlying continuum emission in high-redshift quasars in the southern sky (declination of less than 15°). The [C ii ] line, a strong coolant of the interstellar medium, is the brightest far-infrared emission line at these frequencies 9 , 15 , 16 . It arises ubiquitously in galaxies and is therefore an ideal tracer of gas morphology and dynamics in quasar hosts. The far-infrared continuum emission is associated with the light from young stars that has been reprocessed by dust and is therefore a measure of the dust mass and puts constraints on the star-formation rate of the host galaxies. The parent sample includes 35 luminous (rest-frame 1,450-Å absolute magnitude of less than −25.25 mag) quasars at z > 5.95 (for which the redshifted [C ii ] line would fall in ALMA band 6), most of which were selected from the Pan-STARRS1 survey 17 ; of these, 25 targets were observed with ALMA, all in single pointings with similar depth (0.6–0.9 mJy per beam per 30 km s −1 channel). The survey resulted in a very high detection rate (>90%) in both the continuum and the line emission from the host galaxies of the quasars. We searched the data cubes (in projected sky position and frequency or redshift) for additional sources in the quasar fields. The field of view of ALMA at these frequencies is about 25″, or 140 physical kiloparsecs at the mean redshift of the quasars (assuming a Lambda cold dark matter cosmology with Hubble constant H 0 = 70 km s −1 Mpc −1 , mass density Ω m = 0.3 and vacuum density Ω Λ = 0.7). The detection algorithm and strategy follows previous work with ALMA data 18 . We imposed a conservative significance threshold of 7 σ (corresponding to a [C ii ] luminosity of L [C ii ] ≈ 10 9 L ⊙ , where L ⊙ is the luminosity of the Sun), which excludes any contamination from noise peaks. This search resulted in the discovery of four bright line-emitting sources around four of the targeted quasars ( Fig. 1 ). The modest frequency differences with respect to the nearby quasars, the brightness of the lines compared to the underlying continua, and the lack of optical and near-infrared counterparts (which suggests that the companion sources reside at high redshift; see Fig. 1 ) imply that the detected lines are also [C ii ]. Furthermore, chance alignments of low-redshift CO emitters are expected to be more than 20 times rarer at these fluxes 18 . These newly detected galaxies are also seen (at various degrees of significance) in their dust continuum emission. The line and continuum fluxes are comparable to, and in some cases even brighter than, those of the quasars (see Table 1 ), although the companion sources are not detected in near-infrared images (which sample the rest-frame ultraviolet emission). Any potential accreting supermassive black holes in these companions would therefore be at least one order of magnitude fainter than the quasars, or strongly obscured (see Fig. 1 ). Figure 1: Images and spectra of the quasars and their companion galaxies discovered in this study. a , The dust continuum at 1.2 mm from ALMA is shown by red contours, which mark the ±2 σ , ±4 σ , ±6 σ , … isophotes, with σ = (81, 86, 65, 63) μJy per beam (left to right). The images were obtained with natural weighting, yielding beams of 1.20″ × 1.06″, 0.74″ × 0.63″, 1.24″ × 0.89″ and 0.85″ × 0.65″ (left to right), shown as black ellipses. The grey scale shows the near-infrared images of the Y- + J- (left) or J-band (otherwise) flux of the fields, obtained with (left to right) the WFC3 instrument on<|im_end|> <|im_start|>assistant A team of astronomers including Carnegie's Eduardo Bañados and led by Roberto Decarli of the Max Planck Institute for Astronomy has discovered a new kind of galaxy which, although extremely old—formed less than a billion years after the Big Bang—creates stars more than a hundred times faster than our own Milky Way. Their findings are published by Nature. The team's discovery could help solve a cosmic puzzle—a mysterious population of surprisingly massive galaxies from when the universe was only about 10 percent of its current age. After first observing these galaxies a few years ago, astronomers proposed that they must have been created from hyper-productive precursor galaxies, which is the only way so many stars could have formed so quickly. But astronomers had never seen anything that fit the bill for these precursors until now. This newly discovered population could solve the mystery of how these extremely large galaxies came to have hundreds of billions of stars in them when they formed only 1.5 billion years after the Big Bang, requiring very rapid star formation. The team made this discovery by accident when investigating quasars, which are supermassive black holes that sit at the center of enormous galaxies, accreting matter. They were trying to study star formation in the galaxies that host these quasars. "But what we found, in four separate cases, were neighboring galaxies that were forming stars at a furious pace, producing a hundred solar masses' worth of new stars per year," Decarli explained. "Very likely it is not a coincidence to find these productive galaxies close to bright quasars. Quasars are thought to form in regions of the universe where the large-scale density of matter is much higher than average. Those same conditions should also be conducive to galaxies forming new stars at a greatly increased rate," added Fabian Walter, also of Max Planck. "Whether or not the fast-growing galaxies we discovered are indeed precursors of the massive galaxies first seen a few years back will require more work to see how common they actually are," Bañados explained. Decarli's team already has follow-up investigations planned to explore this question. The team also found what appears to be the earliest known example of two galaxies undergoing a merger, which is another major mechanism of galaxy growth. The new observations provide the first direct evidence that such mergers have been taking place even at the earliest stages of galaxy evolution, less than a billion years after the Big Bang. <|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 Land use change could affect not only local species richness but also community assemblies. Essentially, the possible patterns of plant community assemblies are nonrandom species loss (nestedness) and species turnover. Plant community assemblies in human-mediated land use have a combination of both nestedness and turnover. This is because of historical effects that cause nonrandom species loss due to previous and/or original habitat quality and because of direct effects of human activities that cause species turnover. We investigated the complexity of the process of plant community assemblage in a paddy field, which is a typical agricultural land use in the monsoon season in central Japan. Using multi-temporal plant monitoring records, we tested the relationship between the ratio of species nestedness/turnover through multi-temporal and both the original habitat conditions and the extent of human modification. The findings revealed that paddy fields that originated from wetland habitat had a high nestedness ratio, whereas paddy fields that were largely consolidated had a high turnover ratio. Thus, we could divide the community assembly processes in human-mediated land use based on original habitat conditions and human activities. This concept could help land managers establish conservation and/or restoration plans that take into account community assembly. Introduction Human land use impacts global biodiversity at hierarchical levels, ranging from genes to ecosystems, resulting in many ecosystems having become severely degraded 1 . Many conservation scientists are focusing on the effects of land use as factors driving habitat degradation for biodiversity and ecosystem functions and are seeking tools to counteract their degradation and loss 2 , 3 , 4 . Although conservation research has focused typically on either individual species or species groups in terms of their diversity and/or richness 5 , 6 , the impact of human activities on community assemblies goes beyond just either eradicating some species from the species pool or reducing species richness 2 , 7 . Habitat degradation caused by land use could cause community and metacommunity structures to collapse by inhibiting the ecological processes of assemblies 2 , 7 . In essence, species loss and species turnover are the only processes required to generate all the possible patterns of community assembles 8 . Nestedness, namely, nonrandom species loss, describes the proportion of species in a species assembly that is a subset of a more species-rich assembly 2 , 9 . Nestedness is one of the most frequently used indices to explain patterns of community assemblages 2 , 10 . On the other hand, turnover can describe the proportion of species turnover in assembly processes 2 , 11 , 12 . Nestedness and turnover are antithetic (though not mutually exclusive) ecological processes that produce different patterns of community structure 8 , 13 , 14 . Plant communities in habitat that is maintained over the long-term, for example, historical seminatural grasslands, are characterized by high species diversity and show little turnover, indicating that high multi-temporal species nestedness has occurred 15 . Thus, habitat change resulting from human activities could lead to large turnover of species; in other words, it could result in low multi-temporal species nestedness. However, although human land use change could alter the components of plant communities dramatically and inhibit their recovery 4 , plant communities can occasionally retain their components following habitat degradation, for example, through either fragmentation or reduction in area 16 . This situation is often called “extinction debt,” whereby plant species can initially survive habitat change but may subsequently become extinct without habitat modification 17 . Current plant communities in human-mediated habitats will have been established by both nested species from the original community, including extinction debt, and by species turnover from sources external to the original communities and driven by human activities. Thus, there is a complex combination of nonrandom species loss and turnover for community assemblies within human-mediated land use. Wetlands are generally habitats with high biodiversity, and they are one of the habitats suffering the greatest decline worldwide 18 , 19 . Paddy fields are a typical seminatural land use for rice cropping agriculture in monsoon Asia, and they provide several ecosystem services other than rice production 20 , 21 , 22 . One of the important ecosystem services of paddy fields is provision of habitat for several wetland species 20 , 22 , 23 , 24 . In monsoon Asia, paddy fields originate mainly from the floodplain 24 , which is characterized by both spatial and temporal heterogeneity 25 . Floodplains provide substantial habitat variety for vegetation 26 , 27 . Thus, there is a variety of previous (original) habitat type/quality among current paddy fields as wetland habitat. Although paddy fields occupy the same land use category, individual paddy fields can have different types of plant communities with different assemblage processes that have been influenced both by their original habitats and by current human activities 4 , 24 . We studied the complexity of plant community assemblage processes in paddy fields, which can act as alternative wetland habitats. We predicted that the importance of nonrandom species loss and turnover for plant communities in paddy fields could be assessed on the basis of both their original environmental conditions and the current human activities associated with them. In respect of original environmental conditions, we predicted that paddy fields that have originated from wetland have plant communities with a nested structure based on wetland species, because that type of paddy field is considered to be same as wetland habitat that has been maintained over the long-term. Meanwhile, paddy fields that have originated from non-wetland areas have plant communities that have undergone a relatively large species turnover from the original assemblage because that type of paddy field is considered to be habitat that has been changed from non-wetland to wetland. We used terrain condition which could indicate the surface water storage to find the original wetland potential. In respect of the current human activities, we predicted that agricultural modernization practices, land consolidation in particular, increase the species turnover because of their drastic habitat modification effects 4 , 28 .", "role": "user" }, { "content": "Researchers from Tokyo Metropolitan University studied the biodiversity of wetland plants over time in rice paddies in the Tone River basin, Japan. They found that paddies that were more likely to have been wetland previously retained more wetland plant species. On the other hand, land consolidation and agricultural abandonment were both found to impact biodiversity negatively. Their findings may one day inform conservation efforts and promote sustainable agriculture. The Asian monsoon region is home to a vast number of rice paddies. Not only have they fed its billions of inhabitants for centuries, they are also an important part of the ecosystem, home to a vast array of wetland plant species. But as the population grows and more agricultural land is required, their sheer scale and complexity beg an important question: What is their environmental impact? A team from Tokyo Metropolitan University led by Associate Professor Takeshi Osawa and their collaborators have been studying how rice paddies affect local plant life. In their most recent work, they investigated the biodiversity of wetland plants in rice paddies around the Tone River basin Japan. The Tone River is Japan's second longest river, and runs through the 170,000 square kilometer expanse of the Kanto plains. Previous studies have looked at how a particular species or group of species fare in different conditions. Instead, the team turned their attention to the range of species that make up the plant community, with a particular focus on the number of wetland and non-wetland species present. Changes were tracked over time using extensive survey data from 2002, 2007 and 2012. They found that not all rice paddies are equal when it comes to how well they support original wetland species. In fact, there was a correlation between how likely it was that the land was wetland before it was put to agricultural use, and the number of wetland species that were retained over time. Here, the team measured this using flow accumulation values (FAVs) for different plots of land, a simple metric showing how easily water could accumulate. Importantly, this kind of approach might help researchers to predict how amenable new rice paddies are to the local wetland flora by calculating a simple number using the local terrain. However, they also found that things like land consolidation and agricultural abandonment could also have a negative impact. The emerging story is that both current human use and original geographical conditions play an important role in deciding how amenable rice paddies are for the original wetland ecosystem. The team believes that the same approach could be applied to different locations such as plantation forests which were (or were not) originally woodland. After all, many nations are turning to large scale tree planting to offset carbon emissions. The ability to systematically assign how new land usage might impact local ecosystems could greatly help restoration and conversation efforts. ", "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 Land use change could affect not only local species richness but also community assemblies. Essentially, the possible patterns of plant community assemblies are nonrandom species loss (nestedness) and species turnover. Plant community assemblies in human-mediated land use have a combination of both nestedness and turnover. This is because of historical effects that cause nonrandom species loss due to previous and/or original habitat quality and because of direct effects of human activities that cause species turnover. We investigated the complexity of the process of plant community assemblage in a paddy field, which is a typical agricultural land use in the monsoon season in central Japan. Using multi-temporal plant monitoring records, we tested the relationship between the ratio of species nestedness/turnover through multi-temporal and both the original habitat conditions and the extent of human modification. The findings revealed that paddy fields that originated from wetland habitat had a high nestedness ratio, whereas paddy fields that were largely consolidated had a high turnover ratio. Thus, we could divide the community assembly processes in human-mediated land use based on original habitat conditions and human activities. This concept could help land managers establish conservation and/or restoration plans that take into account community assembly. Introduction Human land use impacts global biodiversity at hierarchical levels, ranging from genes to ecosystems, resulting in many ecosystems having become severely degraded 1 . Many conservation scientists are focusing on the effects of land use as factors driving habitat degradation for biodiversity and ecosystem functions and are seeking tools to counteract their degradation and loss 2 , 3 , 4 . Although conservation research has focused typically on either individual species or species groups in terms of their diversity and/or richness 5 , 6 , the impact of human activities on community assemblies goes beyond just either eradicating some species from the species pool or reducing species richness 2 , 7 . Habitat degradation caused by land use could cause community and metacommunity structures to collapse by inhibiting the ecological processes of assemblies 2 , 7 . In essence, species loss and species turnover are the only processes required to generate all the possible patterns of community assembles 8 . Nestedness, namely, nonrandom species loss, describes the proportion of species in a species assembly that is a subset of a more species-rich assembly 2 , 9 . Nestedness is one of the most frequently used indices to explain patterns of community assemblages 2 , 10 . On the other hand, turnover can describe the proportion of species turnover in assembly processes 2 , 11 , 12 . Nestedness and turnover are antithetic (though not mutually exclusive) ecological processes that produce different patterns of community structure 8 , 13 , 14 . Plant communities in habitat that is maintained over the long-term, for example, historical seminatural grasslands, are characterized by high species diversity and show little turnover, indicating that high multi-temporal species nestedness has occurred 15 . Thus, habitat change resulting from human activities could lead to large turnover of species; in other words, it could result in low multi-temporal species nestedness. However, although human land use change could alter the components of plant communities dramatically and inhibit their recovery 4 , plant communities can occasionally retain their components following habitat degradation, for example, through either fragmentation or reduction in area 16 . This situation is often called “extinction debt,” whereby plant species can initially survive habitat change but may subsequently become extinct without habitat modification 17 . Current plant communities in human-mediated habitats will have been established by both nested species from the original community, including extinction debt, and by species turnover from sources external to the original communities and driven by human activities. Thus, there is a complex combination of nonrandom species loss and turnover for community assemblies within human-mediated land use. Wetlands are generally habitats with high biodiversity, and they are one of the habitats suffering the greatest decline worldwide 18 , 19 . Paddy fields are a typical seminatural land use for rice cropping agriculture in monsoon Asia, and they provide several ecosystem services other than rice production 20 , 21 , 22 . One of the important ecosystem services of paddy fields is provision of habitat for several wetland species 20 , 22 , 23 , 24 . In monsoon Asia, paddy fields originate mainly from the floodplain 24 , which is characterized by both spatial and temporal heterogeneity 25 . Floodplains provide substantial habitat variety for vegetation 26 , 27 . Thus, there is a variety of previous (original) habitat type/quality among current paddy fields as wetland habitat. Although paddy fields occupy the same land use category, individual paddy fields can have different types of plant communities with different assemblage processes that have been influenced both by their original habitats and by current human activities 4 , 24 . We studied the complexity of plant community assemblage processes in paddy fields, which can act as alternative wetland habitats. We predicted that the importance of nonrandom species loss and turnover for plant communities in paddy fields could be assessed on the basis of both their original environmental conditions and the current human activities associated with them. In respect of original environmental conditions, we predicted that paddy fields that have originated from wetland have plant communities with a nested structure based on wetland species, because that type of paddy field is considered to be same as wetland habitat that has been maintained over the long-term. Meanwhile, paddy fields that have originated from non-wetland areas have plant communities that have undergone a relatively large species turnover from the original assemblage because that type of paddy field is considered to be habitat that has been changed from non-wetland to wetland. We used terrain condition which could indicate the surface water storage to find the original wetland potential. In respect of the current human activities, we predicted that agricultural modernization practices, land consolidation in particular, increase the species turnover because of their drastic habitat modification effects 4 , 28 .<|im_end|> <|im_start|>assistant Researchers from Tokyo Metropolitan University studied the biodiversity of wetland plants over time in rice paddies in the Tone River basin, Japan. They found that paddies that were more likely to have been wetland previously retained more wetland plant species. On the other hand, land consolidation and agricultural abandonment were both found to impact biodiversity negatively. Their findings may one day inform conservation efforts and promote sustainable agriculture. The Asian monsoon region is home to a vast number of rice paddies. Not only have they fed its billions of inhabitants for centuries, they are also an important part of the ecosystem, home to a vast array of wetland plant species. But as the population grows and more agricultural land is required, their sheer scale and complexity beg an important question: What is their environmental impact? A team from Tokyo Metropolitan University led by Associate Professor Takeshi Osawa and their collaborators have been studying how rice paddies affect local plant life. In their most recent work, they investigated the biodiversity of wetland plants in rice paddies around the Tone River basin Japan. The Tone River is Japan's second longest river, and runs through the 170,000 square kilometer expanse of the Kanto plains. Previous studies have looked at how a particular species or group of species fare in different conditions. Instead, the team turned their attention to the range of species that make up the plant community, with a particular focus on the number of wetland and non-wetland species present. Changes were tracked over time using extensive survey data from 2002, 2007 and 2012. They found that not all rice paddies are equal when it comes to how well they support original wetland species. In fact, there was a correlation between how likely it was that the land was wetland before it was put to agricultural use, and the number of wetland species that were retained over time. Here, the team measured this using flow accumulation values (FAVs) for different plots of land, a simple metric showing how easily water could accumulate. Importantly, this kind of approach might help researchers to predict how amenable new rice paddies are to the local wetland flora by calculating a simple number using the local terrain. However, they also found that things like land consolidation and agricultural abandonment could also have a negative impact. The emerging story is that both current human use and original geographical conditions play an important role in deciding how amenable rice paddies are for the original wetland ecosystem. The team believes that the same approach could be applied to different locations such as plantation forests which were (or were not) originally woodland. After all, many nations are turning to large scale tree planting to offset carbon emissions. The ability to systematically assign how new land usage might impact local ecosystems could greatly help restoration and conversation efforts. <|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 a firm prediction of the concordance cold-dark-matter cosmological model that galaxy clusters occur at the intersection of large-scale structure filaments 1 . The thread-like structure of this ‘cosmic web’ has been traced by galaxy redshift surveys for decades 2 , 3 . More recently, the warm–hot intergalactic medium (a sparse plasma with temperatures of 10 5 kelvin to 10 7 kelvin) residing in low-redshift filaments has been observed in emission 4 and absorption 5 , 6 . However, a reliable direct detection of the underlying dark-matter skeleton, which should contain more than half of all matter 7 , has remained elusive, because earlier candidates for such detections 8 , 9 , 10 were either falsified 11 , 12 or suffered from low signal-to-noise ratios 8 , 10 and unphysical misalignments of dark and luminous matter 9 , 10 . Here we report the detection of a dark-matter filament connecting the two main components of the Abell 222/223 supercluster system from its weak gravitational lensing signal, both in a non-parametric mass reconstruction and in parametric model fits. This filament is coincident with an overdensity of galaxies 10 , 13 and diffuse, soft-X-ray emission 4 , and contributes a mass comparable to that of an additional galaxy cluster to the total mass of the supercluster. By combining this result with X-ray observations 4 , we can place an upper limit of 0.09 on the hot gas fraction (the mass of X-ray-emitting gas divided by the total mass) in the filament. Main Abell 222 and Abell 223, the latter a double galaxy cluster in itself, form a supercluster system of three galaxy clusters at a redshift of z ≈ 0.21 (ref. 13 ), separated on the sky by about 14′. Gravitational lensing distorts the images of faint background galaxies as their light passes massive foreground structures. The foreground mass and its distribution can be deduced from measuring the shear field imprinted on the shapes of the background galaxies. Additional information on this process is given in the Supplementary Information . The mass reconstruction in Fig. 1 shows a mass bridge connecting Abell 222 and the southern component of Abell 223 (Abell 223-S) at the 4.1 σ significance level. This mass reconstruction does not assume any model or physical prior probability distribution on the mass distribution. Figure 1: Mass reconstruction of Abell 222/223. The background image is a three-colour-composite SuprimeCam image based on observations with the 8.2-m Subaru telescope on Mauna Kea, Hawaii during the nights of 15 October 2001 (Abell 222) and 20 October 2001 (Abell 223) in the V-, R c - and i′-bands. We obtained the data from the SMOKA science archive ( ). The full-width at half-maximum (FWHM) of the stellar point-spread function varies between 0.57″ and 0.70″ in our final co-added images. Overlaid are the reconstructed surface mass density (blue) above κ = 0.0077, corresponding to , and significance contours above the mean of the field edge, rising in steps of 0.5 σ and starting from 2.5 σ . Dashed contours mark underdense regions at the same significance levels. Supplementary Fig. 1 shows the corresponding B-mode map. The reconstruction is based on 40,341 galaxies whose colours are not consistent with early-type galaxies at the cluster redshift. The shear field was smoothed with a 2′ Gaussian. The significance was assessed from the variance of 800 mass maps created from catalogues with randomized background galaxy orientation. We measured the shapes of these galaxies primarily in the R c -band, supplementing the galaxy shape catalogue with measurements from the other two bands for galaxies for which no shapes could be measured in the R c -band, to estimate the gravitational shear 25 , 26 . Abell 222 is detected at about 8.0 σ in the south, and Abell 223 is the double-peaked structure in the north seen at about 7 σ . Black rectangles are regions on the sky not covered by the camera. PowerPoint slide Full size image To show that the mass bridge extending between Abell 222 and Abell 223 is not caused by the overlap of the cluster halos but is in fact due to additional mass, we also fitted parametric models to the three clusters plus a filament component. The clusters were modelled as elliptical Navarro–Frenk–White (NFW) profiles 14 with a fixed mass–concentration relation 15 . We used a simple model for the filament, with a flat ridge line connecting the clusters, exponential cut-offs at the filament endpoints in the clusters, and a King profile 16 describing the radial density distribution, as suggested by previous studies 17 , 18 . We show in the Supplementary Information that the exact ellipticity has little impact on the significance of the filament. The best-fit parameters of this model were determined using a Monte Carlo Markov chain and are shown in Fig. 2 . The likelihood-ratio test prefers models with a filament component with 96.0% confidence over a fit with three NFW halos only. A small degeneracy exists in the model between the strength of the filament and the virial radii of Abell 222 and Abell 223-S. The fitting procedure tries to keep the total amount of mass in the supercluster system constant at the level indicated by the observed reduced shear. Thus, it is not necessarily the case that sample points with a positive filament contribution indeed have more mass in the filament area than has a three-clusters-only model. This is because the additional filament mass might be compensated for with lower cluster masses. We find that the integrated surface mass density along the filament ridge line exceeds that of the clusters-only model in 98.5% of all sample points. Figure 2: Posterior probability distributions for cluster virial radii and filament strength. Shown are the 68% and 95% confidence intervals on the cluster virial radii r 200 (within which the mean density of the clusters is 200 times the critical density of the Universe) and the filament strength κ 0 . The confidence intervals are derived from 30,000 Monte", "role": "user" }, { "content": "(Phys.org) -- As time passes and more research is done, more evidence is compiled supporting the theory that suggests that dark matter is a real thing, even though no direct evidence for its existence has ever been found. Instead, the evidence comes about as measurements of other phenomenon are taken, generally involving gravitational pull on objects in the universe we can see that cannot be explained by other means. One of these instances is where weak gravitational lensing occurs, which is where light appears to bend as it passes by large objects. Theory suggests that in cases where lensing occurs but there is no detectable object behind its cause, the reason for it is dark matter exerting a gravitational influence. That has been the case with what are known as filaments; gravitational effects that connect galactic superclusters, keeping them bound together. Now Jörg Dietrich and colleagues have added credence to the theory by finding a measurable example of lensing in one specific supercluster that cannot be attributable to a visible object. They outline their findings in their paper published in the journal Nature. Abell 222/223 is a galactic supercluster system in the constellation Cetus. It’s made up of two parts, 222 and 223, separated by a gas cloud and something else that cannot be seen. In looking at data collected by telescopes used to study the supercluster in prior research efforts, Dietrich and his team found that lensing occurred as light behind the gas cloud made its way to us by passing between the two parts. But after careful study and mathematical analysis, they found that the observable matter that existed in the gas cloud could only account for about nine percent of the mass required to cause the degree of lensing that was occurring. Because there was nothing else in the area, the only possible explanation was that dark matter in the shape of a filament was the cause. The results from this study are doubly interesting; one because they strengthen all of the theories surrounding dark matter, and two, because the team has found a means of not just demonstrating an example of dark matter at work, but have done so in a way that is so precise that they were able to determine the actual shape of a dark matter filament. This second part came about as measurements of lensing were taken at different parts of the area between 222 and 223 showing different degrees of light bending, a feat that was only possible because of the unique way the supercluster is situated relative to us, allowing a nearly straight on view. ", "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 a firm prediction of the concordance cold-dark-matter cosmological model that galaxy clusters occur at the intersection of large-scale structure filaments 1 . The thread-like structure of this ‘cosmic web’ has been traced by galaxy redshift surveys for decades 2 , 3 . More recently, the warm–hot intergalactic medium (a sparse plasma with temperatures of 10 5 kelvin to 10 7 kelvin) residing in low-redshift filaments has been observed in emission 4 and absorption 5 , 6 . However, a reliable direct detection of the underlying dark-matter skeleton, which should contain more than half of all matter 7 , has remained elusive, because earlier candidates for such detections 8 , 9 , 10 were either falsified 11 , 12 or suffered from low signal-to-noise ratios 8 , 10 and unphysical misalignments of dark and luminous matter 9 , 10 . Here we report the detection of a dark-matter filament connecting the two main components of the Abell 222/223 supercluster system from its weak gravitational lensing signal, both in a non-parametric mass reconstruction and in parametric model fits. This filament is coincident with an overdensity of galaxies 10 , 13 and diffuse, soft-X-ray emission 4 , and contributes a mass comparable to that of an additional galaxy cluster to the total mass of the supercluster. By combining this result with X-ray observations 4 , we can place an upper limit of 0.09 on the hot gas fraction (the mass of X-ray-emitting gas divided by the total mass) in the filament. Main Abell 222 and Abell 223, the latter a double galaxy cluster in itself, form a supercluster system of three galaxy clusters at a redshift of z ≈ 0.21 (ref. 13 ), separated on the sky by about 14′. Gravitational lensing distorts the images of faint background galaxies as their light passes massive foreground structures. The foreground mass and its distribution can be deduced from measuring the shear field imprinted on the shapes of the background galaxies. Additional information on this process is given in the Supplementary Information . The mass reconstruction in Fig. 1 shows a mass bridge connecting Abell 222 and the southern component of Abell 223 (Abell 223-S) at the 4.1 σ significance level. This mass reconstruction does not assume any model or physical prior probability distribution on the mass distribution. Figure 1: Mass reconstruction of Abell 222/223. The background image is a three-colour-composite SuprimeCam image based on observations with the 8.2-m Subaru telescope on Mauna Kea, Hawaii during the nights of 15 October 2001 (Abell 222) and 20 October 2001 (Abell 223) in the V-, R c - and i′-bands. We obtained the data from the SMOKA science archive ( ). The full-width at half-maximum (FWHM) of the stellar point-spread function varies between 0.57″ and 0.70″ in our final co-added images. Overlaid are the reconstructed surface mass density (blue) above κ = 0.0077, corresponding to , and significance contours above the mean of the field edge, rising in steps of 0.5 σ and starting from 2.5 σ . Dashed contours mark underdense regions at the same significance levels. Supplementary Fig. 1 shows the corresponding B-mode map. The reconstruction is based on 40,341 galaxies whose colours are not consistent with early-type galaxies at the cluster redshift. The shear field was smoothed with a 2′ Gaussian. The significance was assessed from the variance of 800 mass maps created from catalogues with randomized background galaxy orientation. We measured the shapes of these galaxies primarily in the R c -band, supplementing the galaxy shape catalogue with measurements from the other two bands for galaxies for which no shapes could be measured in the R c -band, to estimate the gravitational shear 25 , 26 . Abell 222 is detected at about 8.0 σ in the south, and Abell 223 is the double-peaked structure in the north seen at about 7 σ . Black rectangles are regions on the sky not covered by the camera. PowerPoint slide Full size image To show that the mass bridge extending between Abell 222 and Abell 223 is not caused by the overlap of the cluster halos but is in fact due to additional mass, we also fitted parametric models to the three clusters plus a filament component. The clusters were modelled as elliptical Navarro–Frenk–White (NFW) profiles 14 with a fixed mass–concentration relation 15 . We used a simple model for the filament, with a flat ridge line connecting the clusters, exponential cut-offs at the filament endpoints in the clusters, and a King profile 16 describing the radial density distribution, as suggested by previous studies 17 , 18 . We show in the Supplementary Information that the exact ellipticity has little impact on the significance of the filament. The best-fit parameters of this model were determined using a Monte Carlo Markov chain and are shown in Fig. 2 . The likelihood-ratio test prefers models with a filament component with 96.0% confidence over a fit with three NFW halos only. A small degeneracy exists in the model between the strength of the filament and the virial radii of Abell 222 and Abell 223-S. The fitting procedure tries to keep the total amount of mass in the supercluster system constant at the level indicated by the observed reduced shear. Thus, it is not necessarily the case that sample points with a positive filament contribution indeed have more mass in the filament area than has a three-clusters-only model. This is because the additional filament mass might be compensated for with lower cluster masses. We find that the integrated surface mass density along the filament ridge line exceeds that of the clusters-only model in 98.5% of all sample points. Figure 2: Posterior probability distributions for cluster virial radii and filament strength. Shown are the 68% and 95% confidence intervals on the cluster virial radii r 200 (within which the mean density of the clusters is 200 times the critical density of the Universe) and the filament strength κ 0 . The confidence intervals are derived from 30,000 Monte<|im_end|> <|im_start|>assistant (Phys.org) -- As time passes and more research is done, more evidence is compiled supporting the theory that suggests that dark matter is a real thing, even though no direct evidence for its existence has ever been found. Instead, the evidence comes about as measurements of other phenomenon are taken, generally involving gravitational pull on objects in the universe we can see that cannot be explained by other means. One of these instances is where weak gravitational lensing occurs, which is where light appears to bend as it passes by large objects. Theory suggests that in cases where lensing occurs but there is no detectable object behind its cause, the reason for it is dark matter exerting a gravitational influence. That has been the case with what are known as filaments; gravitational effects that connect galactic superclusters, keeping them bound together. Now Jörg Dietrich and colleagues have added credence to the theory by finding a measurable example of lensing in one specific supercluster that cannot be attributable to a visible object. They outline their findings in their paper published in the journal Nature. Abell 222/223 is a galactic supercluster system in the constellation Cetus. It’s made up of two parts, 222 and 223, separated by a gas cloud and something else that cannot be seen. In looking at data collected by telescopes used to study the supercluster in prior research efforts, Dietrich and his team found that lensing occurred as light behind the gas cloud made its way to us by passing between the two parts. But after careful study and mathematical analysis, they found that the observable matter that existed in the gas cloud could only account for about nine percent of the mass required to cause the degree of lensing that was occurring. Because there was nothing else in the area, the only possible explanation was that dark matter in the shape of a filament was the cause. The results from this study are doubly interesting; one because they strengthen all of the theories surrounding dark matter, and two, because the team has found a means of not just demonstrating an example of dark matter at work, but have done so in a way that is so precise that they were able to determine the actual shape of a dark matter filament. This second part came about as measurements of lensing were taken at different parts of the area between 222 and 223 showing different degrees of light bending, a feat that was only possible because of the unique way the supercluster is situated relative to us, allowing a nearly straight on view. <|im_end|>
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1,884
[ { "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 Ran is a nucleocytoplasmic shuttle protein that is involved in cell cycle regulation, nuclear-cytoplasmic transport, and cell transformation. Ran plays an important role in cancer cell survival and cancer progression. Here, we show that, in addition to the nucleocytoplasmic localization of Ran, this GTPase is specifically associated with the plasma membrane/ruffles of ovarian cancer cells. Ran depletion has a drastic effect on RhoA stability and inhibits RhoA localization to the plasma membrane/ruffles and RhoA activity. We further demonstrate that the DEDDDL domain of Ran is required for the interaction with serine 188 of RhoA, which prevents RhoA degradation by the proteasome pathway. Moreover, the knockdown of Ran leads to a reduction of ovarian cancer cell invasion by impairing RhoA signalling. Our findings provide advanced insights into the mode of action of the Ran-RhoA signalling axis and may represent a potential therapeutic avenue for drug development to prevent ovarian tumour metastasis. Introduction Epithelial ovarian cancer (EOC) is the deadliest of all female reproductive system cancers worldwide with 140,000 deaths each year 1 , 2 , 3 . The disease being largely asymptomatic, the vast majority of patients are diagnosed at an advanced stage, which is responsible for a poor prognosis 4 . We have demonstrated that the small GTPAse Ran (Ras-related nuclear protein) is strongly associated with EOC progression, poor overall survival, and a high risk of recurrence 5 , 6 . Ran is a master regulator of nucleocytoplasmic transport 7 , 8 and mitotic spindle formation, which are necessary for cell proliferation and cell cycle progression 7 , 9 . Indeed, we have shown that depletion of Ran prevents EOC cell proliferation in vitro and results in EOC tumor growth arrest in vivo 10 . RhoA is one of the most-studied Rho GTPase, it is activated by guanine-nucleotide exchange factors (GEFs) and is inactivated by guanine-nucleotide dissociation inhibitors (GDIs), which prevent its interaction with the plasma membrane (PM), but not necessarily with downstream targets 11 . In addition, the RhoA protein contains a CAAX motif that influences its targeting to specific plasma membrane (PM) microdomains 12 . However, the CAAX-signaled post-translational modification alone is not sufficient to promote full RhoA membrane association that is required for its proper function 13 , 14 . RhoA GTPase coordinately regulates multiple aspects of tumor cell invasion 15 , and its expression is significantly associated with poor tumor differentiation and advanced stages of ovarian cancer 16 . Here, we investigate the mechanism through which Ran modulates ovarian tumor progression. We find that Ran can localize to the PM where it forms a complex with RhoA GTPase, leading to RhoA stabilization and activation. Our findings describe a signaling pathway involving Ran that regulates EOC invasion through RhoA GTPase activity and may lead to alternative therapeutic strategies for ovarian cancer. Results Ran stabilizes and co-localizes with RhoA Ran, a member of the Ras GTPase family, has been demonstrated to control numerous cellular processes of cancer, including cell proliferation and tumor cell invasion/migration associated with a metastatic phenotype 17 , 18 , 19 . We have previously demonstrated that Ran is overexpressed in invasive high-grade serous EOC cells 6 ; however, the role of Ran in EOC cell invasion remains unclear. To address this, we examined the effect of Ran depletion by RNA interference (RNAi) in two aggressive EOC cell lines (TOV-112D and TOV-1946) derived in our laboratory 20 , 21 (Fig. 1a ; Supplementary Fig. 1a ). Video microscopy analysis revealed that TOV-112D cells with siRNA-mediated knockdown (KD) of Ran elicited reduced spreading and motility while producing long projections that appeared at the trailing end of cells in comparison with control TOV-112D cells (Supplementary Fig. 1b and Movies 1 , 2 ). Fig. 1 Ran GTPase stabilizes and co-localizes with RhoA at the plasma membrane of TOV-112D cells. a Western blot of Ran knockdown (KD) with siRNA (CTRL, Ran #1 or 2) and rescue levels with different RNAi-resistant 2xGFP constructs of Ran as wild-type (WT), dominant active (DA), and dominant-negative (DN) in TOV-112D. Actin served as a loading control for all blots. b Western blot showing RhoA and RhoC protein expression levels after Ran KD in cells. c Western blot showing RhoA protein level after re-expression of 2xGFP-Ran WT (Ran WT rescue) or treatment for 2 h with 20 µM MG-132 in cells transfected with CTRL or Ran #2 siRNA. d Active RhoA was examined in cell lysates of control (CTRL), Ran KD or Ran KD with Ran WT rescued. All values are means ± SEM from three independent experiments. P -values are based on comparisons with CTRL using the t test: * P < 0.05 was considered statistically significant. Western blot showing total RhoA. e , f Cell body (CB) and lamellipodia (LP) of CTRL and Ran KD cells (with or without Ran WT rescued) were fractionated and treated with or without 20 µM MG-132 for 2 h. Equal amounts of proteins were immunoblotted to show RhoA expression in the respective fractions. RhoA was decreased in CB and LP in Ran KD cells, but unchanged in CTRL. RhoA expression is only rescued in CB fractions after treatment with MG-132. g Top, TOV-112D cells were fixed, permeabilized, and subjected to immunofluorescence using Ran and RhoA antibodies and DAPI (Merge). Bottom, TOV-112D cells transfected with 2xGFP-Ran and mCherry-RhoA were visualized by spinning disk microscopy. Arrows show Ran and RhoA colocalization at the plasma membrane. h TOV-112D cells were transfected with RanBP1-GFP. Protein lysates were subjected to IP with Ran or control IgG antibodies. Proteins were separated by SDS-PAGE and immunoblotted for endogenous RhoA and Ran. i Protein lysates from TOV-112D and ARPE-19 cells were subjected to IP with Ran or control IgG antibodies. Proteins were separated by SDS-PAGE and immunoblotted for endogenous RhoA and Ran. Scale bars, 10 µm Full size image This Ran KD-induced phenotype of elongated cells with pronounced tails is similar to the disrupted RhoA signaling phenotype that has been observed in other systems 22 , 23 , 24 . Therefore, experiments were", "role": "user" }, { "content": "Did you know that 90% of cancer patients die from distant metastasis? The latter occurs when cancer cells have the ability to move within the patient's body and invade its healthy tissues. In a study published in Nature Communications, researchers from the University of Montreal Hospital Research Centre (CRCHUM) have shown the key role that a protein called Ran plays in the mobility of ovarian cancer cells. They demonstrated these cells cannot migrate from cancerous sites without the help of Ran. Implicated in cancer development and survival, Ran is often referred to as a shuttle protein mostly supporting transport between the inside of a cell and its nucleus. In ovarian cancer cells, the team of researchers, led by Dr. Anne-Marie Mes-Masson and Dr. Diane Provencher, showed Ran acts as a taxi to the cell membrane for another protein, RhoA, which is important in cell migration. \"In normal cells, RhoA can make its way directly to the cell membrane but in ovarian cancer cells it cannot. It has to link to Ran first in order to reach the cell membrane. It really needs a ride,\" said Mes-Masson, a researcher at the CRCHUM, professor at Université de Montréal and member of the Institute du cancer de Montréal. \"In our study, we showed that in cancer cells where we inhibit the action of Ran, RhoA gets broken down. Without RhoA, cancer cells lose then their ability to move, migrate and invade healthy tissues.\" Thanks to the vast expertise in biochemistry of the first author, Dr. Kossay Zaoui, the science team was able to explain at least in part why Ran is so important in a cancer cell. In many cancers high expression of Ran is often associated with poor outcomes. \"We have previously demonstrated that Ran is a good therapeutic target. Our study helps us understand when and in which cancer patients our approach might be most beneficial. As healthy cells do not need Ran to move around, we can target the cancer cells without touching the healthy cells. Based on our findings, it is probable that inhibiting Ran will also be a winning strategy in other cancers,\" said Dr. Provencher, a researcher at CRCHUM, Head of the Division of Gynecology Oncology, professor at Université de Montréal and member of the Institute du cancer de Montréal. Simultaneous protein labeling: Ran (pink) and tubulin (green) in ovarian cancer cells. The majority of Ran is found in the nucleus, but our study reveals that a portion of it is localized on the surface of cells inducing movement and invasion in ovarian cancer via its partner RhoA Credit: Euridice Carmona, CRCHUM The researchers have already begun to develop small molecules that can inhibit Ran and are testing them in the preclinical models they have developed to show that they can slow or eliminate cancer development. They hope one day that these new drugs will make their way into the clinic to be used to treat ovarian cancer patients. The Importance of Our Biobank For three decades, Drs. Provencher and Mes-Masson have collaborated to create the largest biobank of ovarian cancer specimens from women who have consented to participate in their research program. They managed to develop and characterize cell lines from tumour tissues, and these cell lines were essential to conduct this work. These cell lines are now used by ovarian cancer research groups worldwide to conduct ovarian cancer research. The patient's precious contribution to research is fuelling the type of new discoveries that both researchers hope will help cure this deadly disease. According to the Canadian Cancer Society, 2,800 Canadian women were diagnosed with ovarian cancer in 2017 and 1,800 died from the disease. It is the fifth leading cause of death in North America. ", "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 Ran is a nucleocytoplasmic shuttle protein that is involved in cell cycle regulation, nuclear-cytoplasmic transport, and cell transformation. Ran plays an important role in cancer cell survival and cancer progression. Here, we show that, in addition to the nucleocytoplasmic localization of Ran, this GTPase is specifically associated with the plasma membrane/ruffles of ovarian cancer cells. Ran depletion has a drastic effect on RhoA stability and inhibits RhoA localization to the plasma membrane/ruffles and RhoA activity. We further demonstrate that the DEDDDL domain of Ran is required for the interaction with serine 188 of RhoA, which prevents RhoA degradation by the proteasome pathway. Moreover, the knockdown of Ran leads to a reduction of ovarian cancer cell invasion by impairing RhoA signalling. Our findings provide advanced insights into the mode of action of the Ran-RhoA signalling axis and may represent a potential therapeutic avenue for drug development to prevent ovarian tumour metastasis. Introduction Epithelial ovarian cancer (EOC) is the deadliest of all female reproductive system cancers worldwide with 140,000 deaths each year 1 , 2 , 3 . The disease being largely asymptomatic, the vast majority of patients are diagnosed at an advanced stage, which is responsible for a poor prognosis 4 . We have demonstrated that the small GTPAse Ran (Ras-related nuclear protein) is strongly associated with EOC progression, poor overall survival, and a high risk of recurrence 5 , 6 . Ran is a master regulator of nucleocytoplasmic transport 7 , 8 and mitotic spindle formation, which are necessary for cell proliferation and cell cycle progression 7 , 9 . Indeed, we have shown that depletion of Ran prevents EOC cell proliferation in vitro and results in EOC tumor growth arrest in vivo 10 . RhoA is one of the most-studied Rho GTPase, it is activated by guanine-nucleotide exchange factors (GEFs) and is inactivated by guanine-nucleotide dissociation inhibitors (GDIs), which prevent its interaction with the plasma membrane (PM), but not necessarily with downstream targets 11 . In addition, the RhoA protein contains a CAAX motif that influences its targeting to specific plasma membrane (PM) microdomains 12 . However, the CAAX-signaled post-translational modification alone is not sufficient to promote full RhoA membrane association that is required for its proper function 13 , 14 . RhoA GTPase coordinately regulates multiple aspects of tumor cell invasion 15 , and its expression is significantly associated with poor tumor differentiation and advanced stages of ovarian cancer 16 . Here, we investigate the mechanism through which Ran modulates ovarian tumor progression. We find that Ran can localize to the PM where it forms a complex with RhoA GTPase, leading to RhoA stabilization and activation. Our findings describe a signaling pathway involving Ran that regulates EOC invasion through RhoA GTPase activity and may lead to alternative therapeutic strategies for ovarian cancer. Results Ran stabilizes and co-localizes with RhoA Ran, a member of the Ras GTPase family, has been demonstrated to control numerous cellular processes of cancer, including cell proliferation and tumor cell invasion/migration associated with a metastatic phenotype 17 , 18 , 19 . We have previously demonstrated that Ran is overexpressed in invasive high-grade serous EOC cells 6 ; however, the role of Ran in EOC cell invasion remains unclear. To address this, we examined the effect of Ran depletion by RNA interference (RNAi) in two aggressive EOC cell lines (TOV-112D and TOV-1946) derived in our laboratory 20 , 21 (Fig. 1a ; Supplementary Fig. 1a ). Video microscopy analysis revealed that TOV-112D cells with siRNA-mediated knockdown (KD) of Ran elicited reduced spreading and motility while producing long projections that appeared at the trailing end of cells in comparison with control TOV-112D cells (Supplementary Fig. 1b and Movies 1 , 2 ). Fig. 1 Ran GTPase stabilizes and co-localizes with RhoA at the plasma membrane of TOV-112D cells. a Western blot of Ran knockdown (KD) with siRNA (CTRL, Ran #1 or 2) and rescue levels with different RNAi-resistant 2xGFP constructs of Ran as wild-type (WT), dominant active (DA), and dominant-negative (DN) in TOV-112D. Actin served as a loading control for all blots. b Western blot showing RhoA and RhoC protein expression levels after Ran KD in cells. c Western blot showing RhoA protein level after re-expression of 2xGFP-Ran WT (Ran WT rescue) or treatment for 2 h with 20 µM MG-132 in cells transfected with CTRL or Ran #2 siRNA. d Active RhoA was examined in cell lysates of control (CTRL), Ran KD or Ran KD with Ran WT rescued. All values are means ± SEM from three independent experiments. P -values are based on comparisons with CTRL using the t test: * P < 0.05 was considered statistically significant. Western blot showing total RhoA. e , f Cell body (CB) and lamellipodia (LP) of CTRL and Ran KD cells (with or without Ran WT rescued) were fractionated and treated with or without 20 µM MG-132 for 2 h. Equal amounts of proteins were immunoblotted to show RhoA expression in the respective fractions. RhoA was decreased in CB and LP in Ran KD cells, but unchanged in CTRL. RhoA expression is only rescued in CB fractions after treatment with MG-132. g Top, TOV-112D cells were fixed, permeabilized, and subjected to immunofluorescence using Ran and RhoA antibodies and DAPI (Merge). Bottom, TOV-112D cells transfected with 2xGFP-Ran and mCherry-RhoA were visualized by spinning disk microscopy. Arrows show Ran and RhoA colocalization at the plasma membrane. h TOV-112D cells were transfected with RanBP1-GFP. Protein lysates were subjected to IP with Ran or control IgG antibodies. Proteins were separated by SDS-PAGE and immunoblotted for endogenous RhoA and Ran. i Protein lysates from TOV-112D and ARPE-19 cells were subjected to IP with Ran or control IgG antibodies. Proteins were separated by SDS-PAGE and immunoblotted for endogenous RhoA and Ran. Scale bars, 10 µm Full size image This Ran KD-induced phenotype of elongated cells with pronounced tails is similar to the disrupted RhoA signaling phenotype that has been observed in other systems 22 , 23 , 24 . Therefore, experiments were<|im_end|> <|im_start|>assistant Did you know that 90% of cancer patients die from distant metastasis? The latter occurs when cancer cells have the ability to move within the patient's body and invade its healthy tissues. In a study published in Nature Communications, researchers from the University of Montreal Hospital Research Centre (CRCHUM) have shown the key role that a protein called Ran plays in the mobility of ovarian cancer cells. They demonstrated these cells cannot migrate from cancerous sites without the help of Ran. Implicated in cancer development and survival, Ran is often referred to as a shuttle protein mostly supporting transport between the inside of a cell and its nucleus. In ovarian cancer cells, the team of researchers, led by Dr. Anne-Marie Mes-Masson and Dr. Diane Provencher, showed Ran acts as a taxi to the cell membrane for another protein, RhoA, which is important in cell migration. "In normal cells, RhoA can make its way directly to the cell membrane but in ovarian cancer cells it cannot. It has to link to Ran first in order to reach the cell membrane. It really needs a ride," said Mes-Masson, a researcher at the CRCHUM, professor at Université de Montréal and member of the Institute du cancer de Montréal. "In our study, we showed that in cancer cells where we inhibit the action of Ran, RhoA gets broken down. Without RhoA, cancer cells lose then their ability to move, migrate and invade healthy tissues." Thanks to the vast expertise in biochemistry of the first author, Dr. Kossay Zaoui, the science team was able to explain at least in part why Ran is so important in a cancer cell. In many cancers high expression of Ran is often associated with poor outcomes. "We have previously demonstrated that Ran is a good therapeutic target. Our study helps us understand when and in which cancer patients our approach might be most beneficial. As healthy cells do not need Ran to move around, we can target the cancer cells without touching the healthy cells. Based on our findings, it is probable that inhibiting Ran will also be a winning strategy in other cancers," said Dr. Provencher, a researcher at CRCHUM, Head of the Division of Gynecology Oncology, professor at Université de Montréal and member of the Institute du cancer de Montréal. Simultaneous protein labeling: Ran (pink) and tubulin (green) in ovarian cancer cells. The majority of Ran is found in the nucleus, but our study reveals that a portion of it is localized on the surface of cells inducing movement and invasion in ovarian cancer via its partner RhoA Credit: Euridice Carmona, CRCHUM The researchers have already begun to develop small molecules that can inhibit Ran and are testing them in the preclinical models they have developed to show that they can slow or eliminate cancer development. They hope one day that these new drugs will make their way into the clinic to be used to treat ovarian cancer patients. The Importance of Our Biobank For three decades, Drs. Provencher and Mes-Masson have collaborated to create the largest biobank of ovarian cancer specimens from women who have consented to participate in their research program. They managed to develop and characterize cell lines from tumour tissues, and these cell lines were essential to conduct this work. These cell lines are now used by ovarian cancer research groups worldwide to conduct ovarian cancer research. The patient's precious contribution to research is fuelling the type of new discoveries that both researchers hope will help cure this deadly disease. According to the Canadian Cancer Society, 2,800 Canadian women were diagnosed with ovarian cancer in 2017 and 1,800 died from the disease. It is the fifth leading cause of death in North America. <|im_end|>
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2,265
[ { "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 TYK2 is a member of the JAK family of tyrosine kinases that is involved in chromosomal translocation-induced fusion proteins found in anaplastic large cell lymphomas (ALCL) that lack rearrangements activating the anaplastic lymphoma kinase (ALK). Here we demonstrate that TYK2 is highly expressed in all cases of human ALCL, and that in a mouse model of NPM-ALK-induced lymphoma, genetic disruption of Tyk2 delays the onset of tumors and prolongs survival of the mice. Lymphomas in this model lacking Tyk2 have reduced STAT1 and STAT3 phosphorylation and reduced expression of Mcl1 , a pro-survival member of the BCL2 family. These findings in mice are mirrored in human ALCL cell lines, in which TYK2 is activated by autocrine production of IL-10 and IL-22 and by interaction with specific receptors expressed by the cells. Activated TYK2 leads to STAT1 and STAT3 phosphorylation, activated expression of MCL1 and aberrant ALCL cell survival. Moreover, TYK2 inhibitors are able to induce apoptosis in ALCL cells, regardless of the presence or absence of an ALK-fusion. Thus, TYK2 is a dependency that is required for ALCL cell survival through activation of MCL1 expression. TYK2 represents an attractive drug target due to its essential enzymatic domain, and TYK2-specific inhibitors show promise as novel targeted inhibitors for ALCL. Introduction TYK2 was the first Janus kinase described, and it was shown to collaborate with JAK1 to facilitate interferon-α/β (IFN) responsiveness [ 1 , 2 ]. Recently, activation of TYK2 has been noted in a number of malignancies including T-cell acute lymphoblastic leukemia (T-ALL), anaplastic large cell lymphoma (ALCL) and nerve sheath tumor [ 3 , 4 , 5 , 6 ]. In T-ALL cell lines, activating somatic mutations have been detected in the TYK2 FERM domain (G36D, S47N) and in the kinase domain (E957D, R1072H) [ 3 ]. Unmutated TYK2 also represented a dependency in T-ALL cell lines and patient samples [ 3 ]. Moreover, germline TYK2 mutations potentially causing ALL have been described [ 7 ]. Recently, somatic TYK2 fusion proteins have also been detected in ALL [ 8 ], AML [ 9 ], cutaneous [ 5 ], and systemic ALCLs that lack anaplastic lymphoma kinase (ALK) fusion genes [ 6 ]. Despite involvement of TYK2 in fusion proteins and the presence of activating mutations in some cancers, with the exception of T-ALL [ 3 , 10 ], little is known regarding TYK2’s oncogenic functions and downstream effectors. To elucidate the role of TYK2 in tumorigenesis, we focused on ALCL as a well-defined lymphoma subtype [ 11 ]. ALCL is a CD30 positive, aggressive non-Hodgkin T-cell lymphoma with early onset that is characterized in approximately half of all patients (ALCL, ALK+) by fusion of the catalytic domain of ALK with the N-terminus of the gene encoding the Nucleophosmin 1 (NPM1) protein due to a t (2;5) chromosomal translocation [ 11 ]. Despite initial classification as a T-cell lymphoma arising in mature memory T cells, several recent publications point toward a transformation of early thymic progenitor cells in ALCL [ 12 , 13 ]. ALCL, ALK+ patients can be effectively treated with the poly-chemo- therapy (e.g., CHOP) or ALK inhibitors. However, still 25–30% of patients relapse leading to very aggressive disease [ 14 , 15 ]. An additional targeted agent is provided by the recently introduced armed CD30 antibody brentuximab vedotin, which shows good responses but is often associated with polyneuropathy as a severe side effect [ 16 ]. ALCL patients without ALK translocations cannot be treated by ALK inhibitors and have a worse prognosis compared to ALCL, ALK+ patients creating an urgent need for new and refined molecularly targeted therapeutic options for ALCL [ 15 , 17 , 18 ]. The WHO has classified ALCL, ALK− as a distinct disease with sub-entities defined by chromosomal rearrangements that disrupt the DUSP22 and TP63 tumor suppressors [ 18 ]. Several transplant but also transgenic mouse models for ALCL, ALK+ have been created, with the CD4 -NPM-ALK transgenic mouse being the best established [ 19 , 20 , 21 ]. Similar to ALK, TYK2 is a tyrosine kinase that can be readily inhibited by small molecules and therefore represents an attractive therapeutic target in ALCL. We show here that the TYK2 tyrosine kinase is expressed in human ALCLs irrespective of ALK status and is essential for tumor cell viability. Genetic studies in a transgenic NPM-ALK driven lymphoma model also demonstrate that T cell-specific loss of Tyk2 delays the onset of tumors and prolongs the survival of mice. We furthermore show that TYK2 is activated by an autocrine loop involving IL-10 and IL-22 and that STAT1 and STAT3 are essential mediators of aberrant tumor cell survival through activation of the pro-survival protein MCL1. Our data underscore the potential therapeutic importance in ALCL of TYK2 inhibitors which are currently in late preclinical stages of development. Materials and methods Cell culture ALCL cell lines were obtained from DSMZ, Braunschweig, Germany. For cytokine complementation experiments, recombinant human Interleukin-10 (10 ng/ml, rh IL-10, Immunotools, Friesoythe, Germany) or rhIL-22 (20 ng/ml, Immunotools) were used. For detection of downstream targets, ALCL cells were incubated with TYK2 inhibitors or pan-JAK inhibitors (including 1 µM JAK inhibitor I, Calbiochem, San Diego, CA, USA) for 3 or 6 h and then incubated with IFN-α for 10 min before immunoblot analysis. Description of quantitative RT-PCR, flow cytometry, cytokine arrays and immunohistochemistry, shRNA sources, CRISPR / Cas9 genome editing and murine lymphoma models can be found in Supplementary Methods. Cloning of mutant TYK2 construct and rescue experiment Retroviral constructs encoding the mutant TYK2_E957D cDNA as well as the WT TYK2 cDNA were obtained from Dr. Takaomi Sanda from CSI, Singapore. Production of retrovirus expressing TYK2_E957D and TYK2_WT was performed as previously described [ 3 ]. Cell growth and viability assays For cell counting of shRNA knockdown or CRISPR knockout experiments, cells were seeded into 12-well plates in triplicates at day 1 and counted at days 2, 3, 4, and 5. For drug treatment, cells were incubated with TYK2 inhibitors or pan-JAK inhibitors (Table S", "role": "user" }, { "content": "Anaplastic large-cell lymphomas (ALCL) are rare cancers of the white blood cells. New research from the international ERIA consortium, led by scientists in Vienna, has now shown that the same signaling pathway is essential to the growth of cancer cells in various forms of ALCL: TYK2 (tyrosine kinase 2, an important component of the immune system) prevents apoptotic cell death by increasing the production of Mcl1, a special type of protein belonging to the BCL2 family. Due to its unique enzymatic composition, TYK2 is therefore an interesting therapeutic target, making TYK2-specific inhibitors highly promising as new therapeutic agents in ALCL. A particularly fruitful area of personalised medicine is cancer treatment, where improved diagnostic methods are able to break cancers down into increasingly smaller subcategories, thereby making it possible to apply individual treatment strategies. The molecular analysis of human tumour samples has therefore become a focus of cancer research, to identify new therapeutic targets and validate them in tumour models, in order to improve the clinical management of cancer patients. However, this faces clinicians with several challenges, including increasingly comprehensive diagnostics as well as the problem of adequately validating this data for smaller patient groups. This is all the more urgent in the case of rare cancers such as ALCL, where the number of patients is so small. Nicole Prutsch and Olaf Merkel from the Medical University of Vienna and their international colleagues have now reported in the journal Leukemia that, rather than finding yet another subdivision of the ALCL subgroups, they have managed to identify a common actor in ALCL patients. TYK2 is not only expressed in all patients but produces the same anti-apoptotic reaction, which keeps the lymphoma cells alive and so helps the tumour to grow. \"We were therefore able to regard the TYK2 signals as the Achilles heel of ALCL, since both types of ALCL that we investigated relied on its activity to maintain the essential signal to protect against cell death,\" explains Olaf Merkel, who is co-last author of this publication together with Lukas Kenner. Attenuating the TYK2 signal in the cell culture resulted in rapid cell death and, in ALCL model mice, in which TYK2 was genetically switched off, the researchers observed that the laboratory animals survived for longer. Lukas Kenner from MedUni Vienna and the Ludwig Boltzmann Institute for Cancer Research and co-founder of the European Research Initiative on Alk-mediated diseases (ERIA) emphasises the potential therapeutic significance of TYK2-inhibitors in ALCL. \"We look forward to TYK2 inhibitors, which are currently being developed for treating immunological diseases, being available, since we urgently need better treatments for rare lymphomas,\" 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 TYK2 is a member of the JAK family of tyrosine kinases that is involved in chromosomal translocation-induced fusion proteins found in anaplastic large cell lymphomas (ALCL) that lack rearrangements activating the anaplastic lymphoma kinase (ALK). Here we demonstrate that TYK2 is highly expressed in all cases of human ALCL, and that in a mouse model of NPM-ALK-induced lymphoma, genetic disruption of Tyk2 delays the onset of tumors and prolongs survival of the mice. Lymphomas in this model lacking Tyk2 have reduced STAT1 and STAT3 phosphorylation and reduced expression of Mcl1 , a pro-survival member of the BCL2 family. These findings in mice are mirrored in human ALCL cell lines, in which TYK2 is activated by autocrine production of IL-10 and IL-22 and by interaction with specific receptors expressed by the cells. Activated TYK2 leads to STAT1 and STAT3 phosphorylation, activated expression of MCL1 and aberrant ALCL cell survival. Moreover, TYK2 inhibitors are able to induce apoptosis in ALCL cells, regardless of the presence or absence of an ALK-fusion. Thus, TYK2 is a dependency that is required for ALCL cell survival through activation of MCL1 expression. TYK2 represents an attractive drug target due to its essential enzymatic domain, and TYK2-specific inhibitors show promise as novel targeted inhibitors for ALCL. Introduction TYK2 was the first Janus kinase described, and it was shown to collaborate with JAK1 to facilitate interferon-α/β (IFN) responsiveness [ 1 , 2 ]. Recently, activation of TYK2 has been noted in a number of malignancies including T-cell acute lymphoblastic leukemia (T-ALL), anaplastic large cell lymphoma (ALCL) and nerve sheath tumor [ 3 , 4 , 5 , 6 ]. In T-ALL cell lines, activating somatic mutations have been detected in the TYK2 FERM domain (G36D, S47N) and in the kinase domain (E957D, R1072H) [ 3 ]. Unmutated TYK2 also represented a dependency in T-ALL cell lines and patient samples [ 3 ]. Moreover, germline TYK2 mutations potentially causing ALL have been described [ 7 ]. Recently, somatic TYK2 fusion proteins have also been detected in ALL [ 8 ], AML [ 9 ], cutaneous [ 5 ], and systemic ALCLs that lack anaplastic lymphoma kinase (ALK) fusion genes [ 6 ]. Despite involvement of TYK2 in fusion proteins and the presence of activating mutations in some cancers, with the exception of T-ALL [ 3 , 10 ], little is known regarding TYK2’s oncogenic functions and downstream effectors. To elucidate the role of TYK2 in tumorigenesis, we focused on ALCL as a well-defined lymphoma subtype [ 11 ]. ALCL is a CD30 positive, aggressive non-Hodgkin T-cell lymphoma with early onset that is characterized in approximately half of all patients (ALCL, ALK+) by fusion of the catalytic domain of ALK with the N-terminus of the gene encoding the Nucleophosmin 1 (NPM1) protein due to a t (2;5) chromosomal translocation [ 11 ]. Despite initial classification as a T-cell lymphoma arising in mature memory T cells, several recent publications point toward a transformation of early thymic progenitor cells in ALCL [ 12 , 13 ]. ALCL, ALK+ patients can be effectively treated with the poly-chemo- therapy (e.g., CHOP) or ALK inhibitors. However, still 25–30% of patients relapse leading to very aggressive disease [ 14 , 15 ]. An additional targeted agent is provided by the recently introduced armed CD30 antibody brentuximab vedotin, which shows good responses but is often associated with polyneuropathy as a severe side effect [ 16 ]. ALCL patients without ALK translocations cannot be treated by ALK inhibitors and have a worse prognosis compared to ALCL, ALK+ patients creating an urgent need for new and refined molecularly targeted therapeutic options for ALCL [ 15 , 17 , 18 ]. The WHO has classified ALCL, ALK− as a distinct disease with sub-entities defined by chromosomal rearrangements that disrupt the DUSP22 and TP63 tumor suppressors [ 18 ]. Several transplant but also transgenic mouse models for ALCL, ALK+ have been created, with the CD4 -NPM-ALK transgenic mouse being the best established [ 19 , 20 , 21 ]. Similar to ALK, TYK2 is a tyrosine kinase that can be readily inhibited by small molecules and therefore represents an attractive therapeutic target in ALCL. We show here that the TYK2 tyrosine kinase is expressed in human ALCLs irrespective of ALK status and is essential for tumor cell viability. Genetic studies in a transgenic NPM-ALK driven lymphoma model also demonstrate that T cell-specific loss of Tyk2 delays the onset of tumors and prolongs the survival of mice. We furthermore show that TYK2 is activated by an autocrine loop involving IL-10 and IL-22 and that STAT1 and STAT3 are essential mediators of aberrant tumor cell survival through activation of the pro-survival protein MCL1. Our data underscore the potential therapeutic importance in ALCL of TYK2 inhibitors which are currently in late preclinical stages of development. Materials and methods Cell culture ALCL cell lines were obtained from DSMZ, Braunschweig, Germany. For cytokine complementation experiments, recombinant human Interleukin-10 (10 ng/ml, rh IL-10, Immunotools, Friesoythe, Germany) or rhIL-22 (20 ng/ml, Immunotools) were used. For detection of downstream targets, ALCL cells were incubated with TYK2 inhibitors or pan-JAK inhibitors (including 1 µM JAK inhibitor I, Calbiochem, San Diego, CA, USA) for 3 or 6 h and then incubated with IFN-α for 10 min before immunoblot analysis. Description of quantitative RT-PCR, flow cytometry, cytokine arrays and immunohistochemistry, shRNA sources, CRISPR / Cas9 genome editing and murine lymphoma models can be found in Supplementary Methods. Cloning of mutant TYK2 construct and rescue experiment Retroviral constructs encoding the mutant TYK2_E957D cDNA as well as the WT TYK2 cDNA were obtained from Dr. Takaomi Sanda from CSI, Singapore. Production of retrovirus expressing TYK2_E957D and TYK2_WT was performed as previously described [ 3 ]. Cell growth and viability assays For cell counting of shRNA knockdown or CRISPR knockout experiments, cells were seeded into 12-well plates in triplicates at day 1 and counted at days 2, 3, 4, and 5. For drug treatment, cells were incubated with TYK2 inhibitors or pan-JAK inhibitors (Table S<|im_end|> <|im_start|>assistant Anaplastic large-cell lymphomas (ALCL) are rare cancers of the white blood cells. New research from the international ERIA consortium, led by scientists in Vienna, has now shown that the same signaling pathway is essential to the growth of cancer cells in various forms of ALCL: TYK2 (tyrosine kinase 2, an important component of the immune system) prevents apoptotic cell death by increasing the production of Mcl1, a special type of protein belonging to the BCL2 family. Due to its unique enzymatic composition, TYK2 is therefore an interesting therapeutic target, making TYK2-specific inhibitors highly promising as new therapeutic agents in ALCL. A particularly fruitful area of personalised medicine is cancer treatment, where improved diagnostic methods are able to break cancers down into increasingly smaller subcategories, thereby making it possible to apply individual treatment strategies. The molecular analysis of human tumour samples has therefore become a focus of cancer research, to identify new therapeutic targets and validate them in tumour models, in order to improve the clinical management of cancer patients. However, this faces clinicians with several challenges, including increasingly comprehensive diagnostics as well as the problem of adequately validating this data for smaller patient groups. This is all the more urgent in the case of rare cancers such as ALCL, where the number of patients is so small. Nicole Prutsch and Olaf Merkel from the Medical University of Vienna and their international colleagues have now reported in the journal Leukemia that, rather than finding yet another subdivision of the ALCL subgroups, they have managed to identify a common actor in ALCL patients. TYK2 is not only expressed in all patients but produces the same anti-apoptotic reaction, which keeps the lymphoma cells alive and so helps the tumour to grow. "We were therefore able to regard the TYK2 signals as the Achilles heel of ALCL, since both types of ALCL that we investigated relied on its activity to maintain the essential signal to protect against cell death," explains Olaf Merkel, who is co-last author of this publication together with Lukas Kenner. Attenuating the TYK2 signal in the cell culture resulted in rapid cell death and, in ALCL model mice, in which TYK2 was genetically switched off, the researchers observed that the laboratory animals survived for longer. Lukas Kenner from MedUni Vienna and the Ludwig Boltzmann Institute for Cancer Research and co-founder of the European Research Initiative on Alk-mediated diseases (ERIA) emphasises the potential therapeutic significance of TYK2-inhibitors in ALCL. "We look forward to TYK2 inhibitors, which are currently being developed for treating immunological diseases, being available, since we urgently need better treatments for rare lymphomas," he says. <|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 RNA turnover pathways ensure appropriate gene expression levels by eliminating unwanted transcripts. Dis3-like 2 (Dis3L2) is a 3′–5′ exoribonuclease that plays a critical role in human development. Dis3L2 independently degrades structured substrates, including coding and noncoding 3′ uridylated RNAs. While the basis for Dis3L2’s substrate recognition has been well characterized, the mechanism of structured RNA degradation by this family of enzymes is unknown. We characterized the discrete steps of the degradation cycle by determining cryogenic electron microscopy structures representing snapshots along the RNA turnover pathway and measuring kinetic parameters for RNA processing. We discovered a dramatic conformational change that is triggered by double-stranded RNA (dsRNA), repositioning two cold shock domains by 70 Å. This movement exposes a trihelix linker region, which acts as a wedge to separate the two RNA strands. Furthermore, we show that the trihelix linker is critical for dsRNA, but not single-stranded RNA, degradation. These findings reveal the conformational plasticity of Dis3L2 and detail a mechanism of structured RNA degradation. Main RNA quality control and turnover are vital for cellular function, yet little is known about how nucleases deal with the diverse universe of structured RNAs. Dis3-like 2 (Dis3L2) is an RNase II/R family 3′–5′ hydrolytic exoribonuclease that plays an important role in development and differentiation 1 , 2 , cell proliferation 3 , 4 , 5 , 6 , calcium homeostasis 7 and apoptosis 8 , 9 by effectively removing or processing 3′ uridylated RNAs 1 , 10 , 11 , 12 , 13 . Dis3L2 targets are oligouridylated by the terminal uridylyl transferases (or TUTs) 14 , 15 , 16 . The specificity toward uridylated RNAs is conferred through a network of base-specific hydrogen bonds along the protein’s extensive RNA-binding surface, as demonstrated by the structure of Mus musculus Dis3L2 (MmDis3L2) in complex with a U 13 RNA 17 . Genetic loss of Dis3L2 causes Perlman syndrome, a congenital overgrowth disorder that is characterized by developmental delay, renal abnormalities, neonatal mortality and high rates of Wilms’ tumors 1 . The first reported physiological substrates of Dis3L2 were the uridylated precursors of let-7 microRNAs 10 , 13 , which play an important role in stem cell differentiation by silencing growth and proliferation genes such as HMGA2 , MYC and Ras 18 , 19 , 20 , 21 , 22 , 23 . Many other noncoding RNA targets have since been reported, including other microRNAs 24 , 25 , transfer RNA fragments 16 , small nuclear RNA 26 , the intermediate of 5.8S ribosomal RNA processing 7S B 27 , the long noncoding RNA RMRP 28 , and the 7SL component of the ribonucleoprotein signal recognition particle required for endoplasmic reticulum-targeted translation 7 . The latter is probably responsible for the Perlman syndrome phenotype, with aberrant uridylated 7SL leading to endoplasmic reticulum calcium leakage that perturbs embryonic stem cell differentiation, particularly in the renal lineage 7 . Unlike a number of structurally similar homologs, Dis3L2 can degrade structured RNAs independent of external helicase activity 1 , 10 , 12 , 29 . Little is known about how Dis3L2 or other capable RNase R/II family nucleases independently degrade structured RNA. We determined the structures of an RNase R/II family nuclease bound to a series of structured RNA substrates and analyzed the kinetic profiles of wild-type Homo sapiens Dis3L2 (HsDis3L2) and engineered mutants to reveal how this nuclease achieves highly efficient degradation of structured RNA. Results Initial binding of Dis3L2 to structured substrates To understand the presubstrate binding state, we used cryogenic electron microscopy (cryo-EM) to determine the structure of RNA-free HsDis3L2 to 3.4 Å resolution (construct Dis3L2 D391N residues 1–858: carboxy (C)-terminal truncation of residues 859–885; and an engineered catalytic mutation of Asp for Asn at residue 391 in Dis3L2) (see Methods , Fig. 1a,b and Extended Data Fig. 1a–c ). RNA-free HsDis3L2 has a vase-like conformation in which three oligonucleotide/oligosaccharide-binding (OB) domains—two cold shock domains (CSDs) and an S1 domain—encircle a funnel-like tunnel that reaches into the Ribonuclease B (RNB) domain and leads to the active site (Fig. 1b and Extended Data Fig. 1d ). The OB domains provide a large positively charged surface, which probably acts as a landing pad for the negatively charged RNA (Fig. 1c ). The overall structure of RNA-free Dis3L2 is very similar to the structure of the mouse Dis3L2–ssRNA complex (MmDis3L2–U 13 ) (root mean square deviation (RMSD) = 1.2 Å, calculated over all Cα pairs) 17 . Thus, the apoenzyme is preorganized to bind single-stranded RNA (ssRNA). Fig. 1: RNA-free Dis3L2 is preorganized to bind RNA substrates. a , Domain compositions of Dis3L2 and the homologous proteins Dis3 and RNase R (green, N-terminal PIN domain; pink, CSD1; orange, CSD2; blue, RNB; purple, S1 domain). b , Side (left) and top or apical (right) views of RNA-free Dis3L2 D391N with domain labels. c , Charge distribution of the Dis3L2 surface from a side view (left) and a view of the apical face (right), as calculated using PyMol APBS at an ionic strength of 150 mM ( Methods ) where k B is the Boltzmann constant, T is the temperature in degrees Kelvin and e c is the unit of charge. Full size image To probe the initial binding of Dis3L2 to structured substrates, we designed a short hairpin RNA mimicking the base of the pre-let-7g stem, with a UUCG tetraloop for stability and a 3′ GC(U) 14 (16-nucleotide) overhang as the uridylated tail (hairpinA–GCU 14 ; Fig. 2a ). The resulting 3.1 Å cryo-EM structure of the Dis3L2 D391N –hairpinA–GCU 14 complex revealed that Dis3L2 maintains the same vase conformation as is observed in the RNA-free form (Fig. 2b and Extended Data Fig. 2 ). However, the double-helical stem of the RNA was not resolved, suggesting that double-stranded RNA (dsRNA) is not stably engaged by the nuclease upon initial substrate association. Nonetheless, the quality of the density allowed assignment of 15 of the 16 nucleotides of the single-stranded 3′ overhang. The RNA follows the same path as is seen in", "role": "user" }, { "content": "RNAs are having a moment. The foundation of COVID-19 vaccines, they've made their way from biochemistry textbooks into popular magazines and everyday discussions. Entire companies have been launched that are dedicated to RNA research. These tiny molecules are traditionally known for helping cells make proteins, but they can do much more. They come in many shapes and sizes, from short and simple hairpin loops to long and seemingly tangled arrangements. RNAs can help activate or deactivate genes, change the shape of chromosomes, and even destroy other RNA molecules. Unfortunately, when RNA malfunctions, it can result in cancer and developmental disorders. It takes a lot to keep RNAs in check. Our cells have molecular \"machines\" that eliminate RNAs at the right time and place. Most come equipped with a \"motor\" to generate the energy needed to untangle RNA molecules. But one machine in particular, named Dis3L2, is an exception. The enzyme can unwind and destroy RNA molecules on its own. This action has puzzled scientists for years. Now, Cold Spring Harbor Laboratory (CSHL) biochemists have pieced together what's happening. It turns out Dis3L2 changes shape to unsheathe an RNA-splitting wedge. Using state-of-the-art molecular imaging technology, CSHL Professor and HHMI Investigator Leemor Joshua-Tor and her team captured Dis3L2 at work. They fed the molecular machine hairpin snippets of RNA and imaged it getting \"eaten\" at various stages. After the machine had chewed up the tip of the RNA, it swung open a big arm of its body to peel apart the hairpin and finish the job. \"It's dramatic,\" Joshua-Tor says. \"We know things change conformation. They buckle. But opening something out like that and exposing a region in this way—we didn't quite see something like this before.\" Katarina Meze, the former graduate student in the Joshua-Tor lab who led this study, standing next to the lab’s cryo-EM imaging machine. The machine allows scientists to freeze molecules in place to study their structure and geometry. Credit: Joshua-Tor lab/CSHL Joshua-Tor's team then began tinkering with the Dis3L2 machine, searching for the gears and parts enabling it to unwind and destroy RNA. The researchers narrowed it down to a protruding wedge left unsheathed after the machine shifted shapes. If the researchers removed the wedge, Dis3L2 could no longer untangle the RNA hairpin, putting the machine out of commission. The findings reveal a surprising new way that RNA-controlling machines in our cells execute their tasks. Rather than solid structures, these molecular workhorses need to be considered malleable and versatile. This new outlook may help scientists develop better treatments for diseases and disorders caused by RNA gone haywire. \"We have to start thinking about these things as much more dynamic entities,\" Joshua-Tor says, \"and take that into account when we are designing therapeutics.\" The findings are published in the journal Nature Structural & Molecular Biology. ", "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 RNA turnover pathways ensure appropriate gene expression levels by eliminating unwanted transcripts. Dis3-like 2 (Dis3L2) is a 3′–5′ exoribonuclease that plays a critical role in human development. Dis3L2 independently degrades structured substrates, including coding and noncoding 3′ uridylated RNAs. While the basis for Dis3L2’s substrate recognition has been well characterized, the mechanism of structured RNA degradation by this family of enzymes is unknown. We characterized the discrete steps of the degradation cycle by determining cryogenic electron microscopy structures representing snapshots along the RNA turnover pathway and measuring kinetic parameters for RNA processing. We discovered a dramatic conformational change that is triggered by double-stranded RNA (dsRNA), repositioning two cold shock domains by 70 Å. This movement exposes a trihelix linker region, which acts as a wedge to separate the two RNA strands. Furthermore, we show that the trihelix linker is critical for dsRNA, but not single-stranded RNA, degradation. These findings reveal the conformational plasticity of Dis3L2 and detail a mechanism of structured RNA degradation. Main RNA quality control and turnover are vital for cellular function, yet little is known about how nucleases deal with the diverse universe of structured RNAs. Dis3-like 2 (Dis3L2) is an RNase II/R family 3′–5′ hydrolytic exoribonuclease that plays an important role in development and differentiation 1 , 2 , cell proliferation 3 , 4 , 5 , 6 , calcium homeostasis 7 and apoptosis 8 , 9 by effectively removing or processing 3′ uridylated RNAs 1 , 10 , 11 , 12 , 13 . Dis3L2 targets are oligouridylated by the terminal uridylyl transferases (or TUTs) 14 , 15 , 16 . The specificity toward uridylated RNAs is conferred through a network of base-specific hydrogen bonds along the protein’s extensive RNA-binding surface, as demonstrated by the structure of Mus musculus Dis3L2 (MmDis3L2) in complex with a U 13 RNA 17 . Genetic loss of Dis3L2 causes Perlman syndrome, a congenital overgrowth disorder that is characterized by developmental delay, renal abnormalities, neonatal mortality and high rates of Wilms’ tumors 1 . The first reported physiological substrates of Dis3L2 were the uridylated precursors of let-7 microRNAs 10 , 13 , which play an important role in stem cell differentiation by silencing growth and proliferation genes such as HMGA2 , MYC and Ras 18 , 19 , 20 , 21 , 22 , 23 . Many other noncoding RNA targets have since been reported, including other microRNAs 24 , 25 , transfer RNA fragments 16 , small nuclear RNA 26 , the intermediate of 5.8S ribosomal RNA processing 7S B 27 , the long noncoding RNA RMRP 28 , and the 7SL component of the ribonucleoprotein signal recognition particle required for endoplasmic reticulum-targeted translation 7 . The latter is probably responsible for the Perlman syndrome phenotype, with aberrant uridylated 7SL leading to endoplasmic reticulum calcium leakage that perturbs embryonic stem cell differentiation, particularly in the renal lineage 7 . Unlike a number of structurally similar homologs, Dis3L2 can degrade structured RNAs independent of external helicase activity 1 , 10 , 12 , 29 . Little is known about how Dis3L2 or other capable RNase R/II family nucleases independently degrade structured RNA. We determined the structures of an RNase R/II family nuclease bound to a series of structured RNA substrates and analyzed the kinetic profiles of wild-type Homo sapiens Dis3L2 (HsDis3L2) and engineered mutants to reveal how this nuclease achieves highly efficient degradation of structured RNA. Results Initial binding of Dis3L2 to structured substrates To understand the presubstrate binding state, we used cryogenic electron microscopy (cryo-EM) to determine the structure of RNA-free HsDis3L2 to 3.4 Å resolution (construct Dis3L2 D391N residues 1–858: carboxy (C)-terminal truncation of residues 859–885; and an engineered catalytic mutation of Asp for Asn at residue 391 in Dis3L2) (see Methods , Fig. 1a,b and Extended Data Fig. 1a–c ). RNA-free HsDis3L2 has a vase-like conformation in which three oligonucleotide/oligosaccharide-binding (OB) domains—two cold shock domains (CSDs) and an S1 domain—encircle a funnel-like tunnel that reaches into the Ribonuclease B (RNB) domain and leads to the active site (Fig. 1b and Extended Data Fig. 1d ). The OB domains provide a large positively charged surface, which probably acts as a landing pad for the negatively charged RNA (Fig. 1c ). The overall structure of RNA-free Dis3L2 is very similar to the structure of the mouse Dis3L2–ssRNA complex (MmDis3L2–U 13 ) (root mean square deviation (RMSD) = 1.2 Å, calculated over all Cα pairs) 17 . Thus, the apoenzyme is preorganized to bind single-stranded RNA (ssRNA). Fig. 1: RNA-free Dis3L2 is preorganized to bind RNA substrates. a , Domain compositions of Dis3L2 and the homologous proteins Dis3 and RNase R (green, N-terminal PIN domain; pink, CSD1; orange, CSD2; blue, RNB; purple, S1 domain). b , Side (left) and top or apical (right) views of RNA-free Dis3L2 D391N with domain labels. c , Charge distribution of the Dis3L2 surface from a side view (left) and a view of the apical face (right), as calculated using PyMol APBS at an ionic strength of 150 mM ( Methods ) where k B is the Boltzmann constant, T is the temperature in degrees Kelvin and e c is the unit of charge. Full size image To probe the initial binding of Dis3L2 to structured substrates, we designed a short hairpin RNA mimicking the base of the pre-let-7g stem, with a UUCG tetraloop for stability and a 3′ GC(U) 14 (16-nucleotide) overhang as the uridylated tail (hairpinA–GCU 14 ; Fig. 2a ). The resulting 3.1 Å cryo-EM structure of the Dis3L2 D391N –hairpinA–GCU 14 complex revealed that Dis3L2 maintains the same vase conformation as is observed in the RNA-free form (Fig. 2b and Extended Data Fig. 2 ). However, the double-helical stem of the RNA was not resolved, suggesting that double-stranded RNA (dsRNA) is not stably engaged by the nuclease upon initial substrate association. Nonetheless, the quality of the density allowed assignment of 15 of the 16 nucleotides of the single-stranded 3′ overhang. The RNA follows the same path as is seen in<|im_end|> <|im_start|>assistant RNAs are having a moment. The foundation of COVID-19 vaccines, they've made their way from biochemistry textbooks into popular magazines and everyday discussions. Entire companies have been launched that are dedicated to RNA research. These tiny molecules are traditionally known for helping cells make proteins, but they can do much more. They come in many shapes and sizes, from short and simple hairpin loops to long and seemingly tangled arrangements. RNAs can help activate or deactivate genes, change the shape of chromosomes, and even destroy other RNA molecules. Unfortunately, when RNA malfunctions, it can result in cancer and developmental disorders. It takes a lot to keep RNAs in check. Our cells have molecular "machines" that eliminate RNAs at the right time and place. Most come equipped with a "motor" to generate the energy needed to untangle RNA molecules. But one machine in particular, named Dis3L2, is an exception. The enzyme can unwind and destroy RNA molecules on its own. This action has puzzled scientists for years. Now, Cold Spring Harbor Laboratory (CSHL) biochemists have pieced together what's happening. It turns out Dis3L2 changes shape to unsheathe an RNA-splitting wedge. Using state-of-the-art molecular imaging technology, CSHL Professor and HHMI Investigator Leemor Joshua-Tor and her team captured Dis3L2 at work. They fed the molecular machine hairpin snippets of RNA and imaged it getting "eaten" at various stages. After the machine had chewed up the tip of the RNA, it swung open a big arm of its body to peel apart the hairpin and finish the job. "It's dramatic," Joshua-Tor says. "We know things change conformation. They buckle. But opening something out like that and exposing a region in this way—we didn't quite see something like this before." Katarina Meze, the former graduate student in the Joshua-Tor lab who led this study, standing next to the lab’s cryo-EM imaging machine. The machine allows scientists to freeze molecules in place to study their structure and geometry. Credit: Joshua-Tor lab/CSHL Joshua-Tor's team then began tinkering with the Dis3L2 machine, searching for the gears and parts enabling it to unwind and destroy RNA. The researchers narrowed it down to a protruding wedge left unsheathed after the machine shifted shapes. If the researchers removed the wedge, Dis3L2 could no longer untangle the RNA hairpin, putting the machine out of commission. The findings reveal a surprising new way that RNA-controlling machines in our cells execute their tasks. Rather than solid structures, these molecular workhorses need to be considered malleable and versatile. This new outlook may help scientists develop better treatments for diseases and disorders caused by RNA gone haywire. "We have to start thinking about these things as much more dynamic entities," Joshua-Tor says, "and take that into account when we are designing therapeutics." The findings are published in the journal Nature Structural & Molecular Biology. <|im_end|>
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2,266
[ { "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 Waterfowl hunting in Argentina is a profitable industry that attracts hunters from all over the world. Most hunting occurs as high-end hunting tourism, through which registered outfitters service predominantly foreign clients on private lands. Lead pollution from hunting ammunition is increasingly recognized as a significant local problem, impacting wildlife, aquatic and terrestrial habitats, and extending to vulnerable human rural communities. Regulatory frameworks that restrict lead shot use are a budding success story but remain challenged by their constrained geographic range and limited compliance rooted in unavailable nontoxic ammunition. Changes in hunting practices in Argentina are long overdue. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Introduction Lead pollution from hunting ammunition is a global environmental health problem for which there is a simple and scientifically validated solution, but also an overwhelming resistance to change (Mateo et al. 2014 ; Arnemo et al. 2016 ; Hampton et al. 2018 ). Factors associated with the controversy surrounding lead shot replacement have been addressed elsewhere and remain a standing, unresolved issue of significant health and conservation impact (Friend et al. 2009 ; Cromie et al. 2015 ; Kanstrup 2015 ). Despite worldwide evidence of wildlife and human lead poisoning over nearly a century, rarely have nations acted until local data were garnered and local toxicity demonstrated (Avery and Watson 2009 ; Mateo 2009 ). Hunting pollution was a foreseen yet poorly addressed issue in Argentina until a decade ago when concerns over its magnitude triggered long-delayed research. In this paper, we provide a brief overview of hunting and associated lead pollution in Argentina, describe recent progress in restrictions to toxic ammunition use, highlight remaining obstacles, and recommend actions to overcome these challenges. Hunting in Argentina Sport hunting is significant in Argentina, yet there is a lack of publicly available data to fully assess its extent. An unpublished study conducted by Caselli et al. in 2011 collated information for 16 provinces from government websites ( n = 11) and/or from official responses to email surveys ( n = 5). The remaining seven provinces of the 23 in the country did not respond to the survey and had no accessible information on their websites. At that time, only seven (30%) provinces displayed hunting regulations on their websites, and 3 (13%) had maps showing areas where hunting was and was not allowed. Seven (30%) provinces kept records of annual hunting licenses sold. In terms of government control of hunting, overlap in regulatory mandates between offices charged with natural resource management and hunting control existed in seven provinces (30.4%). In nine provinces (39.1%), government responsibilities were based in different offices. In 2011, small game hunting was allowed for a total 53 native and exotic species and distributed in 16 provinces, with seasons ranging from 1 to 3 months in 6 (37.5%), 4–9 in 8 (50%) and 10–12 in 2 (12.5%). Large game hunting was permitted for 19 native and exotic species, in 12 provinces: during 1–3 months in 1 province (8.3%), 4–9 in 6 (50%), 10–12 in 3 (25%), and 2 (16.6%) provinces had variable seasons per species. Ten provinces allowed waterfowl hunting with daily bag limits for different species ranging from 5 ducks in 2 provinces, to 10 in 3, 12 in 2, and 15 in the remaining 3 provinces. Waterfowl hunting in Argentina Waterfowl hunting in Argentina is a profitable industry that attracts hunters from all over the world (Zaccagnini 2002 ). It has grown considerably since the 1990s (Zaccagnini and Venturino 1992 ; Zaccagnini 2002 ). Most hunting occurs as high-end hunting tourism, through which registered outfitters service predominantly foreign clients on private lands. Footnote 1 While ten provinces allow waterfowl hunting, the largest volume of huntsmen converge at the wetlands of Santa Fe, Corrientes and Entre Ríos provinces. These sites harbor a wide diversity of waterfowl including species protected by the Convention of Migratory Species (CMS) such as flamingos, ducks, swans and plovers, and overlap with several Important Bird Areas (IBA) and Ramsar sites (Benzaquén et al. 2017 ). Although hunting quotas are deemed conservative, there is a paucity of information on waterfowl population status and trends, enforcement is weak and information on registered hunters is often unavailable. Lead toxicity from spent ammunition in waterfowl The massive use of lead ammunition in Argentinean wetlands is relatively recent, compared to Europe and North America. Based on government data, at least 56 tons of ammunition lead were added to wetlands in Santa Fe province alone between 2007 and 2009 by hunting. Non-quantified amounts, but presumably similar levels, are also deposited in other waterfowl hunting hotspots on an annual basis. Since 2007, we have undertaken collaborative studies between local universities (Universidad Nacional del Centro de la Provincia de Buenos Aires - UNICEN, Universidad Nacional del Litoral, and Universidad Nacional del Sur) and various nongovernmental organizations in the provinces of Santa Fe, Corrientes and Buenos Aires. Between 2007 and 2013 we examined 455 hunter-killed ducks for signs of lead exposure. Our study included only authorized species collected during the hunting season by registered hunters. Specifically, we studied the whistling duck ( Dendrocygna bicolor ), white-faced tree duck ( D. viduata ), black-bellied whistling-duck ( D. autumnalis ), rosy-billed pochard ( Netta peposaca ) and Brazilian duck ( Amazonetta brasiliensis ). We found prevalences of lead pellet ingestion that varied between 7.6 and 50%, and lead accumulated in the bones of 100% of these birds due to long-term exposure (Ferreyra et al. 2009 , 2014 ; Natalini et al. 2014 ). We also documented toxic levels of lead in liver (60% prevalence) and blood of ducks (28% of 96 live ducks), which were associated with poor body condition and blood abnormalities (Ferreyra et al. 2014 , 2015 ). Lead pollution from spent ammunition in wetland environments During the same period, we also documented accumulation of lead in natural wetlands and rice fields where waterfowl hunting is practiced. We found spent shot densities in the top 15 cm of wetland sediment", "role": "user" }, { "content": "Pollution from lead ammunition causes environmental health problems in Argentina, and progress is underway to find viable replacements for lead shot, according to an overview of lead pollution from hunting in the country. Argentina's pioneering awareness and attention to this problem may help others address this global health issue that threatens humans, animals and landscapes. The report, compiled by the University of California, Davis' One Health Institute and Universidad Nacional del Centro de la Provincia de Buenos Aires in Argentina, was published April 12 in the journal Ambio. \"Lead pollution is one of the very few environmental problems for which there is a simple solution: Switch from lead to nontoxic ammunition,\" said lead author Marcela Uhart, a wildlife veterinarian with the UC Davis One Health Institute and director of the Latin America Program within UC Davis' Karen C. Drayer Wildlife Health Center. \"We're not saying 'Don't hunt.' We're not asking anyone to change their livelihood or lifestyle. It just needs to be done sustainably, without introducing poison to the land, water, animals and people who live here.\" High-end hunting Hunting is a lucrative industry in Argentina, where registered outfitters cater to mostly foreign clients seeking high-end hunting tourism experiences on private lands, particularly for doves and ducks. Uhart said hunters and outfitters in the country recognize the problem, and some have been working closely with the researchers and government over the past decade to find viable solutions. Many have said they would switch to nontoxic shot if it became more easily available and affordable. A student in Argentina counts birds at a wetland. Waterfowl, wetlands and children near hunting sites in the country have been found to be exposed to lead from ammunition. Credit: Linda C. Alvarez Discussions underway in Argentina indicate that nontoxic steel shot could be manufactured locally as soon as this spring or summer. This would be a very important step forward, as it could help drive down the cost of nontoxic ammunition and encourage the shift away from lead shot. Lead in the land, animals and people Roughly 10,000 hunters visit the \"dove shooting capital\" of Córdoba province each year, adding between 210 and 480 tons of lead to the environment. Conservative estimates suggest at least 56 tons of lead from ammunition were added to wetlands in Santa Fe province between 2007 and 2009, one of Argentina's major sites for waterfowl hunting. Previous studies, referenced in the report, found accumulations of lead from spent shot in: The bones and bodies of hunter-killed ducksWetlands and rice fields where waterfowl hunting is practicedPlants regularly eaten by wildlife and domestic livestock in these areasThe blood and baby teeth of Argentinian children who ate hunted game Lead, a known toxicant that affects humans and animals, accumulates in the body over time, causing severe systemic disorders. Children are particularly vulnerable and can suffer permanent and severe health effects, particularly in their central nervous system. In November 2011, the authors hosted the first national workshop on nontoxic shot in Argentina, which was attended by hunters and ammunition manufacturers. Here, hunters at a shooting range demonstrate ballistics of nontoxic shot during the workshop, which was held to help dispel myths about the efficacy of nontoxic ammunition. Credit: M. Romano Levels of lead referred to in the paper for wildlife and wetlands match reports from other parts of the world with severe contamination problems, and represent just a fraction of the problem. Exposure to lead from bullets has been documented in the near-threatened Andean condor in Argentina, as well. The impacts of lead ammunition pollution on the California condor, demonstrated in part by UC Davis and its partners, was a major reason that state issued a full lead ammunition ban, which goes into effect this July. Science to policy In an example of science leading to policy change, Argentina has taken major steps over the past decade toward addressing this issue. This includes working with the authors to engage key stakeholders at multiple meetings, shooting clinics and through conservation-education community outreach efforts. Some provinces banned lead shot used for waterfowl hunting as soon as the authors shared evidence of the problem. \"We want to commend Argentina for being at the frontier of addressing this while recognizing there is a lot more to be done,\" Uhart said. \"This is a global environmental problem that is serious but avoidable. It's a real One Health example, impacting everyone—humans, the environment and wildlife. But we can change it right now, and there is proof it has worked.\" The paper provides 10 recommendations for policymakers in Argentina to prioritize. They include: Grant state policy status to halting lead toxicity from spent ammunition.Encourage and entice local manufacturing and availability of nontoxic ammunition.Educate foreign hunters visiting Argentina on local efforts to ban lead shot and existing regulations.Increase awareness on ill-effects to human health through dietary intake and the need to avoid exposure through all pathways, particularly in 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 Waterfowl hunting in Argentina is a profitable industry that attracts hunters from all over the world. Most hunting occurs as high-end hunting tourism, through which registered outfitters service predominantly foreign clients on private lands. Lead pollution from hunting ammunition is increasingly recognized as a significant local problem, impacting wildlife, aquatic and terrestrial habitats, and extending to vulnerable human rural communities. Regulatory frameworks that restrict lead shot use are a budding success story but remain challenged by their constrained geographic range and limited compliance rooted in unavailable nontoxic ammunition. Changes in hunting practices in Argentina are long overdue. Access provided by Universität des es, -und Working on a manuscript? Avoid the common mistakes Introduction Lead pollution from hunting ammunition is a global environmental health problem for which there is a simple and scientifically validated solution, but also an overwhelming resistance to change (Mateo et al. 2014 ; Arnemo et al. 2016 ; Hampton et al. 2018 ). Factors associated with the controversy surrounding lead shot replacement have been addressed elsewhere and remain a standing, unresolved issue of significant health and conservation impact (Friend et al. 2009 ; Cromie et al. 2015 ; Kanstrup 2015 ). Despite worldwide evidence of wildlife and human lead poisoning over nearly a century, rarely have nations acted until local data were garnered and local toxicity demonstrated (Avery and Watson 2009 ; Mateo 2009 ). Hunting pollution was a foreseen yet poorly addressed issue in Argentina until a decade ago when concerns over its magnitude triggered long-delayed research. In this paper, we provide a brief overview of hunting and associated lead pollution in Argentina, describe recent progress in restrictions to toxic ammunition use, highlight remaining obstacles, and recommend actions to overcome these challenges. Hunting in Argentina Sport hunting is significant in Argentina, yet there is a lack of publicly available data to fully assess its extent. An unpublished study conducted by Caselli et al. in 2011 collated information for 16 provinces from government websites ( n = 11) and/or from official responses to email surveys ( n = 5). The remaining seven provinces of the 23 in the country did not respond to the survey and had no accessible information on their websites. At that time, only seven (30%) provinces displayed hunting regulations on their websites, and 3 (13%) had maps showing areas where hunting was and was not allowed. Seven (30%) provinces kept records of annual hunting licenses sold. In terms of government control of hunting, overlap in regulatory mandates between offices charged with natural resource management and hunting control existed in seven provinces (30.4%). In nine provinces (39.1%), government responsibilities were based in different offices. In 2011, small game hunting was allowed for a total 53 native and exotic species and distributed in 16 provinces, with seasons ranging from 1 to 3 months in 6 (37.5%), 4–9 in 8 (50%) and 10–12 in 2 (12.5%). Large game hunting was permitted for 19 native and exotic species, in 12 provinces: during 1–3 months in 1 province (8.3%), 4–9 in 6 (50%), 10–12 in 3 (25%), and 2 (16.6%) provinces had variable seasons per species. Ten provinces allowed waterfowl hunting with daily bag limits for different species ranging from 5 ducks in 2 provinces, to 10 in 3, 12 in 2, and 15 in the remaining 3 provinces. Waterfowl hunting in Argentina Waterfowl hunting in Argentina is a profitable industry that attracts hunters from all over the world (Zaccagnini 2002 ). It has grown considerably since the 1990s (Zaccagnini and Venturino 1992 ; Zaccagnini 2002 ). Most hunting occurs as high-end hunting tourism, through which registered outfitters service predominantly foreign clients on private lands. Footnote 1 While ten provinces allow waterfowl hunting, the largest volume of huntsmen converge at the wetlands of Santa Fe, Corrientes and Entre Ríos provinces. These sites harbor a wide diversity of waterfowl including species protected by the Convention of Migratory Species (CMS) such as flamingos, ducks, swans and plovers, and overlap with several Important Bird Areas (IBA) and Ramsar sites (Benzaquén et al. 2017 ). Although hunting quotas are deemed conservative, there is a paucity of information on waterfowl population status and trends, enforcement is weak and information on registered hunters is often unavailable. Lead toxicity from spent ammunition in waterfowl The massive use of lead ammunition in Argentinean wetlands is relatively recent, compared to Europe and North America. Based on government data, at least 56 tons of ammunition lead were added to wetlands in Santa Fe province alone between 2007 and 2009 by hunting. Non-quantified amounts, but presumably similar levels, are also deposited in other waterfowl hunting hotspots on an annual basis. Since 2007, we have undertaken collaborative studies between local universities (Universidad Nacional del Centro de la Provincia de Buenos Aires - UNICEN, Universidad Nacional del Litoral, and Universidad Nacional del Sur) and various nongovernmental organizations in the provinces of Santa Fe, Corrientes and Buenos Aires. Between 2007 and 2013 we examined 455 hunter-killed ducks for signs of lead exposure. Our study included only authorized species collected during the hunting season by registered hunters. Specifically, we studied the whistling duck ( Dendrocygna bicolor ), white-faced tree duck ( D. viduata ), black-bellied whistling-duck ( D. autumnalis ), rosy-billed pochard ( Netta peposaca ) and Brazilian duck ( Amazonetta brasiliensis ). We found prevalences of lead pellet ingestion that varied between 7.6 and 50%, and lead accumulated in the bones of 100% of these birds due to long-term exposure (Ferreyra et al. 2009 , 2014 ; Natalini et al. 2014 ). We also documented toxic levels of lead in liver (60% prevalence) and blood of ducks (28% of 96 live ducks), which were associated with poor body condition and blood abnormalities (Ferreyra et al. 2014 , 2015 ). Lead pollution from spent ammunition in wetland environments During the same period, we also documented accumulation of lead in natural wetlands and rice fields where waterfowl hunting is practiced. We found spent shot densities in the top 15 cm of wetland sediment<|im_end|> <|im_start|>assistant Pollution from lead ammunition causes environmental health problems in Argentina, and progress is underway to find viable replacements for lead shot, according to an overview of lead pollution from hunting in the country. Argentina's pioneering awareness and attention to this problem may help others address this global health issue that threatens humans, animals and landscapes. The report, compiled by the University of California, Davis' One Health Institute and Universidad Nacional del Centro de la Provincia de Buenos Aires in Argentina, was published April 12 in the journal Ambio. "Lead pollution is one of the very few environmental problems for which there is a simple solution: Switch from lead to nontoxic ammunition," said lead author Marcela Uhart, a wildlife veterinarian with the UC Davis One Health Institute and director of the Latin America Program within UC Davis' Karen C. Drayer Wildlife Health Center. "We're not saying 'Don't hunt.' We're not asking anyone to change their livelihood or lifestyle. It just needs to be done sustainably, without introducing poison to the land, water, animals and people who live here." High-end hunting Hunting is a lucrative industry in Argentina, where registered outfitters cater to mostly foreign clients seeking high-end hunting tourism experiences on private lands, particularly for doves and ducks. Uhart said hunters and outfitters in the country recognize the problem, and some have been working closely with the researchers and government over the past decade to find viable solutions. Many have said they would switch to nontoxic shot if it became more easily available and affordable. A student in Argentina counts birds at a wetland. Waterfowl, wetlands and children near hunting sites in the country have been found to be exposed to lead from ammunition. Credit: Linda C. Alvarez Discussions underway in Argentina indicate that nontoxic steel shot could be manufactured locally as soon as this spring or summer. This would be a very important step forward, as it could help drive down the cost of nontoxic ammunition and encourage the shift away from lead shot. Lead in the land, animals and people Roughly 10,000 hunters visit the "dove shooting capital" of Córdoba province each year, adding between 210 and 480 tons of lead to the environment. Conservative estimates suggest at least 56 tons of lead from ammunition were added to wetlands in Santa Fe province between 2007 and 2009, one of Argentina's major sites for waterfowl hunting. Previous studies, referenced in the report, found accumulations of lead from spent shot in: The bones and bodies of hunter-killed ducksWetlands and rice fields where waterfowl hunting is practicedPlants regularly eaten by wildlife and domestic livestock in these areasThe blood and baby teeth of Argentinian children who ate hunted game Lead, a known toxicant that affects humans and animals, accumulates in the body over time, causing severe systemic disorders. Children are particularly vulnerable and can suffer permanent and severe health effects, particularly in their central nervous system. In November 2011, the authors hosted the first national workshop on nontoxic shot in Argentina, which was attended by hunters and ammunition manufacturers. Here, hunters at a shooting range demonstrate ballistics of nontoxic shot during the workshop, which was held to help dispel myths about the efficacy of nontoxic ammunition. Credit: M. Romano Levels of lead referred to in the paper for wildlife and wetlands match reports from other parts of the world with severe contamination problems, and represent just a fraction of the problem. Exposure to lead from bullets has been documented in the near-threatened Andean condor in Argentina, as well. The impacts of lead ammunition pollution on the California condor, demonstrated in part by UC Davis and its partners, was a major reason that state issued a full lead ammunition ban, which goes into effect this July. Science to policy In an example of science leading to policy change, Argentina has taken major steps over the past decade toward addressing this issue. This includes working with the authors to engage key stakeholders at multiple meetings, shooting clinics and through conservation-education community outreach efforts. Some provinces banned lead shot used for waterfowl hunting as soon as the authors shared evidence of the problem. "We want to commend Argentina for being at the frontier of addressing this while recognizing there is a lot more to be done," Uhart said. "This is a global environmental problem that is serious but avoidable. It's a real One Health example, impacting everyone—humans, the environment and wildlife. But we can change it right now, and there is proof it has worked." The paper provides 10 recommendations for policymakers in Argentina to prioritize. They include: Grant state policy status to halting lead toxicity from spent ammunition.Encourage and entice local manufacturing and availability of nontoxic ammunition.Educate foreign hunters visiting Argentina on local efforts to ban lead shot and existing regulations.Increase awareness on ill-effects to human health through dietary intake and the need to avoid exposure through all pathways, particularly in children. <|im_end|>
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37085, 320, 8339, 27625, 46496, 4008, 87778, 7609, 1226, 1766, 26413, 2436, 315, 3063, 68510, 88447, 430, 28830, 1990, 220, 22, 13, 21, 323, 220, 1135, 13689, 323, 3063, 41165, 304, 279, 25896, 315, 220, 1041, 4, 315, 1521, 20229, 4245, 311, 1317, 9860, 14675, 320, 37, 261, 8233, 969, 1880, 453, 13, 220, 1049, 24, 1174, 220, 679, 19, 2652, 42701, 6729, 1880, 453, 13, 220, 679, 19, 7609, 1226, 1101, 27470, 21503, 5990, 315, 3063, 304, 26587, 320, 1399, 4, 38009, 8, 323, 6680, 315, 78878, 320, 1591, 4, 315, 220, 4161, 3974, 78878, 705, 902, 1051, 5938, 449, 8009, 2547, 3044, 323, 6680, 75815, 320, 37, 261, 8233, 969, 1880, 453, 13, 220, 679, 19, 1174, 220, 679, 20, 7609, 30982, 25793, 505, 7543, 37768, 304, 14739, 1974, 22484, 12220, 279, 1890, 4261, 11, 584, 1101, 27470, 46835, 315, 3063, 304, 5933, 14739, 8329, 323, 20228, 5151, 1405, 3090, 69, 9802, 23330, 374, 44664, 13, 1226, 1766, 7543, 6689, 90816, 304, 279, 1948, 220, 868, 10166, 315, 14739, 1974, 59132, 128257, 198, 128256, 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25, 39162, 356, 13, 77815, 98225, 38199, 304, 32164, 13519, 430, 308, 546, 82329, 9699, 6689, 1436, 387, 28648, 24392, 439, 5246, 439, 420, 10683, 477, 7474, 13, 1115, 1053, 387, 264, 1633, 3062, 3094, 4741, 11, 439, 433, 1436, 1520, 6678, 1523, 279, 2853, 315, 308, 546, 82329, 37768, 323, 15253, 279, 6541, 3201, 505, 3063, 6689, 13, 30982, 304, 279, 4363, 11, 10099, 323, 1274, 58421, 398, 220, 605, 11, 931, 49073, 4034, 279, 330, 67, 1009, 10658, 6864, 1, 315, 108430, 6634, 27931, 17271, 1855, 1060, 11, 7999, 1990, 220, 8848, 323, 220, 11738, 20181, 315, 3063, 311, 279, 4676, 13, 30071, 17989, 4284, 520, 3325, 220, 3487, 20181, 315, 3063, 505, 37768, 1051, 3779, 311, 14739, 8329, 304, 16376, 3926, 17271, 1990, 220, 1049, 22, 323, 220, 1049, 24, 11, 832, 315, 32164, 596, 3682, 6732, 369, 3090, 69, 9802, 23330, 13, 30013, 7978, 11, 25819, 304, 279, 1934, 11, 1766, 15783, 7607, 315, 3063, 505, 7543, 6689, 304, 25, 578, 25896, 323, 13162, 315, 40827, 12934, 4473, 78878, 54, 295, 8329, 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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 Serotonin and dopamine are putatively involved in the etiology and treatment of anxiety disorders, but positron emission tomography (PET) studies probing the two neurotransmitters in the same individuals are lacking. The aim of this multitracer PET study was to evaluate the regional expression and co-expression of the transporter proteins for serotonin (SERT) and dopamine (DAT) in patients with social anxiety disorder (SAD). Voxel-wise binding potentials (BP ND ) for SERT and DAT were determined in 27 patients with SAD and 43 age- and sex-matched healthy controls, using the radioligands [ 11 C]DASB (3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile) and [ 11 C]PE2I (N-(3-iodopro-2E-enyl)-2beta-carbomethoxy-3beta-(4′-methylphenyl)nortropane). Results showed that, within transmitter systems, SAD patients exhibited higher SERT binding in the nucleus accumbens while DAT availability in the amygdala, hippocampus, and putamen correlated positively with symptom severity. At a more lenient statistical threshold, SERT and DAT BP ND were also higher in other striatal and limbic regions in patients, and correlated with symptom severity, whereas no brain region showed higher binding in healthy controls. Moreover, SERT/DAT co-expression was significantly higher in SAD patients in the amygdala, nucleus accumbens, caudate, putamen, and posterior ventral thalamus, while lower co-expression was noted in the dorsomedial thalamus. Follow-up logistic regression analysis confirmed that SAD diagnosis was significantly predicted by the statistical interaction between SERT and DAT availability, in the amygdala, putamen, and dorsomedial thalamus. Thus, SAD was associated with mainly increased expression and co-expression of the transporters for serotonin and dopamine in fear and reward-related brain regions. Resultant monoamine dysregulation may underlie SAD symptomatology and constitute a target for treatment. Introduction Social anxiety disorder (SAD) is a highly common psychiatric condition associated with anxious and avoidant behavior in any situation where the individual is subject to scrutiny or becomes the center of attention. This is often a lifelong problem affecting the personal as well as the professional domain [ 1 ]. The biological basis of this disorder is still largely unknown although functional neuroimaging studies of SAD have reported aberrant activation and functional connectivity of the amygdala, and other nodes of the brain’s fear network, in response to socially threatening stimuli [ 2 ]. Serotonin has long been implicated in the regulation of mood and anxiety [ 3 , 4 ] and because this neurotransmitter is a major target for pharmaceuticals that are effective for SAD [ 5 ] it may be of particular etiological relevance. In earlier nuclear imaging research, patients with SAD exhibited reduced serotonin-1A receptor binding in limbic and paralimbic regions including the amygdala and dorsal raphe nuclei [ 6 ]. Moreover, a PET study from our group reported increased presynaptic serotonin synthesis in the amygdala, raphe nuclei, striatum, hippocampus, and anterior cingulate cortex (ACC) [ 7 ] and these results were essentially replicated in a separate cohort of patients and controls [ 8 ]. Interestingly, amygdala serotonin synthesis capacity correlated with social anxiety symptom severity [ 7 ] and was reduced, concomitantly with stress-related amygdala activation, after successful pharmacological treatment [ 9 ]. There are also two previous nuclear imaging studies on the serotonin transporter (SERT), both noting higher SERT binding potential (BP) in SAD patients in the thalamus [ 7 , 10 ] and additionally in the raphe nuclei region, striatum, and insula [ 7 ]. The latter findings were demonstrated by use of PET and [ 11 C]DASB (3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile), a highly selective ligand to the SERT [ 11 ]. Based on these results, we previously suggested that SAD entails an overactive presynaptic serotonergic system [ 7 , 8 ]. While mesocortical [ 12 ] and mesolimbic [ 13 ] dopaminergic neurons are also sensitive to aversive stimuli, the dopamine system has a crucial role in driving prosocial behavior, reward processing, positive affect, and approach motivation [ 14 , 15 , 16 , 17 ]. Because it has been reported that SAD is associated with diminished pleasure from social activity and social-motivational dysfunction, an etiologic role for dopamine has been suggested in this disorder [ 18 ]. However, only a few nuclear imaging studies have examined putative dopamine abnormalities in SAD [ 19 ]. Altered striatal [ 20 , 21 , 22 ] and extra-striatal [ 23 ] dopamine D2 binding have been evaluated but findings have been mixed. Results from studies targeting the dopamine transporter (DAT) are also inconclusive, noting either increased [ 10 ] or decreased [ 24 ] transporter availability in SAD as well as no difference between SAD patients and healthy controls [ 22 ]. Interestingly, Warwick et al. reported increased striatal DAT binding after the treatment of SAD with the SSRI escitalopram [ 25 ] suggesting serotonergic influences on dopamine signaling. It should be noted that all previous nuclear imaging studies targeting the DAT in SAD have used SPECT with ligands that are not specific for DATs. In comparison, PET images have higher resolution than SPECT and radioligands that bind highly selectively to DAT, like [ 11 C]PE2I (N-(3-iodoprop-2E-enyl)-2b-carbomethoxy-3b-(4-methyl-phenyl)nortropane), can now be used to improve data quality [ 26 ]. Biopsychological theories of personality have proposed that approach-avoidance conflicts in social situations, a prominent feature of SAD symptomatology, reflect the balance between serotonin and dopamine signaling in neural pathways underlying fear and reward [ 27 , 28 , 29 , 30 ]. Consistent with these theoretical models, pharmacological and anatomical studies support that the serotonin and dopamine systems have reciprocal functional influences on each other [ 31 , 32 , 33 , 34 ]. At the anatomical level, serotonergic cell bodies in the raphae nuclei project to the striatum where their axon terminals are in close proximity to dopamine cells [ 35 ] and, in rats, there is evidence of a direct serotonergic inhibitory input from the median raphe nucleus to the dopaminergic substantia nigra neurons [ 36 ]. However, it is not known if serotonin-dopamine interactions are involved in the pathophysiology of anxiety disorders like SAD, and nuclear imaging studies directly addressing this topic are therefore needed. Transporter functions may be particularly relevant targets for such studies [ 37 ]. For", "role": "user" }, { "content": "The balance between the neurotransmitters serotonin and dopamine may affect whether a person develops social anxiety disorder. Previous research has mainly focused on either the serotonin or the dopamine system individually. Now researchers at Uppsala University have demonstrated the existence of a previously unknown link between the two. The results are published in Molecular Psychiatry. \"We see that there is a different balance between serotonin and dopamine transport in people with social anxiety disorder compared with control subjects. The interaction between serotonin and dopamine transport explained more of the difference between the groups than each carrier individually. This suggests one should not focus exclusively on one signal substance at a time, the balance between different systems may be more important,\" says Olof Hjorth, Ph.D. student at the Department of Psychology at Uppsala University, Sweden. Social anxiety can be a highly debilitating psychiatric disorder with negative impacts on the individual's relationships and working life. This study shows that affected people may have an imbalance between the serotonin and dopamine transporters in the amygdala and other brain areas that are important for fear, motivation and social behavior. The functioning of the brain's signal substances is affected by the amount of reuptake by the transmitter cell, which is controlled by specific transporter proteins. \"Previously, we have found an increased production and altered reuptake of serotonin in sufferers of social anxiety disorder, a finding we now, in part, replicate,\" says Hjorth. He adds, \"We can now show that dopamine reuptake is also directly related to the severity of the social anxiety symptoms that the individual is experiencing.\" The method used in the study is called positron emission tomography (PET), in which radioactive agents, injected into the blood stream, decay and release a signal that allows the scientists to determine the density of available transporter proteins in different areas of the brain. The researchers hope that the current findings can lead to a better understanding of the causes of social anxiety and ultimately to new, more effective treatments. \"Many of the patients we meet have symptoms that affect all parts of their everyday life, and many of them have suffered for most of their lives, so understanding the cause and finding effective treatments are our highest priority,\" says Hjorth. ", "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 Serotonin and dopamine are putatively involved in the etiology and treatment of anxiety disorders, but positron emission tomography (PET) studies probing the two neurotransmitters in the same individuals are lacking. The aim of this multitracer PET study was to evaluate the regional expression and co-expression of the transporter proteins for serotonin (SERT) and dopamine (DAT) in patients with social anxiety disorder (SAD). Voxel-wise binding potentials (BP ND ) for SERT and DAT were determined in 27 patients with SAD and 43 age- and sex-matched healthy controls, using the radioligands [ 11 C]DASB (3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile) and [ 11 C]PE2I (N-(3-iodopro-2E-enyl)-2beta-carbomethoxy-3beta-(4′-methylphenyl)nortropane). Results showed that, within transmitter systems, SAD patients exhibited higher SERT binding in the nucleus accumbens while DAT availability in the amygdala, hippocampus, and putamen correlated positively with symptom severity. At a more lenient statistical threshold, SERT and DAT BP ND were also higher in other striatal and limbic regions in patients, and correlated with symptom severity, whereas no brain region showed higher binding in healthy controls. Moreover, SERT/DAT co-expression was significantly higher in SAD patients in the amygdala, nucleus accumbens, caudate, putamen, and posterior ventral thalamus, while lower co-expression was noted in the dorsomedial thalamus. Follow-up logistic regression analysis confirmed that SAD diagnosis was significantly predicted by the statistical interaction between SERT and DAT availability, in the amygdala, putamen, and dorsomedial thalamus. Thus, SAD was associated with mainly increased expression and co-expression of the transporters for serotonin and dopamine in fear and reward-related brain regions. Resultant monoamine dysregulation may underlie SAD symptomatology and constitute a target for treatment. Introduction Social anxiety disorder (SAD) is a highly common psychiatric condition associated with anxious and avoidant behavior in any situation where the individual is subject to scrutiny or becomes the center of attention. This is often a lifelong problem affecting the personal as well as the professional domain [ 1 ]. The biological basis of this disorder is still largely unknown although functional neuroimaging studies of SAD have reported aberrant activation and functional connectivity of the amygdala, and other nodes of the brain’s fear network, in response to socially threatening stimuli [ 2 ]. Serotonin has long been implicated in the regulation of mood and anxiety [ 3 , 4 ] and because this neurotransmitter is a major target for pharmaceuticals that are effective for SAD [ 5 ] it may be of particular etiological relevance. In earlier nuclear imaging research, patients with SAD exhibited reduced serotonin-1A receptor binding in limbic and paralimbic regions including the amygdala and dorsal raphe nuclei [ 6 ]. Moreover, a PET study from our group reported increased presynaptic serotonin synthesis in the amygdala, raphe nuclei, striatum, hippocampus, and anterior cingulate cortex (ACC) [ 7 ] and these results were essentially replicated in a separate cohort of patients and controls [ 8 ]. Interestingly, amygdala serotonin synthesis capacity correlated with social anxiety symptom severity [ 7 ] and was reduced, concomitantly with stress-related amygdala activation, after successful pharmacological treatment [ 9 ]. There are also two previous nuclear imaging studies on the serotonin transporter (SERT), both noting higher SERT binding potential (BP) in SAD patients in the thalamus [ 7 , 10 ] and additionally in the raphe nuclei region, striatum, and insula [ 7 ]. The latter findings were demonstrated by use of PET and [ 11 C]DASB (3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile), a highly selective ligand to the SERT [ 11 ]. Based on these results, we previously suggested that SAD entails an overactive presynaptic serotonergic system [ 7 , 8 ]. While mesocortical [ 12 ] and mesolimbic [ 13 ] dopaminergic neurons are also sensitive to aversive stimuli, the dopamine system has a crucial role in driving prosocial behavior, reward processing, positive affect, and approach motivation [ 14 , 15 , 16 , 17 ]. Because it has been reported that SAD is associated with diminished pleasure from social activity and social-motivational dysfunction, an etiologic role for dopamine has been suggested in this disorder [ 18 ]. However, only a few nuclear imaging studies have examined putative dopamine abnormalities in SAD [ 19 ]. Altered striatal [ 20 , 21 , 22 ] and extra-striatal [ 23 ] dopamine D2 binding have been evaluated but findings have been mixed. Results from studies targeting the dopamine transporter (DAT) are also inconclusive, noting either increased [ 10 ] or decreased [ 24 ] transporter availability in SAD as well as no difference between SAD patients and healthy controls [ 22 ]. Interestingly, Warwick et al. reported increased striatal DAT binding after the treatment of SAD with the SSRI escitalopram [ 25 ] suggesting serotonergic influences on dopamine signaling. It should be noted that all previous nuclear imaging studies targeting the DAT in SAD have used SPECT with ligands that are not specific for DATs. In comparison, PET images have higher resolution than SPECT and radioligands that bind highly selectively to DAT, like [ 11 C]PE2I (N-(3-iodoprop-2E-enyl)-2b-carbomethoxy-3b-(4-methyl-phenyl)nortropane), can now be used to improve data quality [ 26 ]. Biopsychological theories of personality have proposed that approach-avoidance conflicts in social situations, a prominent feature of SAD symptomatology, reflect the balance between serotonin and dopamine signaling in neural pathways underlying fear and reward [ 27 , 28 , 29 , 30 ]. Consistent with these theoretical models, pharmacological and anatomical studies support that the serotonin and dopamine systems have reciprocal functional influences on each other [ 31 , 32 , 33 , 34 ]. At the anatomical level, serotonergic cell bodies in the raphae nuclei project to the striatum where their axon terminals are in close proximity to dopamine cells [ 35 ] and, in rats, there is evidence of a direct serotonergic inhibitory input from the median raphe nucleus to the dopaminergic substantia nigra neurons [ 36 ]. However, it is not known if serotonin-dopamine interactions are involved in the pathophysiology of anxiety disorders like SAD, and nuclear imaging studies directly addressing this topic are therefore needed. Transporter functions may be particularly relevant targets for such studies [ 37 ]. For<|im_end|> <|im_start|>assistant The balance between the neurotransmitters serotonin and dopamine may affect whether a person develops social anxiety disorder. Previous research has mainly focused on either the serotonin or the dopamine system individually. Now researchers at Uppsala University have demonstrated the existence of a previously unknown link between the two. The results are published in Molecular Psychiatry. "We see that there is a different balance between serotonin and dopamine transport in people with social anxiety disorder compared with control subjects. The interaction between serotonin and dopamine transport explained more of the difference between the groups than each carrier individually. This suggests one should not focus exclusively on one signal substance at a time, the balance between different systems may be more important," says Olof Hjorth, Ph.D. student at the Department of Psychology at Uppsala University, Sweden. Social anxiety can be a highly debilitating psychiatric disorder with negative impacts on the individual's relationships and working life. This study shows that affected people may have an imbalance between the serotonin and dopamine transporters in the amygdala and other brain areas that are important for fear, motivation and social behavior. The functioning of the brain's signal substances is affected by the amount of reuptake by the transmitter cell, which is controlled by specific transporter proteins. "Previously, we have found an increased production and altered reuptake of serotonin in sufferers of social anxiety disorder, a finding we now, in part, replicate," says Hjorth. He adds, "We can now show that dopamine reuptake is also directly related to the severity of the social anxiety symptoms that the individual is experiencing." The method used in the study is called positron emission tomography (PET), in which radioactive agents, injected into the blood stream, decay and release a signal that allows the scientists to determine the density of available transporter proteins in different areas of the brain. The researchers hope that the current findings can lead to a better understanding of the causes of social anxiety and ultimately to new, more effective treatments. "Many of the patients we meet have symptoms that affect all parts of their everyday life, and many of them have suffered for most of their lives, so understanding the cause and finding effective treatments are our highest priority," says Hjorth. <|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 We demonstrate residual channel attention networks (RCAN) for the restoration and enhancement of volumetric time-lapse (four-dimensional) fluorescence microscopy data. First we modify RCAN to handle image volumes, showing that our network enables denoising competitive with three other state-of-the-art neural networks. We use RCAN to restore noisy four-dimensional super-resolution data, enabling image capture of over tens of thousands of images (thousands of volumes) without apparent photobleaching. Second, using simulations we show that RCAN enables resolution enhancement equivalent to, or better than, other networks. Third, we exploit RCAN for denoising and resolution improvement in confocal microscopy, enabling ~2.5-fold lateral resolution enhancement using stimulated emission depletion microscopy ground truth. Fourth, we develop methods to improve spatial resolution in structured illumination microscopy using expansion microscopy data as ground truth, achieving improvements of ~1.9-fold laterally and ~3.6-fold axially. Finally, we characterize the limits of denoising and resolution enhancement, suggesting practical benchmarks for evaluation and further enhancement of network performance. Main All fluorescence microscopes suffer drawbacks and tradeoffs because they partition a finite signal budget in space and time. These limitations manifest when comparing different microscope types (for example, three-dimensional (3D) structured illumination microscopy 1 (SIM) offers better spatial resolution than high-numerical-aperture light-sheet microscopy 2 but worse photobleaching); different implementations of the same microscope type (for example, traditional implementations of SIM offer better spatial resolution than instant SIM (iSIM) 3 but worse depth penetration and lower speed 4 ); and, within the same microscope, longer exposures and bigger pixels increase signal-to-noise ratio (SNR) at the expense of speed and resolution 5 . Performance tradeoffs are especially severe 6 when considering live-cell super-resolution microscopy applications, in which the desired spatiotemporal resolution must be balanced against sample health 7 . Deep learning 8 , which harnesses neural networks for data-driven statistical inference, has emerged as a promising method for alleviation of the drawbacks in fluorescence microscopy. Content-aware image restoration (CARE 9 ) networks use the popular U-net 10 neural network architecture in conjunction with synthetic, semisynthetic and physically acquired training data to improve resolution, resolution isotropy and SNR in fluorescence images. U-nets have also been incorporated into generative adversarial networks (GAN 11 ) that enable cross-modality super-resolution microscopy, transforming confocal images into stimulated emission depletion (STED) images 12 or transforming a series of wide-field or sparse localization microscopy images into high-resolution (HR) localization microscopy images 13 . Other recent examples include denoising confocal 14 or SIM 15 data and deconvolving light-sheet data 16 . Here we investigate the use of an alternative network architecture, RCAN 17 , for use in super-resolution microscopy applications. RCAN has been shown to preferentially learn high-spatial-frequency detail within natural scene images, but this capability has not been exploited for image restoration in fluorescence microscopy applications, nor on longitudinally acquired image volumes. First we modify RCAN for 3D applications, showing that it matches or exceeds the performance of previous networks in denoising fluorescence microscopy data. We apply this capability for super-resolution imaging over thousands of image volumes (tens of thousands of images). Second, we characterize RCAN and other networks in terms of their ability to extend resolution, finding that RCAN provides better resolution enhancement than alternatives, especially along the axial dimension. Finally, we demonstrate four- to fivefold volumetric resolution improvement in multiple fixed- and live-cell samples when using STED and expansion-microscopy 18 ground truth to train RCAN models. Results RCAN enables super-resolution imaging over thousands of volumes The original RCAN was proposed specifically for resolution enhancement 17 . A key challenge in this task is the need to bypass abundant low spatial frequencies in the input image in favor of HR prediction. The RCAN architecture achieves this by employing multiple skip connections between network layers to bypass low-resolution (LR) content, as well as a ‘channel attention’ mechanism 19 that adaptively rescales each channel-wise feature by modeling interdependencies across feature channels. We modified the original RCAN architecture to handle image volumes rather than images, which also improves network efficiency so that our modified 3D RCAN model fits within graphics processing unit (GPU) memory (Fig. 1a , Methods and Supplementary Note 1 ). Fig. 1: Residual channel attention networks denoise super-resolution data. a , The RCAN architecture used throughout this work. Matched low and high-SNR image volumes are used to train our RCAN, a residual-in-residual structure consisting of several residual groups (dark blue, red outline) with long skip connections. Each residual group contains additional RCAB (light blue, blue outline) with short skip connections, convolution, ReLu, sigmoid and pooling operations. Long and short skip connections, as well as shortcuts within the residual blocks, allow abundant bypassing of low-frequency information through such identity-based skip connections, facilitating the learning of high-frequency information. A channel attention mechanism within the RCAB further aids the representational ability of the network in learning HR information. b , Left: noisy raw iSIM data acquired with low-intensity illumination, low-noise deconvolved GT data acquired with high-intensity illumination, RCAN, CARE, SRResNet and ESRGAN output. Lateral (upper) and axial (lower) cross-sections are shown. Samples are fixed U2OS cells expressing mEmerald-Tomm20 imaged via iSIM. Right: comparison of network output using 3D SSIM and PSNR. Means and standard deviations are reported, obtained from n = 10 volumes (Supplementary Figs. 1– 3 ). c , RCAN performance at different input SNR levels, simulated by the addition of Gaussian and Poisson noise to raw input. Noisy raw input data at SNR 2.1 (top row) and 5.1 (bottom row) were used to generate predictions, which were then compared to ground truth. SNR values are calculated as the mean of values within the yellow rectangular regions. Higher-magnification views of mitochondria (marked in yellow rectangular regions) are shown at lower right (Supplementary Fig. 6 ). d , FWHM values (mean ± s.d.) from ten microtubule filaments for deconvolved, high-SNR GT, noisy iSIM input (Raw) and network output (RCAN). e , RCAN denoising enables the collection of thousands of iSIM volumes without photobleaching. Mitochondria in live U2OS cells were labeled with pShooter pEF-Myc-mito-GFP and imaged with high- (360 W cm –2 ) and low- (4.2", "role": "user" }, { "content": "Fluorescence imaging uses laser light to obtain bright, detailed images of cells and even sub-cellular structures. However, if you want to watch what a living cell is doing, such as dividing into two cells, the laser may fry it and kill it. One answer is to use less light so the cell will not be damaged and can proceed with its various cellular processes. But, with such low levels of light there is not much signal for a microscope to detect. It's a faint, blurry mess. In new work published in the June issue of Nature Methods a team of microscopists and computer scientists used a type of artificial intelligence called a neural network to obtain clearer pictures of cells at work even with extremely low, cell-friendly light levels. The team, led by Hari Shroff, Ph.D., Senior Investigator in the National Institute of Biomedical Imaging and Bioengineering, and Jiji Chen, of the trans-NIH Advanced Imaging and Microscopy Facility call the process \"image restoration.\" The method addresses the two phenomena that cause low-light fuzzy images—low signal to noise ratio (SNR) and low resolution (blurriness). To tackle the problem they trained a neural network to denoise noisy images and deblur blurry images. So what exactly is training a neural network? It involves showing a computer program many matched pairs of images. The pairs consist of a clear, sharp image of, say, the mitochondria of a cell, and the blurry, unrecognizable version of the same mitochondria. The neural network is shown many of these matched sets and therefore \"learns\" to predict what a blurry image would look like if it were sharpened up. Thus, the neural network becomes capable of taking blurry images created using low-light levels and converting them into the sharper, more detailed images scientists need in order to study what is going on in a cell. To work on denoising and deblurring 3D fluorescence microscopy images, Shroff, Chen and their colleagues collaborated with a company, SVision (now part of Leica), to refine a particular kind of neural network called a residual channel attention network or RCAN. Images of nuclear pores created with diffraction-limited confocal microscope (left) are blurry. Using a super-resolution microscope the nuclear pores are much better resolved (GT, ground truth image). At the far right the RCAN network was shown the blurry confocal image and predicted the sharp image, which much better resembles the high resolution GT image. Scale bar = 5 micrometers. Credit: Jiji Chen In particular, the researchers focused on restoring \"super-resolution\" image volumes, so-called because they reveal extremely detailed images of tiny parts that make up a cell. The images are displayed as a 3D block that can be viewed from all angles as it rotates. The team obtained thousands of image volumes using microscopes in their lab and other laboratories at NIH. When they obtained images taken with very low illumination light, the cells were not damaged, but the images were very noisy and unusable—low SNR. By using the RCAN method, the images were denoised to create a sharp, accurate, usable 3D image. \"We were able to 'beat' the limitations of the microscope by using artificial intelligence to 'predict' the high SNR image from the low SNR image,\" explained Shroff. \"Photodamage in super-resolution imaging is a major problem, so the fact that we were able to circumvent it is significant.\" In some cases, the researchers were able to enhance spatial resolution several-fold over the noisy data presented to the 3D RCAN. Another aim of the study was determining just how messy of an image the researchers could present to the RCAN network—challenging it to turn a very low resolution image into a usable picture. In an \"extreme blurring\" exercise, the research team found that at large levels of experimental blurring, the RCAN was no longer able to decipher what it was looking at and turn it into a usable picture. \"One thing I'm particularly proud of is that we pushed this technique until it 'broke,'\" explained Shroff. \"We characterized the SNR regimen on a continuum, showing the point at which the RCAN failed, and we also determined how blurry an image can be before the RCAN cannot reverse the blur. We hope this helps others in setting boundaries for the performance of their own image restoration efforts, as well as pushing further development in this exciting field.\" ", "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 demonstrate residual channel attention networks (RCAN) for the restoration and enhancement of volumetric time-lapse (four-dimensional) fluorescence microscopy data. First we modify RCAN to handle image volumes, showing that our network enables denoising competitive with three other state-of-the-art neural networks. We use RCAN to restore noisy four-dimensional super-resolution data, enabling image capture of over tens of thousands of images (thousands of volumes) without apparent photobleaching. Second, using simulations we show that RCAN enables resolution enhancement equivalent to, or better than, other networks. Third, we exploit RCAN for denoising and resolution improvement in confocal microscopy, enabling ~2.5-fold lateral resolution enhancement using stimulated emission depletion microscopy ground truth. Fourth, we develop methods to improve spatial resolution in structured illumination microscopy using expansion microscopy data as ground truth, achieving improvements of ~1.9-fold laterally and ~3.6-fold axially. Finally, we characterize the limits of denoising and resolution enhancement, suggesting practical benchmarks for evaluation and further enhancement of network performance. Main All fluorescence microscopes suffer drawbacks and tradeoffs because they partition a finite signal budget in space and time. These limitations manifest when comparing different microscope types (for example, three-dimensional (3D) structured illumination microscopy 1 (SIM) offers better spatial resolution than high-numerical-aperture light-sheet microscopy 2 but worse photobleaching); different implementations of the same microscope type (for example, traditional implementations of SIM offer better spatial resolution than instant SIM (iSIM) 3 but worse depth penetration and lower speed 4 ); and, within the same microscope, longer exposures and bigger pixels increase signal-to-noise ratio (SNR) at the expense of speed and resolution 5 . Performance tradeoffs are especially severe 6 when considering live-cell super-resolution microscopy applications, in which the desired spatiotemporal resolution must be balanced against sample health 7 . Deep learning 8 , which harnesses neural networks for data-driven statistical inference, has emerged as a promising method for alleviation of the drawbacks in fluorescence microscopy. Content-aware image restoration (CARE 9 ) networks use the popular U-net 10 neural network architecture in conjunction with synthetic, semisynthetic and physically acquired training data to improve resolution, resolution isotropy and SNR in fluorescence images. U-nets have also been incorporated into generative adversarial networks (GAN 11 ) that enable cross-modality super-resolution microscopy, transforming confocal images into stimulated emission depletion (STED) images 12 or transforming a series of wide-field or sparse localization microscopy images into high-resolution (HR) localization microscopy images 13 . Other recent examples include denoising confocal 14 or SIM 15 data and deconvolving light-sheet data 16 . Here we investigate the use of an alternative network architecture, RCAN 17 , for use in super-resolution microscopy applications. RCAN has been shown to preferentially learn high-spatial-frequency detail within natural scene images, but this capability has not been exploited for image restoration in fluorescence microscopy applications, nor on longitudinally acquired image volumes. First we modify RCAN for 3D applications, showing that it matches or exceeds the performance of previous networks in denoising fluorescence microscopy data. We apply this capability for super-resolution imaging over thousands of image volumes (tens of thousands of images). Second, we characterize RCAN and other networks in terms of their ability to extend resolution, finding that RCAN provides better resolution enhancement than alternatives, especially along the axial dimension. Finally, we demonstrate four- to fivefold volumetric resolution improvement in multiple fixed- and live-cell samples when using STED and expansion-microscopy 18 ground truth to train RCAN models. Results RCAN enables super-resolution imaging over thousands of volumes The original RCAN was proposed specifically for resolution enhancement 17 . A key challenge in this task is the need to bypass abundant low spatial frequencies in the input image in favor of HR prediction. The RCAN architecture achieves this by employing multiple skip connections between network layers to bypass low-resolution (LR) content, as well as a ‘channel attention’ mechanism 19 that adaptively rescales each channel-wise feature by modeling interdependencies across feature channels. We modified the original RCAN architecture to handle image volumes rather than images, which also improves network efficiency so that our modified 3D RCAN model fits within graphics processing unit (GPU) memory (Fig. 1a , Methods and Supplementary Note 1 ). Fig. 1: Residual channel attention networks denoise super-resolution data. a , The RCAN architecture used throughout this work. Matched low and high-SNR image volumes are used to train our RCAN, a residual-in-residual structure consisting of several residual groups (dark blue, red outline) with long skip connections. Each residual group contains additional RCAB (light blue, blue outline) with short skip connections, convolution, ReLu, sigmoid and pooling operations. Long and short skip connections, as well as shortcuts within the residual blocks, allow abundant bypassing of low-frequency information through such identity-based skip connections, facilitating the learning of high-frequency information. A channel attention mechanism within the RCAB further aids the representational ability of the network in learning HR information. b , Left: noisy raw iSIM data acquired with low-intensity illumination, low-noise deconvolved GT data acquired with high-intensity illumination, RCAN, CARE, SRResNet and ESRGAN output. Lateral (upper) and axial (lower) cross-sections are shown. Samples are fixed U2OS cells expressing mEmerald-Tomm20 imaged via iSIM. Right: comparison of network output using 3D SSIM and PSNR. Means and standard deviations are reported, obtained from n = 10 volumes (Supplementary Figs. 1– 3 ). c , RCAN performance at different input SNR levels, simulated by the addition of Gaussian and Poisson noise to raw input. Noisy raw input data at SNR 2.1 (top row) and 5.1 (bottom row) were used to generate predictions, which were then compared to ground truth. SNR values are calculated as the mean of values within the yellow rectangular regions. Higher-magnification views of mitochondria (marked in yellow rectangular regions) are shown at lower right (Supplementary Fig. 6 ). d , FWHM values (mean ± s.d.) from ten microtubule filaments for deconvolved, high-SNR GT, noisy iSIM input (Raw) and network output (RCAN). e , RCAN denoising enables the collection of thousands of iSIM volumes without photobleaching. Mitochondria in live U2OS cells were labeled with pShooter pEF-Myc-mito-GFP and imaged with high- (360 W cm –2 ) and low- (4.2<|im_end|> <|im_start|>assistant Fluorescence imaging uses laser light to obtain bright, detailed images of cells and even sub-cellular structures. However, if you want to watch what a living cell is doing, such as dividing into two cells, the laser may fry it and kill it. One answer is to use less light so the cell will not be damaged and can proceed with its various cellular processes. But, with such low levels of light there is not much signal for a microscope to detect. It's a faint, blurry mess. In new work published in the June issue of Nature Methods a team of microscopists and computer scientists used a type of artificial intelligence called a neural network to obtain clearer pictures of cells at work even with extremely low, cell-friendly light levels. The team, led by Hari Shroff, Ph.D., Senior Investigator in the National Institute of Biomedical Imaging and Bioengineering, and Jiji Chen, of the trans-NIH Advanced Imaging and Microscopy Facility call the process "image restoration." The method addresses the two phenomena that cause low-light fuzzy images—low signal to noise ratio (SNR) and low resolution (blurriness). To tackle the problem they trained a neural network to denoise noisy images and deblur blurry images. So what exactly is training a neural network? It involves showing a computer program many matched pairs of images. The pairs consist of a clear, sharp image of, say, the mitochondria of a cell, and the blurry, unrecognizable version of the same mitochondria. The neural network is shown many of these matched sets and therefore "learns" to predict what a blurry image would look like if it were sharpened up. Thus, the neural network becomes capable of taking blurry images created using low-light levels and converting them into the sharper, more detailed images scientists need in order to study what is going on in a cell. To work on denoising and deblurring 3D fluorescence microscopy images, Shroff, Chen and their colleagues collaborated with a company, SVision (now part of Leica), to refine a particular kind of neural network called a residual channel attention network or RCAN. Images of nuclear pores created with diffraction-limited confocal microscope (left) are blurry. Using a super-resolution microscope the nuclear pores are much better resolved (GT, ground truth image). At the far right the RCAN network was shown the blurry confocal image and predicted the sharp image, which much better resembles the high resolution GT image. Scale bar = 5 micrometers. Credit: Jiji Chen In particular, the researchers focused on restoring "super-resolution" image volumes, so-called because they reveal extremely detailed images of tiny parts that make up a cell. The images are displayed as a 3D block that can be viewed from all angles as it rotates. The team obtained thousands of image volumes using microscopes in their lab and other laboratories at NIH. When they obtained images taken with very low illumination light, the cells were not damaged, but the images were very noisy and unusable—low SNR. By using the RCAN method, the images were denoised to create a sharp, accurate, usable 3D image. "We were able to 'beat' the limitations of the microscope by using artificial intelligence to 'predict' the high SNR image from the low SNR image," explained Shroff. "Photodamage in super-resolution imaging is a major problem, so the fact that we were able to circumvent it is significant." In some cases, the researchers were able to enhance spatial resolution several-fold over the noisy data presented to the 3D RCAN. Another aim of the study was determining just how messy of an image the researchers could present to the RCAN network—challenging it to turn a very low resolution image into a usable picture. In an "extreme blurring" exercise, the research team found that at large levels of experimental blurring, the RCAN was no longer able to decipher what it was looking at and turn it into a usable picture. "One thing I'm particularly proud of is that we pushed this technique until it 'broke,'" explained Shroff. "We characterized the SNR regimen on a continuum, showing the point at which the RCAN failed, and we also determined how blurry an image can be before the RCAN cannot reverse the blur. We hope this helps others in setting boundaries for the performance of their own image restoration efforts, as well as pushing further development in this exciting field." <|im_end|>
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2,367
[ { "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 use the genotyping and death register information of 409,693 individuals of British ancestry to investigate fitness effects of the CCR5 -∆32 mutation. We estimate a 21% increase in the all-cause mortality rate in individuals who are homozygous for the ∆32 allele. A deleterious effect of the ∆32/∆32 mutation is also independently supported by a significant deviation from the Hardy–Weinberg equilibrium (HWE) due to a deficiency of ∆32/∆32 individuals at the time of recruitment. Main In late 2018, a scientist from the Southern University of Science and Technology in Shenzhen, Jiankui He, announced the birth of two babies whose genomes were edited using CRISPR 1 . No presentation of the experiment has appeared in the scientific literature, however online information 2 describes an introduction of mutations in the CCR5 gene with the aim of mimicking the effect of the CCR5 -∆32 mutation, which provides protection against HIV in European individuals 3 . Although the mutations were not identical to CCR5 -∆32 (ref. 2 ), and the consequences of the mutations are unknown, the stated purpose was nevertheless the prevention of HIV. The CRISPR experiment raises a number of obvious ethical issues. In addition, it is not clear whether the ∆32 mutation is beneficial. A mutation can be advantageous or disadvantageous depending on environmental conditions 4 and developmental stages 5 . In fact, despite the protection that ∆32 provides against HIV, and possibly other pathogens such as smallpox 6 and flavivirus 7 , and although it facilitates recovery after stroke 8 , it also appears to reduce protection against certain other infectious diseases such as influenza 9 . Direct fitness effects of individual segregating mutations are expected to be small, and are therefore very hard to measure directly. However, owing to the recent availability of large databases of genomic data, direct studies of fitness effects of individual mutations have now become feasible 10 . We might expect that the ∆32 mutation is deleterious in the homozygous state based on previous reports in smaller data sets, which show that individuals with the ∆32/∆32 genotype have increased mortality when infected by influenza 9 and are four times more likely to develop certain infectious diseases 11 . Here we investigate this hypothesis using the genotyping and death register information of 409,693 individuals of British ancestry in the UK Biobank 12 . ∆32 has a frequency of 0.1159 in the British population and the UK Biobank contains data from thousands of individuals who are homozygous for the ∆32 allele, providing an opportunity to compare the mortality of these individuals to that of ∆32/+ and +/+ individuals. We calculate the survival rate (1 − death rate) per year for each of the three ∆32 genotypes, from age 41 to age 78 (see Methods ), which is the entire range allowed by the data available (Fig. 1a ). Owing to the small sample size at ages 77 and 78, we primarily report the survival probability before age 76 (see Methods ). The death rate from age 70 to 74 in the UK Biobank volunteers is 46–56% lower than that in the general UK population of the same age 13 , probably owing to an ascertainment bias known as the ‘healthy volunteer effect’ 14 . Nevertheless, the relative death rates among different genotypes can still be compared to provide information about the fitness effects of specific mutations. The uncorrected survival probabilities to age 76 of individuals enrolled in the study is 0.8351 for ∆32/∆32, 0.8654 for ∆32/+, and 0.8638 for +/+ (Fig. 1a ), which implies that ∆32/∆32 has an approximately 21% higher aggregated death rate before age 76 than the other genotypes. The average age of enrollment is 56.5 years, so the data largely reflect differences in mortality in individuals above this age. We can partially correct for the death registration delay and biased ascertainment using the general population’s death rate per year. After correction, the individuals with the ∆32/∆32 genotype are approximately 20% less likely to reach age 76 than individuals with the other genotypes (see Methods ). To test the significance of the nominally lower survival rate of ∆32/∆32, we first perform a log-rank test comparing the death rate of ∆32/∆32 individuals to that of the other two genotypes ( Z score = 2.37, one-tailed P = 0.0089). We also bootstrap the sample 1,000 times and find that ∆32/∆32 individuals have a significantly higher death rate than the other two genotypes, whereas ∆32/+ and +/+ individuals have similar death rates (Supplementary Table 1 ). The increase in mortality of ∆32/∆32 individuals is the highest at age 74, at which point it is 26.4% higher than the mortality of +/+ individuals (95% bootstrap confidence interval (3.0%,49.5%)). Similarly, a Cox model 15 for left truncated and right censored data also suggests that ∆32/∆32 individuals have an average 21.4% elevated death rate across all ages (95% confidence interval 3.4% and 42.6%, one-tailed P = 0.0089). The fifth principal component is associated with Irish ancestry 12 and is also associated with a difference in mortality (two-sided P = 2.5 × 10 −16 ) in the Cox model. However, when correcting for this effect using prinicipal component analysis (PCA) loadings as covariates, the increase in mortality of ∆32 is maintained (see Supplementary information ). We note that despite the nominally large detected effect on survivorship, the P value of 0.0089 is only moderately small, owing to the low frequency of ∆32/∆32 individuals and the generally low mortality in the cohort. The accuracy of the estimates will probably improve in future years as the mortality rate of the cohort increases. Fig. 1: CCR5 -∆32 is deleterious in the homozygous state. a , Survival probabilities of the three ∆32 genotypes (+/+, ∆32/+ and ∆32 / ∆32). The one-tailed P values from the log-rank tests up to age 76 are shown. The number of samples for which age information and genotype at ∆32 are both available is 395,704. b , The histogram of inbreeding coefficients, F , from 5,932 SNPs whose allele", "role": "user" }, { "content": "A pair of researchers from the University of California has retracted a paper they had published in the journal Nature Medicine in which they claimed to have found evidence that the Chinese CRISPR twins might die early. In their retraction, Xinzhu Wei and Rasmus Nielsen report that the reason for the retraction was genotyping bias in UK Biobank data that they used to conduct their research. Last year, a team of researchers in China announced that they had used the CRISPR gene-editing technique to disable the CCR5 gene (the result is known as delta-32, found naturally in some people) in twin babies who were described as \"healthy\" when they were born. The team disabled the gene in the twins as part of research toward improving resistance to HIV. The news made headlines, with critics denouncing the use of gene editing on human embryos. The news also led other research efforts to determine if disabling the CCR5 gene in humans might lead to previously unknown side effects. One of those efforts was carried out by Wei and Nielsen—their study involved filtering data from the U.K. Biobank. In so doing, they found evidence that they claimed showed that people with dual copies of delta-32 were slightly more likely to die before reaching the age of 76 than the rest of the population. They also reported finding that the database had fewer people with dual copies of delta-32 than there should be based on evolutionary theory. The paper by Wei and Nielsen, which was published just four months ago, attracted immediate attention from people both in and outside of the field. Other researchers began searching the U.K. Biobank to see if they could replicate what Wei and Nielsen had found, but were unable to do so. Another team at Harvard Medical School found a discrepancy in the way dual copies of delta-32 were counted by Wei and Nielsen—a discrepancy that had led to undercounting many people in the U.K. Biobank with dual copies of delta-32. Wei and Nielsen acknowledge their false result in their retraction, though they continue to refer to it as a genotyping error in the database. They also admit there were tests they could have conducted to verify their results, but neglected to do. ", "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 use the genotyping and death register information of 409,693 individuals of British ancestry to investigate fitness effects of the CCR5 -∆32 mutation. We estimate a 21% increase in the all-cause mortality rate in individuals who are homozygous for the ∆32 allele. A deleterious effect of the ∆32/∆32 mutation is also independently supported by a significant deviation from the Hardy–Weinberg equilibrium (HWE) due to a deficiency of ∆32/∆32 individuals at the time of recruitment. Main In late 2018, a scientist from the Southern University of Science and Technology in Shenzhen, Jiankui He, announced the birth of two babies whose genomes were edited using CRISPR 1 . No presentation of the experiment has appeared in the scientific literature, however online information 2 describes an introduction of mutations in the CCR5 gene with the aim of mimicking the effect of the CCR5 -∆32 mutation, which provides protection against HIV in European individuals 3 . Although the mutations were not identical to CCR5 -∆32 (ref. 2 ), and the consequences of the mutations are unknown, the stated purpose was nevertheless the prevention of HIV. The CRISPR experiment raises a number of obvious ethical issues. In addition, it is not clear whether the ∆32 mutation is beneficial. A mutation can be advantageous or disadvantageous depending on environmental conditions 4 and developmental stages 5 . In fact, despite the protection that ∆32 provides against HIV, and possibly other pathogens such as smallpox 6 and flavivirus 7 , and although it facilitates recovery after stroke 8 , it also appears to reduce protection against certain other infectious diseases such as influenza 9 . Direct fitness effects of individual segregating mutations are expected to be small, and are therefore very hard to measure directly. However, owing to the recent availability of large databases of genomic data, direct studies of fitness effects of individual mutations have now become feasible 10 . We might expect that the ∆32 mutation is deleterious in the homozygous state based on previous reports in smaller data sets, which show that individuals with the ∆32/∆32 genotype have increased mortality when infected by influenza 9 and are four times more likely to develop certain infectious diseases 11 . Here we investigate this hypothesis using the genotyping and death register information of 409,693 individuals of British ancestry in the UK Biobank 12 . ∆32 has a frequency of 0.1159 in the British population and the UK Biobank contains data from thousands of individuals who are homozygous for the ∆32 allele, providing an opportunity to compare the mortality of these individuals to that of ∆32/+ and +/+ individuals. We calculate the survival rate (1 − death rate) per year for each of the three ∆32 genotypes, from age 41 to age 78 (see Methods ), which is the entire range allowed by the data available (Fig. 1a ). Owing to the small sample size at ages 77 and 78, we primarily report the survival probability before age 76 (see Methods ). The death rate from age 70 to 74 in the UK Biobank volunteers is 46–56% lower than that in the general UK population of the same age 13 , probably owing to an ascertainment bias known as the ‘healthy volunteer effect’ 14 . Nevertheless, the relative death rates among different genotypes can still be compared to provide information about the fitness effects of specific mutations. The uncorrected survival probabilities to age 76 of individuals enrolled in the study is 0.8351 for ∆32/∆32, 0.8654 for ∆32/+, and 0.8638 for +/+ (Fig. 1a ), which implies that ∆32/∆32 has an approximately 21% higher aggregated death rate before age 76 than the other genotypes. The average age of enrollment is 56.5 years, so the data largely reflect differences in mortality in individuals above this age. We can partially correct for the death registration delay and biased ascertainment using the general population’s death rate per year. After correction, the individuals with the ∆32/∆32 genotype are approximately 20% less likely to reach age 76 than individuals with the other genotypes (see Methods ). To test the significance of the nominally lower survival rate of ∆32/∆32, we first perform a log-rank test comparing the death rate of ∆32/∆32 individuals to that of the other two genotypes ( Z score = 2.37, one-tailed P = 0.0089). We also bootstrap the sample 1,000 times and find that ∆32/∆32 individuals have a significantly higher death rate than the other two genotypes, whereas ∆32/+ and +/+ individuals have similar death rates (Supplementary Table 1 ). The increase in mortality of ∆32/∆32 individuals is the highest at age 74, at which point it is 26.4% higher than the mortality of +/+ individuals (95% bootstrap confidence interval (3.0%,49.5%)). Similarly, a Cox model 15 for left truncated and right censored data also suggests that ∆32/∆32 individuals have an average 21.4% elevated death rate across all ages (95% confidence interval 3.4% and 42.6%, one-tailed P = 0.0089). The fifth principal component is associated with Irish ancestry 12 and is also associated with a difference in mortality (two-sided P = 2.5 × 10 −16 ) in the Cox model. However, when correcting for this effect using prinicipal component analysis (PCA) loadings as covariates, the increase in mortality of ∆32 is maintained (see Supplementary information ). We note that despite the nominally large detected effect on survivorship, the P value of 0.0089 is only moderately small, owing to the low frequency of ∆32/∆32 individuals and the generally low mortality in the cohort. The accuracy of the estimates will probably improve in future years as the mortality rate of the cohort increases. Fig. 1: CCR5 -∆32 is deleterious in the homozygous state. a , Survival probabilities of the three ∆32 genotypes (+/+, ∆32/+ and ∆32 / ∆32). The one-tailed P values from the log-rank tests up to age 76 are shown. The number of samples for which age information and genotype at ∆32 are both available is 395,704. b , The histogram of inbreeding coefficients, F , from 5,932 SNPs whose allele<|im_end|> <|im_start|>assistant A pair of researchers from the University of California has retracted a paper they had published in the journal Nature Medicine in which they claimed to have found evidence that the Chinese CRISPR twins might die early. In their retraction, Xinzhu Wei and Rasmus Nielsen report that the reason for the retraction was genotyping bias in UK Biobank data that they used to conduct their research. Last year, a team of researchers in China announced that they had used the CRISPR gene-editing technique to disable the CCR5 gene (the result is known as delta-32, found naturally in some people) in twin babies who were described as "healthy" when they were born. The team disabled the gene in the twins as part of research toward improving resistance to HIV. The news made headlines, with critics denouncing the use of gene editing on human embryos. The news also led other research efforts to determine if disabling the CCR5 gene in humans might lead to previously unknown side effects. One of those efforts was carried out by Wei and Nielsen—their study involved filtering data from the U.K. Biobank. In so doing, they found evidence that they claimed showed that people with dual copies of delta-32 were slightly more likely to die before reaching the age of 76 than the rest of the population. They also reported finding that the database had fewer people with dual copies of delta-32 than there should be based on evolutionary theory. The paper by Wei and Nielsen, which was published just four months ago, attracted immediate attention from people both in and outside of the field. Other researchers began searching the U.K. Biobank to see if they could replicate what Wei and Nielsen had found, but were unable to do so. Another team at Harvard Medical School found a discrepancy in the way dual copies of delta-32 were counted by Wei and Nielsen—a discrepancy that had led to undercounting many people in the U.K. Biobank with dual copies of delta-32. Wei and Nielsen acknowledge their false result in their retraction, though they continue to refer to it as a genotyping error in the database. They also admit there were tests they could have conducted to verify their results, but neglected to do. <|im_end|>
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1,917
[ { "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 climate change drives sea-level rise, increasing the frequency of coastal flooding. In most coastal regions, the amount of sea-level rise occurring over years to decades is significantly smaller than normal ocean-level fluctuations caused by tides, waves, and storm surge. However, even gradual sea-level rise can rapidly increase the frequency and severity of coastal flooding. So far, global-scale estimates of increased coastal flooding due to sea-level rise have not considered elevated water levels due to waves, and thus underestimate the potential impact. Here we use extreme value theory to combine sea-level projections with wave, tide, and storm surge models to estimate increases in coastal flooding on a continuous global scale. We find that regions with limited water-level variability, i.e., short-tailed flood-level distributions, located mainly in the Tropics, will experience the largest increases in flooding frequency. The 10 to 20 cm of sea-level rise expected no later than 2050 will more than double the frequency of extreme water-level events in the Tropics, impairing the developing economies of equatorial coastal cities and the habitability of low-lying Pacific island nations. Introduction Global sea level is currently rising at ~3–4 mm/yr 1 , 2 and is expected to accelerate due to ocean warming and land-based ice melt 3 , 4 . Sea-level rise (SLR) projections range from 0.3 to 2.0 m by 2100, depending on methodology and emission scenarios 5 , 6 , and recent work suggests that accepted methodologies significantly underestimate the contribution of Antarctica 7 . Coastal regions experience elevated water levels on an episodic basis due to wave setup and runup 8 , tides 9 , storm surge driven by wind stress and atmospheric pressure, contributions from seasonal and climatic cycles, e.g., El Niño/Southern Oscillation 10 , 11 and Pacific Decadal Oscillation 12 , and oceanic eddies 13 (Fig. 1 ). Figure 1 The water-level components that contribute to coastal flooding. Full size image Coastal flooding often occurs during extreme water-level events that result from simultaneous, combined contributions, such as large waves, storm surge, high tides, and mean sea-level anomalies 11 , 14 . SLR leads to (1) passive high-tide inundation of low-lying coastal areas 15 , (2) increased frequency, severity, and duration of coastal flooding 16 , (3) increased beach erosion 17 , (4) groundwater inundation 18 , 19 , (5) changes to wave dynamics 20 , and (6) displacement of communities 21 . Predicting regions vulnerable to passive inundation is relatively simple with the aid of high-resolution digital elevation models 22 . However, predicting the effect of SLR on episodic flooding events is difficult due to the unpredictable nature of coastal storms, nonlinear interactions of physical processes (e.g., tidal currents and waves), and variations in coastal geomorphology (e.g., sediments, bathymetry, topography, and bed friction). Local-scale assessments of coastal hazard vulnerability typically rely on detailed, computationally-onerous numerical modeling efforts 23 in order to simulate wave-related nearshore water levels, interactions with local topography, and the resulting flooding. Global-scale coastal hazard vulnerability assessments, on the other hand, rely on extreme value theory applied to water-level observations. Extreme-value theory Extreme-value theory 24 , 25 is a statistical method for quantifying the probability or return period of large events. The generalized extreme value (GEV) distribution, sometimes called the Fisher-Tippet distribution, is a powerful and general statistical model for extremes 26 (Coles 2001). The GEV distribution models the probabilities of the maxima of a random variable 24 , 27 , 28 using three parameters μ , σ , and k , the location (mean), scale (width), and shape (family type), respectively 26 . Oceanographic and coastal engineering studies often rely on GEV theory to describe the frequency of extreme waves 29 , water-level events 30 , flooding impacts 31 , and to understand the effects of SLR 32 . As sea level increases, the probability increases that a fixed elevation will experience flooding (Fig. 2 ). Equivalently, the return period or recurrence interval of flooding at a fixed elevation decreases 33 , 34 . In the example shown in Fig. 2B , 1 m of SLR causes the 5 m flood level (the former 100-year flood) to recur every 25 years. Figure 2 Example: by elevating the exceedance probability distribution, a 1 m increase in SL increases the frequency ( A ) and lowers the return period ( B ) of the 5m-flood level. Note that the steeper the probability distribution in A, the flatter the return time curve in B, i.e., the greater the increase in frequency and the reduction in return time. Thus regions with lower variability in flood level will experience larger increases in flooding frequency under SLR. See Methods and extended data Figs 1 and 2 . Full size image SLR can affect flood magnitude and frequency directly (Fig. 2 ) or indirectly via hydrodynamic feedbacks: SLR alters water depths, changing the generation, propagation, and interaction of waves, tides, and storm surges. Thus, SLR and long-term changes in wave climate, e.g., changes in magnitude, frequency, and tracks of storms 35 , 36 , 37 and storm surge, can alter the parameters of extreme water-level distributions and the evolution of coastal hazards over time. In the proposed work, we assume parameter stationarity based on projections of minor changes (5–10% 35 , 36 , 37 ) in mean annual wave conditions and storm surge over large regions of the ocean. In specific locations, such as the Pacific Northwest, trends in extreme wave climate may be significant 38 and lead to a greater flooding hazard than SLR over at least the next several decades 39 , calling for nonstationary methods 40 in future research. Investigations of increased flooding frequency due to SLR are often site-specific and rely only on water-level data from tide stations. For example, Hunter (2012) [ref. 41 ] and the Intergovernmental Panel on Climate Change (IPCC) 2013 report 3 estimate the factor of increase in the frequency of flooding events due to 0.5 m of SLR at locations of 198 tide stations around the globe [Hunter 41 Fig. 4 and", "role": "user" }, { "content": "Rising sea levels driven by global warming are on track to dramatically boost the frequency of coastal flooding worldwide by mid-century, especially in tropical regions, researchers said Thursday. A 10-to-20 centimetre (four-to-eight inch) jump in the global ocean watermark by 2050—a conservative forecast—would double flood risk in high-latitude regions, they reported in the journal Scientific Reports. Major cities along the North American seaboard such as Vancouver, Seattle, San Francisco and Los Angeles, along with the European Atlantic coast, would be highly exposed, they found. But it would only take half as big a jump in ocean levels to double the number of serious flooding incidents in the tropics, including along highly populated river deltas in Asia and Africa. Even at the low end of this sea rise spectrum, Mumbai, Kochi and Abidjan and many other cities would be significantly affected. \"We are 95 percent confident that an added 5-to-10 centimetres will more than double the frequency of flooding in the topics,\" lead author Sean Vitousek, a climate scientist at the University of Illinois at Chicago, told AFP. Small island states, already vulnerable to flooding, would fare even worse, he added. \"An increase in flooding frequency with climate change will challenge the very existence and sustainability of these coastal communities across the globe.\" The Indian metropolis of Mumbai is among many major cities across the globe threatened by rising sea levels which will see coastal flooding dramatically increase over the next 30 years, researchers say Coastal flooding is caused by severe storms, and is made worse when large waves, storm surge and high tides converge. Hurricane Sandy in the United States (2012), which caused tens of billions or dollars in damage, and Typhoon Haiyan in the Philippines (2013), which left more than 7,000 dead or missing, both saw devastating flooding. Rising seas—caused by the expansion of warming ocean water and runoff from melting ice sheets and glaciers—is also a contributing factor. Sea level 'wild card' But up to now, global estimates of future coastal flooding have not adequately taken into account the role of waves, Vitousek said. \"Most of the data used in earlier studies comes from tidal gauge stations, which are in harbours and protected areas,\" he explained. \"They record extreme tide and storm surges, but not waves.\" To make up for the lack of observational data, Vitousek and his colleagues used computer modelling and a statistical method called extreme value theory. \"We asked the question: with waves factored in, how much sea level rise will it take to double the frequency of flooding?\" Los Angeles is one US coastal city which could face the fallout from rising sea levels, amid a feared doubling of the frequency of flooding by 2050, according to a study by climate scientists who also warn of risk to Europe's Atlantic coast Not much, it turned out. Sea levels are currently rising by three to four millimetres (0.10 to 0.15 inches) a year, but the pace has picked up by about 30 percent over the last decade. It could accelerate even more as continent-sized ice blocs near the poles continue to shed mass, especially in Antarctica, which Vitousek described as the sea level \"wild card.\" If oceans go up 25 centimetres by mid-century, \"flood levels that occur every 50 years in the tropics would be happening every year or more,\" he said. The US National Oceanic and Atmospheric Administration (NOAA) predicts global average sea level will rise by as much as 2.5 metres (98 inches) by 2100. Global average temperatures have increased by one degree Celsius (1.6 degrees Fahrenheit) since the mid-19th century, with most of that happening in the last 70 years. The 196-nation Paris Agreement, inked in 2015, calls for capping global warming at well under 2C (3.6F), a goal described by climate scientists as extremely daunting. ", "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 climate change drives sea-level rise, increasing the frequency of coastal flooding. In most coastal regions, the amount of sea-level rise occurring over years to decades is significantly smaller than normal ocean-level fluctuations caused by tides, waves, and storm surge. However, even gradual sea-level rise can rapidly increase the frequency and severity of coastal flooding. So far, global-scale estimates of increased coastal flooding due to sea-level rise have not considered elevated water levels due to waves, and thus underestimate the potential impact. Here we use extreme value theory to combine sea-level projections with wave, tide, and storm surge models to estimate increases in coastal flooding on a continuous global scale. We find that regions with limited water-level variability, i.e., short-tailed flood-level distributions, located mainly in the Tropics, will experience the largest increases in flooding frequency. The 10 to 20 cm of sea-level rise expected no later than 2050 will more than double the frequency of extreme water-level events in the Tropics, impairing the developing economies of equatorial coastal cities and the habitability of low-lying Pacific island nations. Introduction Global sea level is currently rising at ~3–4 mm/yr 1 , 2 and is expected to accelerate due to ocean warming and land-based ice melt 3 , 4 . Sea-level rise (SLR) projections range from 0.3 to 2.0 m by 2100, depending on methodology and emission scenarios 5 , 6 , and recent work suggests that accepted methodologies significantly underestimate the contribution of Antarctica 7 . Coastal regions experience elevated water levels on an episodic basis due to wave setup and runup 8 , tides 9 , storm surge driven by wind stress and atmospheric pressure, contributions from seasonal and climatic cycles, e.g., El Niño/Southern Oscillation 10 , 11 and Pacific Decadal Oscillation 12 , and oceanic eddies 13 (Fig. 1 ). Figure 1 The water-level components that contribute to coastal flooding. Full size image Coastal flooding often occurs during extreme water-level events that result from simultaneous, combined contributions, such as large waves, storm surge, high tides, and mean sea-level anomalies 11 , 14 . SLR leads to (1) passive high-tide inundation of low-lying coastal areas 15 , (2) increased frequency, severity, and duration of coastal flooding 16 , (3) increased beach erosion 17 , (4) groundwater inundation 18 , 19 , (5) changes to wave dynamics 20 , and (6) displacement of communities 21 . Predicting regions vulnerable to passive inundation is relatively simple with the aid of high-resolution digital elevation models 22 . However, predicting the effect of SLR on episodic flooding events is difficult due to the unpredictable nature of coastal storms, nonlinear interactions of physical processes (e.g., tidal currents and waves), and variations in coastal geomorphology (e.g., sediments, bathymetry, topography, and bed friction). Local-scale assessments of coastal hazard vulnerability typically rely on detailed, computationally-onerous numerical modeling efforts 23 in order to simulate wave-related nearshore water levels, interactions with local topography, and the resulting flooding. Global-scale coastal hazard vulnerability assessments, on the other hand, rely on extreme value theory applied to water-level observations. Extreme-value theory Extreme-value theory 24 , 25 is a statistical method for quantifying the probability or return period of large events. The generalized extreme value (GEV) distribution, sometimes called the Fisher-Tippet distribution, is a powerful and general statistical model for extremes 26 (Coles 2001). The GEV distribution models the probabilities of the maxima of a random variable 24 , 27 , 28 using three parameters μ , σ , and k , the location (mean), scale (width), and shape (family type), respectively 26 . Oceanographic and coastal engineering studies often rely on GEV theory to describe the frequency of extreme waves 29 , water-level events 30 , flooding impacts 31 , and to understand the effects of SLR 32 . As sea level increases, the probability increases that a fixed elevation will experience flooding (Fig. 2 ). Equivalently, the return period or recurrence interval of flooding at a fixed elevation decreases 33 , 34 . In the example shown in Fig. 2B , 1 m of SLR causes the 5 m flood level (the former 100-year flood) to recur every 25 years. Figure 2 Example: by elevating the exceedance probability distribution, a 1 m increase in SL increases the frequency ( A ) and lowers the return period ( B ) of the 5m-flood level. Note that the steeper the probability distribution in A, the flatter the return time curve in B, i.e., the greater the increase in frequency and the reduction in return time. Thus regions with lower variability in flood level will experience larger increases in flooding frequency under SLR. See Methods and extended data Figs 1 and 2 . Full size image SLR can affect flood magnitude and frequency directly (Fig. 2 ) or indirectly via hydrodynamic feedbacks: SLR alters water depths, changing the generation, propagation, and interaction of waves, tides, and storm surges. Thus, SLR and long-term changes in wave climate, e.g., changes in magnitude, frequency, and tracks of storms 35 , 36 , 37 and storm surge, can alter the parameters of extreme water-level distributions and the evolution of coastal hazards over time. In the proposed work, we assume parameter stationarity based on projections of minor changes (5–10% 35 , 36 , 37 ) in mean annual wave conditions and storm surge over large regions of the ocean. In specific locations, such as the Pacific Northwest, trends in extreme wave climate may be significant 38 and lead to a greater flooding hazard than SLR over at least the next several decades 39 , calling for nonstationary methods 40 in future research. Investigations of increased flooding frequency due to SLR are often site-specific and rely only on water-level data from tide stations. For example, Hunter (2012) [ref. 41 ] and the Intergovernmental Panel on Climate Change (IPCC) 2013 report 3 estimate the factor of increase in the frequency of flooding events due to 0.5 m of SLR at locations of 198 tide stations around the globe [Hunter 41 Fig. 4 and<|im_end|> <|im_start|>assistant Rising sea levels driven by global warming are on track to dramatically boost the frequency of coastal flooding worldwide by mid-century, especially in tropical regions, researchers said Thursday. A 10-to-20 centimetre (four-to-eight inch) jump in the global ocean watermark by 2050—a conservative forecast—would double flood risk in high-latitude regions, they reported in the journal Scientific Reports. Major cities along the North American seaboard such as Vancouver, Seattle, San Francisco and Los Angeles, along with the European Atlantic coast, would be highly exposed, they found. But it would only take half as big a jump in ocean levels to double the number of serious flooding incidents in the tropics, including along highly populated river deltas in Asia and Africa. Even at the low end of this sea rise spectrum, Mumbai, Kochi and Abidjan and many other cities would be significantly affected. "We are 95 percent confident that an added 5-to-10 centimetres will more than double the frequency of flooding in the topics," lead author Sean Vitousek, a climate scientist at the University of Illinois at Chicago, told AFP. Small island states, already vulnerable to flooding, would fare even worse, he added. "An increase in flooding frequency with climate change will challenge the very existence and sustainability of these coastal communities across the globe." The Indian metropolis of Mumbai is among many major cities across the globe threatened by rising sea levels which will see coastal flooding dramatically increase over the next 30 years, researchers say Coastal flooding is caused by severe storms, and is made worse when large waves, storm surge and high tides converge. Hurricane Sandy in the United States (2012), which caused tens of billions or dollars in damage, and Typhoon Haiyan in the Philippines (2013), which left more than 7,000 dead or missing, both saw devastating flooding. Rising seas—caused by the expansion of warming ocean water and runoff from melting ice sheets and glaciers—is also a contributing factor. Sea level 'wild card' But up to now, global estimates of future coastal flooding have not adequately taken into account the role of waves, Vitousek said. "Most of the data used in earlier studies comes from tidal gauge stations, which are in harbours and protected areas," he explained. "They record extreme tide and storm surges, but not waves." To make up for the lack of observational data, Vitousek and his colleagues used computer modelling and a statistical method called extreme value theory. "We asked the question: with waves factored in, how much sea level rise will it take to double the frequency of flooding?" Los Angeles is one US coastal city which could face the fallout from rising sea levels, amid a feared doubling of the frequency of flooding by 2050, according to a study by climate scientists who also warn of risk to Europe's Atlantic coast Not much, it turned out. Sea levels are currently rising by three to four millimetres (0.10 to 0.15 inches) a year, but the pace has picked up by about 30 percent over the last decade. It could accelerate even more as continent-sized ice blocs near the poles continue to shed mass, especially in Antarctica, which Vitousek described as the sea level "wild card." If oceans go up 25 centimetres by mid-century, "flood levels that occur every 50 years in the tropics would be happening every year or more," he said. The US National Oceanic and Atmospheric Administration (NOAA) predicts global average sea level will rise by as much as 2.5 metres (98 inches) by 2100. Global average temperatures have increased by one degree Celsius (1.6 degrees Fahrenheit) since the mid-19th century, with most of that happening in the last 70 years. The 196-nation Paris Agreement, inked in 2015, calls for capping global warming at well under 2C (3.6F), a goal described by climate scientists as extremely daunting. <|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 Biomarkers have transformed modern medicine but remain largely elusive in psychiatry, partly because there is a weak correspondence between diagnostic labels and their neurobiological substrates. Like other neuropsychiatric disorders, depression is not a unitary disease, but rather a heterogeneous syndrome that encompasses varied, co-occurring symptoms and divergent responses to treatment. By using functional magnetic resonance imaging (fMRI) in a large multisite sample ( n = 1,188), we show here that patients with depression can be subdivided into four neurophysiological subtypes ('biotypes') defined by distinct patterns of dysfunctional connectivity in limbic and frontostriatal networks. Clustering patients on this basis enabled the development of diagnostic classifiers (biomarkers) with high (82–93%) sensitivity and specificity for depression subtypes in multisite validation ( n = 711) and out-of-sample replication ( n = 477) data sets. These biotypes cannot be differentiated solely on the basis of clinical features, but they are associated with differing clinical-symptom profiles. They also predict responsiveness to transcranial magnetic stimulation therapy ( n = 154). Our results define novel subtypes of depression that transcend current diagnostic boundaries and may be useful for identifying the individuals who are most likely to benefit from targeted neurostimulation therapies. Main Depression is a heterogeneous clinical syndrome that is diagnosed when a patient reports at least five of nine symptoms. This allows for several hundred unique combinations of changes in mood, appetite, sleep, energy, cognition and motor activity. Such remarkable heterogeneity reflects the consensus view that there are multiple forms of depression, but their neurobiological basis remains poorly understood 1 , 2 . So far, most efforts to characterize depression subtypes and develop diagnostic biomarkers have begun by identifying clusters of symptoms that tend to co-occur, and by then testing for neurophysiological correlates. These pioneering studies have defined atypical, melancholic, seasonal and agitated subtypes of depression associated with characteristic changes in neuroendocrine activity, circadian rhythms and other potential biomarkers 3 , 4 , 5 . Still, the association between clinical subtypes and their biological substrates is inconsistent and variable at the individual level, and unlike diagnostic biomarkers in other areas of medicine, they have not yet proven useful for differentiating individual patients from healthy controls or for reliably predicting treatment response at the individual level. An alternative to subtyping patients on the basis of co-occurring clinical symptoms is to identify neurophysiological subtypes, or biotypes, by clustering subjects according to shared signatures of brain dysfunction 6 . This type of approach has already begun to yield insights into how differing biological mechanisms may give rise to overlapping, heterogeneous clinical presentations of psychotic disorders 6 , 7 . Neuroimaging biomarkers of abnormal brain function have proven utility in the assessment of pain 8 and have also shown promise for depression, for both the prediction of treatment response 9 , 10 , 11 , 12 , 13 and treatment selection 14 . Resting-state fMRI (rsfMRI) is an especially useful modality because it can be used easily in diverse patient populations to quantify functional network connectivity in terms of correlated, spontaneous MR signal fluctuations. Depression is associated with dysfunction and abnormal functional connectivity in frontostriatal and limbic brain networks 15 , 16 , 17 , 18 , 19 , 20 , in accordance with morphological and synaptic changes in chronic stress models in rodents 21 , 22 , 23 , 24 . These studies raise the intriguing possibility that fMRI measures of connectivity could be leveraged to identify novel subtypes of depression with stronger neurobiological correlates that predict treatment responsiveness. To this end, we developed a method for defining depression subtypes by clustering subjects according to distinct, whole-brain patterns of abnormal functional connectivity in resting-state networks, unbiased by assumptions about the involvement of particular brain regions, and tested it in a large, multisite data set. Our analyses revealed four biotypes that were defined by homogeneous patterns of dysfunctional connectivity in frontostriatal and limbic networks, and that could be diagnosed with high sensitivity and specificity in individual subjects. Importantly, these biotypes were also prognostically informative, predicting which patients responded to repetitive transcranial magnetic stimulation (TMS), a targeted neurostimulation therapy. Results Frontostriatal and limbic connectivity define four depression biotypes We began by designing and implementing a preprocessing procedure (Online Methods ) to control for motion-, scanner- and age-related effects in a multisite data set that comprised rsfMRI scans for 711 subjects (the 'training data set', n = 333 patients with depression; n = 378 healthy controls). No subjects had comorbid substance-abuse disorders, and patients and controls were matched for age and sex. Data that support our approach to controlling for motion-related Blood-oxygen-level dependent (BOLD) signal effects, a particularly important source of rsfMRI artifact 25 , 26 , 27 , are presented in Supplementary Figure 1. After co-registering the functional volumes to a common (Montreal Neurological Institute (MNI)) space, we applied an extensively validated parcellation system 28 to delineate 258 functional network nodes that spanned the whole brain and had stable signals across all sites and scans in this data set ( Fig. 1a ). Next, we extracted BOLD signal residual time series and calculated correlation matrices between each node, which provided an unbiased estimate of the whole-brain architecture of functional connectivity in each subject ( Fig. 1b ). Figure 1: Canonical correlation analysis (CCA) and hierarchical clustering define four connectivity-based biotypes of depression. ( a ) Data analysis schematic and workflow. After preprocessing, BOLD signal time series were extracted from 258 spherical regions of interest (ROIs) distributed across the cortex and subcortical structures. The schematics (top) show lateral (left) and medial (right) views of right-hemisphere ROIs projected onto an inflated cortical surface and colored by functional network (lower left). Left-hemisphere ROIs (data not shown) were similar. For each subject, whole-brain functional-connectivity matrices were generated by calculating pairwise BOLD signal correlations between all ROIs, as in this example of correlated signals ( r 2 = 0.88) for DLPFC (solid line) and PPC (dashed line) nodes of the FPTC network in a representative subject. ( b ) Whole-brain, 258 × 258 functional-connectivity matrix averaged", "role": "user" }, { "content": "Patients with depression can be categorized into four unique subtypes defined by distinct patterns of abnormal connectivity in the brain, according to new research from Weill Cornell Medicine. In a collaborative study published Dec. 5 in Nature Medicine, Dr. Conor Liston, an assistant professor of neuroscience in the Feil Family Brain and Mind Institute and an assistant professor of psychiatry at Weill Cornell Medicine, has identified biomarkers in depression by analyzing more than 1,100 functional magnetic resonance imaging (fMRI) brain scans of patients with clinical depression and of healthy controls, gathered from across the country. These biomarkers may help doctors to better diagnose depression subtypes and determine which patients would most likely benefit from a targeted neuro-stimulation therapy called transcranial magnetic stimulation, which uses magnetic fields to create electrical impulses in the brain. \"The four subtypes of depression that we discovered vary in terms of their clinical symptoms but, more importantly, they differ in their responses to treatment,\" Liston said. \"We can now predict with high accuracy whether or not a patient will respond to transcranial magnetic stimulation therapy, which is significant because it takes five weeks to know if this type of treatment works.\" Approximately 10 percent of Americans are diagnosed with clinical depression each year. It is, by some estimates, the leading cause of disability in many developed countries. Historically, efforts to characterize depression involved looking at groups of symptoms that tend to co-occur, then testing neurophysiological links. And while past pioneering studies have defined different forms of depression, the association between the various types and the underlying biology has been inconsistent. Further, diagnostic biomarkers have yet to prove useful in distinguishing depressed patients from healthy controls or in reliably predicting treatment response among individuals. \"Depression is typically diagnosed based on things that we are experiencing, but as in election polling, the results you get depend a lot on the way you ask the question,\" Liston said. \"Brain scans are objective.\" Researchers from Weill Cornell Medicine and seven other institutions derived the biomarkers by assigning statistical weights to abnormal connections in the brain, then predicting the probability that they belonged to one subtype versus another. The study found that distinct patterns of abnormal functional connectivity in the brain differentiated the four biotypes and were linked with specific symptoms. For example, reduced connectivity in the part of the brain that regulates fear-related behavior and reappraisal of negative emotional stimuli was most severe in biotypes one and four, which exhibited increased anxiety. Liston will seek to replicate and confirm the results of this research and discover if it is broadly applicable to studying the biology of depression and other forms of mental illness. \"Subtyping is a major problem in psychiatry,\" Liston said. \"It's not just an issue for depression, and it would be really valuable to have objective biological tests that can help diagnose subtypes of other mental illnesses, such as psychotic disorders, autism and substance abuse syndromes.\" ", "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 Biomarkers have transformed modern medicine but remain largely elusive in psychiatry, partly because there is a weak correspondence between diagnostic labels and their neurobiological substrates. Like other neuropsychiatric disorders, depression is not a unitary disease, but rather a heterogeneous syndrome that encompasses varied, co-occurring symptoms and divergent responses to treatment. By using functional magnetic resonance imaging (fMRI) in a large multisite sample ( n = 1,188), we show here that patients with depression can be subdivided into four neurophysiological subtypes ('biotypes') defined by distinct patterns of dysfunctional connectivity in limbic and frontostriatal networks. Clustering patients on this basis enabled the development of diagnostic classifiers (biomarkers) with high (82–93%) sensitivity and specificity for depression subtypes in multisite validation ( n = 711) and out-of-sample replication ( n = 477) data sets. These biotypes cannot be differentiated solely on the basis of clinical features, but they are associated with differing clinical-symptom profiles. They also predict responsiveness to transcranial magnetic stimulation therapy ( n = 154). Our results define novel subtypes of depression that transcend current diagnostic boundaries and may be useful for identifying the individuals who are most likely to benefit from targeted neurostimulation therapies. Main Depression is a heterogeneous clinical syndrome that is diagnosed when a patient reports at least five of nine symptoms. This allows for several hundred unique combinations of changes in mood, appetite, sleep, energy, cognition and motor activity. Such remarkable heterogeneity reflects the consensus view that there are multiple forms of depression, but their neurobiological basis remains poorly understood 1 , 2 . So far, most efforts to characterize depression subtypes and develop diagnostic biomarkers have begun by identifying clusters of symptoms that tend to co-occur, and by then testing for neurophysiological correlates. These pioneering studies have defined atypical, melancholic, seasonal and agitated subtypes of depression associated with characteristic changes in neuroendocrine activity, circadian rhythms and other potential biomarkers 3 , 4 , 5 . Still, the association between clinical subtypes and their biological substrates is inconsistent and variable at the individual level, and unlike diagnostic biomarkers in other areas of medicine, they have not yet proven useful for differentiating individual patients from healthy controls or for reliably predicting treatment response at the individual level. An alternative to subtyping patients on the basis of co-occurring clinical symptoms is to identify neurophysiological subtypes, or biotypes, by clustering subjects according to shared signatures of brain dysfunction 6 . This type of approach has already begun to yield insights into how differing biological mechanisms may give rise to overlapping, heterogeneous clinical presentations of psychotic disorders 6 , 7 . Neuroimaging biomarkers of abnormal brain function have proven utility in the assessment of pain 8 and have also shown promise for depression, for both the prediction of treatment response 9 , 10 , 11 , 12 , 13 and treatment selection 14 . Resting-state fMRI (rsfMRI) is an especially useful modality because it can be used easily in diverse patient populations to quantify functional network connectivity in terms of correlated, spontaneous MR signal fluctuations. Depression is associated with dysfunction and abnormal functional connectivity in frontostriatal and limbic brain networks 15 , 16 , 17 , 18 , 19 , 20 , in accordance with morphological and synaptic changes in chronic stress models in rodents 21 , 22 , 23 , 24 . These studies raise the intriguing possibility that fMRI measures of connectivity could be leveraged to identify novel subtypes of depression with stronger neurobiological correlates that predict treatment responsiveness. To this end, we developed a method for defining depression subtypes by clustering subjects according to distinct, whole-brain patterns of abnormal functional connectivity in resting-state networks, unbiased by assumptions about the involvement of particular brain regions, and tested it in a large, multisite data set. Our analyses revealed four biotypes that were defined by homogeneous patterns of dysfunctional connectivity in frontostriatal and limbic networks, and that could be diagnosed with high sensitivity and specificity in individual subjects. Importantly, these biotypes were also prognostically informative, predicting which patients responded to repetitive transcranial magnetic stimulation (TMS), a targeted neurostimulation therapy. Results Frontostriatal and limbic connectivity define four depression biotypes We began by designing and implementing a preprocessing procedure (Online Methods ) to control for motion-, scanner- and age-related effects in a multisite data set that comprised rsfMRI scans for 711 subjects (the 'training data set', n = 333 patients with depression; n = 378 healthy controls). No subjects had comorbid substance-abuse disorders, and patients and controls were matched for age and sex. Data that support our approach to controlling for motion-related Blood-oxygen-level dependent (BOLD) signal effects, a particularly important source of rsfMRI artifact 25 , 26 , 27 , are presented in Supplementary Figure 1. After co-registering the functional volumes to a common (Montreal Neurological Institute (MNI)) space, we applied an extensively validated parcellation system 28 to delineate 258 functional network nodes that spanned the whole brain and had stable signals across all sites and scans in this data set ( Fig. 1a ). Next, we extracted BOLD signal residual time series and calculated correlation matrices between each node, which provided an unbiased estimate of the whole-brain architecture of functional connectivity in each subject ( Fig. 1b ). Figure 1: Canonical correlation analysis (CCA) and hierarchical clustering define four connectivity-based biotypes of depression. ( a ) Data analysis schematic and workflow. After preprocessing, BOLD signal time series were extracted from 258 spherical regions of interest (ROIs) distributed across the cortex and subcortical structures. The schematics (top) show lateral (left) and medial (right) views of right-hemisphere ROIs projected onto an inflated cortical surface and colored by functional network (lower left). Left-hemisphere ROIs (data not shown) were similar. For each subject, whole-brain functional-connectivity matrices were generated by calculating pairwise BOLD signal correlations between all ROIs, as in this example of correlated signals ( r 2 = 0.88) for DLPFC (solid line) and PPC (dashed line) nodes of the FPTC network in a representative subject. ( b ) Whole-brain, 258 × 258 functional-connectivity matrix averaged<|im_end|> <|im_start|>assistant Patients with depression can be categorized into four unique subtypes defined by distinct patterns of abnormal connectivity in the brain, according to new research from Weill Cornell Medicine. In a collaborative study published Dec. 5 in Nature Medicine, Dr. Conor Liston, an assistant professor of neuroscience in the Feil Family Brain and Mind Institute and an assistant professor of psychiatry at Weill Cornell Medicine, has identified biomarkers in depression by analyzing more than 1,100 functional magnetic resonance imaging (fMRI) brain scans of patients with clinical depression and of healthy controls, gathered from across the country. These biomarkers may help doctors to better diagnose depression subtypes and determine which patients would most likely benefit from a targeted neuro-stimulation therapy called transcranial magnetic stimulation, which uses magnetic fields to create electrical impulses in the brain. "The four subtypes of depression that we discovered vary in terms of their clinical symptoms but, more importantly, they differ in their responses to treatment," Liston said. "We can now predict with high accuracy whether or not a patient will respond to transcranial magnetic stimulation therapy, which is significant because it takes five weeks to know if this type of treatment works." Approximately 10 percent of Americans are diagnosed with clinical depression each year. It is, by some estimates, the leading cause of disability in many developed countries. Historically, efforts to characterize depression involved looking at groups of symptoms that tend to co-occur, then testing neurophysiological links. And while past pioneering studies have defined different forms of depression, the association between the various types and the underlying biology has been inconsistent. Further, diagnostic biomarkers have yet to prove useful in distinguishing depressed patients from healthy controls or in reliably predicting treatment response among individuals. "Depression is typically diagnosed based on things that we are experiencing, but as in election polling, the results you get depend a lot on the way you ask the question," Liston said. "Brain scans are objective." Researchers from Weill Cornell Medicine and seven other institutions derived the biomarkers by assigning statistical weights to abnormal connections in the brain, then predicting the probability that they belonged to one subtype versus another. The study found that distinct patterns of abnormal functional connectivity in the brain differentiated the four biotypes and were linked with specific symptoms. For example, reduced connectivity in the part of the brain that regulates fear-related behavior and reappraisal of negative emotional stimuli was most severe in biotypes one and four, which exhibited increased anxiety. Liston will seek to replicate and confirm the results of this research and discover if it is broadly applicable to studying the biology of depression and other forms of mental illness. "Subtyping is a major problem in psychiatry," Liston said. "It's not just an issue for depression, and it would be really valuable to have objective biological tests that can help diagnose subtypes of other mental illnesses, such as psychotic disorders, autism and substance abuse syndromes." <|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 CONSORT 2010 statement provides minimum guidelines for reporting randomized trials. Its widespread use has been instrumental in ensuring transparency in the evaluation of new interventions. More recently, there has been a growing recognition that interventions involving artificial intelligence (AI) need to undergo rigorous, prospective evaluation to demonstrate impact on health outcomes. The CONSORT-AI (Consolidated Standards of Reporting Trials–Artificial Intelligence) extension is a new reporting guideline for clinical trials evaluating interventions with an AI component. It was developed in parallel with its companion statement for clinical trial protocols: SPIRIT-AI (Standard Protocol Items: Recommendations for Interventional Trials–Artificial Intelligence). Both guidelines were developed through a staged consensus process involving literature review and expert consultation to generate 29 candidate items, which were assessed by an international multi-stakeholder group in a two-stage Delphi survey (103 stakeholders), agreed upon in a two-day consensus meeting (31 stakeholders) and refined through a checklist pilot (34 participants). The CONSORT-AI extension includes 14 new items that were considered sufficiently important for AI interventions that they should be routinely reported in addition to the core CONSORT 2010 items. CONSORT-AI recommends that investigators provide clear descriptions of the AI intervention, including instructions and skills required for use, the setting in which the AI intervention is integrated, the handling of inputs and outputs of the AI intervention, the human–AI interaction and provision of an analysis of error cases. CONSORT-AI will help promote transparency and completeness in reporting clinical trials for AI interventions. It will assist editors and peer reviewers, as well as the general readership, to understand, interpret and critically appraise the quality of clinical trial design and risk of bias in the reported outcomes. Main Randomized controlled trials (RCTs) are considered the gold-standard experimental design for providing evidence of the safety and efficacy of an intervention 1 , 2 . Trial results, if adequately reported, have the potential to inform regulatory decisions, clinical guidelines and health policy. It is therefore crucial that RCTs are reported with transparency and completeness so that readers can critically appraise the trial methods and findings and assess the presence of bias in the results 3 , 4 , 5 . The CONSORT statement provides evidence-based recommendations to improve the completeness of the reporting of RCTs. The statement was first introduced in 1996 and has since been widely endorsed by medical journals internationally 5 . Over the past two decades, it has undergone two updates and has demonstrated a substantial positive impact on the quality of RCT reports 6 , 7 . The most recent CONSORT 2010 statement provides a 25-item checklist of the minimum reporting content applicable to all RCTs, but it recognizes that certain interventions may require extension or elaboration of these items. Several such extensions exist 8 , 9 , 10 , 11 , 12 , 13 . AI is an area of enormous interest with strong drivers to accelerate new interventions through to publication, implementation and market 14 . While AI systems have been researched for some time, recent advances in deep learning and neural networks have gained considerable interest for their potential in health applications. Examples of such applications are wide ranging and include AI systems for screening and triage 15 , 16 , diagnosis 17 , 18 , 19 , 20 ,prognostication 21 , 22 , decision support 23 and treatment recommendation 24 . However, in the most recent cases, published evidence has consisted of in silico, early-phase validation. It has been recognized that most recent AI studies are inadequately reported and existing reporting guidelines do not fully cover potential sources of bias specific to AI systems 25 . The welcome emergence of RCTs seeking to evaluate newer interventions based on, or including, an AI component (called ‘AI interventions’ here) 23 , 26 , 27 , 28 , 29 , 30 , 31 has similarly been met with concerns about the design and reporting 25 , 32 , 33 , 34 . This has highlighted the need to provide reporting guidance that is ‘fit for purpose’ in this domain. CONSORT-AI (as part of the SPIRIT-AI and CONSORT-AI initiative) is an international initiative supported by CONSORT and the EQUATOR (Enhancing the Quality and Transparency of Health Research) Network to evaluate the existing CONSORT 2010 statement and to extend or elaborate this guidance where necessary, to support the reporting of clinical trials for AI interventions 35 , 36 . It is complementary to the SPIRIT-AI statement, which aims to promote high-quality protocol reporting for AI trials. This Consensus Statement describes the methods used to identify and evaluate candidate items and gain consensus. In addition, it also provides the CONSORT-AI checklist, which includes the new extension items and their accompanying explanations. Methods The SPIRIT-AI and CONSORT-AI extensions were simultaneously developed for clinical trial protocols and trial reports. An announcement for the SPIRIT-AI and CONSORT-AI initiative was published in October 2019 (ref. 35 ), and the two guidelines were registered as reporting guidelines under development on the EQUATOR library of reporting guidelines in May 2019. Both guidelines were developed in accordance with the EQUATOR Network’s methodological framework 37 . The SPIRIT-AI and CONSORT-AI Steering Group, consisting of 15 international experts, was formed to oversee the conduct and methodology of the study. Definitions of key terms are provided in the glossary (Box 1 ). Box 1 Glossary Artificial Intelligence The science of developing computer systems which can perform tasks normally requiring human intelligence. AI intervention A health intervention that relies upon an AI/ML component to serve its purpose. CONSORT Consolidated Standards of Reporting Trials. CONSORT-AI extension item An additional checklist item to address AI-specific content that is not adequately covered by CONSORT 2010. Class-activation map Class-activation maps are particularly relevant to image classification AI interventions. Class-activation maps are visualizations of the pixels that had the greatest influence on predicted class, by displaying the gradient of the predicted outcome from the model with respect to the input. They are also referred to as ‘saliency maps’ or ‘heat maps’. Health outcome Measured variables in the trial that", "role": "user" }, { "content": "Patients could benefit from faster and more effective introduction of artificial intelligence (AI) innovations to diagnose and treat disease—thanks to the first international standards for reporting of clinical trials for AI. As evaluation of health interventions involving machine learning or other AI systems moves into clinical trials, an international group has developed guidelines aiming to improve the quality of these studies and ensure that they are reported transparently. The use of these international guidelines will enable patients, health care professionals and policy-makers to be more confident on whether an AI intervention is safe and effective. This is a key step towards trustworthy AI in health. Development of new reporting guidelines which expand on the current SPIRIT 2013 and CONSORT 2010 reporting frameworks will boost transparency and robustness for clinical trials evaluating AI health solutions. Future clinical trials evaluating an AI intervention will be expected—and often required—to report their publications to the new standards. The guidelines will also help medical professionals, regulators, funders and other decision-makers assess the quality of planned clinical trials and assess whether the algorithm is safe and likely to bring about patient benefit. Researchers from the University of Birmingham and University Hospitals Birmingham NHS Foundation Trust (UHB) worked with leading insttitutions from across the world—including the United States and Canada—and have published their findings and the new guidelines today in Nature Medicine, the BMJ and The Lancet Digital Health. Researchers developed the additional guidance to tackle concerns that many studies of AI are of insufficient quality and are not transparent. This was highlighted in research published last September, led by several of the same researchers which highlighted that less than one percent of 20,500 analyzed studies relating to health AI were of sufficient quality that independent viewers could have confidence in their results. Professor Alastair Denniston, Lead for AI at Birmingham Health Partners Center for Regulatory Science and Innovation, and Consultant Ophthalmologist at UHB, commented: \"Patients could benefit hugely from the use of AI in medical settings, but before we introduce these technologies into everyday practice we need to know that they have been robustly evaluated and proven to be effective and safe. Our previous work showed just how big a problem this can be and that we needed a way to cut through the hype surrounding AI in healthcare. These new reporting guidelines—SPIRIT-AI and CONSORT-AI—provide a solution to the 'hype' problem. They provide a clear, transparent framework to support the design and reporting of AI trials that will help to improve quality and transparency. These extended guidelines will help to reduce wasted effort and deliver effective AI-led medical interventions to patients quicker.\" SPIRIT-AI extension is a new guideline for clinical trials protocols and CONSORT-AI extension is a new reporting guideline for clinical trial reports, for evaluating interventions with AI components. Professor Melanie Calvert, NIHR Senior Investigator and Director of Birmingham Health Partners Center for Regulatory Science and Innovation commented: \"There is growing recognition that interventions involving AI need rigorous evaluation to demonstrate their impact on health outcomes. Without this, we risk not generating sufficiently robust evidence to decide whether AI interventions should be commissioned in the real world. These new guidelines will help to identify and overcome research challenges associated with AI-led health innovation, but we could not have got to this exciting point without the help of patients involved in research.\" Elaine Manna, from London, has been living with age-related macular degeneration for 20 years and was one of a number of patient partners who helped to develop the new guidelines. She was asked to provide a patient perspective on developing the guidelines after taking part in an AI research study involving Moorfields Eye Hospital NHS Foundation Trust, in London, and British technology company DeepMind. Elaine commented: \"A super-fast algorithm was tested on my eye—diagnosing my condition as well as an expert ophthalmologist or optometrist. This was a development with significant implications for saving sight and reducing waiting times for appointments. It's vital for patients to be equally involved in their healthcare—understanding how decisions are made, being informed and involved in decision making. Helping to develop the SPIRIT-AI and CONSORT-AI guidelines, I went from thinking of myself as someone with a degenerative eye disease to someone who felt empowered.\" The SPIRIT-AI extension includes 15 new items and the CONSORT-AI extension includes 14 new items—all considered sufficiently important for clinical trial protocols of AI interventions to be routinely reported in addition to core items. ", "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 CONSORT 2010 statement provides minimum guidelines for reporting randomized trials. Its widespread use has been instrumental in ensuring transparency in the evaluation of new interventions. More recently, there has been a growing recognition that interventions involving artificial intelligence (AI) need to undergo rigorous, prospective evaluation to demonstrate impact on health outcomes. The CONSORT-AI (Consolidated Standards of Reporting Trials–Artificial Intelligence) extension is a new reporting guideline for clinical trials evaluating interventions with an AI component. It was developed in parallel with its companion statement for clinical trial protocols: SPIRIT-AI (Standard Protocol Items: Recommendations for Interventional Trials–Artificial Intelligence). Both guidelines were developed through a staged consensus process involving literature review and expert consultation to generate 29 candidate items, which were assessed by an international multi-stakeholder group in a two-stage Delphi survey (103 stakeholders), agreed upon in a two-day consensus meeting (31 stakeholders) and refined through a checklist pilot (34 participants). The CONSORT-AI extension includes 14 new items that were considered sufficiently important for AI interventions that they should be routinely reported in addition to the core CONSORT 2010 items. CONSORT-AI recommends that investigators provide clear descriptions of the AI intervention, including instructions and skills required for use, the setting in which the AI intervention is integrated, the handling of inputs and outputs of the AI intervention, the human–AI interaction and provision of an analysis of error cases. CONSORT-AI will help promote transparency and completeness in reporting clinical trials for AI interventions. It will assist editors and peer reviewers, as well as the general readership, to understand, interpret and critically appraise the quality of clinical trial design and risk of bias in the reported outcomes. Main Randomized controlled trials (RCTs) are considered the gold-standard experimental design for providing evidence of the safety and efficacy of an intervention 1 , 2 . Trial results, if adequately reported, have the potential to inform regulatory decisions, clinical guidelines and health policy. It is therefore crucial that RCTs are reported with transparency and completeness so that readers can critically appraise the trial methods and findings and assess the presence of bias in the results 3 , 4 , 5 . The CONSORT statement provides evidence-based recommendations to improve the completeness of the reporting of RCTs. The statement was first introduced in 1996 and has since been widely endorsed by medical journals internationally 5 . Over the past two decades, it has undergone two updates and has demonstrated a substantial positive impact on the quality of RCT reports 6 , 7 . The most recent CONSORT 2010 statement provides a 25-item checklist of the minimum reporting content applicable to all RCTs, but it recognizes that certain interventions may require extension or elaboration of these items. Several such extensions exist 8 , 9 , 10 , 11 , 12 , 13 . AI is an area of enormous interest with strong drivers to accelerate new interventions through to publication, implementation and market 14 . While AI systems have been researched for some time, recent advances in deep learning and neural networks have gained considerable interest for their potential in health applications. Examples of such applications are wide ranging and include AI systems for screening and triage 15 , 16 , diagnosis 17 , 18 , 19 , 20 ,prognostication 21 , 22 , decision support 23 and treatment recommendation 24 . However, in the most recent cases, published evidence has consisted of in silico, early-phase validation. It has been recognized that most recent AI studies are inadequately reported and existing reporting guidelines do not fully cover potential sources of bias specific to AI systems 25 . The welcome emergence of RCTs seeking to evaluate newer interventions based on, or including, an AI component (called ‘AI interventions’ here) 23 , 26 , 27 , 28 , 29 , 30 , 31 has similarly been met with concerns about the design and reporting 25 , 32 , 33 , 34 . This has highlighted the need to provide reporting guidance that is ‘fit for purpose’ in this domain. CONSORT-AI (as part of the SPIRIT-AI and CONSORT-AI initiative) is an international initiative supported by CONSORT and the EQUATOR (Enhancing the Quality and Transparency of Health Research) Network to evaluate the existing CONSORT 2010 statement and to extend or elaborate this guidance where necessary, to support the reporting of clinical trials for AI interventions 35 , 36 . It is complementary to the SPIRIT-AI statement, which aims to promote high-quality protocol reporting for AI trials. This Consensus Statement describes the methods used to identify and evaluate candidate items and gain consensus. In addition, it also provides the CONSORT-AI checklist, which includes the new extension items and their accompanying explanations. Methods The SPIRIT-AI and CONSORT-AI extensions were simultaneously developed for clinical trial protocols and trial reports. An announcement for the SPIRIT-AI and CONSORT-AI initiative was published in October 2019 (ref. 35 ), and the two guidelines were registered as reporting guidelines under development on the EQUATOR library of reporting guidelines in May 2019. Both guidelines were developed in accordance with the EQUATOR Network’s methodological framework 37 . The SPIRIT-AI and CONSORT-AI Steering Group, consisting of 15 international experts, was formed to oversee the conduct and methodology of the study. Definitions of key terms are provided in the glossary (Box 1 ). Box 1 Glossary Artificial Intelligence The science of developing computer systems which can perform tasks normally requiring human intelligence. AI intervention A health intervention that relies upon an AI/ML component to serve its purpose. CONSORT Consolidated Standards of Reporting Trials. CONSORT-AI extension item An additional checklist item to address AI-specific content that is not adequately covered by CONSORT 2010. Class-activation map Class-activation maps are particularly relevant to image classification AI interventions. Class-activation maps are visualizations of the pixels that had the greatest influence on predicted class, by displaying the gradient of the predicted outcome from the model with respect to the input. They are also referred to as ‘saliency maps’ or ‘heat maps’. Health outcome Measured variables in the trial that<|im_end|> <|im_start|>assistant Patients could benefit from faster and more effective introduction of artificial intelligence (AI) innovations to diagnose and treat disease—thanks to the first international standards for reporting of clinical trials for AI. As evaluation of health interventions involving machine learning or other AI systems moves into clinical trials, an international group has developed guidelines aiming to improve the quality of these studies and ensure that they are reported transparently. The use of these international guidelines will enable patients, health care professionals and policy-makers to be more confident on whether an AI intervention is safe and effective. This is a key step towards trustworthy AI in health. Development of new reporting guidelines which expand on the current SPIRIT 2013 and CONSORT 2010 reporting frameworks will boost transparency and robustness for clinical trials evaluating AI health solutions. Future clinical trials evaluating an AI intervention will be expected—and often required—to report their publications to the new standards. The guidelines will also help medical professionals, regulators, funders and other decision-makers assess the quality of planned clinical trials and assess whether the algorithm is safe and likely to bring about patient benefit. Researchers from the University of Birmingham and University Hospitals Birmingham NHS Foundation Trust (UHB) worked with leading insttitutions from across the world—including the United States and Canada—and have published their findings and the new guidelines today in Nature Medicine, the BMJ and The Lancet Digital Health. Researchers developed the additional guidance to tackle concerns that many studies of AI are of insufficient quality and are not transparent. This was highlighted in research published last September, led by several of the same researchers which highlighted that less than one percent of 20,500 analyzed studies relating to health AI were of sufficient quality that independent viewers could have confidence in their results. Professor Alastair Denniston, Lead for AI at Birmingham Health Partners Center for Regulatory Science and Innovation, and Consultant Ophthalmologist at UHB, commented: "Patients could benefit hugely from the use of AI in medical settings, but before we introduce these technologies into everyday practice we need to know that they have been robustly evaluated and proven to be effective and safe. Our previous work showed just how big a problem this can be and that we needed a way to cut through the hype surrounding AI in healthcare. These new reporting guidelines—SPIRIT-AI and CONSORT-AI—provide a solution to the 'hype' problem. They provide a clear, transparent framework to support the design and reporting of AI trials that will help to improve quality and transparency. These extended guidelines will help to reduce wasted effort and deliver effective AI-led medical interventions to patients quicker." SPIRIT-AI extension is a new guideline for clinical trials protocols and CONSORT-AI extension is a new reporting guideline for clinical trial reports, for evaluating interventions with AI components. Professor Melanie Calvert, NIHR Senior Investigator and Director of Birmingham Health Partners Center for Regulatory Science and Innovation commented: "There is growing recognition that interventions involving AI need rigorous evaluation to demonstrate their impact on health outcomes. Without this, we risk not generating sufficiently robust evidence to decide whether AI interventions should be commissioned in the real world. These new guidelines will help to identify and overcome research challenges associated with AI-led health innovation, but we could not have got to this exciting point without the help of patients involved in research." Elaine Manna, from London, has been living with age-related macular degeneration for 20 years and was one of a number of patient partners who helped to develop the new guidelines. She was asked to provide a patient perspective on developing the guidelines after taking part in an AI research study involving Moorfields Eye Hospital NHS Foundation Trust, in London, and British technology company DeepMind. Elaine commented: "A super-fast algorithm was tested on my eye—diagnosing my condition as well as an expert ophthalmologist or optometrist. This was a development with significant implications for saving sight and reducing waiting times for appointments. It's vital for patients to be equally involved in their healthcare—understanding how decisions are made, being informed and involved in decision making. Helping to develop the SPIRIT-AI and CONSORT-AI guidelines, I went from thinking of myself as someone with a degenerative eye disease to someone who felt empowered." The SPIRIT-AI extension includes 15 new items and the CONSORT-AI extension includes 14 new items—all considered sufficiently important for clinical trial protocols of AI interventions to be routinely reported in addition to core items. <|im_end|>
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2,220
[ { "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 Although tuberculosis accounts for the highest mortality from a bacterial infection on a global scale, questions persist regarding its origin. One hypothesis based on modern Mycobacterium tuberculosis complex (MTBC) genomes suggests their most recent common ancestor followed human migrations out of Africa approximately 70,000 years before present. However, studies using ancient genomes as calibration points have yielded much younger dates of less than 6000 years. Here, we aim to address this discrepancy through the analysis of the highest-coverage and highest-quality ancient MTBC genome available to date, reconstructed from a calcified lung nodule of Bishop Peder Winstrup of Lund (b. 1605–d. 1679). Results A metagenomic approach for taxonomic classification of whole DNA content permitted the identification of abundant DNA belonging to the human host and the MTBC, with few non-TB bacterial taxa comprising the background. Genomic enrichment enabled the reconstruction of a 141-fold coverage M . tuberculosis genome. In utilizing this high-quality, high-coverage seventeenth-century genome as a calibration point for dating the MTBC, we employed multiple Bayesian tree models, including birth-death models, which allowed us to model pathogen population dynamics and data sampling strategies more realistically than those based on the coalescent. Conclusions The results of our metagenomic analysis demonstrate the unique preservation environment calcified nodules provide for DNA. Importantly, we estimate a most recent common ancestor date for the MTBC of between 2190 and 4501 before present and for Lineage 4 of between 929 and 2084 before present using multiple models, confirming a Neolithic emergence for the MTBC. Background Tuberculosis, caused by organisms in the Mycobacterium tuberculosis complex (MTBC), has taken on renewed relevance and urgency in the twenty-first century due to its global distribution, its high morbidity, and the rise of antibiotic-resistant strains [ 1 ]. The difficulty in disease management and treatment, combined with the massive reservoir the pathogen maintains in human populations through latent infection [ 2 ], makes tuberculosis a pressing public health challenge. Despite this, controversy exists regarding the history of the relationship between members of the MTBC and their human hosts. Existing literature suggests two estimates for the time to the most recent common ancestor (tMRCA) for the MTBC based on the application of Bayesian molecular dating to genome-wide Mycobacterium tuberculosis data. One estimate suggests the extant MTBC emerged through a bottleneck approximately 70,000 years ago, coincident with major migrations of humans out of Africa [ 3 ]. This estimate was reached using a large global dataset of exclusively modern M . tuberculosis genomes, with internal nodes of the MTBC calibrated by extrapolated dates for major human migrations [ 3 ]. This estimate relied on congruence between the topology of the MTBC and human mitochondrial phylogenies, but this congruence does not extend to human Y chromosome phylogeographic structure [ 4 ]. As an alternative approach, the first publication of ancient MTBC genomes utilized radiocarbon dates as direct calibration points to infer mutation rates and yielded an MRCA date for the complex of less than 6000 years [ 5 ]. This younger emergence was later supported by mutation rates estimated within the pervasive Lineage 4 (L4) of the MTBC, using four M . tuberculosis genomes from the late eighteenth and early nineteenth centuries [ 6 ]. Despite the agreement in studies that have relied on ancient DNA calibration so far, dating of the MTBC emergence remains controversial. The young age suggested by these works cannot account for purported detection of MTBC DNA in archeological material that predates the tMRCA estimate (e.g., Baker et al. [ 7 ]; Hershkovitz et al. [ 8 ]; Masson et al. [ 9 ]; Rothschild et al. [ 10 ]), the authenticity of which has been challenged [ 11 ]. Furthermore, constancy in mutation rates of the MTBC has been questioned on account of observed rate variation in modern lineages, combined with the unquantified effects of latency [ 12 ]. The ancient genomes presented by Bos and colleagues, though isolated from human remains, were most closely related to Mycobacterium pinnipedii , a lineage of the MTBC currently associated with infections in seals and sea lions [ 5 ]. Given our unfamiliarity with the demographic history of tuberculosis in sea mammal populations [ 13 ], identical substitution rates between the pinniped lineage and human-adapted lineages of the MTBC cannot be assumed. Additionally, estimates of genetic diversity in MTBC strains from archeological specimens can be difficult given their similarities to environmental mycobacterial DNA from the depositional context, which increase the risk of false positive genetic characterization [ 14 ]. Though the ancient genomes published by Kay and colleagues belonged to human-adapted lineages of the MTBC, and the confounding environmental signals were significantly reduced by their funerary context in crypts, two of the four genomes used for molecular dating were derived from mixed-strain infections [ 6 ]. By necessity, diversity derived in each genome would have to be ignored for them to be computationally distinguished [ 6 ]. Though ancient DNA is a valuable tool for answering the question of when the MTBC emerged, the available ancient data remains sparse and subject to case-by-case challenges. Here, we offer a higher resolution temporal estimate for the emergence of the MTBC and L4 using multiple Bayesian models of varying complexity through the analysis of a high-coverage seventeenth-century M . tuberculosis genome extracted from a calcified lung nodule. Removed from naturally mummified remains, the nodule provided an excellent preservation environment for the pathogen, and exhibited minimal infiltration by exogenous bacteria. The nodule and surrounding lung tissue also showed exceptional preservation of host DNA, thus showing promise for this tissue type in ancient DNA investigations. Results Pathogen identification Computed tomography (CT) scans of the mummified remains of Bishop Peder Winstrup of Lund, Sweden revealed a calcified granuloma a few millimeters (mm) in size in the collapsed right lung together with two ~ 5 mm calcifications in the right hilum (Fig. 1 ). Primary tuberculosis causes parenchymal changes and ipsilateral hilar lymphadenopathy that is more common on the right side [ 15 ]. Upon resolution, it", "role": "user" }, { "content": "When anthropologist Caroline Arcini and her colleagues at the Swedish Natural Historical Museum discovered small calcifications in the extremely well-preserved lungs of Bishop Peder Winstrup, they knew more investigation was needed. \"We suspected these were remnants of a past lung infection,\" says Arcini, \"and tuberculosis was at the top of our list of candidates. DNA analysis was the best way to prove it.\" Up to one-quarter of the world's population is suspected to have been exposed to bacteria of the Mycobacterium tuberculosis complex, which cause tuberculosis (TB). Bishop Winstrup would have been one of many to fall ill during the onset of the so-called \"white plague\" TB pandemic that ravaged post-medieval Europe. Today, TB is among the most prevalent diseases, accounting for the highest worldwide mortality from a bacterial infection. The global distribution of TB has led to the prevailing assumption that the pathogen evolved early in human history and reached its global distribution via the hallmark human migrations tens of thousands of years ago, but recent work on ancient TB genomes has stirred up controversy over when this host-pathogen relationship began. In 2014, a team led by scientists from the University of Tübingen and Arizona State University reconstructed three ancient TB genomes from pre-contact South America—not only were the ancient strains unexpectedly related to those circulating in present-day seals, but comparison against a large number of human strains suggested that TB emerged within the last 6000 years. Understandably, skepticism surrounded this new estimate since it was based entirely on ancient genomes that are not representative of the TB strains associated with humans today. \"Discovery of the Bishop's lung calcification gave us the opportunity to revisit the question of tuberculosis emergence with data from an ancient European,\" comments Kirsten Bos, group leader for Molecular Paleopathology at the Max Planck Institute for the Science of Human History (MPI-SHH), who co-led the study. \"If we could reconstruct a TB genome from Bishop Winstrup, where we know his date of death to the day, it would give a secure and independent calibration for our estimates of how old TB, as we know it, actually is.\" The highest quality ancient TB genome to date In a new study published this week in Genome Biology, Susanna Sabin of MPI-SHH and colleagues have reconstructed a tuberculosis genome from the calcified nodule discovered in Bishop Winstrup's remains. Scanning electron micrograph of Mycobacterium tuberculosis bacteria, which cause TB. Credit: NIAID \"The genome is of incredible quality—preservation on this scale is extremely rare in ancient DNA,\" says Bos. Together with a handful of tuberculosis genomes from other work, the researchers revisited the question of the age of the Mycobacterium tuberculosis complex, with the year of the Bishop's death as a fine-tuned calibration point. Using multiple molecular dating models, all angles indeed point to a relatively young age of the Mycobacterium tuberculosis complex. \"A more recent emergence of the tuberculosis pathogen complex is now supported by genetic evidence from multiple geographic regions and time periods,\" says Sabin, first author of the study. \"It's the strongest evidence available to date for this emergence having been a Neolithic phenomenon.\" This most recent shift in the narrative for when bacteria in the Mycobacterium tuberculosis complex became highly infectious to humans raises further questions about the context of its emergence, as it appears to have coincided with the rise of pastoralism and sedentary lifestyles. \"The Neolithic transition seems to have played an important role for the emergence of a number of human pathogens,\" says Denise Kühnert, group leader for disease transmission research at MPI-SHH who co-led the investigation. \"For TB in particular, stronger evidence could only come from an older genome, though these deeper time periods are unlikely to yield preservation on the scale of what we've seen for Bishop Winstrup,\" adds Bos. \"Moving forward,\" Sabin further comments, \"the hope is we will find adequately preserved DNA from time periods close to the emergence of the complex, or perhaps from its ancestor.\" ", "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 Although tuberculosis accounts for the highest mortality from a bacterial infection on a global scale, questions persist regarding its origin. One hypothesis based on modern Mycobacterium tuberculosis complex (MTBC) genomes suggests their most recent common ancestor followed human migrations out of Africa approximately 70,000 years before present. However, studies using ancient genomes as calibration points have yielded much younger dates of less than 6000 years. Here, we aim to address this discrepancy through the analysis of the highest-coverage and highest-quality ancient MTBC genome available to date, reconstructed from a calcified lung nodule of Bishop Peder Winstrup of Lund (b. 1605–d. 1679). Results A metagenomic approach for taxonomic classification of whole DNA content permitted the identification of abundant DNA belonging to the human host and the MTBC, with few non-TB bacterial taxa comprising the background. Genomic enrichment enabled the reconstruction of a 141-fold coverage M . tuberculosis genome. In utilizing this high-quality, high-coverage seventeenth-century genome as a calibration point for dating the MTBC, we employed multiple Bayesian tree models, including birth-death models, which allowed us to model pathogen population dynamics and data sampling strategies more realistically than those based on the coalescent. Conclusions The results of our metagenomic analysis demonstrate the unique preservation environment calcified nodules provide for DNA. Importantly, we estimate a most recent common ancestor date for the MTBC of between 2190 and 4501 before present and for Lineage 4 of between 929 and 2084 before present using multiple models, confirming a Neolithic emergence for the MTBC. Background Tuberculosis, caused by organisms in the Mycobacterium tuberculosis complex (MTBC), has taken on renewed relevance and urgency in the twenty-first century due to its global distribution, its high morbidity, and the rise of antibiotic-resistant strains [ 1 ]. The difficulty in disease management and treatment, combined with the massive reservoir the pathogen maintains in human populations through latent infection [ 2 ], makes tuberculosis a pressing public health challenge. Despite this, controversy exists regarding the history of the relationship between members of the MTBC and their human hosts. Existing literature suggests two estimates for the time to the most recent common ancestor (tMRCA) for the MTBC based on the application of Bayesian molecular dating to genome-wide Mycobacterium tuberculosis data. One estimate suggests the extant MTBC emerged through a bottleneck approximately 70,000 years ago, coincident with major migrations of humans out of Africa [ 3 ]. This estimate was reached using a large global dataset of exclusively modern M . tuberculosis genomes, with internal nodes of the MTBC calibrated by extrapolated dates for major human migrations [ 3 ]. This estimate relied on congruence between the topology of the MTBC and human mitochondrial phylogenies, but this congruence does not extend to human Y chromosome phylogeographic structure [ 4 ]. As an alternative approach, the first publication of ancient MTBC genomes utilized radiocarbon dates as direct calibration points to infer mutation rates and yielded an MRCA date for the complex of less than 6000 years [ 5 ]. This younger emergence was later supported by mutation rates estimated within the pervasive Lineage 4 (L4) of the MTBC, using four M . tuberculosis genomes from the late eighteenth and early nineteenth centuries [ 6 ]. Despite the agreement in studies that have relied on ancient DNA calibration so far, dating of the MTBC emergence remains controversial. The young age suggested by these works cannot account for purported detection of MTBC DNA in archeological material that predates the tMRCA estimate (e.g., Baker et al. [ 7 ]; Hershkovitz et al. [ 8 ]; Masson et al. [ 9 ]; Rothschild et al. [ 10 ]), the authenticity of which has been challenged [ 11 ]. Furthermore, constancy in mutation rates of the MTBC has been questioned on account of observed rate variation in modern lineages, combined with the unquantified effects of latency [ 12 ]. The ancient genomes presented by Bos and colleagues, though isolated from human remains, were most closely related to Mycobacterium pinnipedii , a lineage of the MTBC currently associated with infections in seals and sea lions [ 5 ]. Given our unfamiliarity with the demographic history of tuberculosis in sea mammal populations [ 13 ], identical substitution rates between the pinniped lineage and human-adapted lineages of the MTBC cannot be assumed. Additionally, estimates of genetic diversity in MTBC strains from archeological specimens can be difficult given their similarities to environmental mycobacterial DNA from the depositional context, which increase the risk of false positive genetic characterization [ 14 ]. Though the ancient genomes published by Kay and colleagues belonged to human-adapted lineages of the MTBC, and the confounding environmental signals were significantly reduced by their funerary context in crypts, two of the four genomes used for molecular dating were derived from mixed-strain infections [ 6 ]. By necessity, diversity derived in each genome would have to be ignored for them to be computationally distinguished [ 6 ]. Though ancient DNA is a valuable tool for answering the question of when the MTBC emerged, the available ancient data remains sparse and subject to case-by-case challenges. Here, we offer a higher resolution temporal estimate for the emergence of the MTBC and L4 using multiple Bayesian models of varying complexity through the analysis of a high-coverage seventeenth-century M . tuberculosis genome extracted from a calcified lung nodule. Removed from naturally mummified remains, the nodule provided an excellent preservation environment for the pathogen, and exhibited minimal infiltration by exogenous bacteria. The nodule and surrounding lung tissue also showed exceptional preservation of host DNA, thus showing promise for this tissue type in ancient DNA investigations. Results Pathogen identification Computed tomography (CT) scans of the mummified remains of Bishop Peder Winstrup of Lund, Sweden revealed a calcified granuloma a few millimeters (mm) in size in the collapsed right lung together with two ~ 5 mm calcifications in the right hilum (Fig. 1 ). Primary tuberculosis causes parenchymal changes and ipsilateral hilar lymphadenopathy that is more common on the right side [ 15 ]. Upon resolution, it<|im_end|> <|im_start|>assistant When anthropologist Caroline Arcini and her colleagues at the Swedish Natural Historical Museum discovered small calcifications in the extremely well-preserved lungs of Bishop Peder Winstrup, they knew more investigation was needed. "We suspected these were remnants of a past lung infection," says Arcini, "and tuberculosis was at the top of our list of candidates. DNA analysis was the best way to prove it." Up to one-quarter of the world's population is suspected to have been exposed to bacteria of the Mycobacterium tuberculosis complex, which cause tuberculosis (TB). Bishop Winstrup would have been one of many to fall ill during the onset of the so-called "white plague" TB pandemic that ravaged post-medieval Europe. Today, TB is among the most prevalent diseases, accounting for the highest worldwide mortality from a bacterial infection. The global distribution of TB has led to the prevailing assumption that the pathogen evolved early in human history and reached its global distribution via the hallmark human migrations tens of thousands of years ago, but recent work on ancient TB genomes has stirred up controversy over when this host-pathogen relationship began. In 2014, a team led by scientists from the University of Tübingen and Arizona State University reconstructed three ancient TB genomes from pre-contact South America—not only were the ancient strains unexpectedly related to those circulating in present-day seals, but comparison against a large number of human strains suggested that TB emerged within the last 6000 years. Understandably, skepticism surrounded this new estimate since it was based entirely on ancient genomes that are not representative of the TB strains associated with humans today. "Discovery of the Bishop's lung calcification gave us the opportunity to revisit the question of tuberculosis emergence with data from an ancient European," comments Kirsten Bos, group leader for Molecular Paleopathology at the Max Planck Institute for the Science of Human History (MPI-SHH), who co-led the study. "If we could reconstruct a TB genome from Bishop Winstrup, where we know his date of death to the day, it would give a secure and independent calibration for our estimates of how old TB, as we know it, actually is." The highest quality ancient TB genome to date In a new study published this week in Genome Biology, Susanna Sabin of MPI-SHH and colleagues have reconstructed a tuberculosis genome from the calcified nodule discovered in Bishop Winstrup's remains. Scanning electron micrograph of Mycobacterium tuberculosis bacteria, which cause TB. Credit: NIAID "The genome is of incredible quality—preservation on this scale is extremely rare in ancient DNA," says Bos. Together with a handful of tuberculosis genomes from other work, the researchers revisited the question of the age of the Mycobacterium tuberculosis complex, with the year of the Bishop's death as a fine-tuned calibration point. Using multiple molecular dating models, all angles indeed point to a relatively young age of the Mycobacterium tuberculosis complex. "A more recent emergence of the tuberculosis pathogen complex is now supported by genetic evidence from multiple geographic regions and time periods," says Sabin, first author of the study. "It's the strongest evidence available to date for this emergence having been a Neolithic phenomenon." This most recent shift in the narrative for when bacteria in the Mycobacterium tuberculosis complex became highly infectious to humans raises further questions about the context of its emergence, as it appears to have coincided with the rise of pastoralism and sedentary lifestyles. "The Neolithic transition seems to have played an important role for the emergence of a number of human pathogens," says Denise Kühnert, group leader for disease transmission research at MPI-SHH who co-led the investigation. "For TB in particular, stronger evidence could only come from an older genome, though these deeper time periods are unlikely to yield preservation on the scale of what we've seen for Bishop Winstrup," adds Bos. "Moving forward," Sabin further comments, "the hope is we will find adequately preserved DNA from time periods close to the emergence of the complex, or perhaps from its ancestor." <|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 Microbial biocontainment is an essential goal for engineering safe, next-generation living therapeutics. However, the genetic stability of biocontainment circuits, including kill switches, is a challenge that must be addressed. Kill switches are among the most difficult circuits to maintain due to the strong selection pressure they impart, leading to high potential for evolution of escape mutant populations. Here we engineer two CRISPR-based kill switches in the probiotic Escherichia coli Nissle 1917, a single-input chemical-responsive switch and a 2-input chemical- and temperature-responsive switch. We employ parallel strategies to address kill switch stability, including functional redundancy within the circuit, modulation of the SOS response, antibiotic-independent plasmid maintenance, and provision of intra-niche competition by a closely related strain. We demonstrate that strains harboring either kill switch can be selectively and efficiently killed inside the murine gut, while strains harboring the 2-input switch are additionally killed upon excretion. Leveraging redundant strategies, we demonstrate robust biocontainment of our kill switch strains and provide a template for future kill switch development. Introduction Probiotic microbes have become effective chasses for engineering diagnostic and therapeutic technologies. One of the most commonly engineered probiotic strains is Escherichia coli Nissle 1917 (EcN). Engineered strains of EcN have been successfully used to diagnose and treat bacterial infections 1 , 2 , cancers 3 , 4 , 5 , gastrointestinal bleeding 6 , inflammatory disorders 7 , 8 , 9 , and obesity 10 in a variety of animal models. EcN strains engineered to treat metabolic disorders are being evaluated in human clinical trials with promising early-phase results 11 , 12 . However, there are important safety concerns associated with organisms genetically engineered for medical applications. Probiotics are living organisms that have the potential to mutate and evolve undesirable traits over the course of diagnosis or treatment. Such adaptations can include loss of beneficial functions of the engineered system, gain of deleterious functions such as competitive exclusion of native microbes, pathogenic potential against the host, or environmental contamination if they spread outside the host 13 , 14 , 15 , 16 . To mitigate these concerns, engineered probiotics should possess biocontainment systems that enable both selective removal from the host and prevent their environmental dissemination 17 . Biocontainment circuit designs are focused on preventing proliferation in the wild, and typically involve an input that is specific to the permissive environment and repressive to the killing circuit, such that upon exit of the permissive environment, the lethal components are expressed 18 . Several such biocontainment strategies have been developed with varying degrees of efficacy and stability, including use of auxotrophy 11 , 19 , 20 and synthetic amino acids 21 , 22 , 23 . While approaches like synthetic auxotrophy are evolutionarily stable in that they do not readily give rise to escape mutants 21 , a limitation of these methods is that they may require the probiotic environment to be supplemented with additional survival factors (‘permissive molecules’). Completely withholding these molecules in the gut, for example by administering an auxotrophic strain without the essential compound, effectively limits probiotic lifespan in vivo 11 , but it may also limit therapeutic potential depending on the rate of probiotic cell death in the absence of the permissive molecules. Alternatively, the permissive molecules may theoretically be supplied to patients in conjunction with the probiotic, but this design complicates administration as well as the selective removal of probiotics from the gut since the time to full clearance of the permissive molecules may be difficult to control. In addition, if the permissive molecules are natively present in the gut, these circuits can be compromised by cross-feeding 20 , 21 , 24 . An inverse kill switch design would then be one in which the baseline state in the gut is permissive without supplementation of exogenous molecules; correspondingly, the lethal components of the circuit are expressed in response to supplied inducers, or environmental signals external to the gut. Numerous genetic circuits have been developed that initiate cell death in response to a chemical inducer 25 , 26 , 27 , 28 . Similarly, biocontainment circuits have been developed in E. coli using temperature sensors tuned to differentiate physiological and environmental temperatures 18 , 29 , 30 . These kill switches control cell survival using a variety of mechanisms, including expression of toxins and lysis proteins 18 , 25 , 26 , 27 , degradation of essential proteins 26 , and cleavage and degradation of the genome by Cas3 proteins 28 . Both temperature-sensitive circuits designed by Piraner et al. and Stirling et al. used the E. coli CcdB-CcdA toxin-antitoxin system to control cell survival. The kill switch engineered by Piraner et al. used a modified version of the Salmonella typhimurium -native P tlpA - tlpA sensor and achieved a 4-log reduction in fecal cell number 30 , while the kill switch engineered by Stirling et al. used the E. coli- native P cspA promoter and achieved a 5-log reduction in fecal cell number 29 . Notably, functional redundancy offered by the combination of the P cspA -controlled temperature-sensitive kill switch with an orthogonal pH-sensitive kill switch mechanism synergistically improved in vitro killing efficacy such that surviving colony counts were below the 11-log limit of detection 18 . However, kill switches that induce cell death by expressing toxins, lysis proteins, and proteases are prone to mutational inactivation, often leading to population dominance of non-functional variants, or have not been characterized for genetic stability 26 . To overcome this stringent evolutionary selection, such kill switch systems must be designed to be highly stable. The temperature-inducible toxin-antitoxin kill switch engineered by Stirling et al. was shown to be stable over 140 generations of growth in vitro and at least 10 days of growth in the mouse gut 29 , while the combined temperature- and pH-inducible kill switch was stable over at least 100 generations in vitro 18 . In contrast, a CRISPR-Cas3-based system has been shown to be stable for 1700 generations when applied to plasmid removal 28 . However, it", "role": "user" }, { "content": "Tae Seok Moon, associate professor of energy, environmental and chemical engineering at the McKelvey School of Engineering at Washington University in St. Louis, has taken a big step forward in his quest to design a modular, genetically engineered kill switch that integrates into any genetically engineered microbe, causing it to self-destruct under certain defined conditions. His research was published Feb. 3 in the journal Nature Communications. Moon's lab understands microbes in a way that only engineers would, as systems made up of sensors, circuits and actuators. These are the components that allow microbes to sense the world around them, interpret it and then act on the interpretation. In some cases, the actuator may act on the information by moving toward a certain protein or attacking a foreign invader. Moon is developing actuators that go against millions of years of evolution that have acted in favor of self-preservation, asking instead that an actuator tells a microbe to self-destruct. The kill switch activator is an effort to quell anxiety about the potential for genetically modified microbes to make their way into the environment. So far, he has developed several: one, for instance, causes a microbe to self-destruct once the ambient environment around it reaches a certain temperature. \"But the previous work had either a base-level activation that was either too high or too low,\" Moon said. And every time he solved that problem, \"the bacteria would mutate.\" During experiments, that meant there were too many microbes left alive after the kill switch should have turned on. Additionally, in some situations, a kill switch may not be triggered for days. This additional time means additional opportunities for the microbes to mutate, possibly affecting the switch's ability to work. For instance, Moon is interested in developing genetically engineered microbes to eat plastic as a way of disposing of harmful waste. \"But we don't know how many days we need to keep these microbes stable until they finish cleaning up our environment. It might be a few days, or a few weeks,\" Moon said, \"because we have so much waste.\" To overcome these roadblocks, Moon inserted multiple kill switches—up to four—in the microbial DNA. The result: During experimentation, of a billion microbes, only one or none may survive. During the experiments, researchers tested the microbes daily. The switches remained functional for 28 days. \"This is the best kill switch ever developed,\" Moon said. These experiments were also done in mice, but looking forward, Moon would like to build kill switches for microbes that will be used in soil—maybe to kill pathogens that are deadly to crops—or even in the human gut to cure diseases. The end game is getting microbes to do what we want and then go away, Moon said. He thinks these microbes could be used to solve a whole host of global problems. \"Bacteria may seem dumb,\" he said, \"but they can be very smart as long as we teach them well.\" ", "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 Microbial biocontainment is an essential goal for engineering safe, next-generation living therapeutics. However, the genetic stability of biocontainment circuits, including kill switches, is a challenge that must be addressed. Kill switches are among the most difficult circuits to maintain due to the strong selection pressure they impart, leading to high potential for evolution of escape mutant populations. Here we engineer two CRISPR-based kill switches in the probiotic Escherichia coli Nissle 1917, a single-input chemical-responsive switch and a 2-input chemical- and temperature-responsive switch. We employ parallel strategies to address kill switch stability, including functional redundancy within the circuit, modulation of the SOS response, antibiotic-independent plasmid maintenance, and provision of intra-niche competition by a closely related strain. We demonstrate that strains harboring either kill switch can be selectively and efficiently killed inside the murine gut, while strains harboring the 2-input switch are additionally killed upon excretion. Leveraging redundant strategies, we demonstrate robust biocontainment of our kill switch strains and provide a template for future kill switch development. Introduction Probiotic microbes have become effective chasses for engineering diagnostic and therapeutic technologies. One of the most commonly engineered probiotic strains is Escherichia coli Nissle 1917 (EcN). Engineered strains of EcN have been successfully used to diagnose and treat bacterial infections 1 , 2 , cancers 3 , 4 , 5 , gastrointestinal bleeding 6 , inflammatory disorders 7 , 8 , 9 , and obesity 10 in a variety of animal models. EcN strains engineered to treat metabolic disorders are being evaluated in human clinical trials with promising early-phase results 11 , 12 . However, there are important safety concerns associated with organisms genetically engineered for medical applications. Probiotics are living organisms that have the potential to mutate and evolve undesirable traits over the course of diagnosis or treatment. Such adaptations can include loss of beneficial functions of the engineered system, gain of deleterious functions such as competitive exclusion of native microbes, pathogenic potential against the host, or environmental contamination if they spread outside the host 13 , 14 , 15 , 16 . To mitigate these concerns, engineered probiotics should possess biocontainment systems that enable both selective removal from the host and prevent their environmental dissemination 17 . Biocontainment circuit designs are focused on preventing proliferation in the wild, and typically involve an input that is specific to the permissive environment and repressive to the killing circuit, such that upon exit of the permissive environment, the lethal components are expressed 18 . Several such biocontainment strategies have been developed with varying degrees of efficacy and stability, including use of auxotrophy 11 , 19 , 20 and synthetic amino acids 21 , 22 , 23 . While approaches like synthetic auxotrophy are evolutionarily stable in that they do not readily give rise to escape mutants 21 , a limitation of these methods is that they may require the probiotic environment to be supplemented with additional survival factors (‘permissive molecules’). Completely withholding these molecules in the gut, for example by administering an auxotrophic strain without the essential compound, effectively limits probiotic lifespan in vivo 11 , but it may also limit therapeutic potential depending on the rate of probiotic cell death in the absence of the permissive molecules. Alternatively, the permissive molecules may theoretically be supplied to patients in conjunction with the probiotic, but this design complicates administration as well as the selective removal of probiotics from the gut since the time to full clearance of the permissive molecules may be difficult to control. In addition, if the permissive molecules are natively present in the gut, these circuits can be compromised by cross-feeding 20 , 21 , 24 . An inverse kill switch design would then be one in which the baseline state in the gut is permissive without supplementation of exogenous molecules; correspondingly, the lethal components of the circuit are expressed in response to supplied inducers, or environmental signals external to the gut. Numerous genetic circuits have been developed that initiate cell death in response to a chemical inducer 25 , 26 , 27 , 28 . Similarly, biocontainment circuits have been developed in E. coli using temperature sensors tuned to differentiate physiological and environmental temperatures 18 , 29 , 30 . These kill switches control cell survival using a variety of mechanisms, including expression of toxins and lysis proteins 18 , 25 , 26 , 27 , degradation of essential proteins 26 , and cleavage and degradation of the genome by Cas3 proteins 28 . Both temperature-sensitive circuits designed by Piraner et al. and Stirling et al. used the E. coli CcdB-CcdA toxin-antitoxin system to control cell survival. The kill switch engineered by Piraner et al. used a modified version of the Salmonella typhimurium -native P tlpA - tlpA sensor and achieved a 4-log reduction in fecal cell number 30 , while the kill switch engineered by Stirling et al. used the E. coli- native P cspA promoter and achieved a 5-log reduction in fecal cell number 29 . Notably, functional redundancy offered by the combination of the P cspA -controlled temperature-sensitive kill switch with an orthogonal pH-sensitive kill switch mechanism synergistically improved in vitro killing efficacy such that surviving colony counts were below the 11-log limit of detection 18 . However, kill switches that induce cell death by expressing toxins, lysis proteins, and proteases are prone to mutational inactivation, often leading to population dominance of non-functional variants, or have not been characterized for genetic stability 26 . To overcome this stringent evolutionary selection, such kill switch systems must be designed to be highly stable. The temperature-inducible toxin-antitoxin kill switch engineered by Stirling et al. was shown to be stable over 140 generations of growth in vitro and at least 10 days of growth in the mouse gut 29 , while the combined temperature- and pH-inducible kill switch was stable over at least 100 generations in vitro 18 . In contrast, a CRISPR-Cas3-based system has been shown to be stable for 1700 generations when applied to plasmid removal 28 . However, it<|im_end|> <|im_start|>assistant Tae Seok Moon, associate professor of energy, environmental and chemical engineering at the McKelvey School of Engineering at Washington University in St. Louis, has taken a big step forward in his quest to design a modular, genetically engineered kill switch that integrates into any genetically engineered microbe, causing it to self-destruct under certain defined conditions. His research was published Feb. 3 in the journal Nature Communications. Moon's lab understands microbes in a way that only engineers would, as systems made up of sensors, circuits and actuators. These are the components that allow microbes to sense the world around them, interpret it and then act on the interpretation. In some cases, the actuator may act on the information by moving toward a certain protein or attacking a foreign invader. Moon is developing actuators that go against millions of years of evolution that have acted in favor of self-preservation, asking instead that an actuator tells a microbe to self-destruct. The kill switch activator is an effort to quell anxiety about the potential for genetically modified microbes to make their way into the environment. So far, he has developed several: one, for instance, causes a microbe to self-destruct once the ambient environment around it reaches a certain temperature. "But the previous work had either a base-level activation that was either too high or too low," Moon said. And every time he solved that problem, "the bacteria would mutate." During experiments, that meant there were too many microbes left alive after the kill switch should have turned on. Additionally, in some situations, a kill switch may not be triggered for days. This additional time means additional opportunities for the microbes to mutate, possibly affecting the switch's ability to work. For instance, Moon is interested in developing genetically engineered microbes to eat plastic as a way of disposing of harmful waste. "But we don't know how many days we need to keep these microbes stable until they finish cleaning up our environment. It might be a few days, or a few weeks," Moon said, "because we have so much waste." To overcome these roadblocks, Moon inserted multiple kill switches—up to four—in the microbial DNA. The result: During experimentation, of a billion microbes, only one or none may survive. During the experiments, researchers tested the microbes daily. The switches remained functional for 28 days. "This is the best kill switch ever developed," Moon said. These experiments were also done in mice, but looking forward, Moon would like to build kill switches for microbes that will be used in soil—maybe to kill pathogens that are deadly to crops—or even in the human gut to cure diseases. The end game is getting microbes to do what we want and then go away, Moon said. He thinks these microbes could be used to solve a whole host of global problems. "Bacteria may seem dumb," he said, "but they can be very smart as long as we teach them well." <|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 Systemic immune suppression may curtail the ability to mount the protective, cell-mediated immune responses that are needed for brain repair. By using mouse models of Alzheimer's disease (AD), we show that immune checkpoint blockade directed against the programmed death-1 (PD-1) pathway evokes an interferon (IFN)-γ–dependent systemic immune response, which is followed by the recruitment of monocyte-derived macrophages to the brain. When induced in mice with established pathology, this immunological response leads to clearance of cerebral amyloid-β (Aβ) plaques and improved cognitive performance. Repeated treatment sessions were required to maintain a long-lasting beneficial effect on disease pathology. These findings suggest that immune checkpoints may be targeted therapeutically in AD. Main Chronic neuroinflammation is common to nearly all neurodegenerative diseases, and it contributes to their pathophysiology 1 . Nevertheless, although anti-inflammatory and immunosuppressive therapies have demonstrated some efficacy in neurodegenerative disease models, these treatments have largely failed in the clinic 2 , 3 . In mouse models of AD, the trafficking of blood-borne myeloid cells (monocyte-derived macrophages) to the central nervous system (CNS) was shown to be neuroprotective. Yet, spontaneous recruitment of these cells seems to be insufficient 4 . By using the five familial AD mutations (5XFAD) mouse model of AD 5 , we recently showed that transient depletion of forkhead box P3 (FOXP3) + regulatory T (T reg ) cells induces an IFN-γ–associated systemic immune response and the activation of the brain's choroid plexus 6 , which is a selective gateway for leukocyte trafficking to the CNS 7 , 8 . This response was followed by the accumulation of monocyte-derived macrophages and T reg cells at sites of CNS pathology and by Aβ plaque clearance and a reversal of cognitive decline 6 . We therefore suggested that in chronic neurodegenerative conditions, systemic immunity should be boosted, rather than suppressed, to drive an immune-dependent cascade needed for brain repair 4 . Immune checkpoints are regulatory pathways for maintaining systemic immune homeostasis and tolerance 9 . Selective blockade of immune checkpoints, such as the PD-1 pathway, enhances anti-tumor immunity by mobilizing the immune system 10 . The IFN-γ–dependent activity induced by PD-1 blockade in cancer immunotherapy 11 , in addition to our observations that leukocyte trafficking to the CNS for repair involves an IFN-γ–dependent response 7 , 12 , prompted us to explore the therapeutic potential of PD-1 immune checkpoint blockade in AD. 5XFAD mice aged 10 months—an age of advanced cerebral pathology—received two intraperitoneal (i.p.) injections (at 3-d intervals) of either a blocking antibody directed at PD-1 (anti–PD-1) or an IgG control, and were examined 7 d after the first injection. PD-1 blockade increased splenocyte frequencies of IFN-γ–producing CD4 + T cells ( Supplementary Fig. 1a,b ), and genome-wide RNA-sequencing of the choroid plexus ( Supplementary Table 1 ) revealed an expression profile associated with an IFN-γ–response ( Fig. 1a and Supplementary Table 2 ). Real-time quantitative PCR (RT-qPCR) showed elevated IFN-γ ( Ifng ) mRNA levels at the choroid plexus ( Fig. 1b ). These findings pointed to a systemic IFN-γ immune response in 5XFAD mice following PD-1 blockade, particularly at the choroid plexus. Figure 1: PD-1 blockade promotes myeloid cell recruitment to the CNS via IFN-γ. ( a ) Gene Ontology (GO) annotation terms enriched in the choroid plexus of 10-month-old 5XFAD mice treated with anti–PD-1 ( n = 5) and examined on day 10 after the first injection, when compared to IgG-treated ( n = 5) and untreated ( n = 4) 5XFAD controls (based on Supplementary Table 2 ; color scale corresponds to negative log 10 of P value). ( b ) mRNA expression levels of Ifng (encoding IFN-γ) in the choroid plexus of anti–PD-1–treated ( n = 5), IgG-treated ( n = 5) and untreated ( n = 3) 5XFAD mice (one-way analysis of variance (ANOVA) and Bonferroni post-test; data are representative of three independent experiments). ( c ) 5- to 6-month-old 5XFAD mice ( n = 3 per group) were i.p. injected on days 1 and 4 with either anti–PD-1 or IgG, and examined at days 7 (d7) and 14 (d14). Flow cytometry sorting gating strategy and quantitative analysis of brain CD45 low CD11b + (indicated by blue gates and bar fills) and CD45 high CD11b + (indicated in orange) myeloid cells. Myeloid cell populations showed distinct differential expression of Ly6c. ( d ) 6-month-old 5XFAD mice were injected with IFN-γ–neutralizing antibodies 1 d before PD-1–specific antibody injections and were then examined on day 7. Flow cytometry analysis of CD45 high CD11b + cell frequencies in the brains of IgG-treated ( n = 4) and anti–PD-1–treated (with ( n = 5) or without ( n = 6) anti−IFN-γ) 5XFAD mice. ( e ) mRNA expression levels of Ccl2 and Icam1 in the choroid plexus of the same mice (one-way ANOVA and Bonferroni post-test). Error bars represent mean ± s.e.m.; * P < 0.05; ** P < 0.01; *** P < 0.001. Full size image We next examined whether the effect of PD-1 blockade on systemic immunity involves CNS recruitment of monocyte-derived macrophages. We analyzed myeloid cell populations in the brains of 5XFAD mice at 7 d and 14 d after the first injection of anti–PD-1 (two i.p. injections at 3-d intervals) by separately sorting CD45 low CD11b + microglia and CD45 high CD11b + cells, which represent mostly infiltrating myeloid cells 13 . We observed higher frequencies of CD45 high CD11b + cells in the brains of 5XFAD mice following PD-1 blockade, relative to IgG-treated 5XFAD and wild-type (WT) controls ( Fig. 1c ). Genome-wide transcriptome analysis ( Supplementary Table 3 ) of the myeloid cell populations, sorted from 5XFAD brains after PD-1 blockade, indicated that the CD45 high CD11b + cells expressed a distinct mRNA profile relative to that expressed by the CD45 low CD11b + cells. The CD45 high CD11b + expression profile included features of infiltrating myeloid cells (characterized by high expression of lymphocyte antigen 6c (Ly6C)) ( Fig. 1c ), and expression of the chemokine receptor CCR2 ( Supplementary Fig.", "role": "user" }, { "content": "(MedicalXpress)—A team of researchers working at the Weizmann Institute of Science in Israel has found that a type of drug meant to help the immune system kill tumors also reduces Alzheimer's type symptoms in mouse models. In their paper published in the journal Nature Medicine, the team describes their study of drugs known as PD-1 immune checkpoint blockades, on mouse models, and the results they found. As scientists close in on the cause of Alzheimer's disease and hopefully find a cure, more and more evidence points at problems with the immune system and inflammation as a factor. For the past several years, the prevailing view has been that an overactive immune system might be the root cause, but new studies have begun to suggest the opposite might be true—and that boosting the immune response in the brain might help reduce symptoms of the disease. In this new effort, the researchers looked at PD-1 immune checkpoint blockades because they do their work by disabling immunity checkpoints which is where the body sets up roadblocks to stop the immune system from attacking normal body parts. But tumors have been found to trick this same part of the immune system to prevent it from attacking them. Thus, the idea behind PD-1 blockers is to override the checkpoints and force the immune system to attack the tumor anyway, causing it to shrink and disappear. In this new effort, the goal was to learn if such drugs might help stop or reverse the symptoms of Alzheimer's disease by boosting an immune response in the brain. To find out, the researchers genetically engineered test mice to develop Alzheimer's symptoms, both memory loss and the buildup of amyloid in the brain, and then gave each of them PD-1 blockers to see if it caused any improvement. They report that amyloid buildup in the brain of the mice was reduced by half and that most of them were once again able to make their way through a maze—a test of their memory abilities. The research team notes that some PD-1 blockers are already on the market, Keytruda, for example has already been approved for use in treating tumors—thus, testing the drug on human patients in clinical trials should go rather quickly if further tests suggest it might actually work on people with Alzheimer's 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 Systemic immune suppression may curtail the ability to mount the protective, cell-mediated immune responses that are needed for brain repair. By using mouse models of Alzheimer's disease (AD), we show that immune checkpoint blockade directed against the programmed death-1 (PD-1) pathway evokes an interferon (IFN)-γ–dependent systemic immune response, which is followed by the recruitment of monocyte-derived macrophages to the brain. When induced in mice with established pathology, this immunological response leads to clearance of cerebral amyloid-β (Aβ) plaques and improved cognitive performance. Repeated treatment sessions were required to maintain a long-lasting beneficial effect on disease pathology. These findings suggest that immune checkpoints may be targeted therapeutically in AD. Main Chronic neuroinflammation is common to nearly all neurodegenerative diseases, and it contributes to their pathophysiology 1 . Nevertheless, although anti-inflammatory and immunosuppressive therapies have demonstrated some efficacy in neurodegenerative disease models, these treatments have largely failed in the clinic 2 , 3 . In mouse models of AD, the trafficking of blood-borne myeloid cells (monocyte-derived macrophages) to the central nervous system (CNS) was shown to be neuroprotective. Yet, spontaneous recruitment of these cells seems to be insufficient 4 . By using the five familial AD mutations (5XFAD) mouse model of AD 5 , we recently showed that transient depletion of forkhead box P3 (FOXP3) + regulatory T (T reg ) cells induces an IFN-γ–associated systemic immune response and the activation of the brain's choroid plexus 6 , which is a selective gateway for leukocyte trafficking to the CNS 7 , 8 . This response was followed by the accumulation of monocyte-derived macrophages and T reg cells at sites of CNS pathology and by Aβ plaque clearance and a reversal of cognitive decline 6 . We therefore suggested that in chronic neurodegenerative conditions, systemic immunity should be boosted, rather than suppressed, to drive an immune-dependent cascade needed for brain repair 4 . Immune checkpoints are regulatory pathways for maintaining systemic immune homeostasis and tolerance 9 . Selective blockade of immune checkpoints, such as the PD-1 pathway, enhances anti-tumor immunity by mobilizing the immune system 10 . The IFN-γ–dependent activity induced by PD-1 blockade in cancer immunotherapy 11 , in addition to our observations that leukocyte trafficking to the CNS for repair involves an IFN-γ–dependent response 7 , 12 , prompted us to explore the therapeutic potential of PD-1 immune checkpoint blockade in AD. 5XFAD mice aged 10 months—an age of advanced cerebral pathology—received two intraperitoneal (i.p.) injections (at 3-d intervals) of either a blocking antibody directed at PD-1 (anti–PD-1) or an IgG control, and were examined 7 d after the first injection. PD-1 blockade increased splenocyte frequencies of IFN-γ–producing CD4 + T cells ( Supplementary Fig. 1a,b ), and genome-wide RNA-sequencing of the choroid plexus ( Supplementary Table 1 ) revealed an expression profile associated with an IFN-γ–response ( Fig. 1a and Supplementary Table 2 ). Real-time quantitative PCR (RT-qPCR) showed elevated IFN-γ ( Ifng ) mRNA levels at the choroid plexus ( Fig. 1b ). These findings pointed to a systemic IFN-γ immune response in 5XFAD mice following PD-1 blockade, particularly at the choroid plexus. Figure 1: PD-1 blockade promotes myeloid cell recruitment to the CNS via IFN-γ. ( a ) Gene Ontology (GO) annotation terms enriched in the choroid plexus of 10-month-old 5XFAD mice treated with anti–PD-1 ( n = 5) and examined on day 10 after the first injection, when compared to IgG-treated ( n = 5) and untreated ( n = 4) 5XFAD controls (based on Supplementary Table 2 ; color scale corresponds to negative log 10 of P value). ( b ) mRNA expression levels of Ifng (encoding IFN-γ) in the choroid plexus of anti–PD-1–treated ( n = 5), IgG-treated ( n = 5) and untreated ( n = 3) 5XFAD mice (one-way analysis of variance (ANOVA) and Bonferroni post-test; data are representative of three independent experiments). ( c ) 5- to 6-month-old 5XFAD mice ( n = 3 per group) were i.p. injected on days 1 and 4 with either anti–PD-1 or IgG, and examined at days 7 (d7) and 14 (d14). Flow cytometry sorting gating strategy and quantitative analysis of brain CD45 low CD11b + (indicated by blue gates and bar fills) and CD45 high CD11b + (indicated in orange) myeloid cells. Myeloid cell populations showed distinct differential expression of Ly6c. ( d ) 6-month-old 5XFAD mice were injected with IFN-γ–neutralizing antibodies 1 d before PD-1–specific antibody injections and were then examined on day 7. Flow cytometry analysis of CD45 high CD11b + cell frequencies in the brains of IgG-treated ( n = 4) and anti–PD-1–treated (with ( n = 5) or without ( n = 6) anti−IFN-γ) 5XFAD mice. ( e ) mRNA expression levels of Ccl2 and Icam1 in the choroid plexus of the same mice (one-way ANOVA and Bonferroni post-test). Error bars represent mean ± s.e.m.; * P < 0.05; ** P < 0.01; *** P < 0.001. Full size image We next examined whether the effect of PD-1 blockade on systemic immunity involves CNS recruitment of monocyte-derived macrophages. We analyzed myeloid cell populations in the brains of 5XFAD mice at 7 d and 14 d after the first injection of anti–PD-1 (two i.p. injections at 3-d intervals) by separately sorting CD45 low CD11b + microglia and CD45 high CD11b + cells, which represent mostly infiltrating myeloid cells 13 . We observed higher frequencies of CD45 high CD11b + cells in the brains of 5XFAD mice following PD-1 blockade, relative to IgG-treated 5XFAD and wild-type (WT) controls ( Fig. 1c ). Genome-wide transcriptome analysis ( Supplementary Table 3 ) of the myeloid cell populations, sorted from 5XFAD brains after PD-1 blockade, indicated that the CD45 high CD11b + cells expressed a distinct mRNA profile relative to that expressed by the CD45 low CD11b + cells. The CD45 high CD11b + expression profile included features of infiltrating myeloid cells (characterized by high expression of lymphocyte antigen 6c (Ly6C)) ( Fig. 1c ), and expression of the chemokine receptor CCR2 ( Supplementary Fig.<|im_end|> <|im_start|>assistant (MedicalXpress)—A team of researchers working at the Weizmann Institute of Science in Israel has found that a type of drug meant to help the immune system kill tumors also reduces Alzheimer's type symptoms in mouse models. In their paper published in the journal Nature Medicine, the team describes their study of drugs known as PD-1 immune checkpoint blockades, on mouse models, and the results they found. As scientists close in on the cause of Alzheimer's disease and hopefully find a cure, more and more evidence points at problems with the immune system and inflammation as a factor. For the past several years, the prevailing view has been that an overactive immune system might be the root cause, but new studies have begun to suggest the opposite might be true—and that boosting the immune response in the brain might help reduce symptoms of the disease. In this new effort, the researchers looked at PD-1 immune checkpoint blockades because they do their work by disabling immunity checkpoints which is where the body sets up roadblocks to stop the immune system from attacking normal body parts. But tumors have been found to trick this same part of the immune system to prevent it from attacking them. Thus, the idea behind PD-1 blockers is to override the checkpoints and force the immune system to attack the tumor anyway, causing it to shrink and disappear. In this new effort, the goal was to learn if such drugs might help stop or reverse the symptoms of Alzheimer's disease by boosting an immune response in the brain. To find out, the researchers genetically engineered test mice to develop Alzheimer's symptoms, both memory loss and the buildup of amyloid in the brain, and then gave each of them PD-1 blockers to see if it caused any improvement. They report that amyloid buildup in the brain of the mice was reduced by half and that most of them were once again able to make their way through a maze—a test of their memory abilities. The research team notes that some PD-1 blockers are already on the market, Keytruda, for example has already been approved for use in treating tumors—thus, testing the drug on human patients in clinical trials should go rather quickly if further tests suggest it might actually work on people with Alzheimer's disease. <|im_end|>
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2,043
[ { "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 Mode division multiplexing (MDM) is mooted as a technology to address future bandwidth issues and has been successfully demonstrated in free space using spatial modes with orbital angular momentum (OAM). To further increase the data transmission rate, more degrees of freedom are required to form a densely packed mode space. Here we move beyond OAM and demonstrate multiplexing and demultiplexing using both the radial and azimuthal degrees of freedom. We achieve this with a holographic approach that allows over 100 modes to be encoded on a single hologram, across a wide wavelength range, in a wavelength independent manner. Our results offer a new tool that will prove useful in realizing higher bit rates for next generation optical networks. Introduction Since the beginning of the 21st century there has been a growing interest in increasing the capacity of telecommunication systems to eventually overcome our pending bandwidth crunch. Significant improvements in networks transmission capacity has been achieved through the use of polarization division multiplexing (PDM) and wavelength division multiplexing (WDM) techniques and also through implementing high order modulation formats 1 , 2 , 3 . However, it might not be possible to satisfy the exponential global capacity demand in the near future. One potential solution to eventually cope with bandwidth issues is space division multiplexing (SDM) 4 , 5 , 6 and in particular the special case of mode division multiplexing (MDM), which was first suggested in the 1980s 7 . In MDM based communication systems, each spatial mode, from an orthogonal modal basis, can carry an independent data stream, thereby increasing the overall capacity by a factor equal to the number of modes used 8 . A particular mode basis for data communication is orbital angular momentum (OAM) 9 , 10 which has become the mode of choice in many studies due to its topical nature and ease of detection with phase-only optical elements 11 , 12 . Indeed, OAM multiplexing implementation results have reported Tbit/s transmission capacity over both free space and optical fibers 13 , 14 . More recent reports have shown free space communication with a bit rate of 1.036 Pbit/s and a spectral efficiency of 112.6-bit/s/Hz using 26 OAM modes 15 . But, by taking into account the effects of atmospheric turbulence on the crosstalk and system bit error rate (BER) in an OAM multiplexed free space optics (FSO) link, experimental results have indicated that turbulence-induced signal fading will significantly deteriorate link performance and might cause link outage in the strong turbulence regime 16 , 17 , 18 . Recently, Zhao et al . claimed that OAM is outperformed by any conventional mode division multiplexing technique with a complete basis or conventional line of sight (LOS) multiple-input multiple-output (MIMO) systems 19 , 20 . Indeed, OAM is only a subspace of the full space of Laguerre Gaussian (LG) beams where modes have two degrees of freedom: an azimuthal index and a radial index p , the former responsible for the OAM. The addition of the radial degree of freedom certainly increases the bandwidth capacity, since for each value of an infinite number of p values can be used to have access to many more information channels. In this study, we demonstrate a new holographic tool to realise a communication link using a densely packed LG mode set incorporating both radial and azimuthal degrees of freedom. We show that it is possible to multiplex/demultiplex over 100 spatial modes on a single hologram, written to a spatial light modulator, in a manner that is independent of wavelength. Our subset of the LG modes were successfully used as information carriers over a free space link to illustrate the robustness of our technique. The information is recovered by simultaneously detecting all 100 modes employing a single hologram. Using this approach we are able to transmit several images with correlations higher than 98%. Although our scheme is a proof-of-concept, it provides a useful basis for increasing the capacity of future optical communication systems. Results Consider a LG mode in cylindrical coordinates, at its waist plane ( z = 0), described by: where p and are the radial and azimuthal indices respectively, ( r , ϕ) are the transverse coordinates, is the generalized Laguerre polynomial and w 0 is a scalar parameter corresponding to the Gaussian (fundamental mode) radius. The mode size is a function of the indices and is given by . Such modes are shape invariant during propagation and are reduced to the special case of the Gaussian beam when . This full set of modes can be experimentally generated using complex-amplitude modulation. For this experiment we use the CGH type 3 as described in 21 to generate a subset of 35 modes given by combination of p = {0, 1, 2, 3, 4} and . In this way, the amplitude and phase of the modes set ( Eq. 1 ) can be encoded into phase-only digital holograms and displayed on phase-only SLMs to generate any mode. Moreover, the holograms can be multiplexed into a single hologram to generate multiple modes simultaneously. Figure 1(a) shows the generated holograms to create the desired subset of modes for this experiment. Their corresponding theoretical intensity profile can be seen in Fig. 2(a) . Figure 1 Complex amplitude modulation and spatial-multiplexing. ( a ) Holograms encoded via complex-amplitude modulation to generate different modes. ( b ) Holograms encoded with different carrier frequencies are superimposed into a single hologram to produce a spatial separation of all modes in the Fourier plane. Full size image Figure 2 Schematic of our Multiplexing and Demultiplexing setup. ( a ) Intensity profiles of modes generated from combinations of p = {0, 1, 2, 3, 4} and . ( b ) Experimental setup: Three components of a multiline Ion-Argon laser, λ 1 = 457 nm, λ 2 = 488 nm and λ 3 = 514 nm, are separated using a grating and sent to a Spatial Light Modulator (SLM-1). ( c ) The SLM is split into three independent screens", "role": "user" }, { "content": "The rise of big data and advances in information technology has serious implications for our ability to deliver sufficient bandwidth to meet the growing demand. Researchers at the University of the Witwatersrand in Johannesburg, South Africa, and the Council for Scientific and Industrial Research (CSIR) are looking at alternative sources that will be able to take over where traditional optical communications systems are likely to fail in future. In their latest research, published online today (10 June 2016) in the scientific journal, Scientific Reports, the team from South Africa and Tunisia demonstrate over 100 patterns of light used in an optical communication link, potentially increasing the bandwidth of communication systems by 100 times. The idea was conceived by Professor Andrew Forbes from Wits University, who led the collaboration. The key experiment was performed by Dr Carmelo Rosales-Guzman, a Research Fellow in the Structured Light group in the Wits School of Physics, and Dr Angela Dudley of the CSIR, an honorary academic at Wits. The first experiments on the topic were carried out by Abderrahmen Trichili of Sup'Com (Tunisia) as a visiting student to South Africa as part of an African Laser Centre funded research project. The other team members included Bienvenu Ndagano (Wits), Dr Amine Ben Salem (Sup'Com) and Professor Mourad Zghal (Sup'Com), all of who contributed significantly to the work. Bracing for the bandwidth ceiling Traditional optical communication systems modulate the amplitude, phase, polarisation, colour and frequency of the light that is transmitted. Yet despite these technologies, we are predicted to reach a bandwidth ceiling in the near future. Dr. Carmelo Rosales-Guzman from Wits University. Credit: Wits University But light also has a \"pattern\" - the intensity distribution of the light, that is, how it looks on a camera or a screen. Since these patterns are unique, they can be used to encode information: pattern 1 = channel 1 or the letter A,pattern 2 = channel 2 or the letter B, and so on. What does this mean? That future bandwidth can be increased by precisely the number of patterns of light we are able to use. Ten patterns mean a 10x increase in existing bandwidth, as 10 new channels would emerge for data transfer. At the moment modern optical communication systems only use one pattern. This is due to technical hurdles in how to pack information into these patterns of light, and how to get the information back out again. How the research was done In this latest work, the team showed data transmission with over 100 patterns of light, exploiting three degrees of freedom in the process. They used digital holograms written to a small liquid crystal display (LCD) and showed that it is possible to have a hologram encoded with over 100 patterns in multiple colours. Researchers demonstrate a 100x (times) increase in the amount of information that can be \"packed into light\" by showing how information was encoded into patterns of light by \"sending\" and \"receiving\" this example of a Rubik's cube. Credit: Wits University \"This is the highest number of patterns created and detected on such a device to date, far exceeding the previous state-of-the-art,\" says Forbes. One of the novel steps was to make the device 'colour blind', so the same holograms can be used to encode many wavelengths. According to Rosales-Guzman to make this work \"100 holograms were combined into a single, complex hologram. Moreover, each sub-hologram was individually tailored to correct for any optical aberrations due to the colour difference, angular offset and so on\". What's next? The next stage is to move out of the laboratory and demonstrate the technology in a real-world system. \"We are presently working with a commercial entity to test in just such an environment,\" says Forbes. The approach of the team could be used in both free-space and optical fibre networks. ", "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 Mode division multiplexing (MDM) is mooted as a technology to address future bandwidth issues and has been successfully demonstrated in free space using spatial modes with orbital angular momentum (OAM). To further increase the data transmission rate, more degrees of freedom are required to form a densely packed mode space. Here we move beyond OAM and demonstrate multiplexing and demultiplexing using both the radial and azimuthal degrees of freedom. We achieve this with a holographic approach that allows over 100 modes to be encoded on a single hologram, across a wide wavelength range, in a wavelength independent manner. Our results offer a new tool that will prove useful in realizing higher bit rates for next generation optical networks. Introduction Since the beginning of the 21st century there has been a growing interest in increasing the capacity of telecommunication systems to eventually overcome our pending bandwidth crunch. Significant improvements in networks transmission capacity has been achieved through the use of polarization division multiplexing (PDM) and wavelength division multiplexing (WDM) techniques and also through implementing high order modulation formats 1 , 2 , 3 . However, it might not be possible to satisfy the exponential global capacity demand in the near future. One potential solution to eventually cope with bandwidth issues is space division multiplexing (SDM) 4 , 5 , 6 and in particular the special case of mode division multiplexing (MDM), which was first suggested in the 1980s 7 . In MDM based communication systems, each spatial mode, from an orthogonal modal basis, can carry an independent data stream, thereby increasing the overall capacity by a factor equal to the number of modes used 8 . A particular mode basis for data communication is orbital angular momentum (OAM) 9 , 10 which has become the mode of choice in many studies due to its topical nature and ease of detection with phase-only optical elements 11 , 12 . Indeed, OAM multiplexing implementation results have reported Tbit/s transmission capacity over both free space and optical fibers 13 , 14 . More recent reports have shown free space communication with a bit rate of 1.036 Pbit/s and a spectral efficiency of 112.6-bit/s/Hz using 26 OAM modes 15 . But, by taking into account the effects of atmospheric turbulence on the crosstalk and system bit error rate (BER) in an OAM multiplexed free space optics (FSO) link, experimental results have indicated that turbulence-induced signal fading will significantly deteriorate link performance and might cause link outage in the strong turbulence regime 16 , 17 , 18 . Recently, Zhao et al . claimed that OAM is outperformed by any conventional mode division multiplexing technique with a complete basis or conventional line of sight (LOS) multiple-input multiple-output (MIMO) systems 19 , 20 . Indeed, OAM is only a subspace of the full space of Laguerre Gaussian (LG) beams where modes have two degrees of freedom: an azimuthal index and a radial index p , the former responsible for the OAM. The addition of the radial degree of freedom certainly increases the bandwidth capacity, since for each value of an infinite number of p values can be used to have access to many more information channels. In this study, we demonstrate a new holographic tool to realise a communication link using a densely packed LG mode set incorporating both radial and azimuthal degrees of freedom. We show that it is possible to multiplex/demultiplex over 100 spatial modes on a single hologram, written to a spatial light modulator, in a manner that is independent of wavelength. Our subset of the LG modes were successfully used as information carriers over a free space link to illustrate the robustness of our technique. The information is recovered by simultaneously detecting all 100 modes employing a single hologram. Using this approach we are able to transmit several images with correlations higher than 98%. Although our scheme is a proof-of-concept, it provides a useful basis for increasing the capacity of future optical communication systems. Results Consider a LG mode in cylindrical coordinates, at its waist plane ( z = 0), described by: where p and are the radial and azimuthal indices respectively, ( r , ϕ) are the transverse coordinates, is the generalized Laguerre polynomial and w 0 is a scalar parameter corresponding to the Gaussian (fundamental mode) radius. The mode size is a function of the indices and is given by . Such modes are shape invariant during propagation and are reduced to the special case of the Gaussian beam when . This full set of modes can be experimentally generated using complex-amplitude modulation. For this experiment we use the CGH type 3 as described in 21 to generate a subset of 35 modes given by combination of p = {0, 1, 2, 3, 4} and . In this way, the amplitude and phase of the modes set ( Eq. 1 ) can be encoded into phase-only digital holograms and displayed on phase-only SLMs to generate any mode. Moreover, the holograms can be multiplexed into a single hologram to generate multiple modes simultaneously. Figure 1(a) shows the generated holograms to create the desired subset of modes for this experiment. Their corresponding theoretical intensity profile can be seen in Fig. 2(a) . Figure 1 Complex amplitude modulation and spatial-multiplexing. ( a ) Holograms encoded via complex-amplitude modulation to generate different modes. ( b ) Holograms encoded with different carrier frequencies are superimposed into a single hologram to produce a spatial separation of all modes in the Fourier plane. Full size image Figure 2 Schematic of our Multiplexing and Demultiplexing setup. ( a ) Intensity profiles of modes generated from combinations of p = {0, 1, 2, 3, 4} and . ( b ) Experimental setup: Three components of a multiline Ion-Argon laser, λ 1 = 457 nm, λ 2 = 488 nm and λ 3 = 514 nm, are separated using a grating and sent to a Spatial Light Modulator (SLM-1). ( c ) The SLM is split into three independent screens<|im_end|> <|im_start|>assistant The rise of big data and advances in information technology has serious implications for our ability to deliver sufficient bandwidth to meet the growing demand. Researchers at the University of the Witwatersrand in Johannesburg, South Africa, and the Council for Scientific and Industrial Research (CSIR) are looking at alternative sources that will be able to take over where traditional optical communications systems are likely to fail in future. In their latest research, published online today (10 June 2016) in the scientific journal, Scientific Reports, the team from South Africa and Tunisia demonstrate over 100 patterns of light used in an optical communication link, potentially increasing the bandwidth of communication systems by 100 times. The idea was conceived by Professor Andrew Forbes from Wits University, who led the collaboration. The key experiment was performed by Dr Carmelo Rosales-Guzman, a Research Fellow in the Structured Light group in the Wits School of Physics, and Dr Angela Dudley of the CSIR, an honorary academic at Wits. The first experiments on the topic were carried out by Abderrahmen Trichili of Sup'Com (Tunisia) as a visiting student to South Africa as part of an African Laser Centre funded research project. The other team members included Bienvenu Ndagano (Wits), Dr Amine Ben Salem (Sup'Com) and Professor Mourad Zghal (Sup'Com), all of who contributed significantly to the work. Bracing for the bandwidth ceiling Traditional optical communication systems modulate the amplitude, phase, polarisation, colour and frequency of the light that is transmitted. Yet despite these technologies, we are predicted to reach a bandwidth ceiling in the near future. Dr. Carmelo Rosales-Guzman from Wits University. Credit: Wits University But light also has a "pattern" - the intensity distribution of the light, that is, how it looks on a camera or a screen. Since these patterns are unique, they can be used to encode information: pattern 1 = channel 1 or the letter A,pattern 2 = channel 2 or the letter B, and so on. What does this mean? That future bandwidth can be increased by precisely the number of patterns of light we are able to use. Ten patterns mean a 10x increase in existing bandwidth, as 10 new channels would emerge for data transfer. At the moment modern optical communication systems only use one pattern. This is due to technical hurdles in how to pack information into these patterns of light, and how to get the information back out again. How the research was done In this latest work, the team showed data transmission with over 100 patterns of light, exploiting three degrees of freedom in the process. They used digital holograms written to a small liquid crystal display (LCD) and showed that it is possible to have a hologram encoded with over 100 patterns in multiple colours. Researchers demonstrate a 100x (times) increase in the amount of information that can be "packed into light" by showing how information was encoded into patterns of light by "sending" and "receiving" this example of a Rubik's cube. Credit: Wits University "This is the highest number of patterns created and detected on such a device to date, far exceeding the previous state-of-the-art," says Forbes. One of the novel steps was to make the device 'colour blind', so the same holograms can be used to encode many wavelengths. According to Rosales-Guzman to make this work "100 holograms were combined into a single, complex hologram. Moreover, each sub-hologram was individually tailored to correct for any optical aberrations due to the colour difference, angular offset and so on". What's next? The next stage is to move out of the laboratory and demonstrate the technology in a real-world system. "We are presently working with a commercial entity to test in just such an environment," says Forbes. The approach of the team could be used in both free-space and optical fibre networks. <|im_end|>
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2,138
[ { "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 evaluate the risk of myocardial infarction and death from coronary heart disease after discontinuation of low dose aspirin in primary care patients with a history of cardiovascular events. Design Nested case-control study. Setting The Health Improvement Network (THIN) database in the United Kingdom. Participants Individuals aged 50-84 with a first prescription for aspirin (75-300 mg/day) for secondary prevention of cardiovascular outcomes in 2000-7 (n=39 513). Main outcome measures Individuals were followed up for a mean of 3.2 years to identify cases of non-fatal myocardial infarction or death from coronary heart disease. A nested case-control analysis assessed the risk of these events in those who had stopped taking low dose aspirin compared with those who had continued treatment. Results There were 876 non-fatal myocardial infarctions and 346 deaths from coronary heart disease. Compared with current users, people who had recently stopped taking aspirin had a significantly increased risk of non-fatal myocardial infarction or death from coronary heart disease combined (rate ratio 1.43, 95% confidence interval 1.12 to 1.84) and non-fatal myocardial infarction alone (1.63, 1.23 to 2.14). There was no significant association between recently stopping low dose aspirin and the risk of death from coronary heart disease (1.07, 0.67 to 1.69). For every 1000 patients, over a period of one year there were about four more cases of non-fatal myocardial infarction among patients who discontinued treatment with low dose aspirin (recent discontinuers) compared with patients who continued treatment. Conclusions Individuals with a history of cardiovascular events who stop taking low dose aspirin are at increased risk of non-fatal myocardial infarction compared with those who continue treatment. Introduction Low dose regimens of the antiplatelet agent aspirin (acetylsalicylic acid) are a standard treatment for the secondary prevention of cardiovascular outcomes. Meta-analysis of randomised controlled trials has shown that low dose aspirin is protective in most types of patient at increased risk of occlusive vascular events, including those who have had an acute myocardial infarction or ischaemic stroke and those who have stable or unstable angina, peripheral artery disease, or atrial fibrillation. 1 Guidelines recommend long term use of low dose aspirin (75-150 mg/day) as an effective antiplatelet regimen for patients with cardiovascular disease, unless contraindicated. 2 3 Despite the strong evidence supporting the protective effects of low dose aspirin, discontinuation rates of around 50% have been reported in patients who have been taking this medication for several years. 4 5 It is therefore of concern that recent discontinuation has been linked to an increase in the risk of ischaemic events and death. Cessation of treatment with oral antiplatelet agents (including aspirin and thienopyridines) has been shown to be an independent predictor of an increase in mortality after acute coronary syndromes, 6 and multivariate analysis has shown an increased risk of transient ischaemic attack in the four weeks after discontinuation of aspirin. 7 Another study of a cohort of patients with acute coronary syndromes found that acute coronary syndrome events occurred on average 10 days after discontinuation of low dose aspirin. 8 A systematic review of the literature to date showed that withdrawal of low dose aspirin is associated with a threefold increase in the risk of adverse cardiovascular events. 9 All the studies on this topic to date, however, have taken place in secondary care centres. We used a validated primary care database to evaluate the risk of non-fatal myocardial infarction and of death from coronary heart disease (both as separate end points and as a combined measure) after discontinuation of low dose aspirin in primary care patients taking it as secondary prevention for cardiovascular disease. Methods Data source The Health Improvement Network is a computerised medical research database that contains systematically recorded data on more than three million patients enrolled in primary care practices in the United Kingdom. Almost all of the UK population is registered with a primary care practitioner, and the network is representative of the UK population with regard to age, sex, and geographical distribution. It has also been validated for use in pharmacoepidemiological research. 10 Participating primary care practitioners record data as part of their routine care of patients, including demographic factors, consultation rates, referrals, hospital admissions, results of laboratory tests, diagnoses, and prescriptions written, and send them to the network for use in research projects. The Read classification is used to code specific diagnoses, 11 and a drug dictionary based on data from the MULTILEX classification is used to code drug prescriptions. 12 Studies have shown that 60-80% of UK patients who take aspirin for secondary prevention obtain their treatment by prescription rather than over the counter. 13 14 15 This proportion increases with age 13 and in those patients who do not have to pay prescription charges. 15 The Health Improvement Network should therefore be a representative source of data on low dose aspirin use in the UK. Source population We used the network to identify individuals aged 50-84 with a first ever prescription of low dose aspirin (defined as 75-300 mg/day) for the secondary prevention of cardiovascular or cerebrovascular events (defined as a diagnosis of angina (including stable angina), unstable angina, ischaemic heart disease, myocardial infarction, cerebrovascular disease, stroke, or transient ischaemic attack) from 1 January 2000 to 31 December 2007 (figure ⇓ ). Indications for first ever prescriptions for low dose aspirin were identified from the patients’ computerised records. This was done manually when there was more than one potential indication. Study participants were required to have been registered with their primary care practitioner for at least two years and to have a computerised prescription history for at least a year before the start of the study. They were also required to have no diagnosis of cancer, alcohol abuse, or alcohol related disease. Study design and case ascertainment of non-fatal myocardial infarction and death from coronary heart disease among people prescribed aspirin in primary care Download figure Open in new tab Download powerpoint All individuals in the study cohort were followed up from the day after their first prescription of low", "role": "user" }, { "content": "(Medical Xpress) -- A new study published in the British Medical Journal suggests that people who have been diagnosed with heart disease and placed on a daily aspirin dose are at an increased risk of a heart attack if they stop taking the aspirin. Low dose aspirin, usually in a dose range between 75 and 300 milligrams, are prescribed to patients to reduce the risk of blood clots and a possible heart attack. However, for many different reasons, half of these patients eventually stop this routine. The researchers, led by Dr. Luis Garcia Rodriguez from the Spanish Center for Pharmacoepidemiologic Research, gathered data from medical records located in a large database in the United Kingdom called the Health Improvement Network. They looked at 39,513 patients between the ages of 50 and 84 that had been prescribed low dose aspirin between 2000 and 2007. What they discovered after a three year follow-up was that there was a 60 percent increase of a non-fatal heart attack in those patients who had discontinued taking their aspirin therapy. This breaks down to about four heart attacks per 1,000 patients who cease taking their aspirin therapy. Rodriguez emphasizes that patients should never stop taking their aspirin therapy unless directed to do so by their physician. This research shows how important just a tiny little pill once a day can make a big difference in decreasing the risk of another heart attack. The authors believe that more research needs to be done to look at what reasons might be causing patients to stop their aspirin therapy. Researchers believe that reasons such as simply forgetting, not believing it is therapeutically beneficial or possible adverse reactions that are not being discussed with their physician could be behind the discontinuation of aspirin treatment. They believe that more awareness needs to be made on the importance of adhering to an aspirin therapy treatment plan and advise all patients currently on aspirin therapy to make sure they take their aspirin every day to reduce their risk of another heart attack. ", "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 evaluate the risk of myocardial infarction and death from coronary heart disease after discontinuation of low dose aspirin in primary care patients with a history of cardiovascular events. Design Nested case-control study. Setting The Health Improvement Network (THIN) database in the United Kingdom. Participants Individuals aged 50-84 with a first prescription for aspirin (75-300 mg/day) for secondary prevention of cardiovascular outcomes in 2000-7 (n=39 513). Main outcome measures Individuals were followed up for a mean of 3.2 years to identify cases of non-fatal myocardial infarction or death from coronary heart disease. A nested case-control analysis assessed the risk of these events in those who had stopped taking low dose aspirin compared with those who had continued treatment. Results There were 876 non-fatal myocardial infarctions and 346 deaths from coronary heart disease. Compared with current users, people who had recently stopped taking aspirin had a significantly increased risk of non-fatal myocardial infarction or death from coronary heart disease combined (rate ratio 1.43, 95% confidence interval 1.12 to 1.84) and non-fatal myocardial infarction alone (1.63, 1.23 to 2.14). There was no significant association between recently stopping low dose aspirin and the risk of death from coronary heart disease (1.07, 0.67 to 1.69). For every 1000 patients, over a period of one year there were about four more cases of non-fatal myocardial infarction among patients who discontinued treatment with low dose aspirin (recent discontinuers) compared with patients who continued treatment. Conclusions Individuals with a history of cardiovascular events who stop taking low dose aspirin are at increased risk of non-fatal myocardial infarction compared with those who continue treatment. Introduction Low dose regimens of the antiplatelet agent aspirin (acetylsalicylic acid) are a standard treatment for the secondary prevention of cardiovascular outcomes. Meta-analysis of randomised controlled trials has shown that low dose aspirin is protective in most types of patient at increased risk of occlusive vascular events, including those who have had an acute myocardial infarction or ischaemic stroke and those who have stable or unstable angina, peripheral artery disease, or atrial fibrillation. 1 Guidelines recommend long term use of low dose aspirin (75-150 mg/day) as an effective antiplatelet regimen for patients with cardiovascular disease, unless contraindicated. 2 3 Despite the strong evidence supporting the protective effects of low dose aspirin, discontinuation rates of around 50% have been reported in patients who have been taking this medication for several years. 4 5 It is therefore of concern that recent discontinuation has been linked to an increase in the risk of ischaemic events and death. Cessation of treatment with oral antiplatelet agents (including aspirin and thienopyridines) has been shown to be an independent predictor of an increase in mortality after acute coronary syndromes, 6 and multivariate analysis has shown an increased risk of transient ischaemic attack in the four weeks after discontinuation of aspirin. 7 Another study of a cohort of patients with acute coronary syndromes found that acute coronary syndrome events occurred on average 10 days after discontinuation of low dose aspirin. 8 A systematic review of the literature to date showed that withdrawal of low dose aspirin is associated with a threefold increase in the risk of adverse cardiovascular events. 9 All the studies on this topic to date, however, have taken place in secondary care centres. We used a validated primary care database to evaluate the risk of non-fatal myocardial infarction and of death from coronary heart disease (both as separate end points and as a combined measure) after discontinuation of low dose aspirin in primary care patients taking it as secondary prevention for cardiovascular disease. Methods Data source The Health Improvement Network is a computerised medical research database that contains systematically recorded data on more than three million patients enrolled in primary care practices in the United Kingdom. Almost all of the UK population is registered with a primary care practitioner, and the network is representative of the UK population with regard to age, sex, and geographical distribution. It has also been validated for use in pharmacoepidemiological research. 10 Participating primary care practitioners record data as part of their routine care of patients, including demographic factors, consultation rates, referrals, hospital admissions, results of laboratory tests, diagnoses, and prescriptions written, and send them to the network for use in research projects. The Read classification is used to code specific diagnoses, 11 and a drug dictionary based on data from the MULTILEX classification is used to code drug prescriptions. 12 Studies have shown that 60-80% of UK patients who take aspirin for secondary prevention obtain their treatment by prescription rather than over the counter. 13 14 15 This proportion increases with age 13 and in those patients who do not have to pay prescription charges. 15 The Health Improvement Network should therefore be a representative source of data on low dose aspirin use in the UK. Source population We used the network to identify individuals aged 50-84 with a first ever prescription of low dose aspirin (defined as 75-300 mg/day) for the secondary prevention of cardiovascular or cerebrovascular events (defined as a diagnosis of angina (including stable angina), unstable angina, ischaemic heart disease, myocardial infarction, cerebrovascular disease, stroke, or transient ischaemic attack) from 1 January 2000 to 31 December 2007 (figure ⇓ ). Indications for first ever prescriptions for low dose aspirin were identified from the patients’ computerised records. This was done manually when there was more than one potential indication. Study participants were required to have been registered with their primary care practitioner for at least two years and to have a computerised prescription history for at least a year before the start of the study. They were also required to have no diagnosis of cancer, alcohol abuse, or alcohol related disease. Study design and case ascertainment of non-fatal myocardial infarction and death from coronary heart disease among people prescribed aspirin in primary care Download figure Open in new tab Download powerpoint All individuals in the study cohort were followed up from the day after their first prescription of low<|im_end|> <|im_start|>assistant (Medical Xpress) -- A new study published in the British Medical Journal suggests that people who have been diagnosed with heart disease and placed on a daily aspirin dose are at an increased risk of a heart attack if they stop taking the aspirin. Low dose aspirin, usually in a dose range between 75 and 300 milligrams, are prescribed to patients to reduce the risk of blood clots and a possible heart attack. However, for many different reasons, half of these patients eventually stop this routine. The researchers, led by Dr. Luis Garcia Rodriguez from the Spanish Center for Pharmacoepidemiologic Research, gathered data from medical records located in a large database in the United Kingdom called the Health Improvement Network. They looked at 39,513 patients between the ages of 50 and 84 that had been prescribed low dose aspirin between 2000 and 2007. What they discovered after a three year follow-up was that there was a 60 percent increase of a non-fatal heart attack in those patients who had discontinued taking their aspirin therapy. This breaks down to about four heart attacks per 1,000 patients who cease taking their aspirin therapy. Rodriguez emphasizes that patients should never stop taking their aspirin therapy unless directed to do so by their physician. This research shows how important just a tiny little pill once a day can make a big difference in decreasing the risk of another heart attack. The authors believe that more research needs to be done to look at what reasons might be causing patients to stop their aspirin therapy. Researchers believe that reasons such as simply forgetting, not believing it is therapeutically beneficial or possible adverse reactions that are not being discussed with their physician could be behind the discontinuation of aspirin treatment. They believe that more awareness needs to be made on the importance of adhering to an aspirin therapy treatment plan and advise all patients currently on aspirin therapy to make sure they take their aspirin every day to reduce their risk of another heart attack. <|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 brain codes continuous spatial, temporal and sensory changes in daily experience. Recent studies suggest that the brain also tracks experience as segmented subdivisions (events), but the neural basis for encoding events remains unclear. Here, we designed a maze for mice, composed of four materially indistinguishable lap events, and identify hippocampal CA1 neurons whose activity are modulated not only by spatial location but also lap number. These ‘event-specific rate remapping’ (ESR) cells remain lap-specific even when the maze length is unpredictably altered within trials, which suggests that ESR cells treat lap events as fundamental units. The activity pattern of ESR cells is reused to represent lap events when the maze geometry is altered from square to circle, which suggests that it helps transfer knowledge between experiences. ESR activity is separately manipulable from spatial activity, and may therefore constitute an independent hippocampal code: an ‘event code’ dedicated to organizing experience by events as discrete and transferable units. Main How is daily experience represented in the brain? Most daily experiences involve traveling to different places and/or seeing different things, and so contain a multitude of spatial and sensory variations (Fig. 1a , top and middle). Hippocampal cells monitor these continuous changes in space, passing time and sensory stimuli 1 , 2 , 3 , 4 , 5 . Fig. 1: Experimental design to study the segmentation of experience into units. a , Illustration of experience as a sequence of continuous, moment-to-moment variations in space, time and sensory stimuli (top) or as a sequence of discrete events as fundamental units of the experience (middle). In our behavioral task (bottom), a skeletal experience stripped of sensory and spatial differences was used to identify neuronal representations that track events as fundamental units. b , Schematic of implantation of the microendoscope into the dCA1 of Wfs1 -Cre mice with AAV2/5-Syn-flex-GCaMP6f-WPRE-SV40 virus injected in the dCA1 for imaging CA1 pyramidal cells. c , Top: a coronal section of hippocampus showing the area of cortex aspiration (white dotted line) and labeled Wfs1 + cells (green). The image is representative of aspiration surgeries from n = 14 mice. Bottom: Δ F/F calcium traces of n = 15 Wfs1 + (pyramidal) cells in the CA1, where red traces denote significant calcium transients. d , During the standard four-lap-per-trial experiment, reward was delivered to the animal at the beginning of lap 1 in the reward box once every four laps. e , CA1 calcium activity sorted by spatial position and lap number showed activity in the same place on every lap, but displayed a higher activity level during a specific lap compared with other laps (263 cells from an example animal shown). The red label on the x axis indicates the reward box spatial bin, and the green label on the x axis indicates the 100-cm-long maze track. f , Trial-by-trial calcium activity of lap-specific neurons for example laps 1, 2, 3 and 4 (L1–L4), organized by the location of activity along the track and by lap number. The top panels show trial-by-trial calcium activities, while the bottom panels show trial-averaged calcium activities (mean ± s.e.m.). The standard error was cut off at 0 because negative activity does not exist. g , Model correction of lap-dependent neuronal activity. Top left: example neuron with the raw calcium activity level (light blue) sorted by the lap number and spatial bin. Bottom left: the peak spatial bin was analyzed to detect lap-specific calcium activity. The plotted calcium rate was explained by the speed and head orientation fitted linear model (pink trace; see Methods ). Top and bottom right: the same as the left charts, but plotted with the lap-specific remaining calcium rate after the linear model was subtracted, resulting in the MC calcium activity. h , Summary statistics of the percentage of ESR cells in the entire CA1 pyramidal population that were tuned to laps 1, 2, 3 or 4 in the standard 4-lap experiment ( n = 14 animals). i – k , For this set of experiments, reward was given to the animal at every lap ( i ). The percentage of significant ESR cells (9%; 101 out of 1,072 cells) was significantly reduced when reward was given at every lap (1R/L) compared with the same animals running the standard 4-lap-per-trial task (1R/4L; 28%; 371 out of 1,328 cells) ( χ 2 = 128.7, *** P <1 × 10 −16 , blue lines represent five mice) ( j ). Summary statistics of the percentage of ESR cells in the entire CA1 pyramidal population that were tuned to laps 1, 2, 3 or 4 during the reward every lap experiment ( k ). Full size image Meanwhile others, based on recent human imaging studies 6 , 7 , 8 , 9 , have suggested that besides tracking the continuously changing sensory environment, the brain tracks daily experience as a chain of discrete, segmented subdivisions or events. Each event arises as a discrete epoch of experience, with its continuous sensory and spatial changes grouped together as a unit. It has been suggested that events are abstract and generalizable entities and can be divorced from specific sensory details 10 , 11 , 12 , 13 . Take dining in a restaurant as an example. Two different dinner experiences can share the same set of events; that is, eating an appetizer, main course and dessert, even if they occur at different restaurants, involve different foods and last varying amounts of time (Fig. 1a , middle). In other words, each of these events has a degree of invariance to the variations of their actual physical and sensory contents. Instead, these events are defined by the abstract, ordered relationships to one another; that is, an appetizer is eaten first, followed by a main dish, which is followed by dessert. This allows events to describe widely varying experiences in a generalized manner. Encoding these abstract events is important to behave perspicaciously in the world. Beyond representing continuous changes in space, there is evidence to indicate that hippocampal neurons", "role": "user" }, { "content": "Imagine you are meeting a friend for dinner at a new restaurant. You may try dishes you haven't had before, and your surroundings will be completely new to you. However, your brain knows that you have had similar experiences—perusing a menu, ordering appetizers, and splurging on dessert are all things that you have probably done when dining out. MIT neuroscientists have now identified populations of cells that encode each of these distinctive segments of an overall experience. These chunks of memory, stored in the hippocampus, are activated whenever a similar type of experience takes place, and are distinct from the neural code that stores detailed memories of a specific location. The researchers believe that this kind of \"event code,\" which they discovered in a study of mice, may help the brain interpret novel situations and learn new information by using the same cells to represent similar experiences. \"When you encounter something new, there are some really new and notable stimuli, but you already know quite a bit about that particular experience, because it's a similar kind of experience to what you have already had before,\" says Susumu Tonegawa, a professor of biology and neuroscience at the RIKEN-MIT Laboratory of Neural Circuit Genetics at MIT's Picower Institute for Learning and Memory. Tonegawa is the senior author of the study, which appears today in Nature Neuroscience. Chen Sun, an MIT graduate student, is the lead author of the paper. New York University graduate student Wannan Yang and Picower Institute technical associate Jared Martin are also authors of the paper. Encoding abstraction It is well-established that certain cells in the brain's hippocampus are specialized to store memories of specific locations. Research in mice has shown that within the hippocampus, neurons called place cells fire when the animals are in a specific location, or even if they are dreaming about that location. In the new study, the MIT team wanted to investigate whether the hippocampus also stores representations of more abstract elements of a memory. That is, instead of firing whenever you enter a particular restaurant, such cells might encode \"dessert,\" no matter where you're eating it. To test this hypothesis, the researchers measured activity in neurons of the CA1 region of the mouse hippocampus as the mice repeatedly ran a four-lap maze. At the end of every fourth lap, the mice were given a reward. As expected, the researchers found place cells that lit up when the mice reached certain points along the track. However, the researchers also found sets of cells that were active during one of the four laps, but not the others. About 30 percent of the neurons in CA1 appeared to be involved in creating this \"event code.\" \"This gave us the initial inkling that besides a code for space, cells in the hippocampus also care about this discrete chunk of experience called lap 1, or this discrete chunk of experience called lap 2, or lap 3, or lap 4,\" Sun says. To further explore this idea, the researchers trained mice to run a square maze on day 1 and then a circular maze on day 2, in which they also received a reward after every fourth lap. They found that the place cells changed their activity, reflecting the new environment. However, the same sets of lap-specific cells were activated during each of the four laps, regardless of the shape of the track. The lap-encoding cells' activity also remained consistent when laps were randomly shortened or lengthened. \"Even in the new spatial locations, cells still maintain their coding for the lap number, suggesting that cells that were coding for a square lap 1 have now been transferred to code for a circular lap 1,\" Sun says. The researchers also showed that if they used optogenetics to inhibit sensory input from a part of the brain called the medial entorhinal cortex (MEC), lap-encoding did not occur. They are now investigating what kind of input the MEC region provides to help the hippocampus create memories consisting of chunks of an experience. Two distinct codes These findings suggest that, indeed, every time you eat dinner, similar memory cells are activated, no matter where or what you're eating. The researchers theorize that the hippocampus contains \"two mutually and independently manipulatable codes,\" Sun says. One encodes continuous changes in location, time, and sensory input, while the other organizes an overall experience into smaller chunks that fit into known categories such as appetizer and dessert. \"We believe that both types of hippocampal codes are useful, and both are important,\" Tonegawa says. \"If we want to remember all the details of what happened in a specific experience, moment-to-moment changes that occurred, then the continuous monitoring is effective. But on the other hand, when we have a longer experience, if you put it into chunks, and remember the abstract order of the abstract chunks, that's more effective than monitoring this long process of continuous changes.\" Tonegawa and Sun believe that networks of cells that encode chunks of experiences may also be useful for a type of learning called transfer learning, which allows you to apply knowledge you already have to help you interpret new experiences or learn new things. Tonegawa's lab is now working on trying to find cell populations that might encode these specific pieces of knowledge. ", "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 brain codes continuous spatial, temporal and sensory changes in daily experience. Recent studies suggest that the brain also tracks experience as segmented subdivisions (events), but the neural basis for encoding events remains unclear. Here, we designed a maze for mice, composed of four materially indistinguishable lap events, and identify hippocampal CA1 neurons whose activity are modulated not only by spatial location but also lap number. These ‘event-specific rate remapping’ (ESR) cells remain lap-specific even when the maze length is unpredictably altered within trials, which suggests that ESR cells treat lap events as fundamental units. The activity pattern of ESR cells is reused to represent lap events when the maze geometry is altered from square to circle, which suggests that it helps transfer knowledge between experiences. ESR activity is separately manipulable from spatial activity, and may therefore constitute an independent hippocampal code: an ‘event code’ dedicated to organizing experience by events as discrete and transferable units. Main How is daily experience represented in the brain? Most daily experiences involve traveling to different places and/or seeing different things, and so contain a multitude of spatial and sensory variations (Fig. 1a , top and middle). Hippocampal cells monitor these continuous changes in space, passing time and sensory stimuli 1 , 2 , 3 , 4 , 5 . Fig. 1: Experimental design to study the segmentation of experience into units. a , Illustration of experience as a sequence of continuous, moment-to-moment variations in space, time and sensory stimuli (top) or as a sequence of discrete events as fundamental units of the experience (middle). In our behavioral task (bottom), a skeletal experience stripped of sensory and spatial differences was used to identify neuronal representations that track events as fundamental units. b , Schematic of implantation of the microendoscope into the dCA1 of Wfs1 -Cre mice with AAV2/5-Syn-flex-GCaMP6f-WPRE-SV40 virus injected in the dCA1 for imaging CA1 pyramidal cells. c , Top: a coronal section of hippocampus showing the area of cortex aspiration (white dotted line) and labeled Wfs1 + cells (green). The image is representative of aspiration surgeries from n = 14 mice. Bottom: Δ F/F calcium traces of n = 15 Wfs1 + (pyramidal) cells in the CA1, where red traces denote significant calcium transients. d , During the standard four-lap-per-trial experiment, reward was delivered to the animal at the beginning of lap 1 in the reward box once every four laps. e , CA1 calcium activity sorted by spatial position and lap number showed activity in the same place on every lap, but displayed a higher activity level during a specific lap compared with other laps (263 cells from an example animal shown). The red label on the x axis indicates the reward box spatial bin, and the green label on the x axis indicates the 100-cm-long maze track. f , Trial-by-trial calcium activity of lap-specific neurons for example laps 1, 2, 3 and 4 (L1–L4), organized by the location of activity along the track and by lap number. The top panels show trial-by-trial calcium activities, while the bottom panels show trial-averaged calcium activities (mean ± s.e.m.). The standard error was cut off at 0 because negative activity does not exist. g , Model correction of lap-dependent neuronal activity. Top left: example neuron with the raw calcium activity level (light blue) sorted by the lap number and spatial bin. Bottom left: the peak spatial bin was analyzed to detect lap-specific calcium activity. The plotted calcium rate was explained by the speed and head orientation fitted linear model (pink trace; see Methods ). Top and bottom right: the same as the left charts, but plotted with the lap-specific remaining calcium rate after the linear model was subtracted, resulting in the MC calcium activity. h , Summary statistics of the percentage of ESR cells in the entire CA1 pyramidal population that were tuned to laps 1, 2, 3 or 4 in the standard 4-lap experiment ( n = 14 animals). i – k , For this set of experiments, reward was given to the animal at every lap ( i ). The percentage of significant ESR cells (9%; 101 out of 1,072 cells) was significantly reduced when reward was given at every lap (1R/L) compared with the same animals running the standard 4-lap-per-trial task (1R/4L; 28%; 371 out of 1,328 cells) ( χ 2 = 128.7, *** P <1 × 10 −16 , blue lines represent five mice) ( j ). Summary statistics of the percentage of ESR cells in the entire CA1 pyramidal population that were tuned to laps 1, 2, 3 or 4 during the reward every lap experiment ( k ). Full size image Meanwhile others, based on recent human imaging studies 6 , 7 , 8 , 9 , have suggested that besides tracking the continuously changing sensory environment, the brain tracks daily experience as a chain of discrete, segmented subdivisions or events. Each event arises as a discrete epoch of experience, with its continuous sensory and spatial changes grouped together as a unit. It has been suggested that events are abstract and generalizable entities and can be divorced from specific sensory details 10 , 11 , 12 , 13 . Take dining in a restaurant as an example. Two different dinner experiences can share the same set of events; that is, eating an appetizer, main course and dessert, even if they occur at different restaurants, involve different foods and last varying amounts of time (Fig. 1a , middle). In other words, each of these events has a degree of invariance to the variations of their actual physical and sensory contents. Instead, these events are defined by the abstract, ordered relationships to one another; that is, an appetizer is eaten first, followed by a main dish, which is followed by dessert. This allows events to describe widely varying experiences in a generalized manner. Encoding these abstract events is important to behave perspicaciously in the world. Beyond representing continuous changes in space, there is evidence to indicate that hippocampal neurons<|im_end|> <|im_start|>assistant Imagine you are meeting a friend for dinner at a new restaurant. You may try dishes you haven't had before, and your surroundings will be completely new to you. However, your brain knows that you have had similar experiences—perusing a menu, ordering appetizers, and splurging on dessert are all things that you have probably done when dining out. MIT neuroscientists have now identified populations of cells that encode each of these distinctive segments of an overall experience. These chunks of memory, stored in the hippocampus, are activated whenever a similar type of experience takes place, and are distinct from the neural code that stores detailed memories of a specific location. The researchers believe that this kind of "event code," which they discovered in a study of mice, may help the brain interpret novel situations and learn new information by using the same cells to represent similar experiences. "When you encounter something new, there are some really new and notable stimuli, but you already know quite a bit about that particular experience, because it's a similar kind of experience to what you have already had before," says Susumu Tonegawa, a professor of biology and neuroscience at the RIKEN-MIT Laboratory of Neural Circuit Genetics at MIT's Picower Institute for Learning and Memory. Tonegawa is the senior author of the study, which appears today in Nature Neuroscience. Chen Sun, an MIT graduate student, is the lead author of the paper. New York University graduate student Wannan Yang and Picower Institute technical associate Jared Martin are also authors of the paper. Encoding abstraction It is well-established that certain cells in the brain's hippocampus are specialized to store memories of specific locations. Research in mice has shown that within the hippocampus, neurons called place cells fire when the animals are in a specific location, or even if they are dreaming about that location. In the new study, the MIT team wanted to investigate whether the hippocampus also stores representations of more abstract elements of a memory. That is, instead of firing whenever you enter a particular restaurant, such cells might encode "dessert," no matter where you're eating it. To test this hypothesis, the researchers measured activity in neurons of the CA1 region of the mouse hippocampus as the mice repeatedly ran a four-lap maze. At the end of every fourth lap, the mice were given a reward. As expected, the researchers found place cells that lit up when the mice reached certain points along the track. However, the researchers also found sets of cells that were active during one of the four laps, but not the others. About 30 percent of the neurons in CA1 appeared to be involved in creating this "event code." "This gave us the initial inkling that besides a code for space, cells in the hippocampus also care about this discrete chunk of experience called lap 1, or this discrete chunk of experience called lap 2, or lap 3, or lap 4," Sun says. To further explore this idea, the researchers trained mice to run a square maze on day 1 and then a circular maze on day 2, in which they also received a reward after every fourth lap. They found that the place cells changed their activity, reflecting the new environment. However, the same sets of lap-specific cells were activated during each of the four laps, regardless of the shape of the track. The lap-encoding cells' activity also remained consistent when laps were randomly shortened or lengthened. "Even in the new spatial locations, cells still maintain their coding for the lap number, suggesting that cells that were coding for a square lap 1 have now been transferred to code for a circular lap 1," Sun says. The researchers also showed that if they used optogenetics to inhibit sensory input from a part of the brain called the medial entorhinal cortex (MEC), lap-encoding did not occur. They are now investigating what kind of input the MEC region provides to help the hippocampus create memories consisting of chunks of an experience. Two distinct codes These findings suggest that, indeed, every time you eat dinner, similar memory cells are activated, no matter where or what you're eating. The researchers theorize that the hippocampus contains "two mutually and independently manipulatable codes," Sun says. One encodes continuous changes in location, time, and sensory input, while the other organizes an overall experience into smaller chunks that fit into known categories such as appetizer and dessert. "We believe that both types of hippocampal codes are useful, and both are important," Tonegawa says. "If we want to remember all the details of what happened in a specific experience, moment-to-moment changes that occurred, then the continuous monitoring is effective. But on the other hand, when we have a longer experience, if you put it into chunks, and remember the abstract order of the abstract chunks, that's more effective than monitoring this long process of continuous changes." Tonegawa and Sun believe that networks of cells that encode chunks of experiences may also be useful for a type of learning called transfer learning, which allows you to apply knowledge you already have to help you interpret new experiences or learn new things. Tonegawa's lab is now working on trying to find cell populations that might encode these specific pieces of knowledge. <|im_end|>
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2,419
[ { "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 Homeostasis is a recurring theme in biology that ensures that regulated variables robustly—and in some systems, completely—adapt to environmental perturbations. This robust perfect adaptation feature is achieved in natural circuits by using integral control, a negative feedback strategy that performs mathematical integration to achieve structurally robust regulation 1 , 2 . Despite its benefits, the synthetic realization of integral feedback in living cells has remained elusive owing to the complexity of the required biological computations. Here we prove mathematically that there is a single fundamental biomolecular controller topology 3 that realizes integral feedback and achieves robust perfect adaptation in arbitrary intracellular networks with noisy dynamics. This adaptation property is guaranteed both for the population-average and for the time-average of single cells. On the basis of this concept, we genetically engineer a synthetic integral feedback controller in living cells 4 and demonstrate its tunability and adaptation properties. A growth-rate control application in Escherichia coli shows the intrinsic capacity of our integral controller to deliver robustness and highlights its potential use as a versatile controller for regulation of biological variables in uncertain networks. Our results provide conceptual and practical tools in the area of cybergenetics 3 , 5 , for engineering synthetic controllers that steer the dynamics of living systems 3 , 4 , 5 , 6 , 7 , 8 , 9 . Main Integral feedback control is arguably one of the most fundamental regulation strategies in engineering practice. From modern jetliners to industrial plants, integral feedback loops reliably drive physical variables to their desired values with great robustness and precision 10 . It is increasingly appreciated that nature’s evolutionary explorations had already discovered the same strategy, which has functioned at various levels of biological organization to achieve homeostasis and robust adaptation to perturbations 1 , 2 , 11 , 12 , 13 . Integral feedback occurs by sensing the deviation of a variable of interest (controlled variable) from the desired target value (set point), computing the mathematical integral of that deviation (error) over time, and then using it in a negative feedback configuration to drive processes that counteract the deviation and drive it to zero (Fig. 1a, b ). This can be achieved despite considerable uncertainty in process dynamics and constant or slowly varying perturbations. This fundamental network property is known as robust perfect adaptation (RPA), and the importance of integral feedback as a regulation strategy derives from its capacity to realize RPA. Given the complexity of required sensing and computation (for example, subtraction, integration and so on), the in vivo synthetic implementation and demonstration of full integral feedback has remained unrealized. In a recent theoretical work 3 , we introduced the antithetic feedback motif (Fig. 1c ) as a network topology that realizes integral feedback while lending itself to biomolecular implementation. We showed analytically that for cells with intrinsically noisy dynamics, this regulatory motif endows the network with guaranteed robustness properties for the population average and also for the single-cell time average. This motif subtly exploits intrinsic noise, using it as a stabilization force in scenarios in which noise-free dynamics exhibit oscillations. Fig. 1: Integral feedback enables robust perfect adaptation. a , In a circuit without feedback regulation (open-loop circuit), the output is sensitive to external perturbations, which drive it away from the desired value (no adaptation). b , Integral feedback confers robustness to perturbations and keeps the output tightly regulated at desired levels (RPA). c , The antithetic integral control motif offers a biologically realizable integral feedback scheme using two regulator species. The output of interest, X L is sensed by a reaction the product of which, Z 2 , is produced at a rate proportional to X L (rate constant \\(\\theta \\) ). A reference reaction yields Z 1 with rate constant μ . Z 1 and Z 2 annihilate (or sequester) each other, an operation that is central to the integral feedback computation. In turn, Z 1 works as an actuator by affecting processes that lead to the increase in the production of the output of interest, thereby closing the feedback loop. In this scheme, as long as the closed dynamics are stable, the steady-state value of the output is determined solely by the ratio μ/θ . Notably, it does not depend on the topology and parameters of the circuit of interest, which are usually uncertain and noisy, nor on any constant external perturbations that afflict the network. Full size image Consider the problem of controlling an uncertain and noisy biomolecular network by augmenting it with another feedback-controller network (see the Box 1 Figure, panel a). The control objective is to achieve RPA for some variable in the controlled network (output); that is, this variable must be steered to a desired set point and maintained there, even in the presence of unknown constant external perturbations and in spite of uncertainty in the network topology and parameters, including the parameters of the controller network. Insisting on robustness to topology and parameters is particularly important in synthetic biology, in which the controlled network is often unknown or poorly characterized and fine-tuning the parameters of the controller network can be extremely difficult. It is well established in control theory 14 , 15 that in the noise-free setting, such general-purpose controller networks must implement an integral feedback component, but designing one is challenging because of the realizability and other constraints imposed by the biomolecular reaction network 16 , 17 . These challenges are further amplified if we take into account the noisy nature of the intracellular dynamics, in which not all integral feedback-controller implementations lead to RPA and hence the particular topology used is critical. In this stochastic setting, when the dynamics are stable, RPA refers to the steady-state population average of the output variable or—equivalently—its long-term single-cell time average. Given this context, several fundamental questions arise. These include how one can determine definitively whether a candidate network of any size achieves RPA in the presence of intrinsic noise; which architectural features are necessary and sufficient for a biomolecular", "role": "user" }, { "content": "The human body keeps the calcium concentration in the blood constant, similarly to an aircraft's autopilot keeping the plane at a constant altitude. What they have in common is that both the body and the autopilot employ sophisticated integral feedback control mechanisms. Researchers in the Department of Biosystems Science and Engineering at ETH Zurich in Basel have now built such an integral controller completely from scratch within a living cell, as they report in the latest issue of the journal Nature. In the future, their synthetic biology approach could make it possible to optimize biotechnological production processes and to regulate hormonal activity through cell therapy. Constant despite environmental disturbances Marine engineers were the first to build such an integral feedback control system, using it to automate ship steering over 100 years ago. Since then, it has been applied wherever there is a need to maintain steady, stable conditions of direction, temperature, speed or altitude in the face of outside influences. The role of integration is that it allows the control system to make corrections based on both the amount and duration of the deviation from the desired constant value. In biology, too, mechanisms have evolved to maintain such conditions as a steady concentration of substances in the blood. Several years ago, researchers led by Mustafa Khammash, professor at the Department of Biosystems Science and Engineering, showed that these biological mechanisms are also examples of integral feedback control. \"These kinds of integral controllers are extremely resistant to unexpected environmental disturbances,\" Khammash says, \"which probably explains why the principle prevailed in evolution, and is why it is ubiquitous in technology.\" Interplay of two molecules Khammash and his interdisciplinary team of control theorists, mathematicians and experimental biologists have now engineered such an integral feedback controller in the form of a synthetic genetic regulatory network inside a bacterium. Their feedback mechanism relies on two molecules—A and B—that bind to each other to become inactive. Together, these two molecules have the ability to maintain a constant concentration of a third molecule, C. The system is designed so that molecule B promotes the production of C, while the production rate of A depends on the concentration of C. The feedback loop is such that when C is abundant, more A will be produced, which will inactivate more B, which in turn will cause production of C to fall. As a proof of concept, the ETH scientists made use of this principle to control the production of a green fluorescent protein in Escherichia coli bacteria. Thanks to the feedback controller, the bacteria produced a constant amount of the fluorescent protein—even when the scientists, who wanted to test the system, attempted to suppress its production using strong inhibitors. In a second experiment, the researchers produced a bacterial population that grew at a constant rate in spite of the scientists' attempts to disrupt growth, again in an effort to test the feedback mechanism. Improving biotech and therapies Biotechnology could now put this new control mechanism to work in bacteria to produce vitamins, medications, chemicals or biofuels, with the mechanism ensuring that the production rate within the bacteria is held constant at its optimum level. The ETH scientists are developing an analogous control mechanism for mammalian cells in subsequent research work, which will pave the way for further applications, including designer cells featuring genetic regulatory networks to produce hormones inside a patient's body. Among those who would stand to benefit from such an approach are people with diabetes or thyroid deficiency. The synthetic feedback controllers could also be used to improve cancer immunotherapy. \"In this form of therapy, immune cells need to be active enough to fight the tumor, but not overactive, as they would then attack healthy tissue,\" Khammash says. \"A mechanism like ours would be able to fine-tune their activity.\" Integral controller According to ETH Professor Mustafa Khammash, regulation of the calcium concentration in the blood is a good example with which to illustrate the principle of integral controllers in biology. This concentration is tightly regulated at a value of approximately 95 milligrams per liter of blood, regardless of how much calcium a person ingests in food. This rate even remains constant during lactation when lots of calcium is drawn from the blood in order to produce milk. \"A constant level of calcium is essential to the proper functioning of many physiological processes, including muscle and nerve function or blood clotting,\" Khammash says. The hormone PTH works as one of two feedback agents in the body in this context: PTH promotes the mobilization of calcium from bone tissue into the bloodstream. The lower the concentration of calcium in the blood, the more PTH is produced by the parathyroid glands. \"This is one part of the body's response when the levels of calcium are too low,\" Khammash says. But to bring the concentration of calcium completely back to normal after a sudden spike or drop, he adds, a second mechanism is required. This role falls to a biologically active form of vitamin D3, which promotes the absorption into the bloodstream of calcium from partially digested food in the small intestine. However, production of this active form of vitamin D3 in the kidneys is dependent on the concentration of PTH. Together, these two hormones are responsible for ensuring that the calcium concentration in the blood over time strays as little as possible and for as short a time as possible from its normal level—or, in other words, that the \"integral of deviation with respect to time,\" as a mathematician would put it, approaches a constant. Therefore, such a control mechanism is called integral. ", "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 Homeostasis is a recurring theme in biology that ensures that regulated variables robustly—and in some systems, completely—adapt to environmental perturbations. This robust perfect adaptation feature is achieved in natural circuits by using integral control, a negative feedback strategy that performs mathematical integration to achieve structurally robust regulation 1 , 2 . Despite its benefits, the synthetic realization of integral feedback in living cells has remained elusive owing to the complexity of the required biological computations. Here we prove mathematically that there is a single fundamental biomolecular controller topology 3 that realizes integral feedback and achieves robust perfect adaptation in arbitrary intracellular networks with noisy dynamics. This adaptation property is guaranteed both for the population-average and for the time-average of single cells. On the basis of this concept, we genetically engineer a synthetic integral feedback controller in living cells 4 and demonstrate its tunability and adaptation properties. A growth-rate control application in Escherichia coli shows the intrinsic capacity of our integral controller to deliver robustness and highlights its potential use as a versatile controller for regulation of biological variables in uncertain networks. Our results provide conceptual and practical tools in the area of cybergenetics 3 , 5 , for engineering synthetic controllers that steer the dynamics of living systems 3 , 4 , 5 , 6 , 7 , 8 , 9 . Main Integral feedback control is arguably one of the most fundamental regulation strategies in engineering practice. From modern jetliners to industrial plants, integral feedback loops reliably drive physical variables to their desired values with great robustness and precision 10 . It is increasingly appreciated that nature’s evolutionary explorations had already discovered the same strategy, which has functioned at various levels of biological organization to achieve homeostasis and robust adaptation to perturbations 1 , 2 , 11 , 12 , 13 . Integral feedback occurs by sensing the deviation of a variable of interest (controlled variable) from the desired target value (set point), computing the mathematical integral of that deviation (error) over time, and then using it in a negative feedback configuration to drive processes that counteract the deviation and drive it to zero (Fig. 1a, b ). This can be achieved despite considerable uncertainty in process dynamics and constant or slowly varying perturbations. This fundamental network property is known as robust perfect adaptation (RPA), and the importance of integral feedback as a regulation strategy derives from its capacity to realize RPA. Given the complexity of required sensing and computation (for example, subtraction, integration and so on), the in vivo synthetic implementation and demonstration of full integral feedback has remained unrealized. In a recent theoretical work 3 , we introduced the antithetic feedback motif (Fig. 1c ) as a network topology that realizes integral feedback while lending itself to biomolecular implementation. We showed analytically that for cells with intrinsically noisy dynamics, this regulatory motif endows the network with guaranteed robustness properties for the population average and also for the single-cell time average. This motif subtly exploits intrinsic noise, using it as a stabilization force in scenarios in which noise-free dynamics exhibit oscillations. Fig. 1: Integral feedback enables robust perfect adaptation. a , In a circuit without feedback regulation (open-loop circuit), the output is sensitive to external perturbations, which drive it away from the desired value (no adaptation). b , Integral feedback confers robustness to perturbations and keeps the output tightly regulated at desired levels (RPA). c , The antithetic integral control motif offers a biologically realizable integral feedback scheme using two regulator species. The output of interest, X L is sensed by a reaction the product of which, Z 2 , is produced at a rate proportional to X L (rate constant \(\theta \) ). A reference reaction yields Z 1 with rate constant μ . Z 1 and Z 2 annihilate (or sequester) each other, an operation that is central to the integral feedback computation. In turn, Z 1 works as an actuator by affecting processes that lead to the increase in the production of the output of interest, thereby closing the feedback loop. In this scheme, as long as the closed dynamics are stable, the steady-state value of the output is determined solely by the ratio μ/θ . Notably, it does not depend on the topology and parameters of the circuit of interest, which are usually uncertain and noisy, nor on any constant external perturbations that afflict the network. Full size image Consider the problem of controlling an uncertain and noisy biomolecular network by augmenting it with another feedback-controller network (see the Box 1 Figure, panel a). The control objective is to achieve RPA for some variable in the controlled network (output); that is, this variable must be steered to a desired set point and maintained there, even in the presence of unknown constant external perturbations and in spite of uncertainty in the network topology and parameters, including the parameters of the controller network. Insisting on robustness to topology and parameters is particularly important in synthetic biology, in which the controlled network is often unknown or poorly characterized and fine-tuning the parameters of the controller network can be extremely difficult. It is well established in control theory 14 , 15 that in the noise-free setting, such general-purpose controller networks must implement an integral feedback component, but designing one is challenging because of the realizability and other constraints imposed by the biomolecular reaction network 16 , 17 . These challenges are further amplified if we take into account the noisy nature of the intracellular dynamics, in which not all integral feedback-controller implementations lead to RPA and hence the particular topology used is critical. In this stochastic setting, when the dynamics are stable, RPA refers to the steady-state population average of the output variable or—equivalently—its long-term single-cell time average. Given this context, several fundamental questions arise. These include how one can determine definitively whether a candidate network of any size achieves RPA in the presence of intrinsic noise; which architectural features are necessary and sufficient for a biomolecular<|im_end|> <|im_start|>assistant The human body keeps the calcium concentration in the blood constant, similarly to an aircraft's autopilot keeping the plane at a constant altitude. What they have in common is that both the body and the autopilot employ sophisticated integral feedback control mechanisms. Researchers in the Department of Biosystems Science and Engineering at ETH Zurich in Basel have now built such an integral controller completely from scratch within a living cell, as they report in the latest issue of the journal Nature. In the future, their synthetic biology approach could make it possible to optimize biotechnological production processes and to regulate hormonal activity through cell therapy. Constant despite environmental disturbances Marine engineers were the first to build such an integral feedback control system, using it to automate ship steering over 100 years ago. Since then, it has been applied wherever there is a need to maintain steady, stable conditions of direction, temperature, speed or altitude in the face of outside influences. The role of integration is that it allows the control system to make corrections based on both the amount and duration of the deviation from the desired constant value. In biology, too, mechanisms have evolved to maintain such conditions as a steady concentration of substances in the blood. Several years ago, researchers led by Mustafa Khammash, professor at the Department of Biosystems Science and Engineering, showed that these biological mechanisms are also examples of integral feedback control. "These kinds of integral controllers are extremely resistant to unexpected environmental disturbances," Khammash says, "which probably explains why the principle prevailed in evolution, and is why it is ubiquitous in technology." Interplay of two molecules Khammash and his interdisciplinary team of control theorists, mathematicians and experimental biologists have now engineered such an integral feedback controller in the form of a synthetic genetic regulatory network inside a bacterium. Their feedback mechanism relies on two molecules—A and B—that bind to each other to become inactive. Together, these two molecules have the ability to maintain a constant concentration of a third molecule, C. The system is designed so that molecule B promotes the production of C, while the production rate of A depends on the concentration of C. The feedback loop is such that when C is abundant, more A will be produced, which will inactivate more B, which in turn will cause production of C to fall. As a proof of concept, the ETH scientists made use of this principle to control the production of a green fluorescent protein in Escherichia coli bacteria. Thanks to the feedback controller, the bacteria produced a constant amount of the fluorescent protein—even when the scientists, who wanted to test the system, attempted to suppress its production using strong inhibitors. In a second experiment, the researchers produced a bacterial population that grew at a constant rate in spite of the scientists' attempts to disrupt growth, again in an effort to test the feedback mechanism. Improving biotech and therapies Biotechnology could now put this new control mechanism to work in bacteria to produce vitamins, medications, chemicals or biofuels, with the mechanism ensuring that the production rate within the bacteria is held constant at its optimum level. The ETH scientists are developing an analogous control mechanism for mammalian cells in subsequent research work, which will pave the way for further applications, including designer cells featuring genetic regulatory networks to produce hormones inside a patient's body. Among those who would stand to benefit from such an approach are people with diabetes or thyroid deficiency. The synthetic feedback controllers could also be used to improve cancer immunotherapy. "In this form of therapy, immune cells need to be active enough to fight the tumor, but not overactive, as they would then attack healthy tissue," Khammash says. "A mechanism like ours would be able to fine-tune their activity." Integral controller According to ETH Professor Mustafa Khammash, regulation of the calcium concentration in the blood is a good example with which to illustrate the principle of integral controllers in biology. This concentration is tightly regulated at a value of approximately 95 milligrams per liter of blood, regardless of how much calcium a person ingests in food. This rate even remains constant during lactation when lots of calcium is drawn from the blood in order to produce milk. "A constant level of calcium is essential to the proper functioning of many physiological processes, including muscle and nerve function or blood clotting," Khammash says. The hormone PTH works as one of two feedback agents in the body in this context: PTH promotes the mobilization of calcium from bone tissue into the bloodstream. The lower the concentration of calcium in the blood, the more PTH is produced by the parathyroid glands. "This is one part of the body's response when the levels of calcium are too low," Khammash says. But to bring the concentration of calcium completely back to normal after a sudden spike or drop, he adds, a second mechanism is required. This role falls to a biologically active form of vitamin D3, which promotes the absorption into the bloodstream of calcium from partially digested food in the small intestine. However, production of this active form of vitamin D3 in the kidneys is dependent on the concentration of PTH. Together, these two hormones are responsible for ensuring that the calcium concentration in the blood over time strays as little as possible and for as short a time as possible from its normal level—or, in other words, that the "integral of deviation with respect to time," as a mathematician would put it, approaches a constant. Therefore, such a control mechanism is called integral. <|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 failure to develop effective therapies for pediatric glioblastoma (pGBM) and diffuse intrinsic pontine glioma (DIPG) is in part due to their intrinsic heterogeneity. We aimed to quantitatively assess the extent to which this was present in these tumors through subclonal genomic analyses and to determine whether distinct tumor subpopulations may interact to promote tumorigenesis by generating subclonal patient-derived models in vitro and in vivo. Analysis of 142 sequenced tumors revealed multiple tumor subclones, spatially and temporally coexisting in a stable manner as observed by multiple sampling strategies. We isolated genotypically and phenotypically distinct subpopulations that we propose cooperate to enhance tumorigenicity and resistance to therapy. Inactivating mutations in the H4K20 histone methyltransferase KMT5B ( SUV420H1 ), present in <1% of cells, abrogate DNA repair and confer increased invasion and migration on neighboring cells, in vitro and in vivo, through chemokine signaling and modulation of integrins. These data indicate that even rare tumor subpopulations may exert profound effects on tumorigenesis as a whole and may represent a new avenue for therapeutic development. Unraveling the mechanisms of subclonal diversity and communication in pGBM and DIPG will be an important step toward overcoming barriers to effective treatments. Main pGBM and DIPG are a highly heterogeneous group of high-grade glial tumors with no effective treatments 1 . Integrated molecular profiling 2 , 3 , 4 , 5 , 6 , 7 has revealed unique, specific and highly recurrent mutations in genes encoding histone H3 variants that mark robust subgroups of pGBM and DIPG with distinct age of onset, anatomical distribution, clinical outcome, and histopathological and radiological features 8 , 9 . A paradigm shift away from extrapolating from inappropriate adult GBM data and toward a more pediatric-biology-specific approach to developing new therapies has been a positive consequence of the discovery of these mechanisms of tumorigenesis 10 , 11 , 12 . Despite these advances in our understanding of the unique biological drivers of these diseases 13 , a major challenge to improving outcomes for children with these tumors is likely to overlap with morphologically similar tumors in adults: their extensive intratumoral heterogeneity 14 . This has been demonstrated spatially by the application of genomic analyses of topographically distinct areas of the tumor at resection 15 , through longitudinal studies of tumor progression and recurrence 16 , and through single-cell RNA sequencing of bulk primary tumor specimens 17 . All of these analyses suggest the presence of multiple coexisting tumor subclones that may be important to the proliferative and invasive capacities of the tumor, as well as cell fate decisions in response to the tumor microenvironment and selective pressure associated with therapeutic intervention. The relative contributions to the tumorigenic phenotype of these subclones is unclear, as is to what extent they interact during the tumor’s evolutionary history—key factors in understanding the implications for new treatment strategies 18 . In adult GBM, multiple subclones may also be marked by differential, mutually exclusive gene amplification events present in an individual tumor 19 , 20 , 21 , an observation also reported in isolated specimens of DIPG 22 , 23 . In these examples, cells harboring distinct receptor tyrosine kinase gene amplifications were found intermingled throughout tumor specimens in a manner that suggested an environment conducive to the coexistence of multiple cellular subpopulations 19 , 20 , 21 . Two-dimensional (2D) mapping of these subclones across specimens showed some evidence of a predilection of certain subclones for perivascular niches, invasive tumor fronts, or the periphery of necrotic areas 19 , 20 . In evolutionary biology terms, this stable coexistence in conjunction with a degree of specialization appears to imply cooperativity 24 . This posits a selective advantage for an interactive cellular network and promotes biological diversity within a tumor population as an important driver of the malignant phenotype in these cancers. With pGBM and DIPG harboring considerably fewer somatic mutations than adult GBM 13 , we sought to investigate the possibility of tumor heterogeneity reflecting cooperation of subclones in what we consider to be an ideal model system for cancers sharing these histologies. Through an integrated approach of single and multiple sequencing strategies of patient samples coupled with in vitro isolation of subclonal populations, we concluded that biological diversity is selected for across time and space, with genotypically and phenotypically distinct tumor compartments working together to enhance key tumorigenic features such as invasion and migration. Results pGBM and DIPG comprise multiple subclones We reanalyzed whole-genome and exome sequencing from 142 recently published pGBM and DIPG specimens for which matched germline data were available 2 , 3 , 4 , 5 , 6 , 7 . We calculated the cancer cell fractions (CCF) for all somatic single nucleotide variants (SNVs) and small insertions or deletions, taking into account the implied tumor cell percentage, overall ploidy, local copy number alterations and loss of heterozygosity 25 , 26 (Supplementary Table 1 ). In almost all cases, we observed a complex inferred subclonal architecture suggestive not of a single clonal expansion, but of multiple codominant subclonal populations, regardless of tumor location ( n = 93 DIPG, n = 20 other midline, n = 29 cerebral hemispheres) or histone mutation subgroup ( n = 10 H3.3 G34R ( H3F3A ), n = 61 H3.3 K27M ( H3F3A ), n = 23 H3.1 K27M ( HIST1H3B , HIST1H3C ), n = 48 histone wild-type) (Fig. 1a ). Despite this variability in the fraction of any tumor harboring a given mutation, at a gene level there were certain recurrent mutations that were found to be consistently clonal ( H3F3A , HIST1H3B , HIST1H3C , ATRX , NF1 ), some that were found to be predominantly clonal, but with some subclonal examples ( ACVR1 , TP53 ), and some frequently found in subclonal populations ( ATM , PIK3R1 , PPM1D , PDGFRA , BRAF , PIK3CA ) (Fig. 1b ). These data provide important evidence for the likely timing of these mutations during tumor evolution. Using the EXPANDS package 27 , 28 , we", "role": "user" }, { "content": "Scientists have discovered that cancerous cells in an aggressive type of childhood brain tumour work together to infiltrate the brain, and this finding could ultimately lead to much needed new treatments, according to a new study published in Nature Medicine today. In the study, funded by Cancer Research UK with support from Abbie's Army and the DIPG Collaborative, the researchers investigated a type of childhood brain tumour called diffuse intrinsic pontine glioma (DIPG), shining a light on its most aggressive characteristic—its ability to leave the brain stem and send cancer cells to invade the rest of the brain. DIPG is incredibly difficult to treat. Nearly all children with this type of cancer die within two years. The researchers, led by a team at The Institute of Cancer Research, London, used donations of biopsy tissue and the brains of children who had died as a consequence of DIPG to look deep into the tumour and learn more about its cells. They found that DIPGs are heterogenous, meaning they are made up of more than one type of cell. This enables the cells to 'work' together to leave the original tumour and travel into the brain. The scientists say this shows how complex the genetic make-up of the disease is and that a multi-pronged attack is likely to be necessary for treatment. Professor Chris Jones, who led the study at The Institute of Cancer Research, London, said: \"This is the first time we've observed this sort of interaction between different tumour cells in DIPG. The idea that the cells are working together to make the disease grow and become aggressive is new and surprising. Childhood cancers were thought to be very simple but this shows us that isn't always the case. Crucially, this gives us hope that we can develop new treatments. \"We desperately want to prevent more families going through the heartbreak of losing a child to this disease. Unfortunately, there is currently no cure for this illness. Children usually can't have surgery because of the tumour's location in the brain stem which controls functions such as breathing, heart rate, blood pressure, and swallowing. And other treatment options such as chemotherapy don't work because it's relatively difficult to get drugs into the brain stem and many DIPG tumours have an inbuilt resistance to chemotherapy.\" The study also shows that even cells that exist in relatively small numbers in DIPG can exert a profound influence, by leading cells from the main tumour into the rest of the brain to stimulate tumour growth and spread. In this study, researchers saw one type of cell leaving the original DIPG tumour site and migrating into the rest of the brain. This happens early in the evolution of the disease and is a cell type found in relatively small numbers. As it migrates, the cells release a chemical messenger called CXCL2, which has the effect of calling other cells from the tumour to follow it. The next stage of research will see the researchers looking for treatments that target the most important subpopulations of cells in the tumour and/or interfere with the cooperation between cells. Professor Richard Gilbertson, Director of the Cancer Research UK Cambridge Centre at the University of Cambridge, said: \"This research begins to unravel the complex community of cells that make up DIPG. Through an elegant combination of molecular and cell biology techniques, this study provides a window into the heart of these tumours, allowing us to begin to decipher how their different cell populations interact with each other to promote the disease. It is exactly this sort of research that is needed if we are to beat this devastating cancer. \"Cancer Research UK recognises more must be done to tackle this devastating disease and has committed £25 million to brain tumour research over the next five years. Brain tumours have been identified as a cancer of unmet need; survival rates have not changed significantly in a generation.\" ", "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 failure to develop effective therapies for pediatric glioblastoma (pGBM) and diffuse intrinsic pontine glioma (DIPG) is in part due to their intrinsic heterogeneity. We aimed to quantitatively assess the extent to which this was present in these tumors through subclonal genomic analyses and to determine whether distinct tumor subpopulations may interact to promote tumorigenesis by generating subclonal patient-derived models in vitro and in vivo. Analysis of 142 sequenced tumors revealed multiple tumor subclones, spatially and temporally coexisting in a stable manner as observed by multiple sampling strategies. We isolated genotypically and phenotypically distinct subpopulations that we propose cooperate to enhance tumorigenicity and resistance to therapy. Inactivating mutations in the H4K20 histone methyltransferase KMT5B ( SUV420H1 ), present in <1% of cells, abrogate DNA repair and confer increased invasion and migration on neighboring cells, in vitro and in vivo, through chemokine signaling and modulation of integrins. These data indicate that even rare tumor subpopulations may exert profound effects on tumorigenesis as a whole and may represent a new avenue for therapeutic development. Unraveling the mechanisms of subclonal diversity and communication in pGBM and DIPG will be an important step toward overcoming barriers to effective treatments. Main pGBM and DIPG are a highly heterogeneous group of high-grade glial tumors with no effective treatments 1 . Integrated molecular profiling 2 , 3 , 4 , 5 , 6 , 7 has revealed unique, specific and highly recurrent mutations in genes encoding histone H3 variants that mark robust subgroups of pGBM and DIPG with distinct age of onset, anatomical distribution, clinical outcome, and histopathological and radiological features 8 , 9 . A paradigm shift away from extrapolating from inappropriate adult GBM data and toward a more pediatric-biology-specific approach to developing new therapies has been a positive consequence of the discovery of these mechanisms of tumorigenesis 10 , 11 , 12 . Despite these advances in our understanding of the unique biological drivers of these diseases 13 , a major challenge to improving outcomes for children with these tumors is likely to overlap with morphologically similar tumors in adults: their extensive intratumoral heterogeneity 14 . This has been demonstrated spatially by the application of genomic analyses of topographically distinct areas of the tumor at resection 15 , through longitudinal studies of tumor progression and recurrence 16 , and through single-cell RNA sequencing of bulk primary tumor specimens 17 . All of these analyses suggest the presence of multiple coexisting tumor subclones that may be important to the proliferative and invasive capacities of the tumor, as well as cell fate decisions in response to the tumor microenvironment and selective pressure associated with therapeutic intervention. The relative contributions to the tumorigenic phenotype of these subclones is unclear, as is to what extent they interact during the tumor’s evolutionary history—key factors in understanding the implications for new treatment strategies 18 . In adult GBM, multiple subclones may also be marked by differential, mutually exclusive gene amplification events present in an individual tumor 19 , 20 , 21 , an observation also reported in isolated specimens of DIPG 22 , 23 . In these examples, cells harboring distinct receptor tyrosine kinase gene amplifications were found intermingled throughout tumor specimens in a manner that suggested an environment conducive to the coexistence of multiple cellular subpopulations 19 , 20 , 21 . Two-dimensional (2D) mapping of these subclones across specimens showed some evidence of a predilection of certain subclones for perivascular niches, invasive tumor fronts, or the periphery of necrotic areas 19 , 20 . In evolutionary biology terms, this stable coexistence in conjunction with a degree of specialization appears to imply cooperativity 24 . This posits a selective advantage for an interactive cellular network and promotes biological diversity within a tumor population as an important driver of the malignant phenotype in these cancers. With pGBM and DIPG harboring considerably fewer somatic mutations than adult GBM 13 , we sought to investigate the possibility of tumor heterogeneity reflecting cooperation of subclones in what we consider to be an ideal model system for cancers sharing these histologies. Through an integrated approach of single and multiple sequencing strategies of patient samples coupled with in vitro isolation of subclonal populations, we concluded that biological diversity is selected for across time and space, with genotypically and phenotypically distinct tumor compartments working together to enhance key tumorigenic features such as invasion and migration. Results pGBM and DIPG comprise multiple subclones We reanalyzed whole-genome and exome sequencing from 142 recently published pGBM and DIPG specimens for which matched germline data were available 2 , 3 , 4 , 5 , 6 , 7 . We calculated the cancer cell fractions (CCF) for all somatic single nucleotide variants (SNVs) and small insertions or deletions, taking into account the implied tumor cell percentage, overall ploidy, local copy number alterations and loss of heterozygosity 25 , 26 (Supplementary Table 1 ). In almost all cases, we observed a complex inferred subclonal architecture suggestive not of a single clonal expansion, but of multiple codominant subclonal populations, regardless of tumor location ( n = 93 DIPG, n = 20 other midline, n = 29 cerebral hemispheres) or histone mutation subgroup ( n = 10 H3.3 G34R ( H3F3A ), n = 61 H3.3 K27M ( H3F3A ), n = 23 H3.1 K27M ( HIST1H3B , HIST1H3C ), n = 48 histone wild-type) (Fig. 1a ). Despite this variability in the fraction of any tumor harboring a given mutation, at a gene level there were certain recurrent mutations that were found to be consistently clonal ( H3F3A , HIST1H3B , HIST1H3C , ATRX , NF1 ), some that were found to be predominantly clonal, but with some subclonal examples ( ACVR1 , TP53 ), and some frequently found in subclonal populations ( ATM , PIK3R1 , PPM1D , PDGFRA , BRAF , PIK3CA ) (Fig. 1b ). These data provide important evidence for the likely timing of these mutations during tumor evolution. Using the EXPANDS package 27 , 28 , we<|im_end|> <|im_start|>assistant Scientists have discovered that cancerous cells in an aggressive type of childhood brain tumour work together to infiltrate the brain, and this finding could ultimately lead to much needed new treatments, according to a new study published in Nature Medicine today. In the study, funded by Cancer Research UK with support from Abbie's Army and the DIPG Collaborative, the researchers investigated a type of childhood brain tumour called diffuse intrinsic pontine glioma (DIPG), shining a light on its most aggressive characteristic—its ability to leave the brain stem and send cancer cells to invade the rest of the brain. DIPG is incredibly difficult to treat. Nearly all children with this type of cancer die within two years. The researchers, led by a team at The Institute of Cancer Research, London, used donations of biopsy tissue and the brains of children who had died as a consequence of DIPG to look deep into the tumour and learn more about its cells. They found that DIPGs are heterogenous, meaning they are made up of more than one type of cell. This enables the cells to 'work' together to leave the original tumour and travel into the brain. The scientists say this shows how complex the genetic make-up of the disease is and that a multi-pronged attack is likely to be necessary for treatment. Professor Chris Jones, who led the study at The Institute of Cancer Research, London, said: "This is the first time we've observed this sort of interaction between different tumour cells in DIPG. The idea that the cells are working together to make the disease grow and become aggressive is new and surprising. Childhood cancers were thought to be very simple but this shows us that isn't always the case. Crucially, this gives us hope that we can develop new treatments. "We desperately want to prevent more families going through the heartbreak of losing a child to this disease. Unfortunately, there is currently no cure for this illness. Children usually can't have surgery because of the tumour's location in the brain stem which controls functions such as breathing, heart rate, blood pressure, and swallowing. And other treatment options such as chemotherapy don't work because it's relatively difficult to get drugs into the brain stem and many DIPG tumours have an inbuilt resistance to chemotherapy." The study also shows that even cells that exist in relatively small numbers in DIPG can exert a profound influence, by leading cells from the main tumour into the rest of the brain to stimulate tumour growth and spread. In this study, researchers saw one type of cell leaving the original DIPG tumour site and migrating into the rest of the brain. This happens early in the evolution of the disease and is a cell type found in relatively small numbers. As it migrates, the cells release a chemical messenger called CXCL2, which has the effect of calling other cells from the tumour to follow it. The next stage of research will see the researchers looking for treatments that target the most important subpopulations of cells in the tumour and/or interfere with the cooperation between cells. Professor Richard Gilbertson, Director of the Cancer Research UK Cambridge Centre at the University of Cambridge, said: "This research begins to unravel the complex community of cells that make up DIPG. Through an elegant combination of molecular and cell biology techniques, this study provides a window into the heart of these tumours, allowing us to begin to decipher how their different cell populations interact with each other to promote the disease. It is exactly this sort of research that is needed if we are to beat this devastating cancer. "Cancer Research UK recognises more must be done to tackle this devastating disease and has committed £25 million to brain tumour research over the next five years. Brain tumours have been identified as a cancer of unmet need; survival rates have not changed significantly in a generation." <|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 Alzheimer's disease causes a progressive dementia that currently affects over 35 million individuals worldwide and is expected to affect 115 million by 2050 (ref. 1 ). There are no cures or disease-modifying therapies, and this may be due to our inability to detect the disease before it has progressed to produce evident memory loss and functional decline. Biomarkers of preclinical disease will be critical to the development of disease-modifying or even preventative therapies 2 . Unfortunately, current biomarkers for early disease, including cerebrospinal fluid tau and amyloid-β levels 3 , structural and functional magnetic resonance imaging 4 and the recent use of brain amyloid imaging 5 or inflammaging 6 , are limited because they are either invasive, time-consuming or expensive. Blood-based biomarkers may be a more attractive option, but none can currently detect preclinical Alzheimer's disease with the required sensitivity and specificity 7 . Herein, we describe our lipidomic approach to detecting preclinical Alzheimer's disease in a group of cognitively normal older adults. We discovered and validated a set of ten lipids from peripheral blood that predicted phenoconversion to either amnestic mild cognitive impairment or Alzheimer's disease within a 2–3 year timeframe with over 90% accuracy. This biomarker panel, reflecting cell membrane integrity, may be sensitive to early neurodegeneration of preclinical Alzheimer's disease. Main We enrolled 525 community-dwelling participants, aged 70 and older and otherwise healthy, into this 5-year observational study. Over the course of the study, 74 participants met criteria for amnestic mild cognitive impairment (aMCI) or mild Alzheimer's disease (AD) (Online Methods); 46 were incidental cases at entry, and 28 phenoconverted (Converters) from nonimpaired memory status at entry (Converter pre ). The average time for phenoconversion to either aMCI or AD was 2.1 years (range 1–5 years). We defined three main participant groups in this paper: aMCI/AD, Converter and Normal Control (NC). The participants with aMCI and mild AD were combined into a single group (aMCI/AD) because this group was defined by a primary memory impairment, and aMCI is generally thought to reflect the earliest clinically detectable stage of AD. The aMCI/AD group included the Converters after phenoconversion. The Converters were included at two time points, prior to phenoconversion (Converter pre ), when memory was not impaired, and after phenoconversion ( post ), when memory was impaired and they met criteria for either aMCI or AD. The NC group was selected to match the whole aMCI/AD group on the basis of age, education and sex. In the third year of the study, we selected 53 participants with either aMCI or AD for metabolomic and lipidomic biomarker discovery. Included in this aMCI/AD group were 18 Converters. We also selected 53 matched cognitively normal control (NC) participants. For the Converters, blood from both time 0 (at entry to the study) and after phenoconversion was used; for the other subjects, blood from the last available visit was used. We used an internal cross-validation procedure to evaluate the accuracy of the discovered lipidomics profile in classifying 41 additional subjects, consisting of the remaining subset of 21 participants with aMCI/AD, including 10 Converters, and 20 matched NC participants ( Supplementary Table 1 and Supplementary Fig. 1 ). The aMCI/AD, Converter and NC groups were defined primarily using a composite measure of memory performance (the decline in Z mem for the Converters (C pre versus C post ) is shown Fig. 1a ). In addition, composite measures of other cognitive abilities ( Supplementary Fig. 2 ) and measures of memory complaints and functional capacities were compiled ( Supplementary Tables 2 and 3 ). The discovery and validation groups did not differ on clinical measures ( F (4,170) = 1.376, P = 0.244) or on any composite z -score ( F (5,169) = 2.118, P = 0.066), demonstrating the general equivalence of the participants used for the discovery and validation phases of the biomarker analysis. Figure 1: Memory composite z -scores and trend plots for the ten-metabolite panel in the discovery phase. ( a ) Box and whisker plot shows the composite memory z -scores ( Z mem ) of the combined discovery and validation samples ( Supplementary Table 3 ). The performance of the Converter group (C pre , Converters at baseline) after phenoconversion (C post ) is plotted for direct comparison. The plot shows Z mem , as described in Supplementary Table 3 . The dotted line centered on 0 represents the median memory composite z -score for the entire cohort of 525 participants, and the black horizontal line represents the cut-off for impairment (−1.35 s.d.). Error bars represent ±s.e.m. As defined, all converters had nonimpaired memory at baseline and impaired memory after phenoconversion. NC, n = 73; C pre , n = 28; C post , n = 28; and aMCI/AD, n = 46. ( b ) The SID-MRM-MS–based quantitative profiling data was subjected to the nonparametric Kruskal-Wallis test using the STAT pack module (Biocrates). Results are shown for a panel of ten metabolites in the NC group ( n = 53), C pre ( n = 18), C post ( n = 18) and aMCI/AD ( n = 35) groups, respectively. The abundance of each metabolite is plotted as normalized concentrations units (nM). The black solid bars within the boxplot represent the median abundance, and the dotted line represents mean abundance for the given group. Error bars represent ± s.d. QC, quality control samples. The P values for analytes between groups were P ≤ 0.05. The two metabolites with P values <0.005 are indicated with an asterisk. Each Kruskal-Wallis test was followed by Mann-Whitney U -tests for post hoc pairwise comparisons (NC versus C pre and NC versus aMCI/AD). Significance was adjusted for multiple comparisons using Bonferroni's method ( P < 0.025). Source data Source data Full size image We examined 124 plasma samples from the 106 discovery-phase participants for untargeted metabolomic analysis (Online Methods). Metabolomic and lipidomic profiling yielded 2,700 positive-mode features and 1,900 negative-mode features. Metabolites defining the participant groups were selected using the least absolute shrinkage and", "role": "user" }, { "content": "Researchers have discovered and validated a blood test that can predict with greater than 90 percent accuracy if a healthy person will develop mild cognitive impairment or Alzheimer's disease within three years. Described in Nature Medicine published online today, the study heralds the potential for developing treatment strategies for Alzheimer's at an earlier stage, when therapy would be more effective at slowing or preventing onset of symptoms. It is the first known published report of blood-based biomarkers for preclinical Alzheimer's. The test identifies 10 lipids, or fats, in the blood that predict disease onset. It could be ready for use in clinical studies in as few as two years and, researchers say, other diagnostic uses are possible. \"Our novel blood test offers the potential to identify people at risk for progressive cognitive decline and can change how patients, their families and treating physicians plan for and manage the disorder,\" says the study's corresponding author Howard J. Federoff, MD, PhD, professor of neurology and executive vice president for health sciences at Georgetown University Medical Center. There is no cure or effective treatment for Alzheimer's. Worldwide, about 35.6 million individuals have the disease and, according to the World Health Organization, the number will double every 20 years to 115.4 million people with Alzheimer's by 2050. Howard J. Federoff, M.D., Ph.D., of Georgetown University Medical Center, explains a new blood test that can predict onset of MCI or Alzheimer's. Credit: Georgetown University Medical Center Federoff explains there have been many efforts to develop drugs to slow or reverse the progression of Alzheimer's disease, but all of them have failed. He says one reason may be the drugs were evaluated too late in the disease process. \"The preclinical state of the disease offers a window of opportunity for timely disease-modifying intervention,\" Federoff says. \"Biomarkers such as ours that define this asymptomatic period are critical for successful development and application of these therapeutics.\" The study included 525 healthy participants aged 70 and older who gave blood samples upon enrolling and at various points in the study. Over the course of the five-year study, 74 participants met the criteria for either mild Alzheimer's disease (AD) or a condition known as amnestic mild cognitive impairment (aMCI), in which memory loss is prominent. Of these, 46 were diagnosed upon enrollment and 28 developed aMCI or mild AD during the study (the latter group called converters). In the study's third year, the researchers selected 53 participants who developed aMCI/AD (including 18 converters) and 53 cognitively normal matched controls for the lipid biomarker discovery phase of the study. The lipids were not targeted before the start of the study, but rather, were an outcome of the study. A panel of 10 lipids was discovered, which researchers say appears to reveal the breakdown of neural cell membranes in participants who develop symptoms of cognitive impairment or AD. The panel was subsequently validated using the remaining 21 aMCI/AD participants (including 10 converters), and 20 controls. Blinded data were analyzed to determine if the subjects could be characterized into the correct diagnostic categories based solely on the 10 lipids identified in the discovery phase. \"The lipid panel was able to distinguish with 90 percent accuracy these two distinct groups: cognitively normal participants who would progress to MCI or AD within two to three years, and those who would remain normal in the near future,\" Federoff says. The researchers examined if the presence of the APOE4 gene, a known risk factor for developing AD, would contribute to accurate classification of the groups, but found it was not a significant predictive factor in this study. \"We consider our results a major step toward the commercialization of a preclinical disease biomarker test that could be useful for large-scale screening to identify at-risk individuals,\" Federoff says. \"We're designing a clinical trial where we'll use this panel to identify people at high risk for Alzheimer's to test a therapeutic agent that might delay or prevent the emergence of the 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 Alzheimer's disease causes a progressive dementia that currently affects over 35 million individuals worldwide and is expected to affect 115 million by 2050 (ref. 1 ). There are no cures or disease-modifying therapies, and this may be due to our inability to detect the disease before it has progressed to produce evident memory loss and functional decline. Biomarkers of preclinical disease will be critical to the development of disease-modifying or even preventative therapies 2 . Unfortunately, current biomarkers for early disease, including cerebrospinal fluid tau and amyloid-β levels 3 , structural and functional magnetic resonance imaging 4 and the recent use of brain amyloid imaging 5 or inflammaging 6 , are limited because they are either invasive, time-consuming or expensive. Blood-based biomarkers may be a more attractive option, but none can currently detect preclinical Alzheimer's disease with the required sensitivity and specificity 7 . Herein, we describe our lipidomic approach to detecting preclinical Alzheimer's disease in a group of cognitively normal older adults. We discovered and validated a set of ten lipids from peripheral blood that predicted phenoconversion to either amnestic mild cognitive impairment or Alzheimer's disease within a 2–3 year timeframe with over 90% accuracy. This biomarker panel, reflecting cell membrane integrity, may be sensitive to early neurodegeneration of preclinical Alzheimer's disease. Main We enrolled 525 community-dwelling participants, aged 70 and older and otherwise healthy, into this 5-year observational study. Over the course of the study, 74 participants met criteria for amnestic mild cognitive impairment (aMCI) or mild Alzheimer's disease (AD) (Online Methods); 46 were incidental cases at entry, and 28 phenoconverted (Converters) from nonimpaired memory status at entry (Converter pre ). The average time for phenoconversion to either aMCI or AD was 2.1 years (range 1–5 years). We defined three main participant groups in this paper: aMCI/AD, Converter and Normal Control (NC). The participants with aMCI and mild AD were combined into a single group (aMCI/AD) because this group was defined by a primary memory impairment, and aMCI is generally thought to reflect the earliest clinically detectable stage of AD. The aMCI/AD group included the Converters after phenoconversion. The Converters were included at two time points, prior to phenoconversion (Converter pre ), when memory was not impaired, and after phenoconversion ( post ), when memory was impaired and they met criteria for either aMCI or AD. The NC group was selected to match the whole aMCI/AD group on the basis of age, education and sex. In the third year of the study, we selected 53 participants with either aMCI or AD for metabolomic and lipidomic biomarker discovery. Included in this aMCI/AD group were 18 Converters. We also selected 53 matched cognitively normal control (NC) participants. For the Converters, blood from both time 0 (at entry to the study) and after phenoconversion was used; for the other subjects, blood from the last available visit was used. We used an internal cross-validation procedure to evaluate the accuracy of the discovered lipidomics profile in classifying 41 additional subjects, consisting of the remaining subset of 21 participants with aMCI/AD, including 10 Converters, and 20 matched NC participants ( Supplementary Table 1 and Supplementary Fig. 1 ). The aMCI/AD, Converter and NC groups were defined primarily using a composite measure of memory performance (the decline in Z mem for the Converters (C pre versus C post ) is shown Fig. 1a ). In addition, composite measures of other cognitive abilities ( Supplementary Fig. 2 ) and measures of memory complaints and functional capacities were compiled ( Supplementary Tables 2 and 3 ). The discovery and validation groups did not differ on clinical measures ( F (4,170) = 1.376, P = 0.244) or on any composite z -score ( F (5,169) = 2.118, P = 0.066), demonstrating the general equivalence of the participants used for the discovery and validation phases of the biomarker analysis. Figure 1: Memory composite z -scores and trend plots for the ten-metabolite panel in the discovery phase. ( a ) Box and whisker plot shows the composite memory z -scores ( Z mem ) of the combined discovery and validation samples ( Supplementary Table 3 ). The performance of the Converter group (C pre , Converters at baseline) after phenoconversion (C post ) is plotted for direct comparison. The plot shows Z mem , as described in Supplementary Table 3 . The dotted line centered on 0 represents the median memory composite z -score for the entire cohort of 525 participants, and the black horizontal line represents the cut-off for impairment (−1.35 s.d.). Error bars represent ±s.e.m. As defined, all converters had nonimpaired memory at baseline and impaired memory after phenoconversion. NC, n = 73; C pre , n = 28; C post , n = 28; and aMCI/AD, n = 46. ( b ) The SID-MRM-MS–based quantitative profiling data was subjected to the nonparametric Kruskal-Wallis test using the STAT pack module (Biocrates). Results are shown for a panel of ten metabolites in the NC group ( n = 53), C pre ( n = 18), C post ( n = 18) and aMCI/AD ( n = 35) groups, respectively. The abundance of each metabolite is plotted as normalized concentrations units (nM). The black solid bars within the boxplot represent the median abundance, and the dotted line represents mean abundance for the given group. Error bars represent ± s.d. QC, quality control samples. The P values for analytes between groups were P ≤ 0.05. The two metabolites with P values <0.005 are indicated with an asterisk. Each Kruskal-Wallis test was followed by Mann-Whitney U -tests for post hoc pairwise comparisons (NC versus C pre and NC versus aMCI/AD). Significance was adjusted for multiple comparisons using Bonferroni's method ( P < 0.025). Source data Source data Full size image We examined 124 plasma samples from the 106 discovery-phase participants for untargeted metabolomic analysis (Online Methods). Metabolomic and lipidomic profiling yielded 2,700 positive-mode features and 1,900 negative-mode features. Metabolites defining the participant groups were selected using the least absolute shrinkage and<|im_end|> <|im_start|>assistant Researchers have discovered and validated a blood test that can predict with greater than 90 percent accuracy if a healthy person will develop mild cognitive impairment or Alzheimer's disease within three years. Described in Nature Medicine published online today, the study heralds the potential for developing treatment strategies for Alzheimer's at an earlier stage, when therapy would be more effective at slowing or preventing onset of symptoms. It is the first known published report of blood-based biomarkers for preclinical Alzheimer's. The test identifies 10 lipids, or fats, in the blood that predict disease onset. It could be ready for use in clinical studies in as few as two years and, researchers say, other diagnostic uses are possible. "Our novel blood test offers the potential to identify people at risk for progressive cognitive decline and can change how patients, their families and treating physicians plan for and manage the disorder," says the study's corresponding author Howard J. Federoff, MD, PhD, professor of neurology and executive vice president for health sciences at Georgetown University Medical Center. There is no cure or effective treatment for Alzheimer's. Worldwide, about 35.6 million individuals have the disease and, according to the World Health Organization, the number will double every 20 years to 115.4 million people with Alzheimer's by 2050. Howard J. Federoff, M.D., Ph.D., of Georgetown University Medical Center, explains a new blood test that can predict onset of MCI or Alzheimer's. Credit: Georgetown University Medical Center Federoff explains there have been many efforts to develop drugs to slow or reverse the progression of Alzheimer's disease, but all of them have failed. He says one reason may be the drugs were evaluated too late in the disease process. "The preclinical state of the disease offers a window of opportunity for timely disease-modifying intervention," Federoff says. "Biomarkers such as ours that define this asymptomatic period are critical for successful development and application of these therapeutics." The study included 525 healthy participants aged 70 and older who gave blood samples upon enrolling and at various points in the study. Over the course of the five-year study, 74 participants met the criteria for either mild Alzheimer's disease (AD) or a condition known as amnestic mild cognitive impairment (aMCI), in which memory loss is prominent. Of these, 46 were diagnosed upon enrollment and 28 developed aMCI or mild AD during the study (the latter group called converters). In the study's third year, the researchers selected 53 participants who developed aMCI/AD (including 18 converters) and 53 cognitively normal matched controls for the lipid biomarker discovery phase of the study. The lipids were not targeted before the start of the study, but rather, were an outcome of the study. A panel of 10 lipids was discovered, which researchers say appears to reveal the breakdown of neural cell membranes in participants who develop symptoms of cognitive impairment or AD. The panel was subsequently validated using the remaining 21 aMCI/AD participants (including 10 converters), and 20 controls. Blinded data were analyzed to determine if the subjects could be characterized into the correct diagnostic categories based solely on the 10 lipids identified in the discovery phase. "The lipid panel was able to distinguish with 90 percent accuracy these two distinct groups: cognitively normal participants who would progress to MCI or AD within two to three years, and those who would remain normal in the near future," Federoff says. The researchers examined if the presence of the APOE4 gene, a known risk factor for developing AD, would contribute to accurate classification of the groups, but found it was not a significant predictive factor in this study. "We consider our results a major step toward the commercialization of a preclinical disease biomarker test that could be useful for large-scale screening to identify at-risk individuals," Federoff says. "We're designing a clinical trial where we'll use this panel to identify people at high risk for Alzheimer's to test a therapeutic agent that might delay or prevent the emergence of the 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 Heavy metal contamination is one of the leading causes of water pollution, with known adverse effects on human health and the environment. This work demonstrates a novel custom-made 3D printable eco-friendly hydrogel and fabrication process that produces stable biocompatible adsorbents with the ability to capture and remove heavy metals from aqueous environments quickly and economically. The 3D printable ink contains alginate, gelatin, and polyethyleneimine (PEI), which binds heavy metals through primary and secondary amine side chains favoring heavy metal adsorption. The ink's rheological properties are optimized to create mechanically stable constructs, in the form of 3D-printed tablets, fabricated entirely by printing. The optimized tablets have high porosity and accessible surface area with multiple binding sites for heavy metal ion adsorption while the printing process enables rapid and affordable production with the potential for scale-up. The results demonstrate the contribution of hydrogel composition and rheology in determining the printability, stability, and heavy metal binding characteristics of the hydrogel, and indicate the critical role of the PEI in increasing stability of the printed construct, in addition to its metal binding properties. The highest removal capacity was obtained for copper, followed by cadmium, cobalt, and nickel ions. In the optimized formulation, each hydrogel tablet removed 60% from 100 ppm copper in 5 h and up to 98% in 18 h. For more concentrated solutions (1000 ppm), ∼25% of copper was removed in 18 h. The printed tablets are stable, robust, and can be produced in a single simple step from inexpensive biomaterials. The ink's tunability, excellent printability, and stability offer a universally applicable procedure for creating hydrogel-based structures for environmental remediation. These unique capabilities open new avenues for manufacturing tailor-made constructs with integrated functionality for water treatment and environmental applications. This article is part of the themed collection: Best Papers 2022 – Environmental Science: Advances Environmental significance Hydrogel-based adsorbents offer excellent opportunities for the development of eco-friendly technologies for heavy metal ions removal. In this study, an additive manufacturing technique is reported that provides an easy and effective way to rapidly and reproducibly fabricate structured 3D printing hydrogel-based adsorbents for environmental remediation. The results indicate the importance of achieving multifunctionality through reinforcing the hydrogel with PEI and establishes the essential role of hydrogel composition and rheology in determining the printability, stability, functionality and metal binding capacity. An improved understanding of the factors regulating the stability of these hydrogels will allow further development of 3D printable formulations and additive manufacturing techniques for a variety of water treatment and environmental applications. The 3D printing technique described here offers a cost effective, scalable and facile approach to create tunable adsorbents for use in environmental remediation that can be used broadly by the environmental community to custom-made 3D printed structures for environmental removal and sensing applications. This work can contribute to the development of bio-based methods for environmental remediation to achieve the global WHO goals for clean and sustainable water. 1. Introduction Globally, heavy metal pollution with metals such as copper, nickel, mercury, cadmium, lead, and chromium is a significant environmental and health hazard, recognized by the World Health Organization (WHO) as a critical problem with significant consequences worldwide. 1,2 Heavy metals cannot be biodegraded; they are toxic and carcinogenic, and the potential for human exposure is high. 3 Electroplating, mining, tanneries, painting, and semiconductors are a few of the industries that are significant sources of heavy metal pollution. Others include livestock manure, fertilizers, herbicides, atmospheric deposition, and irrigation with polluted wastewater. 4 As a result of heavy metal pollution, plants experience oxidative stress, cellular damage, and disruption of respiratory and photosynthetic activity, 5 the intake of crops contaminated by root transfer from soil to plant tissues can pose substantial health risks for humans. 4,6 Excess metal concentrations in soil alter food quality, leading to various disorders. 7 High levels of heavy metals such as copper, cadmium, nickel, and cobalt have been attributed to increased occurrences of cancer and industries that release an excess of these metal ions are known to pollute the environment. 8 Since heavy metals are not usually degraded by natural processes, they can persist in the environment for a long time. Soil, water, and air are directly impacted by heavy metal contamination. Water runoff from factories, agricultural farms, and water treatment facilities in cities, villages, and towns can transport heavy metals, which eventually accumulate in water bodies, and river beds and is extremely hazardous to the local ecosystem. 9 Particulate matters of heavy metals that are discharged from anthropogenic sources and natural sources cause corrosion, haze, eutrophication, and even acid rains that can further pollute water bodies and soil. 10 Improper waste disposal and landfills, mining, and drilling can pollute soil by resulting in high heavy metal levels, that are further absorbed by living organisms and affect water quality. 11 Copper ions (Cu 2+ ) for example are used heavily in agriculture as an antifungal agent and can enter the water from the electroplating and mining industries. 12 The discharge of these wastes in streams, lakes, and groundwater reservoirs is responsible for health problems in humans and plants. The average Cu 2+ concentration in soil ranges from 5 to 70 ppm but can reach 100 to 1500 ppm in the soil around vineyards where Cu 2+ treatments are used to reduce the growth of mildew. 13 In sediments found in bays and estuaries, the Cu 2+ concentration is less than 50 ppm, but polluted sediments may contain several thousand ppm. Around 4500 ppm of Cu 2+ was reported in the soil around a Cu/Ni smelter. 14 The presence of high concentrations of heavy metals in polluted environments requires efficient and economical ways to remove them to ensure pollutant-free water. Multiple techniques can be used to remove heavy metals from the water. 15,16 These include chemical precipitation, electrochemical reduction, membrane separation, and adsorption. 16 Though chemical precipitation is low-cost and straightforward, 15 the method generates significant waste, leading to secondary pollution. Electrochemical methods are rapid and provide good reduction yields, but the initial", "role": "user" }, { "content": "One of the leading causes of water pollution is heavy metal contamination which has profound adverse effects on human health and the environment. That's why Clarkson University researchers have developed a cost-effective, 3D printing technology to create sustainable bio-based adsorbents that can effectively remove toxic heavy metal ions from contaminated environments. The 3D printing technique offers a cost-effective, scalable and simple approach to creating tunable adsorbents for environmental remediation that can be used broadly by the community for environmental remediation and sensing applications. The work performed in the laboratory of Professor Silvana Andreescu, the Egon Matijevic Chair in Chemistry, was recently featured on the front cover page of the journal, Environmental Science Advances. Nadia Cheng, a biomolecular science undergraduate, and two chemistry graduate students, Abraham S. Finny and Oluwatossin Popoola, were involved in the project. Nadia started her work on this project as a senior in high school and then as a Clarkson School student. \"Our work demonstrates unique capabilities of green and sustainable materials to be additively manufactured and designed so that they have the ability to capture and remove toxic contaminants, providing innovative solutions for next-generation detection and remediation technologies. This work contributes to the development of materials and methods for environmental monitoring and clean up to achieve the global WHO goals for clean and sustainable water,\" said Professor Andreescu. Abraham S. Finny PHD, a Senior Scientist at Waters Corporation and a former member of Prof. Andreescu's lab, says, \"Exposure to such innovative, application-focused, and cutting-edge scientific research at Clarkson makes Clarkson graduates excellent problem solvers who go on to become impactful leaders tackling global challenges; another reason why employers find Clarkson graduates highly attractive.\" ", "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 Heavy metal contamination is one of the leading causes of water pollution, with known adverse effects on human health and the environment. This work demonstrates a novel custom-made 3D printable eco-friendly hydrogel and fabrication process that produces stable biocompatible adsorbents with the ability to capture and remove heavy metals from aqueous environments quickly and economically. The 3D printable ink contains alginate, gelatin, and polyethyleneimine (PEI), which binds heavy metals through primary and secondary amine side chains favoring heavy metal adsorption. The ink's rheological properties are optimized to create mechanically stable constructs, in the form of 3D-printed tablets, fabricated entirely by printing. The optimized tablets have high porosity and accessible surface area with multiple binding sites for heavy metal ion adsorption while the printing process enables rapid and affordable production with the potential for scale-up. The results demonstrate the contribution of hydrogel composition and rheology in determining the printability, stability, and heavy metal binding characteristics of the hydrogel, and indicate the critical role of the PEI in increasing stability of the printed construct, in addition to its metal binding properties. The highest removal capacity was obtained for copper, followed by cadmium, cobalt, and nickel ions. In the optimized formulation, each hydrogel tablet removed 60% from 100 ppm copper in 5 h and up to 98% in 18 h. For more concentrated solutions (1000 ppm), ∼25% of copper was removed in 18 h. The printed tablets are stable, robust, and can be produced in a single simple step from inexpensive biomaterials. The ink's tunability, excellent printability, and stability offer a universally applicable procedure for creating hydrogel-based structures for environmental remediation. These unique capabilities open new avenues for manufacturing tailor-made constructs with integrated functionality for water treatment and environmental applications. This article is part of the themed collection: Best Papers 2022 – Environmental Science: Advances Environmental significance Hydrogel-based adsorbents offer excellent opportunities for the development of eco-friendly technologies for heavy metal ions removal. In this study, an additive manufacturing technique is reported that provides an easy and effective way to rapidly and reproducibly fabricate structured 3D printing hydrogel-based adsorbents for environmental remediation. The results indicate the importance of achieving multifunctionality through reinforcing the hydrogel with PEI and establishes the essential role of hydrogel composition and rheology in determining the printability, stability, functionality and metal binding capacity. An improved understanding of the factors regulating the stability of these hydrogels will allow further development of 3D printable formulations and additive manufacturing techniques for a variety of water treatment and environmental applications. The 3D printing technique described here offers a cost effective, scalable and facile approach to create tunable adsorbents for use in environmental remediation that can be used broadly by the environmental community to custom-made 3D printed structures for environmental removal and sensing applications. This work can contribute to the development of bio-based methods for environmental remediation to achieve the global WHO goals for clean and sustainable water. 1. Introduction Globally, heavy metal pollution with metals such as copper, nickel, mercury, cadmium, lead, and chromium is a significant environmental and health hazard, recognized by the World Health Organization (WHO) as a critical problem with significant consequences worldwide. 1,2 Heavy metals cannot be biodegraded; they are toxic and carcinogenic, and the potential for human exposure is high. 3 Electroplating, mining, tanneries, painting, and semiconductors are a few of the industries that are significant sources of heavy metal pollution. Others include livestock manure, fertilizers, herbicides, atmospheric deposition, and irrigation with polluted wastewater. 4 As a result of heavy metal pollution, plants experience oxidative stress, cellular damage, and disruption of respiratory and photosynthetic activity, 5 the intake of crops contaminated by root transfer from soil to plant tissues can pose substantial health risks for humans. 4,6 Excess metal concentrations in soil alter food quality, leading to various disorders. 7 High levels of heavy metals such as copper, cadmium, nickel, and cobalt have been attributed to increased occurrences of cancer and industries that release an excess of these metal ions are known to pollute the environment. 8 Since heavy metals are not usually degraded by natural processes, they can persist in the environment for a long time. Soil, water, and air are directly impacted by heavy metal contamination. Water runoff from factories, agricultural farms, and water treatment facilities in cities, villages, and towns can transport heavy metals, which eventually accumulate in water bodies, and river beds and is extremely hazardous to the local ecosystem. 9 Particulate matters of heavy metals that are discharged from anthropogenic sources and natural sources cause corrosion, haze, eutrophication, and even acid rains that can further pollute water bodies and soil. 10 Improper waste disposal and landfills, mining, and drilling can pollute soil by resulting in high heavy metal levels, that are further absorbed by living organisms and affect water quality. 11 Copper ions (Cu 2+ ) for example are used heavily in agriculture as an antifungal agent and can enter the water from the electroplating and mining industries. 12 The discharge of these wastes in streams, lakes, and groundwater reservoirs is responsible for health problems in humans and plants. The average Cu 2+ concentration in soil ranges from 5 to 70 ppm but can reach 100 to 1500 ppm in the soil around vineyards where Cu 2+ treatments are used to reduce the growth of mildew. 13 In sediments found in bays and estuaries, the Cu 2+ concentration is less than 50 ppm, but polluted sediments may contain several thousand ppm. Around 4500 ppm of Cu 2+ was reported in the soil around a Cu/Ni smelter. 14 The presence of high concentrations of heavy metals in polluted environments requires efficient and economical ways to remove them to ensure pollutant-free water. Multiple techniques can be used to remove heavy metals from the water. 15,16 These include chemical precipitation, electrochemical reduction, membrane separation, and adsorption. 16 Though chemical precipitation is low-cost and straightforward, 15 the method generates significant waste, leading to secondary pollution. Electrochemical methods are rapid and provide good reduction yields, but the initial<|im_end|> <|im_start|>assistant One of the leading causes of water pollution is heavy metal contamination which has profound adverse effects on human health and the environment. That's why Clarkson University researchers have developed a cost-effective, 3D printing technology to create sustainable bio-based adsorbents that can effectively remove toxic heavy metal ions from contaminated environments. The 3D printing technique offers a cost-effective, scalable and simple approach to creating tunable adsorbents for environmental remediation that can be used broadly by the community for environmental remediation and sensing applications. The work performed in the laboratory of Professor Silvana Andreescu, the Egon Matijevic Chair in Chemistry, was recently featured on the front cover page of the journal, Environmental Science Advances. Nadia Cheng, a biomolecular science undergraduate, and two chemistry graduate students, Abraham S. Finny and Oluwatossin Popoola, were involved in the project. Nadia started her work on this project as a senior in high school and then as a Clarkson School student. "Our work demonstrates unique capabilities of green and sustainable materials to be additively manufactured and designed so that they have the ability to capture and remove toxic contaminants, providing innovative solutions for next-generation detection and remediation technologies. This work contributes to the development of materials and methods for environmental monitoring and clean up to achieve the global WHO goals for clean and sustainable water," said Professor Andreescu. Abraham S. Finny PHD, a Senior Scientist at Waters Corporation and a former member of Prof. Andreescu's lab, says, "Exposure to such innovative, application-focused, and cutting-edge scientific research at Clarkson makes Clarkson graduates excellent problem solvers who go on to become impactful leaders tackling global challenges; another reason why employers find Clarkson graduates highly attractive." <|im_end|>
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1,706
[ { "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 all of the diverse areas of science where waves play an important role, one of the most fundamental solutions of the corresponding wave equation is a stationary wave with constant intensity. The most familiar example is that of a plane wave propagating in free space. In the presence of any Hermitian potential, a wave’s constant intensity is, however, immediately destroyed due to scattering. Here we show that this fundamental restriction is conveniently lifted when working with non-Hermitian potentials. In particular, we present a whole class of waves that have constant intensity in the presence of linear as well as of nonlinear inhomogeneous media with gain and loss. These solutions allow us to study the fundamental phenomenon of modulation instability in an inhomogeneous environment. Our results pose a new challenge for the experiments on non-Hermitian scattering that have recently been put forward. Introduction Our intuition tells us that stationary waves, which have a constant intensity throughout an extended region of space, can only exist when no obstacles hamper the wave’s free propagation. Such an obstacle could be an electrostatic potential for an electronic matter wave, the non-uniform distribution of a dielectric medium for an electromagnetic wave or a wall that reflects an acoustic pressure wave. All of these cases lead to scattering, diffraction and wave interference, resulting in the highly complex variation of a wave’s spatial profile that continues to fascinate us in all its different manifestations. Suppressing or merely controlling these effects, which are at the heart of wave physics, is a challenging task, as the quest for a cloaking device 1 or the research in adaptive optics 2 , and in wavefront shaping through complex media 3 make us very much aware. Strategies in this direction are thus in high demand and would fall on a fertile ground in many of the different disciplines of science and technology in which wave propagation is a key element. A new avenue to explore various wave phenomena has recently been opened up when it was realized that waves give rise to very unconventional features when being subject to a suitably chosen spatial distribution of both gain and loss. Such non-Hermitian potential regions 4 , 5 , which serve as sources and sinks for waves, respectively, can give rise to novel wave effects that are impossible to realize with conventional, Hermitian potentials. Examples of this kind, which were meanwhile also realized in the experiment 6 , 7 , 8 , 9 , 10 , are the unidirectional invisibility of a gain–loss potential 11 , devices that can simultaneously act as laser and as a perfect absorber 12 , 13 , 14 and resonant structures with unusual features like non-reciprocal light transmission 10 or loss-induced lasing 15 , 16 , 17 . In particular, systems with a so-called parity-time ( ) symmetry 18 , where gain and loss are carefully balanced, have recently attracted enormous interest in the context of non-Hermitian photonics 19 , 20 , 21 , 22 , 23 , 24 . Inspired by these recent advances, we show here that for a general class of potentials with gain and loss, it is possible to construct constant-intensity wave solutions. Quite surprisingly, these are solutions to both the paraxial equation of diffraction and the nonlinear Schrödinger equation (NLSE). In the linear regime, such constant-intensity waves resemble Bessel beams of free space 25 . They carry infinite energy, but retain many of their exciting properties when being truncated by a finite-size input aperture. In the nonlinear regime, this class of waves turns out to be of fundamental importance, as they provide the first instance to investigate the best known symmetry breaking instability, that is, the so-called modulational instability (MI) 26 , 27 , 28 , 29 , 30 , 31 , in inhomogeneous potentials. Using these solutions for studying the phenomenon of MI, we find that in the self-focusing case, unstable periodic modes appear causing the wave to disintegrate and to generate a train of complex solitons. In the defocusing regime, the uniform intensity solution is modulationally unstable for some wavenumbers. Results One-dimensional constant-intensity waves Our starting point is the well-known NLSE. This scalar wave equation encompasses many aspects of optical wave propagation as well as the physics of matter waves. Specifically, we will consider the NLSE with a general, non-Hermitian potential V ( x ) and a Kerr nonlinearity, The scalar, complex valued function ψ ( x , z ) describes the electric field envelope along a scaled propagation distance z or the wave function of a matter wave as it evolves in time. The nonlinearity can either be self-focusing or defocusing, depending on the sign of g . For this general setting, we now investigate a whole family of recently introduced potentials V ( x ) (ref. 32 ), which are determined by the following relation, where W ( x ) is a given real function. In the special case where W ( x ) is even, the actual optical potential V ( x ) turns out to be -symmetric, since V ( x )= V *(− x ). We emphasize, however, that our analysis is also valid for confined, periodic or disordered potentials W ( x ), which do not necessarily lead to a -symmetric form of V ( x ) (but for which gain and loss are always balanced since in the case of localized or periodic potentials.). For the entire non-Hermitian family of potentials that are determined by equation 2 (see Methods), we can prove that the following analytical and stationary constant-intensity wave is a solution to the NLSE in equation 1, notably with a constant and real amplitude A . We emphasize here the remarkable fact that this family of solutions exists in the linear regime ( g =0) as well as for arbitrary strength of nonlinearity ( g =±1). Under linear conditions ( g =0), the constant-intensity wave given by equation 3 is one of the radiation eigenmodes (not confined) of the potential with propagation", "role": "user" }, { "content": "Materials that locally amplify or absorb light allow surprising new kinds of light waves – this has now been shown by calculations at TU Wien (Vienna). When a light wave penetrates a material, it is usually changed drastically. Scattering and diffraction leads to a superposition of waves, resulting in a complicated pattern of darker and brighter light spots inside the material. In specially tailored high-tech materials, which can locally amplify or absorb light, such effects can be completely suppressed. Calculations at TU Wien (Vienna University of Technology) have now shown that these materials allow new kinds of light waves, which have the same intensity everywhere inside the material, as if there was no wave interference at all. Due to their unusual properties, these new solutions of the wave equation could be useful for technological applications. Obstacles Change the Wave When a light wave travels through free space, its intensity can be the same everywhere. But as soon as it hits an obstacle, the wave is diffracted. At some points in space, the wave becomes brighter, in other places it becomes darker than it would have been without hitting the object. This is the reason we can see objects that do not emit light by themselves. In recent years, however, experiments have been carried out with new materials which have the ability to modify light in a special way: they can locally amplify light, similar to a laser, or absorb light, like sunglasses do. \"When such processes are possible, we have to employ a mathematical description of the light wave which is quite different from the one we use for normal, transparent materials,\" says Professor Stefan Rotter (TU Wien). \"In this case we speak of non-hermitian media.\" Specially designed non-hermitian materials remain completely unperturbed. New Solutions for the Wave Equation Konstantinos Makris and Stefan Rotter from TU Wien, together with Ziad Musslimani and Demetrios Christodoulides from Florida (USA), discovered that this alternative description allows new kinds of solutions for the wave equation. \"The result is a light wave with the same brightness at each point in space, just like a wave in free space, even though it travels through a complex, highly structured material\", says Konstantinos Makris. \"In some sense, the material is completely invisible to the wave, even though the light passes through the material and interacts with it.\" The new concept is reminiscent of so-called \"meta-materials\", which have been created in recent years. These materials have a special structure, which allows them to diffract light in unusual ways. In certain cases the structure can bend the light around the object, so that the object becomes invisible, much like Harry Potter's invisibility cloak. \"The principle of our non-hermitian materials, however, is quite different\", says Stefan Rotter. \"The light wave is not bent around the object, but fully penetrates it. The way the material influences the wave is, however, fully cancelled by a carefully tuned interplay of amplification and absorption.\" In the end, the light wave is exactly as bright as it would have been without the object – at each and every point in space. Several technical problems still have to be solved until such materials can be routinely fabricated, but scientists are already working on that. The theoretical work now published, however, shows that besides meta-materials there is another, extremely promising way to manipulate waves in unconventional ways. \"With our work we have opened a door, behind which we expect to find a multitude of exciting new insights\", says Konstantinos Makris. ", "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 all of the diverse areas of science where waves play an important role, one of the most fundamental solutions of the corresponding wave equation is a stationary wave with constant intensity. The most familiar example is that of a plane wave propagating in free space. In the presence of any Hermitian potential, a wave’s constant intensity is, however, immediately destroyed due to scattering. Here we show that this fundamental restriction is conveniently lifted when working with non-Hermitian potentials. In particular, we present a whole class of waves that have constant intensity in the presence of linear as well as of nonlinear inhomogeneous media with gain and loss. These solutions allow us to study the fundamental phenomenon of modulation instability in an inhomogeneous environment. Our results pose a new challenge for the experiments on non-Hermitian scattering that have recently been put forward. Introduction Our intuition tells us that stationary waves, which have a constant intensity throughout an extended region of space, can only exist when no obstacles hamper the wave’s free propagation. Such an obstacle could be an electrostatic potential for an electronic matter wave, the non-uniform distribution of a dielectric medium for an electromagnetic wave or a wall that reflects an acoustic pressure wave. All of these cases lead to scattering, diffraction and wave interference, resulting in the highly complex variation of a wave’s spatial profile that continues to fascinate us in all its different manifestations. Suppressing or merely controlling these effects, which are at the heart of wave physics, is a challenging task, as the quest for a cloaking device 1 or the research in adaptive optics 2 , and in wavefront shaping through complex media 3 make us very much aware. Strategies in this direction are thus in high demand and would fall on a fertile ground in many of the different disciplines of science and technology in which wave propagation is a key element. A new avenue to explore various wave phenomena has recently been opened up when it was realized that waves give rise to very unconventional features when being subject to a suitably chosen spatial distribution of both gain and loss. Such non-Hermitian potential regions 4 , 5 , which serve as sources and sinks for waves, respectively, can give rise to novel wave effects that are impossible to realize with conventional, Hermitian potentials. Examples of this kind, which were meanwhile also realized in the experiment 6 , 7 , 8 , 9 , 10 , are the unidirectional invisibility of a gain–loss potential 11 , devices that can simultaneously act as laser and as a perfect absorber 12 , 13 , 14 and resonant structures with unusual features like non-reciprocal light transmission 10 or loss-induced lasing 15 , 16 , 17 . In particular, systems with a so-called parity-time ( ) symmetry 18 , where gain and loss are carefully balanced, have recently attracted enormous interest in the context of non-Hermitian photonics 19 , 20 , 21 , 22 , 23 , 24 . Inspired by these recent advances, we show here that for a general class of potentials with gain and loss, it is possible to construct constant-intensity wave solutions. Quite surprisingly, these are solutions to both the paraxial equation of diffraction and the nonlinear Schrödinger equation (NLSE). In the linear regime, such constant-intensity waves resemble Bessel beams of free space 25 . They carry infinite energy, but retain many of their exciting properties when being truncated by a finite-size input aperture. In the nonlinear regime, this class of waves turns out to be of fundamental importance, as they provide the first instance to investigate the best known symmetry breaking instability, that is, the so-called modulational instability (MI) 26 , 27 , 28 , 29 , 30 , 31 , in inhomogeneous potentials. Using these solutions for studying the phenomenon of MI, we find that in the self-focusing case, unstable periodic modes appear causing the wave to disintegrate and to generate a train of complex solitons. In the defocusing regime, the uniform intensity solution is modulationally unstable for some wavenumbers. Results One-dimensional constant-intensity waves Our starting point is the well-known NLSE. This scalar wave equation encompasses many aspects of optical wave propagation as well as the physics of matter waves. Specifically, we will consider the NLSE with a general, non-Hermitian potential V ( x ) and a Kerr nonlinearity, The scalar, complex valued function ψ ( x , z ) describes the electric field envelope along a scaled propagation distance z or the wave function of a matter wave as it evolves in time. The nonlinearity can either be self-focusing or defocusing, depending on the sign of g . For this general setting, we now investigate a whole family of recently introduced potentials V ( x ) (ref. 32 ), which are determined by the following relation, where W ( x ) is a given real function. In the special case where W ( x ) is even, the actual optical potential V ( x ) turns out to be -symmetric, since V ( x )= V *(− x ). We emphasize, however, that our analysis is also valid for confined, periodic or disordered potentials W ( x ), which do not necessarily lead to a -symmetric form of V ( x ) (but for which gain and loss are always balanced since in the case of localized or periodic potentials.). For the entire non-Hermitian family of potentials that are determined by equation 2 (see Methods), we can prove that the following analytical and stationary constant-intensity wave is a solution to the NLSE in equation 1, notably with a constant and real amplitude A . We emphasize here the remarkable fact that this family of solutions exists in the linear regime ( g =0) as well as for arbitrary strength of nonlinearity ( g =±1). Under linear conditions ( g =0), the constant-intensity wave given by equation 3 is one of the radiation eigenmodes (not confined) of the potential with propagation<|im_end|> <|im_start|>assistant Materials that locally amplify or absorb light allow surprising new kinds of light waves – this has now been shown by calculations at TU Wien (Vienna). When a light wave penetrates a material, it is usually changed drastically. Scattering and diffraction leads to a superposition of waves, resulting in a complicated pattern of darker and brighter light spots inside the material. In specially tailored high-tech materials, which can locally amplify or absorb light, such effects can be completely suppressed. Calculations at TU Wien (Vienna University of Technology) have now shown that these materials allow new kinds of light waves, which have the same intensity everywhere inside the material, as if there was no wave interference at all. Due to their unusual properties, these new solutions of the wave equation could be useful for technological applications. Obstacles Change the Wave When a light wave travels through free space, its intensity can be the same everywhere. But as soon as it hits an obstacle, the wave is diffracted. At some points in space, the wave becomes brighter, in other places it becomes darker than it would have been without hitting the object. This is the reason we can see objects that do not emit light by themselves. In recent years, however, experiments have been carried out with new materials which have the ability to modify light in a special way: they can locally amplify light, similar to a laser, or absorb light, like sunglasses do. "When such processes are possible, we have to employ a mathematical description of the light wave which is quite different from the one we use for normal, transparent materials," says Professor Stefan Rotter (TU Wien). "In this case we speak of non-hermitian media." Specially designed non-hermitian materials remain completely unperturbed. New Solutions for the Wave Equation Konstantinos Makris and Stefan Rotter from TU Wien, together with Ziad Musslimani and Demetrios Christodoulides from Florida (USA), discovered that this alternative description allows new kinds of solutions for the wave equation. "The result is a light wave with the same brightness at each point in space, just like a wave in free space, even though it travels through a complex, highly structured material", says Konstantinos Makris. "In some sense, the material is completely invisible to the wave, even though the light passes through the material and interacts with it." The new concept is reminiscent of so-called "meta-materials", which have been created in recent years. These materials have a special structure, which allows them to diffract light in unusual ways. In certain cases the structure can bend the light around the object, so that the object becomes invisible, much like Harry Potter's invisibility cloak. "The principle of our non-hermitian materials, however, is quite different", says Stefan Rotter. "The light wave is not bent around the object, but fully penetrates it. The way the material influences the wave is, however, fully cancelled by a carefully tuned interplay of amplification and absorption." In the end, the light wave is exactly as bright as it would have been without the object – at each and every point in space. Several technical problems still have to be solved until such materials can be routinely fabricated, but scientists are already working on that. The theoretical work now published, however, shows that besides meta-materials there is another, extremely promising way to manipulate waves in unconventional ways. "With our work we have opened a door, behind which we expect to find a multitude of exciting new insights", says Konstantinos Makris. <|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 Extrachromosomal DNAs (ecDNAs) are common in cancer, but many questions about their origin, structural dynamics and impact on intratumor heterogeneity are still unresolved. Here we describe single-cell extrachromosomal circular DNA and transcriptome sequencing (scEC&T-seq), a method for parallel sequencing of circular DNAs and full-length mRNA from single cells. By applying scEC&T-seq to cancer cells, we describe intercellular differences in ecDNA content while investigating their structural heterogeneity and transcriptional impact. Oncogene-containing ecDNAs were clonally present in cancer cells and drove intercellular oncogene expression differences. In contrast, other small circular DNAs were exclusive to individual cells, indicating differences in their selection and propagation. Intercellular differences in ecDNA structure pointed to circular recombination as a mechanism of ecDNA evolution. These results demonstrate scEC&T-seq as an approach to systematically characterize both small and large circular DNA in cancer cells, which will facilitate the analysis of these DNA elements in cancer and beyond. Main Measuring multiple parameters in the same cells is key to accurately understand biological systems and their changes during diseases 1 . In the case of circular DNAs, it is critical to integrate DNA sequence information with transcriptional output measurements to assess their functional impact on cells. At least three types of circular DNAs can be distinguished in human cells 2 , 3 , 4 , 5 : (1) small circular DNAs (<100 kb) 6 , which have been described under different names including eccDNAs 6 , microDNAs 4 , apoptotic circular DNAs 6 , small polydispersed circular DNAs 7 and telomeric circular DNAs or C-circles 8 ; (2) T cell receptor excision circles (TRECs) 9 ; and (3) large (>100 kb), oncogenic, copy number-amplified circular extrachromosomal DNAs 10 , 11 (referred to as ecDNA and visible as double minute chromosomes during metaphase 12 ). Despite our increasing ability to characterize multiple features in single cells 13 , an in-depth characterization of circular DNA content, structure and sequence in single cells remains elusive with current approaches. In cancer, oncogene amplifications on ecDNA are of particular interest because they potently drive intercellular copy number heterogeneity through their unique ability to be replicated and unequally segregated during mitosis 14 , 15 , 16 , 17 , 18 , 19 . This heterogeneity enables tumors to adapt and evade therapies 2 , 20 , 21 , 22 . Indeed, patients with ecDNA-harboring cancers have adverse clinical outcomes 11 . Recent investigations indicate that enhancer-containing ecDNAs interact with each other in nuclear hubs 17 , 23 and can influence distant chromosomal locations in trans 23 , 24 . This suggests that even ecDNAs not harboring oncogenes may be functional 23 , 24 . Furthermore, we recently revealed that tumors harbor an unanticipated repertoire of smaller, copy number-neutral circular DNAs of yet unknown functional relevance 3 . In this study, we report single-cell extrachromosomal circular DNA and transcriptome sequencing (scEC&T-seq), a method that enables parallel sequencing of all circular DNA types, independent of their size, content and copy number, and full-length mRNA in single cells. We demonstrate its utility for profiling single cancer cells containing both structurally complex multifragmented ecDNAs and small circular DNAs. Results scEC&T-seq detects circular DNA and mRNA in single cells Current state-of-the-art circular DNA purification approaches involve three sequential steps, that is, isolation of DNA followed by removal of linear DNA through exonuclease digestion and enrichment of circular DNA by rolling circle amplification 3 , 6 , 25 . We reasoned that this approach may be scaled down to single cells and when combined with Smart-seq2 (ref. 26 ) may allow the parallel sequencing of circular DNA and mRNA. To benchmark our method in single cells, we used neuroblastoma cancer cell lines, which we had previously characterized in bulk populations 3 . We used FACS to separate cells into 96-well plates (Fig. 1a , Supplementary Fig. 1a,b and Supplementary Table 1 ). DNA was separated from polyadenylated RNA, which was captured on magnetic beads coupled to single-stranded sequences of deoxythymidine (Oligo dT) primers, similarly to previous approaches 27 . DNA was subjected to exonuclease digestion, as successfully performed in bulk cell populations in the past, to enrich for circular DNA 3 , 6 , 25 (Fig. 1b ). DNA subjected to PmeI endonuclease before exonuclease digestion served as a negative control 3 . In a subset of cases, DNA was left undigested as an additional control (Fig. 1b ). The DNA remaining after the different digestion regimens was amplified. The amplified DNA was subjected to Illumina paired-end sequencing and in some cases to long-read Nanopore sequencing (Fig. 1a ). The sequence composition of circular DNAs was analyzed and genomic origin was inferred in circularized regions using previously established computational algorithms for circular DNA analysis 3 . Fig. 1: scEC&T-seq enables enrichment and detection of circular DNA in single cells. a , Schematic of the scEC&T-seq method. b , Schematic representation of the experimental conditions and expected outcomes. c , Genome tracks comparing read densities on mtDNA (chrM) in three exemplary CHP-212 cells for each experimental condition tested. Top to bottom, No digestion (purple), 1-day exonuclease digestion (light green), 5-day exonuclease digestion (dark green) and endonuclease digestion with PmeI before 5-day exonuclease digestion (gray). d , Fraction of sequencing reads mapping to mtDNA in each experimental condition in CHP-212 (red) and TR14 (blue) cells. e , Fraction of sequencing reads mapping to circular DNA regions identified by scEC&T-seq in each experimental condition in CHP-212 and TR14 cells. f , Fraction of sequencing reads mapping to circular DNA regions with the endonuclease PmeI targeting the sequence identified by scEC&T-seq in each experimental condition in CHP-212 and TR14 cells. d – f , Sample size is identical across conditions: no digestion ( n = 16 TR14 cells, n = 28 CHP-212 cells); 1-day exonuclease digestion ( n = 37 TR14 cells, n = 31 CHP-212 cells); 5-day exonuclease digestion ( n = 25 TR14 cells, n = 150 CHP-212 cells); and endonuclease digestion with PmeI before 5-day exonuclease digestion ( n = 6 TR14 cells,", "role": "user" }, { "content": "Tumors sometimes seem to take on a life of their own, growing at an unusually fast rate or suddenly developing resistance to a cancer drug. This behavior is often explained by cancer genes separating from the cell's own chromosomes and \"striking out on their own\" in ring shapes. So far, little has been known about how exactly these DNA rings arise and how they continue to develop as the tumor grows. An international team of researchers led by Charité–Universitätsmedizin Berlin and the Max Delbrück Center has now harnessed a new method to trace this path in neuroblastoma, a type of cancer. The results have been published in the journal Nature Genetics. Considered one of the biggest challenges in cancer research, DNA rings are tiny loops of genetic material floating around the nucleus of the cell by the hundreds, detached from the chromosomes. They were first discovered in 1965 and still pose many questions for researchers. Where do all these rings come from? What is their function? How do they affect the cells and the organism as a whole? One thing is clear: Nearly one-third of all tumors in pediatric and adult patients have DNA rings inside their cells—and those tumors are almost always highly aggressive. Ring-shaped DNA, termed extrachromosomal DNA (ecDNA), is also often implicated when a tumor develops resistance to a previously effective medication. Researchers around the world hope to identify new approaches to treating cancer by studying this specific form of genetic information. However, ecDNA does not always have a detrimental effect on cancer growth. Some of the rings also seem to be harmless. \"To tell the difference between dangerous and harmless DNA rings and be able to trace their evolution within the tumor, we have to look at the tissue one cell at a time,\" explains the head of the study, Prof. Dr. Anton Henssen. He works at the Department of Pediatric Oncology and Hematology at Charité and does research at the Experimental and Clinical Research Center (ECRC), a joint institution of Charité and the Max Delbrück Center. Together with his team, he has now developed a technology that can read the genetic code of the existing DNA rings for each individual cell. At the same time, it tells which genes are active on the rings. \"This lets us simply count how many cells in the tumor are home to a specific ring,\" Henssen says. \"If there aren't many, then that ring is not highly relevant to the growth of the cancer. But if there are a lot of them, it evidently gives a tumor cell a selective advantage.\" Which DNA rings spur tumor growth? The researchers initially used the new method to take a snapshot of all DNA rings in cultured neuroblastoma cells. Neuroblastoma is a form of highly malignant cancer that is especially prevalent in very young children. The research showed that no two cancer cells are alike—where one might have 100 DNA rings floating around, the next might have 2,000. The rings also vary greatly in size, with the smallest of them consisting of only 30 genetic components and the largest comprising more than a million. \"The big DNA rings are loaded with cancer genes originating in the chromosomes of the cell,\" explains Rocío Chamorro González, the study's first author, who also does research at the Department of Pediatric Oncology and Hematology at Charité and the ECRC. \"The ring shape lets them circumvent the classic laws of genetics, so they take on a kind of autonomy. These cancer genes have struck out on their own, if you will. We are only just starting to understand the ramifications. In our study, we found the large DNA rings in many neuroblastoma cells, so they are evidently spurring cell growth. The small rings were only found in isolation, so they are probably not very relevant to the cancer cells.\" Evolution of an independent cancer gene To understand how an ecDNA originates in the first place and then evolves within a tumor, the second step for the research group was to analyze a pediatric neuroblastoma—cell by cell. Their findings suggest that MYCN, a known cancer gene, first detached from its chromosome of origin and formed a ring shape at the start of the tumor's growth in this case. Then two of the rings merged to form a larger one, which went on to lose a shorter segment and then a longer one. \"The last ring seems to have been the first to confer a growth advantage, because it is the only one that appears in many of the neuroblastoma cells,\" Henssen says. \"This shows that the cancer gene not only became independent through these processes, but also continued to 'improve.'\" This kind of insight into the evolution of DNA rings within a tumor would have been impossible if not for the newly developed method. The team of researchers now plans to use the same method to reconstruct the stages of development in further cases of cancer. The researchers hope this will allow them to distinguish better between dangerous and harmless DNA rings. \"Our hope is that in the future, we will be able to see in an individual case whether or not that tumor is especially aggressive, just from looking at the DNA rings,\" Henssen says. \"And then we could adjust the treatment. That's why testing the predictive power of specific DNA rings is the next target for our research.\" ", "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 Extrachromosomal DNAs (ecDNAs) are common in cancer, but many questions about their origin, structural dynamics and impact on intratumor heterogeneity are still unresolved. Here we describe single-cell extrachromosomal circular DNA and transcriptome sequencing (scEC&T-seq), a method for parallel sequencing of circular DNAs and full-length mRNA from single cells. By applying scEC&T-seq to cancer cells, we describe intercellular differences in ecDNA content while investigating their structural heterogeneity and transcriptional impact. Oncogene-containing ecDNAs were clonally present in cancer cells and drove intercellular oncogene expression differences. In contrast, other small circular DNAs were exclusive to individual cells, indicating differences in their selection and propagation. Intercellular differences in ecDNA structure pointed to circular recombination as a mechanism of ecDNA evolution. These results demonstrate scEC&T-seq as an approach to systematically characterize both small and large circular DNA in cancer cells, which will facilitate the analysis of these DNA elements in cancer and beyond. Main Measuring multiple parameters in the same cells is key to accurately understand biological systems and their changes during diseases 1 . In the case of circular DNAs, it is critical to integrate DNA sequence information with transcriptional output measurements to assess their functional impact on cells. At least three types of circular DNAs can be distinguished in human cells 2 , 3 , 4 , 5 : (1) small circular DNAs (<100 kb) 6 , which have been described under different names including eccDNAs 6 , microDNAs 4 , apoptotic circular DNAs 6 , small polydispersed circular DNAs 7 and telomeric circular DNAs or C-circles 8 ; (2) T cell receptor excision circles (TRECs) 9 ; and (3) large (>100 kb), oncogenic, copy number-amplified circular extrachromosomal DNAs 10 , 11 (referred to as ecDNA and visible as double minute chromosomes during metaphase 12 ). Despite our increasing ability to characterize multiple features in single cells 13 , an in-depth characterization of circular DNA content, structure and sequence in single cells remains elusive with current approaches. In cancer, oncogene amplifications on ecDNA are of particular interest because they potently drive intercellular copy number heterogeneity through their unique ability to be replicated and unequally segregated during mitosis 14 , 15 , 16 , 17 , 18 , 19 . This heterogeneity enables tumors to adapt and evade therapies 2 , 20 , 21 , 22 . Indeed, patients with ecDNA-harboring cancers have adverse clinical outcomes 11 . Recent investigations indicate that enhancer-containing ecDNAs interact with each other in nuclear hubs 17 , 23 and can influence distant chromosomal locations in trans 23 , 24 . This suggests that even ecDNAs not harboring oncogenes may be functional 23 , 24 . Furthermore, we recently revealed that tumors harbor an unanticipated repertoire of smaller, copy number-neutral circular DNAs of yet unknown functional relevance 3 . In this study, we report single-cell extrachromosomal circular DNA and transcriptome sequencing (scEC&T-seq), a method that enables parallel sequencing of all circular DNA types, independent of their size, content and copy number, and full-length mRNA in single cells. We demonstrate its utility for profiling single cancer cells containing both structurally complex multifragmented ecDNAs and small circular DNAs. Results scEC&T-seq detects circular DNA and mRNA in single cells Current state-of-the-art circular DNA purification approaches involve three sequential steps, that is, isolation of DNA followed by removal of linear DNA through exonuclease digestion and enrichment of circular DNA by rolling circle amplification 3 , 6 , 25 . We reasoned that this approach may be scaled down to single cells and when combined with Smart-seq2 (ref. 26 ) may allow the parallel sequencing of circular DNA and mRNA. To benchmark our method in single cells, we used neuroblastoma cancer cell lines, which we had previously characterized in bulk populations 3 . We used FACS to separate cells into 96-well plates (Fig. 1a , Supplementary Fig. 1a,b and Supplementary Table 1 ). DNA was separated from polyadenylated RNA, which was captured on magnetic beads coupled to single-stranded sequences of deoxythymidine (Oligo dT) primers, similarly to previous approaches 27 . DNA was subjected to exonuclease digestion, as successfully performed in bulk cell populations in the past, to enrich for circular DNA 3 , 6 , 25 (Fig. 1b ). DNA subjected to PmeI endonuclease before exonuclease digestion served as a negative control 3 . In a subset of cases, DNA was left undigested as an additional control (Fig. 1b ). The DNA remaining after the different digestion regimens was amplified. The amplified DNA was subjected to Illumina paired-end sequencing and in some cases to long-read Nanopore sequencing (Fig. 1a ). The sequence composition of circular DNAs was analyzed and genomic origin was inferred in circularized regions using previously established computational algorithms for circular DNA analysis 3 . Fig. 1: scEC&T-seq enables enrichment and detection of circular DNA in single cells. a , Schematic of the scEC&T-seq method. b , Schematic representation of the experimental conditions and expected outcomes. c , Genome tracks comparing read densities on mtDNA (chrM) in three exemplary CHP-212 cells for each experimental condition tested. Top to bottom, No digestion (purple), 1-day exonuclease digestion (light green), 5-day exonuclease digestion (dark green) and endonuclease digestion with PmeI before 5-day exonuclease digestion (gray). d , Fraction of sequencing reads mapping to mtDNA in each experimental condition in CHP-212 (red) and TR14 (blue) cells. e , Fraction of sequencing reads mapping to circular DNA regions identified by scEC&T-seq in each experimental condition in CHP-212 and TR14 cells. f , Fraction of sequencing reads mapping to circular DNA regions with the endonuclease PmeI targeting the sequence identified by scEC&T-seq in each experimental condition in CHP-212 and TR14 cells. d – f , Sample size is identical across conditions: no digestion ( n = 16 TR14 cells, n = 28 CHP-212 cells); 1-day exonuclease digestion ( n = 37 TR14 cells, n = 31 CHP-212 cells); 5-day exonuclease digestion ( n = 25 TR14 cells, n = 150 CHP-212 cells); and endonuclease digestion with PmeI before 5-day exonuclease digestion ( n = 6 TR14 cells,<|im_end|> <|im_start|>assistant Tumors sometimes seem to take on a life of their own, growing at an unusually fast rate or suddenly developing resistance to a cancer drug. This behavior is often explained by cancer genes separating from the cell's own chromosomes and "striking out on their own" in ring shapes. So far, little has been known about how exactly these DNA rings arise and how they continue to develop as the tumor grows. An international team of researchers led by Charité–Universitätsmedizin Berlin and the Max Delbrück Center has now harnessed a new method to trace this path in neuroblastoma, a type of cancer. The results have been published in the journal Nature Genetics. Considered one of the biggest challenges in cancer research, DNA rings are tiny loops of genetic material floating around the nucleus of the cell by the hundreds, detached from the chromosomes. They were first discovered in 1965 and still pose many questions for researchers. Where do all these rings come from? What is their function? How do they affect the cells and the organism as a whole? One thing is clear: Nearly one-third of all tumors in pediatric and adult patients have DNA rings inside their cells—and those tumors are almost always highly aggressive. Ring-shaped DNA, termed extrachromosomal DNA (ecDNA), is also often implicated when a tumor develops resistance to a previously effective medication. Researchers around the world hope to identify new approaches to treating cancer by studying this specific form of genetic information. However, ecDNA does not always have a detrimental effect on cancer growth. Some of the rings also seem to be harmless. "To tell the difference between dangerous and harmless DNA rings and be able to trace their evolution within the tumor, we have to look at the tissue one cell at a time," explains the head of the study, Prof. Dr. Anton Henssen. He works at the Department of Pediatric Oncology and Hematology at Charité and does research at the Experimental and Clinical Research Center (ECRC), a joint institution of Charité and the Max Delbrück Center. Together with his team, he has now developed a technology that can read the genetic code of the existing DNA rings for each individual cell. At the same time, it tells which genes are active on the rings. "This lets us simply count how many cells in the tumor are home to a specific ring," Henssen says. "If there aren't many, then that ring is not highly relevant to the growth of the cancer. But if there are a lot of them, it evidently gives a tumor cell a selective advantage." Which DNA rings spur tumor growth? The researchers initially used the new method to take a snapshot of all DNA rings in cultured neuroblastoma cells. Neuroblastoma is a form of highly malignant cancer that is especially prevalent in very young children. The research showed that no two cancer cells are alike—where one might have 100 DNA rings floating around, the next might have 2,000. The rings also vary greatly in size, with the smallest of them consisting of only 30 genetic components and the largest comprising more than a million. "The big DNA rings are loaded with cancer genes originating in the chromosomes of the cell," explains Rocío Chamorro González, the study's first author, who also does research at the Department of Pediatric Oncology and Hematology at Charité and the ECRC. "The ring shape lets them circumvent the classic laws of genetics, so they take on a kind of autonomy. These cancer genes have struck out on their own, if you will. We are only just starting to understand the ramifications. In our study, we found the large DNA rings in many neuroblastoma cells, so they are evidently spurring cell growth. The small rings were only found in isolation, so they are probably not very relevant to the cancer cells." Evolution of an independent cancer gene To understand how an ecDNA originates in the first place and then evolves within a tumor, the second step for the research group was to analyze a pediatric neuroblastoma—cell by cell. Their findings suggest that MYCN, a known cancer gene, first detached from its chromosome of origin and formed a ring shape at the start of the tumor's growth in this case. Then two of the rings merged to form a larger one, which went on to lose a shorter segment and then a longer one. "The last ring seems to have been the first to confer a growth advantage, because it is the only one that appears in many of the neuroblastoma cells," Henssen says. "This shows that the cancer gene not only became independent through these processes, but also continued to 'improve.'" This kind of insight into the evolution of DNA rings within a tumor would have been impossible if not for the newly developed method. The team of researchers now plans to use the same method to reconstruct the stages of development in further cases of cancer. The researchers hope this will allow them to distinguish better between dangerous and harmless DNA rings. "Our hope is that in the future, we will be able to see in an individual case whether or not that tumor is especially aggressive, just from looking at the DNA rings," Henssen says. "And then we could adjust the treatment. That's why testing the predictive power of specific DNA rings is the next target for our research." <|im_end|>
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2,545
[ { "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 Rare earth elements (REEs) are widely used in electronic devices and renewable energy technology, but their supply is geopolitically-limited and they are extracted by environmentally unsustainable mining practices. Coal fly ash (CFA), which is mostly discarded as waste, has recently gained attention as a potential low-grade REE source, motivating the development of greener and highly specific processes for recovering and enriching REEs. Here we present a proof-of-concept for a novel REE extraction process in which supercritical fluid enhances the ability of tributyl phosphate (TBP) to selectively extract REEs directly from solid CFA matrices. For the first time, we show that supercritical nitrogen and supercritical air can work like supercritical carbon dioxide for selective extraction. Moreover, using a prototype multistage stripping process with an aqueous solution, we collected REEs with concentrations up to 21.4 mg L −1 from the extractant. Our final products contain up to 6.47% REEs, whereas the coal fly ash source initially contained only 0.0234% REEs. Using supercritical fluid, our novel process can recover valuable and critical resources from materials previously considered to be waste. Sustainability spotlight Large amounts of coal fly ash (CFA) deposited in landfills and wet impoundments are considered a threat to the local environment due to possible toxic element leaching. Recently, CFA has been found to be a potential source of rare earth elements (REEs), but current extraction technologies are challenged by low selectivity, organic waste production, and high energy consumption. Here, we report the use of supercritical fluids (carbon dioxide, nitrogen, and air) as greener solvents assisting a phosphonate extractant in directly and selectively extracting REEs, without energy- and material-intensive leaching. Our work shows promise to recover valuable resources from waste materials. Therefore, our work can help to realize the “Responsible Consumption and Production” of the Sustainable Development Goals (SDGs). Introduction Rare earth elements (REEs) are a group of 17 chemical elements in the periodic table, specifically the 15 lanthanides plus scandium and yttrium. The wide application of REEs in computer memory, rechargeable batteries, cell phones, and fluorescent lighting manifests their indispensable roles in our daily life. 1 Moreover, they are also critical to a variety of high tech applications, such as clean energy generation and catalysis, and their production is closely linked to the speed of technology development and implementation. 2–4 However, due to their geopolitically-constrained supply, environmentally-unsustainable mining practices, and rapidly growing demand, 3 both the United States (US) and the European Union have classified REEs as “critical materials”. 5,6 To address such a limited supply, alternative domestic sources will be most welcome. 7–10 Recently, coal fly ash (CFA) has emerged as a promising REE resource. 11,12 The average total REE concentration in CFAs has been characterized as 200–1220 ppm, and the potential annual value of the REEs that can be extracted from CFAs in the US is estimated to be $4.3 billion. 12 According to American Coal Ash Association's 2019 production and use survey, approximately 79 million metric tonnes (t) of CFAs are generated annually in the US, with only 52% beneficially used and the rest discarded. 13 The remaining CFAs, deposited in landfills or wet impoundments, are considered as a threat to local environment due to possible leaching of toxic elements. 14,15 Notably, obtaining REEs from CFAs is less environmentally destructive and capital intensive than extraction from traditional mineral ores, because it does not generate large quantities of waste rock that is typically radioactive. 11,16,17 In this regard, recovering REEs from CFAs turns waste into valuable resources with impactful environmental and societal benefits. To successfully obtain high purities of individual REEs from mineral ores, current industrial REE extraction operations include many processes, such as alkaline roasting, acid leaching, fractional separation, ion exchange, and solvent extraction. 18–20 In the initial attempt to recover REEs from CFAs, these methods were adopted first. Although previous studies have applied different methods to extract REEs from CFAs, 21–23 these processes still present many challenges. First, they all require a high temperature alkaline roasting process (>400 °C), followed by an acid leaching process (using strong acid) to obtain REE-containing leachate. Their high energy and chemical demands have proven burdensome in the commercial extraction of REEs from mineral ores, and these burdens will be more severe for low grade REEs resources like CFAs. 24 Notably, a strong acid is indispensable in all the REEs extraction processes. Second, an extractant that selectively complexes with REE 3+ is also necessary for the extraction. For example, in the solvent extraction, di-2-ethylhexylphosphoric acid (DEHPA) was dispersed in kerosene, and together they can selectively extract REEs from the aqueous solutions. 21 In addition, DEHPA-dispersed mineral oil inside a membrane was used for selectively transferring REEs from a CFA leachate to a highly acidic solution. 22 However, these processes all use toxic organic solvent to disperse the extractant, and thus it is highly desirable to find environmentally-friendly solvents to replace the organic solvent. Third, and most importantly, CFAs have extremely low concentrations of REEs (<0.2%) and more than 90% major impurities (Ca, Fe, Al, Mg), so the REEs purity in the final products is only 0.5–0.7%. 22 Overcoming these drawbacks requires a novel REEs extraction process that is environmentally-benign and highly selective for REEs over impurities. Supercritical fluid (SCF) extraction has emerged as a promising option because SCFs have little environmental impact, are non-flammable, and facilitate the mass transfer of extractants. 25 Applying SCF can reduce the usage of organic solvent, and we also expect that it can improve the selective recovery of REEs from CFAs. To selectively extract REEs from a solid matrix, studies have explored using extractants to complex with REE 3+ ions under supercritical carbon dioxide (scCO 2 ). 26,27 Tributyl phosphate–nitric acid (TBP–HNO 3 ) has shown selective extraction of REEs. This extractant was prepared by contacting pure TBP with concentrated HNO 3 . A current hypothesis for the extraction mechanism in a scCO 2 system is that TBP selectively chelates with the neutral salt formed by REE 3+ and NO 3 − . 27,28 Although scCO", "role": "user" }, { "content": "Rare earth elements (REE), a group of 17 metallic elements, are in nearly every piece of technology, including cell phones, televisions, computers and almost every part of a vehicle. The demand for these elements increases annually, however the supply is limited geopolitically and is mined with environmentally unsustainable practices. Young-Shin Jun, professor of energy, environmental & chemical engineering in the McKelvey School of Engineering at Washington University in St. Louis, and her team have created a proof-of-concept solution: extracting REEs from coal fly ash, a fine, powdery waste product from the combustion of coal. \"We wanted to use a greener process to extract REEs than traditionally more harmful processes,\" Jun said. \"Since the coal has already been used, this process is ultimately a pathway toward reduction and remediation of waste products.\" Jun and her former doctoral student, Yaguang Zhu, now a postdoctoral scholar at Princeton University, developed this novel extraction process using supercritical fluid, commonly used to decaffeinate coffee, to recover these critically needed REEs from material that would have otherwise been discarded in a landfill. Supercritical fluid is a substance at a temperature and pressure above its critical point with properties between a liquid and a gas. With more than 79 million metric tons of coal fly ash generated in the U.S. annually, Jun's team reported that the potential value of the REEs that could be extracted from coal fly ash in the U.S. is estimated at more than $4 billion annually. Their work, which appears in RSC Sustainability, is the first to show that common and accessible supercritical fluids, including carbon dioxide, nitrogen and air, were able to extract REEs and separate impurities very efficiently. In addition, through experiments using coal fly ash, they found that supercritical carbon dioxide decreased the concentrations of impurities in the final REE product. Ultimately, their final products contained up to 6.47% REEs, compared with 0.0234% in the initial coal fly ash source. \"The uniqueness of our work is not only using the supercritical CO2, but also showing that supercritical air and nitrogen, with much lower temperature and pressure than those required for CO2, can extract REE effectively,\" said Jun, who leads the Environmental NanoChemistry Laboratory. \"We can use lower temperatures and pressures with nitrogen or air to extract the rare earth elements from coal fly ash, which means lower energy cost. Of course, the supercritical CO2 works best, but supercritical air or nitrogen could do a much better job compared with traditional high temperature boiling with acids and organic solvents for REE extraction.\" Jun's team's extraction process involved two steps: First, metal ions in the coal fly ash, including REEs and impurities, leach from the coal fly ash and react with nitric acid to form metal nitrates; and second, the metal nitrates react with tributyl phosphate (TBP). They found that with supercritical carbon dioxide, nitrogen or air, the REEs formed complexes that could be extracted from the coal fly ash. After extraction, their multistage stripping process collected REEs and decreased the concentration of impurities. The nitric acid and TBP used in the process can be fully recycled multiple times without sacrificing efficiency, which minimizes their disposal concerns. Jun's method also eliminates the need to roast raw materials at extremely high temperatures, or greater than 500 C, and the need to extract the REEs with strong acids and a large quantity of toxic organic solvents, which also become a waste product in traditional extraction processes. \"Supercritical fluid is considered as a greener solvent, is less invasive to the environment and allows us to extract REE directly from solid waste without leaching and roasting raw materials, so less energy is required for our new process, which also produces less waste,\" Jun said. \"We are seeking a more environmentally benign process for critical element recycling and recovery from materials previously considered to be waste.\" ", "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 Rare earth elements (REEs) are widely used in electronic devices and renewable energy technology, but their supply is geopolitically-limited and they are extracted by environmentally unsustainable mining practices. Coal fly ash (CFA), which is mostly discarded as waste, has recently gained attention as a potential low-grade REE source, motivating the development of greener and highly specific processes for recovering and enriching REEs. Here we present a proof-of-concept for a novel REE extraction process in which supercritical fluid enhances the ability of tributyl phosphate (TBP) to selectively extract REEs directly from solid CFA matrices. For the first time, we show that supercritical nitrogen and supercritical air can work like supercritical carbon dioxide for selective extraction. Moreover, using a prototype multistage stripping process with an aqueous solution, we collected REEs with concentrations up to 21.4 mg L −1 from the extractant. Our final products contain up to 6.47% REEs, whereas the coal fly ash source initially contained only 0.0234% REEs. Using supercritical fluid, our novel process can recover valuable and critical resources from materials previously considered to be waste. Sustainability spotlight Large amounts of coal fly ash (CFA) deposited in landfills and wet impoundments are considered a threat to the local environment due to possible toxic element leaching. Recently, CFA has been found to be a potential source of rare earth elements (REEs), but current extraction technologies are challenged by low selectivity, organic waste production, and high energy consumption. Here, we report the use of supercritical fluids (carbon dioxide, nitrogen, and air) as greener solvents assisting a phosphonate extractant in directly and selectively extracting REEs, without energy- and material-intensive leaching. Our work shows promise to recover valuable resources from waste materials. Therefore, our work can help to realize the “Responsible Consumption and Production” of the Sustainable Development Goals (SDGs). Introduction Rare earth elements (REEs) are a group of 17 chemical elements in the periodic table, specifically the 15 lanthanides plus scandium and yttrium. The wide application of REEs in computer memory, rechargeable batteries, cell phones, and fluorescent lighting manifests their indispensable roles in our daily life. 1 Moreover, they are also critical to a variety of high tech applications, such as clean energy generation and catalysis, and their production is closely linked to the speed of technology development and implementation. 2–4 However, due to their geopolitically-constrained supply, environmentally-unsustainable mining practices, and rapidly growing demand, 3 both the United States (US) and the European Union have classified REEs as “critical materials”. 5,6 To address such a limited supply, alternative domestic sources will be most welcome. 7–10 Recently, coal fly ash (CFA) has emerged as a promising REE resource. 11,12 The average total REE concentration in CFAs has been characterized as 200–1220 ppm, and the potential annual value of the REEs that can be extracted from CFAs in the US is estimated to be $4.3 billion. 12 According to American Coal Ash Association's 2019 production and use survey, approximately 79 million metric tonnes (t) of CFAs are generated annually in the US, with only 52% beneficially used and the rest discarded. 13 The remaining CFAs, deposited in landfills or wet impoundments, are considered as a threat to local environment due to possible leaching of toxic elements. 14,15 Notably, obtaining REEs from CFAs is less environmentally destructive and capital intensive than extraction from traditional mineral ores, because it does not generate large quantities of waste rock that is typically radioactive. 11,16,17 In this regard, recovering REEs from CFAs turns waste into valuable resources with impactful environmental and societal benefits. To successfully obtain high purities of individual REEs from mineral ores, current industrial REE extraction operations include many processes, such as alkaline roasting, acid leaching, fractional separation, ion exchange, and solvent extraction. 18–20 In the initial attempt to recover REEs from CFAs, these methods were adopted first. Although previous studies have applied different methods to extract REEs from CFAs, 21–23 these processes still present many challenges. First, they all require a high temperature alkaline roasting process (>400 °C), followed by an acid leaching process (using strong acid) to obtain REE-containing leachate. Their high energy and chemical demands have proven burdensome in the commercial extraction of REEs from mineral ores, and these burdens will be more severe for low grade REEs resources like CFAs. 24 Notably, a strong acid is indispensable in all the REEs extraction processes. Second, an extractant that selectively complexes with REE 3+ is also necessary for the extraction. For example, in the solvent extraction, di-2-ethylhexylphosphoric acid (DEHPA) was dispersed in kerosene, and together they can selectively extract REEs from the aqueous solutions. 21 In addition, DEHPA-dispersed mineral oil inside a membrane was used for selectively transferring REEs from a CFA leachate to a highly acidic solution. 22 However, these processes all use toxic organic solvent to disperse the extractant, and thus it is highly desirable to find environmentally-friendly solvents to replace the organic solvent. Third, and most importantly, CFAs have extremely low concentrations of REEs (<0.2%) and more than 90% major impurities (Ca, Fe, Al, Mg), so the REEs purity in the final products is only 0.5–0.7%. 22 Overcoming these drawbacks requires a novel REEs extraction process that is environmentally-benign and highly selective for REEs over impurities. Supercritical fluid (SCF) extraction has emerged as a promising option because SCFs have little environmental impact, are non-flammable, and facilitate the mass transfer of extractants. 25 Applying SCF can reduce the usage of organic solvent, and we also expect that it can improve the selective recovery of REEs from CFAs. To selectively extract REEs from a solid matrix, studies have explored using extractants to complex with REE 3+ ions under supercritical carbon dioxide (scCO 2 ). 26,27 Tributyl phosphate–nitric acid (TBP–HNO 3 ) has shown selective extraction of REEs. This extractant was prepared by contacting pure TBP with concentrated HNO 3 . A current hypothesis for the extraction mechanism in a scCO 2 system is that TBP selectively chelates with the neutral salt formed by REE 3+ and NO 3 − . 27,28 Although scCO<|im_end|> <|im_start|>assistant Rare earth elements (REE), a group of 17 metallic elements, are in nearly every piece of technology, including cell phones, televisions, computers and almost every part of a vehicle. The demand for these elements increases annually, however the supply is limited geopolitically and is mined with environmentally unsustainable practices. Young-Shin Jun, professor of energy, environmental & chemical engineering in the McKelvey School of Engineering at Washington University in St. Louis, and her team have created a proof-of-concept solution: extracting REEs from coal fly ash, a fine, powdery waste product from the combustion of coal. "We wanted to use a greener process to extract REEs than traditionally more harmful processes," Jun said. "Since the coal has already been used, this process is ultimately a pathway toward reduction and remediation of waste products." Jun and her former doctoral student, Yaguang Zhu, now a postdoctoral scholar at Princeton University, developed this novel extraction process using supercritical fluid, commonly used to decaffeinate coffee, to recover these critically needed REEs from material that would have otherwise been discarded in a landfill. Supercritical fluid is a substance at a temperature and pressure above its critical point with properties between a liquid and a gas. With more than 79 million metric tons of coal fly ash generated in the U.S. annually, Jun's team reported that the potential value of the REEs that could be extracted from coal fly ash in the U.S. is estimated at more than $4 billion annually. Their work, which appears in RSC Sustainability, is the first to show that common and accessible supercritical fluids, including carbon dioxide, nitrogen and air, were able to extract REEs and separate impurities very efficiently. In addition, through experiments using coal fly ash, they found that supercritical carbon dioxide decreased the concentrations of impurities in the final REE product. Ultimately, their final products contained up to 6.47% REEs, compared with 0.0234% in the initial coal fly ash source. "The uniqueness of our work is not only using the supercritical CO2, but also showing that supercritical air and nitrogen, with much lower temperature and pressure than those required for CO2, can extract REE effectively," said Jun, who leads the Environmental NanoChemistry Laboratory. "We can use lower temperatures and pressures with nitrogen or air to extract the rare earth elements from coal fly ash, which means lower energy cost. Of course, the supercritical CO2 works best, but supercritical air or nitrogen could do a much better job compared with traditional high temperature boiling with acids and organic solvents for REE extraction." Jun's team's extraction process involved two steps: First, metal ions in the coal fly ash, including REEs and impurities, leach from the coal fly ash and react with nitric acid to form metal nitrates; and second, the metal nitrates react with tributyl phosphate (TBP). They found that with supercritical carbon dioxide, nitrogen or air, the REEs formed complexes that could be extracted from the coal fly ash. After extraction, their multistage stripping process collected REEs and decreased the concentration of impurities. The nitric acid and TBP used in the process can be fully recycled multiple times without sacrificing efficiency, which minimizes their disposal concerns. Jun's method also eliminates the need to roast raw materials at extremely high temperatures, or greater than 500 C, and the need to extract the REEs with strong acids and a large quantity of toxic organic solvents, which also become a waste product in traditional extraction processes. "Supercritical fluid is considered as a greener solvent, is less invasive to the environment and allows us to extract REE directly from solid waste without leaching and roasting raw materials, so less energy is required for our new process, which also produces less waste," Jun said. "We are seeking a more environmentally benign process for critical element recycling and recovery from materials previously considered to be waste." <|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 dimensionality of an electronic quantum system is decisive for its properties. In one dimension, electrons form a Luttinger liquid, and in two dimensions, they exhibit the quantum Hall effect. However, very little is known about the behaviour of electrons in non-integer, or fractional dimensions 1 . Here, we show how arrays of artificial atoms can be defined by controlled positioning of CO molecules on a Cu (111) surface 2 , 3 , 4 , and how these sites couple to form electronic Sierpiński fractals. We characterize the electron wavefunctions at different energies with scanning tunnelling microscopy and spectroscopy, and show that they inherit the fractional dimension. Wavefunctions delocalized over the Sierpiński structure decompose into self-similar parts at higher energy, and this scale invariance can also be retrieved in reciprocal space. Our results show that electronic quantum fractals can be artificially created by atomic manipulation in a scanning tunnelling microscope. The same methodology will allow future studies to address fundamental questions about the effects of spin–orbit interactions and magnetic fields on electrons in non-integer dimensions. Moreover, the rational concept of artificial atoms can readily be transferred to planar semiconductor electronics, allowing for the exploration of electrons in a well-defined fractal geometry, including interactions and external fields. Main Fractals have been investigated in a wide variety of research areas, ranging from polymers 5 , porous systems 6 , electrical storage 7 and stretchable electronics 8 down to molecular 5 , 9 , 10 , 11 and plasmonic 12 fractals. On the quantum level, fractal properties emerge in the behaviour of electrons under perpendicular magnetic fields; for example, in the Hofstadter butterfly 13 and in quantum Hall resistivity 14 , 15 . In addition, a multi-fractal behaviour has been observed for the wavefunctions at the transition from a localized to delocalized regime in disordered electronic systems 16 , 17 , 18 . However, these systems do not allow one to study the influence of non-integer dimensions on the electronic properties. Geometric electronic fractals, in which electrons are confined to a self-similar fractal geometry with a dimension between one and two, have been studied only from a theoretical perspective. For these fractals, a recurrent pattern in the density of states as well as extended and localized electronic states were predicted 19 , 20 , 21 , 22 . Recently, simulations of quantum transport in fractals revealed that the conductance fluctuations are related to the fractal dimension 23 , and that the conductance in a Sierpiński fractal shows scale-invariant properties 24 , 25 , 26 . Here, we report how to construct and characterize, in a controlled fashion, a fractal lattice with electrons: the electrons that reside on a Cu(111) surface are confined to a self-similar Sierpiński geometry through atomic manipulation of CO molecules on the Cu(111) surface. The manipulation of surface-state electrons by adsorbates has been pioneered by Crommie et al. 27 and has been used to create electronic lattices ‘on demand’, such as a molecular graphene 2 , an electronic Lieb lattice 3 , 28 , a checkerboard and stripe-shaped lattice 29 , and a quasiperiodic Penrose tiling 4 . We characterized the first three generations of an electronic Sierpiński triangle by scanning tunnelling microscopy and spectroscopy, acquiring the spatially and energy-resolved electronic local density of states (LDOS). These results were corroborated by muffin-tin calculations as well as tight-binding simulations based on artificial atomic s -orbitals coupled in the Sierpiński geometry. The Sierpiński triangle with Hausdorff dimension log(3)/log(2) = 1.58 is presented in Fig. 1a . We define atomic sites at the corners and in the centre of the light blue triangles, as shown in Fig. 1b for the first generation G (1) 10 , 30 . G (1) has three inequivalent atomic sites, indicated in red, green and blue, which differ by their connectivity. A triangle of generation G ( N ) consists of three triangles G ( N −1), sharing the red corner sites. The surface-state electrons of Cu(111) are confined to the atomic sites by adsorbed CO molecules, acting as repulsive scatterers. Figure 1c shows the experimental realization of the first three generations of the Sierpiński triangle and Fig. 1d shows the relation with the artificial atomic sites. The distance between neighbouring sites is 1.1 nm, such that the electronic structure of the fractal will emerge in an experimentally suitable energy range 2 . Fig. 1: Geometry of the Sierpiński triangle fractal. a , Schematic of Sierpiński triangles of the first three generations G (1)– G (3). G (1) is an equilateral triangle subdivided into four identical triangles, from which the centre triangle is removed. Three G (1) ( G (2)) triangles are combined to form a G (2) ( G (3)) triangle. b , Geometry of a G (1) Sierpiński triangle with red, green and blue atomic sites. t and t ′ indicate nearest-neighbour and next-nearest-neighbour hopping between the sites in the tight-binding model. c , Constant-current STM images of the realized G (1)– G (3) Sierpiński triangles. The atomic sites of one G (1) building block are indicated as a guide to the eye. Imaging parameters: I = 1 nA, V = 1 V for G (1) and G (2) and 0.30 V for G (3). Scale bar, 2 nm. d , The configuration of CO molecules (black) on Cu(111) to confine the surface-state electrons to the atomic sites of the Sierpiński triangle. e , Normalized differential conductance spectra acquired above the positions of red, blue and green open circles in c (and equivalent positions). f , LDOS at the same positions, simulated using a tight-binding model with t = 0.12 eV, t ′ = 0.01 eV and an overlap s = 0.2. a.u., arbitrary units. Full size image Figure 1e presents the experimental LDOS at the red, blue and green atomic sites in the G (3) Sierpiński triangle (indicated by the open circles in Fig. 1c ). The differential conductance (d I /d V ) spectra were normalized by the average spectrum taken on the", "role": "user" }, { "content": "In physics, it is well-known that electrons behave very differently in three dimensions, two dimensions or one dimension. These behaviours give rise to different possibilities for technological applications and electronic systems. But what happens if electrons live in 1.58 dimensions – and what does it actually mean? Theoretical and experimental physicists at Utrecht University investigated these questions in a new study that will be published in Nature Physics on 12 November. It may be difficult to imagine 1.58 dimensions, but the idea is more familiar to you than you think at first glance. Non-integer dimensions, such as 1.58, can be found in fractal structures, such as lungs. A fractal is a self-similar structure that scales in a different way than normal objects: If you zoom in, you will see the same structure again. For example, a small piece of Romanesco broccoli typically looks similar to the whole head of broccoli. In electronics, fractals are used in antennas for their properties of receiving and transmitting signals in a large frequency range. A relatively new topic in fractals is the quantum behaviour that emerges if you zoom in all the way to the scale of electrons. Using a quantum simulator, Utrecht physicists Sander Kempkes and Marlou Slot were able to build such a fractal out of electrons. The researchers made a 'muffin tin' in which the electrons would confine to a fractal shape, by placing carbon monoxide molecules in just the right shape on a copper background with a scanning tunneling microscope. The resulting triangular fractal shape in which the electrons were confined is called a Sierpiński triangle, which has a fractal dimension of 1.58. The researchers observed that the electrons in the triangle actually behave as if they live in 1.58 dimensions. The results from the study show how bonding (left image) and non-bonding Sierpiński (right image) triangles are separated in energy, yielding nice opportunities for transmitting currents through these fractal structures. In the bonding case, the electrons are connected and can easily go from one place to another (high transmission), whereas in the non-bonding case they are not connected and need to \"jump\" to another place (low transmission). Also, by calculating the dimension of the electronic wavefunction, the researchers observed that the electrons themselves are confined to this dimension and the wavefunctions inherit this fractional dimension. \"From a theoretical point of view, this is a very interesting and groundbreaking result,\" says theoretical physicist Cristiane de Morais Smith, who supervised the study together with experimental physicists Ingmar Swart and Daniel Vanmaekelbergh. \"It opens a whole new line of research, raising questions such as: what does it actually mean for electrons to be confined in non-integer dimensions? Do they behave more like in one dimension or in two dimensions? And what happens if a magnetic field is turned on perpendicularly to the sample? Fractals already have a very large number of applications, so these results may have a big impact on research at the quantum scale.\" ", "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 dimensionality of an electronic quantum system is decisive for its properties. In one dimension, electrons form a Luttinger liquid, and in two dimensions, they exhibit the quantum Hall effect. However, very little is known about the behaviour of electrons in non-integer, or fractional dimensions 1 . Here, we show how arrays of artificial atoms can be defined by controlled positioning of CO molecules on a Cu (111) surface 2 , 3 , 4 , and how these sites couple to form electronic Sierpiński fractals. We characterize the electron wavefunctions at different energies with scanning tunnelling microscopy and spectroscopy, and show that they inherit the fractional dimension. Wavefunctions delocalized over the Sierpiński structure decompose into self-similar parts at higher energy, and this scale invariance can also be retrieved in reciprocal space. Our results show that electronic quantum fractals can be artificially created by atomic manipulation in a scanning tunnelling microscope. The same methodology will allow future studies to address fundamental questions about the effects of spin–orbit interactions and magnetic fields on electrons in non-integer dimensions. Moreover, the rational concept of artificial atoms can readily be transferred to planar semiconductor electronics, allowing for the exploration of electrons in a well-defined fractal geometry, including interactions and external fields. Main Fractals have been investigated in a wide variety of research areas, ranging from polymers 5 , porous systems 6 , electrical storage 7 and stretchable electronics 8 down to molecular 5 , 9 , 10 , 11 and plasmonic 12 fractals. On the quantum level, fractal properties emerge in the behaviour of electrons under perpendicular magnetic fields; for example, in the Hofstadter butterfly 13 and in quantum Hall resistivity 14 , 15 . In addition, a multi-fractal behaviour has been observed for the wavefunctions at the transition from a localized to delocalized regime in disordered electronic systems 16 , 17 , 18 . However, these systems do not allow one to study the influence of non-integer dimensions on the electronic properties. Geometric electronic fractals, in which electrons are confined to a self-similar fractal geometry with a dimension between one and two, have been studied only from a theoretical perspective. For these fractals, a recurrent pattern in the density of states as well as extended and localized electronic states were predicted 19 , 20 , 21 , 22 . Recently, simulations of quantum transport in fractals revealed that the conductance fluctuations are related to the fractal dimension 23 , and that the conductance in a Sierpiński fractal shows scale-invariant properties 24 , 25 , 26 . Here, we report how to construct and characterize, in a controlled fashion, a fractal lattice with electrons: the electrons that reside on a Cu(111) surface are confined to a self-similar Sierpiński geometry through atomic manipulation of CO molecules on the Cu(111) surface. The manipulation of surface-state electrons by adsorbates has been pioneered by Crommie et al. 27 and has been used to create electronic lattices ‘on demand’, such as a molecular graphene 2 , an electronic Lieb lattice 3 , 28 , a checkerboard and stripe-shaped lattice 29 , and a quasiperiodic Penrose tiling 4 . We characterized the first three generations of an electronic Sierpiński triangle by scanning tunnelling microscopy and spectroscopy, acquiring the spatially and energy-resolved electronic local density of states (LDOS). These results were corroborated by muffin-tin calculations as well as tight-binding simulations based on artificial atomic s -orbitals coupled in the Sierpiński geometry. The Sierpiński triangle with Hausdorff dimension log(3)/log(2) = 1.58 is presented in Fig. 1a . We define atomic sites at the corners and in the centre of the light blue triangles, as shown in Fig. 1b for the first generation G (1) 10 , 30 . G (1) has three inequivalent atomic sites, indicated in red, green and blue, which differ by their connectivity. A triangle of generation G ( N ) consists of three triangles G ( N −1), sharing the red corner sites. The surface-state electrons of Cu(111) are confined to the atomic sites by adsorbed CO molecules, acting as repulsive scatterers. Figure 1c shows the experimental realization of the first three generations of the Sierpiński triangle and Fig. 1d shows the relation with the artificial atomic sites. The distance between neighbouring sites is 1.1 nm, such that the electronic structure of the fractal will emerge in an experimentally suitable energy range 2 . Fig. 1: Geometry of the Sierpiński triangle fractal. a , Schematic of Sierpiński triangles of the first three generations G (1)– G (3). G (1) is an equilateral triangle subdivided into four identical triangles, from which the centre triangle is removed. Three G (1) ( G (2)) triangles are combined to form a G (2) ( G (3)) triangle. b , Geometry of a G (1) Sierpiński triangle with red, green and blue atomic sites. t and t ′ indicate nearest-neighbour and next-nearest-neighbour hopping between the sites in the tight-binding model. c , Constant-current STM images of the realized G (1)– G (3) Sierpiński triangles. The atomic sites of one G (1) building block are indicated as a guide to the eye. Imaging parameters: I = 1 nA, V = 1 V for G (1) and G (2) and 0.30 V for G (3). Scale bar, 2 nm. d , The configuration of CO molecules (black) on Cu(111) to confine the surface-state electrons to the atomic sites of the Sierpiński triangle. e , Normalized differential conductance spectra acquired above the positions of red, blue and green open circles in c (and equivalent positions). f , LDOS at the same positions, simulated using a tight-binding model with t = 0.12 eV, t ′ = 0.01 eV and an overlap s = 0.2. a.u., arbitrary units. Full size image Figure 1e presents the experimental LDOS at the red, blue and green atomic sites in the G (3) Sierpiński triangle (indicated by the open circles in Fig. 1c ). The differential conductance (d I /d V ) spectra were normalized by the average spectrum taken on the<|im_end|> <|im_start|>assistant In physics, it is well-known that electrons behave very differently in three dimensions, two dimensions or one dimension. These behaviours give rise to different possibilities for technological applications and electronic systems. But what happens if electrons live in 1.58 dimensions – and what does it actually mean? Theoretical and experimental physicists at Utrecht University investigated these questions in a new study that will be published in Nature Physics on 12 November. It may be difficult to imagine 1.58 dimensions, but the idea is more familiar to you than you think at first glance. Non-integer dimensions, such as 1.58, can be found in fractal structures, such as lungs. A fractal is a self-similar structure that scales in a different way than normal objects: If you zoom in, you will see the same structure again. For example, a small piece of Romanesco broccoli typically looks similar to the whole head of broccoli. In electronics, fractals are used in antennas for their properties of receiving and transmitting signals in a large frequency range. A relatively new topic in fractals is the quantum behaviour that emerges if you zoom in all the way to the scale of electrons. Using a quantum simulator, Utrecht physicists Sander Kempkes and Marlou Slot were able to build such a fractal out of electrons. The researchers made a 'muffin tin' in which the electrons would confine to a fractal shape, by placing carbon monoxide molecules in just the right shape on a copper background with a scanning tunneling microscope. The resulting triangular fractal shape in which the electrons were confined is called a Sierpiński triangle, which has a fractal dimension of 1.58. The researchers observed that the electrons in the triangle actually behave as if they live in 1.58 dimensions. The results from the study show how bonding (left image) and non-bonding Sierpiński (right image) triangles are separated in energy, yielding nice opportunities for transmitting currents through these fractal structures. In the bonding case, the electrons are connected and can easily go from one place to another (high transmission), whereas in the non-bonding case they are not connected and need to "jump" to another place (low transmission). Also, by calculating the dimension of the electronic wavefunction, the researchers observed that the electrons themselves are confined to this dimension and the wavefunctions inherit this fractional dimension. "From a theoretical point of view, this is a very interesting and groundbreaking result," says theoretical physicist Cristiane de Morais Smith, who supervised the study together with experimental physicists Ingmar Swart and Daniel Vanmaekelbergh. "It opens a whole new line of research, raising questions such as: what does it actually mean for electrons to be confined in non-integer dimensions? Do they behave more like in one dimension or in two dimensions? And what happens if a magnetic field is turned on perpendicularly to the sample? Fractals already have a very large number of applications, so these results may have a big impact on research at the quantum scale." <|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 Osteoarthritis is a common complex disease imposing a large public-health burden. Here, we performed a genome-wide association study for osteoarthritis, using data across 16.5 million variants from the UK Biobank resource. After performing replication and meta-analysis in up to 30,727 cases and 297,191 controls, we identified nine new osteoarthritis loci, in all of which the most likely causal variant was noncoding. For three loci, we detected association with biologically relevant radiographic endophenotypes, and in five signals we identified genes that were differentially expressed in degraded compared with intact articular cartilage from patients with osteoarthritis. We established causal effects on osteoarthritis for higher body mass index but not for triglyceride levels or genetic predisposition to type 2 diabetes. Main Osteoarthritis is the most prevalent musculoskeletal disease and the most common form of arthritis 1 . The hallmarks of osteoarthritis are degeneration of articular cartilage, remodeling of the underlying bone and synovitis 2 . A leading cause of disability worldwide, osteoarthritis affects 40% of individuals over the age of 70 and is associated with an elevated risk of comorbidity and death 3 . The rising health economic burden of osteoarthritis is commensurate with rising longevity and obesity rates, and there is currently no curative therapy. The heritability of osteoarthritis is ~50%, and previous genetic studies have identified 21 loci in total, traversing hip, knee and hand osteoarthritis with limited overlap 3 . Here, we conducted a large osteoarthritis genome-wide association study (GWAS), using genotype data across 16.5 million variants from UK Biobank. We defined osteoarthritis on the basis of both self-reported status and linkage to Hospital Episode Statistics data, as well as the joint specificity of the disease (knee and/or hip) (Supplementary Fig. 1 ). Results Disease definition and power to detect genetic associations We compared and contrasted the hospital-diagnosed ( n = 10,083 cases) and self-reported ( n = 12,658 cases) osteoarthritis GWAS drawn from the same UK Biobank dataset (with selection of approximately four times more nonosteoarthritis controls than cases to preserve power for common alleles while avoiding case–control imbalance that might cause association tests to misbehave for low-frequency variants 4 ) (Supplementary Tables 1 – 3 , Supplementary Figs. 2 – 4 and Methods ). We found power advantages with the self-reported dataset, thus indicating that the higher sample size overcame the limitations associated with phenotype uncertainty. When evaluating the accuracy of disease definition, we found that self-reported osteoarthritis had a modest positive predictive value (PPV; 30%) and sensitivity (37%), but high negative predictive value (95%) and specificity, correctly identifying 93% of individuals who did not have osteoarthritis (Supplementary Table 4 ). In terms of power to detect genetic associations, the self-reported-osteoarthritis dataset had clear advantages commensurate with its larger sample size (Fig. 1 ). For example, for a representative complex-disease-associated variant with a minor allele frequency (MAF) of 30% and an allelic odds ratio (OR) of 1.10, the self-reported and hospital-diagnosed osteoarthritis analyses had 80% and 56% power, respectively, to detect an effect at genome-wide significance (i.e., P < 5.0 × 10 −8 ; Supplementary Table 5 ). Fig. 1: Power to detect association in the discovery stage. OR and 95% CI values are shown as a function of MAF. Diamonds, newly reported variants; circles, known variants. The curves indicate 80% power at the genome-wide-significance threshold of P < 5.0 × 10 −8 for the number of cases and controls of each trait at the discovery stage (likelihood ratio test). OA, osteoarthritis. Full size image We found nominally significant evidence of concordance between the direction of effect at previously reported osteoarthritis loci and the discovery analyses for hospital-diagnosed-osteoarthritis definitions (Supplementary Tables 6 and 7 , and Supplementary Note ), thus indicating that a narrower definition of disease may provide better effect-size estimates despite being limited by power to identify robust statistical evidence of association. Heritability estimates across osteoarthritis definitions We found that common-frequency variants explained 12% of osteoarthritis heritability when using self-reported status and explained 16% of osteoarthritis heritability when using hospital records (19% of hip-osteoarthritis and 15% of knee-osteoarthritis heritability) (Supplementary Table 8 ). The heritability estimates from self-reported and hospital records were not significantly different (Supplementary Table 9 ). The concordance between self-reported and hospital-diagnosed osteoarthritis was further substantiated by the high genetic-correlation estimate of the two disease definitions (87%, P = 3.14 × 10 −53 ) (Supplementary Table 10 ). We found strong genome-wide correlation between hip osteoarthritis and knee osteoarthritis (88%, P = 1.96 × 10 −6 ), even though the previously reported osteoarthritis loci are predominantly not shared between the two osteoarthritis joint sites. From this new observation of a substantial shared genetic etiology, we sought replication of association signals across joint sites. Identification of novel osteoarthritis loci We used 173 variants with P <1.0 × 10 −5 and MAF >0.01 for replication in an Icelandic cohort of up to 18,069 cases and 246,293 controls (Supplementary Fig. 1 , Supplementary Tables 11 – 15 and Methods ). Given the number of variants, the replication significance threshold was P <2.9 × 10 −4 . After meta-analysis in up to 30,727 cases and 297,191 controls, we identified six genome-wide-significant associations at novel loci and three further replicating signals just below the corrected genome-wide-significance threshold (Table 1 and Fig. 2 ). Table 1 Association summary statistics for the nine signals Full size table Fig. 2: Regional association plots for the nine novel osteoarthritis loci. The y axis represents the negative logarithm (base 10) of the variant P value (likelihood ratio test), and the x axis represents the position on the chromosome (chr), with the names and location of genes and nearest genes shown at the bottom. The variant with the lowest P value in the region after combined discovery and replication is marked by a purple diamond. The same variant is marked by a purple dot showing the discovery P value. The colors of the other variants indicate their r 2 with the lead variant. Full size image We identified association between rs2521349 and hip", "role": "user" }, { "content": "In the largest study of its kind, nine novel genes for osteoarthritis have been discovered by scientists from the Wellcome Sanger Institute and their collaborators. Results of the study, published today (19 March) in Nature Genetics, could open the door to new targeted therapies for this debilitating disease in the future. Almost nine million people in the UK suffer from osteoarthritis, a degenerative joint disease in which a person's joints become damaged, stop moving freely and become painful. Osteoarthritis is the most prevalent musculoskeletal disease and a leading cause of disability worldwide. There is no treatment for osteoarthritis. The disease is managed with pain relief and culminates in joint replacement surgery, which has variable outcomes. In the largest study of its kind, scientists from the Wellcome Sanger Institute and their collaborators investigated the genetics behind osteoarthritis, as well as the diseases and traits that are linked to it. To understand more about the genetic basis of osteoarthritis, the team studied 16.5 million DNA variations from the UK Biobank resource. Following combined analysis in up to 30,727 people with osteoarthritis and nearly 300,000 people without osteoarthritis in total—the controls—scientists discovered nine new genes that were associated with osteoarthritis, a significant result for this disease. Professor Eleftheria Zeggini, senior author from the Wellcome Sanger Institute, said: \"Osteoarthritis is challenging to study because the disease can vary among people, and also between the different joints affected, for example knee, hip, hand and spine. Using data from the UK Biobank resource, we have undertaken the largest genetic study of osteoarthritis to date and uncovered nine new genes associated with the disease.\" Researchers then investigated the role of the nine new genes in osteoarthritis, by studying both normal cartilage and diseased cartilage from individuals who had a joint replacement. The team looked for genes that were active in the progression of the disease by extracting the relevant cells from healthy and diseased tissue, studying the levels of proteins in the tissue and sequencing the RNA—the messenger that carries instructions from DNA for controlling the production of proteins. Of the nine genes associated with osteoarthritis, researchers identified five genes in particular that differed significantly in their expression in healthy and diseased tissue. The five genes present novel targets for future research into therapies. Ms Eleni Zengini, joint first author from the University of Sheffield and Dromokaiteio Psychiatric Hospital in Athens, said: \"These results are an important step towards understanding the genetic causes of osteoarthritis and take us closer to uncovering the mechanism behind the disease. Once we know that, it opens the door to developing new therapies for this debilitating disease.\" The team also explored genetic correlations between osteoarthritis and obesity, bone mineral density, type 2 diabetes, and raised blood lipid levels. Researchers applied a statistical technique known as causal inference analysis to uncover which traits and diseases cause osteoarthritis, and which do not. Within the limits of their study, scientists discovered that type 2 diabetes and high levels of lipids in the blood do not have causal effects on osteoarthritis, but reaffirm that obesity does. Dr Konstantinos Hatzikotoulas, joint first author from the Wellcome Sanger Institute, said: \"Using genetic data, we have shown that type 2 diabetes and increased blood lipid levels do not appear to be on the causal path to osteoarthritis. We also reconfirmed that obesity is on the causal path to osteoarthritis.\" Dr Natalie Carter, Head of research liaison & evaluation at Arthritis Research UK, who did not fund the study, said: \"The discovery of these genes is positive news for the 8.5 million people in the UK living with osteoarthritis. People living with this debilitating condition currently have limited treatment options. Meanwhile, they can struggle to do the day-to-day things most of us take for granted, like going to work or getting dressed independently. By revealing how these genes contribute to osteoarthritis, this research could open the door for new treatments to help millions of people live the pain free life they deserve.\" ", "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 Osteoarthritis is a common complex disease imposing a large public-health burden. Here, we performed a genome-wide association study for osteoarthritis, using data across 16.5 million variants from the UK Biobank resource. After performing replication and meta-analysis in up to 30,727 cases and 297,191 controls, we identified nine new osteoarthritis loci, in all of which the most likely causal variant was noncoding. For three loci, we detected association with biologically relevant radiographic endophenotypes, and in five signals we identified genes that were differentially expressed in degraded compared with intact articular cartilage from patients with osteoarthritis. We established causal effects on osteoarthritis for higher body mass index but not for triglyceride levels or genetic predisposition to type 2 diabetes. Main Osteoarthritis is the most prevalent musculoskeletal disease and the most common form of arthritis 1 . The hallmarks of osteoarthritis are degeneration of articular cartilage, remodeling of the underlying bone and synovitis 2 . A leading cause of disability worldwide, osteoarthritis affects 40% of individuals over the age of 70 and is associated with an elevated risk of comorbidity and death 3 . The rising health economic burden of osteoarthritis is commensurate with rising longevity and obesity rates, and there is currently no curative therapy. The heritability of osteoarthritis is ~50%, and previous genetic studies have identified 21 loci in total, traversing hip, knee and hand osteoarthritis with limited overlap 3 . Here, we conducted a large osteoarthritis genome-wide association study (GWAS), using genotype data across 16.5 million variants from UK Biobank. We defined osteoarthritis on the basis of both self-reported status and linkage to Hospital Episode Statistics data, as well as the joint specificity of the disease (knee and/or hip) (Supplementary Fig. 1 ). Results Disease definition and power to detect genetic associations We compared and contrasted the hospital-diagnosed ( n = 10,083 cases) and self-reported ( n = 12,658 cases) osteoarthritis GWAS drawn from the same UK Biobank dataset (with selection of approximately four times more nonosteoarthritis controls than cases to preserve power for common alleles while avoiding case–control imbalance that might cause association tests to misbehave for low-frequency variants 4 ) (Supplementary Tables 1 – 3 , Supplementary Figs. 2 – 4 and Methods ). We found power advantages with the self-reported dataset, thus indicating that the higher sample size overcame the limitations associated with phenotype uncertainty. When evaluating the accuracy of disease definition, we found that self-reported osteoarthritis had a modest positive predictive value (PPV; 30%) and sensitivity (37%), but high negative predictive value (95%) and specificity, correctly identifying 93% of individuals who did not have osteoarthritis (Supplementary Table 4 ). In terms of power to detect genetic associations, the self-reported-osteoarthritis dataset had clear advantages commensurate with its larger sample size (Fig. 1 ). For example, for a representative complex-disease-associated variant with a minor allele frequency (MAF) of 30% and an allelic odds ratio (OR) of 1.10, the self-reported and hospital-diagnosed osteoarthritis analyses had 80% and 56% power, respectively, to detect an effect at genome-wide significance (i.e., P < 5.0 × 10 −8 ; Supplementary Table 5 ). Fig. 1: Power to detect association in the discovery stage. OR and 95% CI values are shown as a function of MAF. Diamonds, newly reported variants; circles, known variants. The curves indicate 80% power at the genome-wide-significance threshold of P < 5.0 × 10 −8 for the number of cases and controls of each trait at the discovery stage (likelihood ratio test). OA, osteoarthritis. Full size image We found nominally significant evidence of concordance between the direction of effect at previously reported osteoarthritis loci and the discovery analyses for hospital-diagnosed-osteoarthritis definitions (Supplementary Tables 6 and 7 , and Supplementary Note ), thus indicating that a narrower definition of disease may provide better effect-size estimates despite being limited by power to identify robust statistical evidence of association. Heritability estimates across osteoarthritis definitions We found that common-frequency variants explained 12% of osteoarthritis heritability when using self-reported status and explained 16% of osteoarthritis heritability when using hospital records (19% of hip-osteoarthritis and 15% of knee-osteoarthritis heritability) (Supplementary Table 8 ). The heritability estimates from self-reported and hospital records were not significantly different (Supplementary Table 9 ). The concordance between self-reported and hospital-diagnosed osteoarthritis was further substantiated by the high genetic-correlation estimate of the two disease definitions (87%, P = 3.14 × 10 −53 ) (Supplementary Table 10 ). We found strong genome-wide correlation between hip osteoarthritis and knee osteoarthritis (88%, P = 1.96 × 10 −6 ), even though the previously reported osteoarthritis loci are predominantly not shared between the two osteoarthritis joint sites. From this new observation of a substantial shared genetic etiology, we sought replication of association signals across joint sites. Identification of novel osteoarthritis loci We used 173 variants with P <1.0 × 10 −5 and MAF >0.01 for replication in an Icelandic cohort of up to 18,069 cases and 246,293 controls (Supplementary Fig. 1 , Supplementary Tables 11 – 15 and Methods ). Given the number of variants, the replication significance threshold was P <2.9 × 10 −4 . After meta-analysis in up to 30,727 cases and 297,191 controls, we identified six genome-wide-significant associations at novel loci and three further replicating signals just below the corrected genome-wide-significance threshold (Table 1 and Fig. 2 ). Table 1 Association summary statistics for the nine signals Full size table Fig. 2: Regional association plots for the nine novel osteoarthritis loci. The y axis represents the negative logarithm (base 10) of the variant P value (likelihood ratio test), and the x axis represents the position on the chromosome (chr), with the names and location of genes and nearest genes shown at the bottom. The variant with the lowest P value in the region after combined discovery and replication is marked by a purple diamond. The same variant is marked by a purple dot showing the discovery P value. The colors of the other variants indicate their r 2 with the lead variant. Full size image We identified association between rs2521349 and hip<|im_end|> <|im_start|>assistant In the largest study of its kind, nine novel genes for osteoarthritis have been discovered by scientists from the Wellcome Sanger Institute and their collaborators. Results of the study, published today (19 March) in Nature Genetics, could open the door to new targeted therapies for this debilitating disease in the future. Almost nine million people in the UK suffer from osteoarthritis, a degenerative joint disease in which a person's joints become damaged, stop moving freely and become painful. Osteoarthritis is the most prevalent musculoskeletal disease and a leading cause of disability worldwide. There is no treatment for osteoarthritis. The disease is managed with pain relief and culminates in joint replacement surgery, which has variable outcomes. In the largest study of its kind, scientists from the Wellcome Sanger Institute and their collaborators investigated the genetics behind osteoarthritis, as well as the diseases and traits that are linked to it. To understand more about the genetic basis of osteoarthritis, the team studied 16.5 million DNA variations from the UK Biobank resource. Following combined analysis in up to 30,727 people with osteoarthritis and nearly 300,000 people without osteoarthritis in total—the controls—scientists discovered nine new genes that were associated with osteoarthritis, a significant result for this disease. Professor Eleftheria Zeggini, senior author from the Wellcome Sanger Institute, said: "Osteoarthritis is challenging to study because the disease can vary among people, and also between the different joints affected, for example knee, hip, hand and spine. Using data from the UK Biobank resource, we have undertaken the largest genetic study of osteoarthritis to date and uncovered nine new genes associated with the disease." Researchers then investigated the role of the nine new genes in osteoarthritis, by studying both normal cartilage and diseased cartilage from individuals who had a joint replacement. The team looked for genes that were active in the progression of the disease by extracting the relevant cells from healthy and diseased tissue, studying the levels of proteins in the tissue and sequencing the RNA—the messenger that carries instructions from DNA for controlling the production of proteins. Of the nine genes associated with osteoarthritis, researchers identified five genes in particular that differed significantly in their expression in healthy and diseased tissue. The five genes present novel targets for future research into therapies. Ms Eleni Zengini, joint first author from the University of Sheffield and Dromokaiteio Psychiatric Hospital in Athens, said: "These results are an important step towards understanding the genetic causes of osteoarthritis and take us closer to uncovering the mechanism behind the disease. Once we know that, it opens the door to developing new therapies for this debilitating disease." The team also explored genetic correlations between osteoarthritis and obesity, bone mineral density, type 2 diabetes, and raised blood lipid levels. Researchers applied a statistical technique known as causal inference analysis to uncover which traits and diseases cause osteoarthritis, and which do not. Within the limits of their study, scientists discovered that type 2 diabetes and high levels of lipids in the blood do not have causal effects on osteoarthritis, but reaffirm that obesity does. Dr Konstantinos Hatzikotoulas, joint first author from the Wellcome Sanger Institute, said: "Using genetic data, we have shown that type 2 diabetes and increased blood lipid levels do not appear to be on the causal path to osteoarthritis. We also reconfirmed that obesity is on the causal path to osteoarthritis." Dr Natalie Carter, Head of research liaison & evaluation at Arthritis Research UK, who did not fund the study, said: "The discovery of these genes is positive news for the 8.5 million people in the UK living with osteoarthritis. People living with this debilitating condition currently have limited treatment options. Meanwhile, they can struggle to do the day-to-day things most of us take for granted, like going to work or getting dressed independently. By revealing how these genes contribute to osteoarthritis, this research could open the door for new treatments to help millions of people live the pain free life they deserve." <|im_end|>
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2,385
[ { "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 To perform detailed fine-mapping of the major-histocompatibility-complex region, we conducted next-generation sequencing (NGS)-based typing of the 33 human leukocyte antigen (HLA) genes in 1,120 individuals of Japanese ancestry, providing a high-resolution allele catalog and linkage-disequilibrium structure of both classical and nonclassical HLA genes. Together with population-specific deep-whole-genome-sequencing data ( n = 1,276), we conducted NGS-based HLA, single-nucleotide-variant and indel imputation of large-scale genome-wide-association-study data from 166,190 Japanese individuals. A phenome-wide association study assessing 106 clinical phenotypes identified abundant, significant genotype–phenotype associations across 52 phenotypes. Fine-mapping highlighted multiple association patterns conferring independent risks from classical HLA genes. Region-wide heritability estimates and genetic-correlation network analysis elucidated the polygenic architecture shared across the phenotypes. Main Genetic variants of the major histocompatibilty complex (MHC) region at 6p21.3 confer the largest number of associations that explain substantial phenotypic variations of a wide range of complex human diseases and quantitative traits 1 . The MHC region is one of the most polymorphic sites in the human genome and is characterized by population-specific complex linkage disequilibrium (LD) structure and long-range haplotypes 2 , 3 , 4 , 5 . Among the >200 genes densely contained in the MHC region 6 , 7 , human leukocyte antigen (HLA) genes are considered to explain most of the genetic risk of MHC. Fine-mapping efforts to identity causal variants within the MHC region reported many HLA alleles and amino acid polymorphisms associated with complex human traits 8 . In particular, development of the HLA imputation method and construction of population-specific reference panels have successfully accelerated the identification of causal variants that should be useful for personalized medicine 9 , 10 , 11 , 12 . However, several points have yet to be implemented in genetic and phenotypic studies of MHC. The first point is the use of NGS for fine-mapping MHC risk. Compared with traditional HLA typing methods, such as sequence-specific oligonucleotide hybridization (SSO) and sequencing-based typing, HLA typing by NGS could provide higher resolution of alleles for a wider spectrum of HLA and HLA-related genes beyond a limited number of classical HLA genes 13 , 14 , 15 , 16 . Population-specific whole-genome sequencing (WGS) data contribute to imputing functional rare variants with high accuracy 17 . Given that variants of the nonclassical HLA genes are responsible for disease risk, as well as those of the classical HLA genes, and that functional variants of non-HLA genes within the MHC region affect clinical phenotypes 18 , 19 , MHC risk analyses using the NGS-based reference panel are warranted to achieve more accurate fine-mapping of the causal variants. The second point is the application of the HLA imputation method to large-scale genome-wide association study (GWAS) data that represent all the participants of population-level cohorts. Many nation-wide biobanks have recently been launched to capture the genetic and phenotypic variation of these populations. To date, large-scale GWAS data from >100,000 samples have been publicly released from several biobanks (for example, >500,000 from UK Biobank 17 , 20 and >170,000 from BioBank Japan Project (BBJ) 21 , 22 ). Although HLA imputation of such big genotype data needs further tuning in the analytic pipeline, achievement of this task should enhance the knowledge of the genetic landscape of MHC in these populations. The third point is a phenome-wide assessment of risk variants in the MHC region. Cross-phenotype analysis has identified shared genetic correlations among human traits, which are represented as pleiotropic associations of the variants and cross-phenotype network that are linked to disease biology 23 , 24 , 25 , 26 . Phenome-wide association studies (PheWASs) that use electronic medical records or medical information collected throughout a cohort have successfully identified clinically useful genotype–phenotype correlations 27 , 28 . MHC is one of the most pleiotropic sites in the genome 1 , and thus application of the PheWAS approach should elucidate the phenotypic landscape of the MHC variants as well 29 . Here we report a comprehensive analysis that characterizes the genetic and phenotypic landscape of MHC in the Japanese population. We newly constructed an HLA imputation reference panel of Japanese individuals ( n = 1,120) through high-resolution NGS typing of both classical and nonclassical HLA genes ( n = 33). Together with accurate imputation of single-nucleotide variants (SNVs) and indels in a broad allele-frequency spectrum by using the population-specific deep-WGS reference data ( n = 1,276) 30 , HLA imputation of the 166,190 Japanese individuals from the BBJ genotype data was conducted to apply a PheWAS of 106 complex human diseases and quantitative traits extracted from clinical records. Results NGS typing of HLA genes in the Japanese population For the 1,120 unrelated Japanese individuals, we conducted high-resolution typing of 33 HLA-related genes with up to six-digit-level allele information (study design in Supplementary Fig. 1 ). We adopted target-capture technique and sequencing with relatively longer read lengths (350 base pairs (bp) and 250 bp for paired-end, an average depth of 260.1×) 31 , 32 . By conducting validation with the traditional SSO method for some individuals ( n = 182), we observed higher accuracy in classical HLA allele typing than that in previous NGS-based reports (<0.56% potentially inaccurate typing). NGS-based HLA typing was able to update allele information that was incorrectly assigned by traditional typing methods (for example, HLA-DRB1*14:01 by SSO was corrected as HLA-DRB1*14:54 by NGS 33 ; details in Supplementary Table 1 ). Among the 33 sequenced HLA genes, 9 are classical HLA genes (3 for class I and 6 for class II), and 24 are nonclassical HLA genes (Supplementary Table 2 ; HLA gene classification criteria in Methods ). Whereas alleles of classical HLA genes were highly polymorphic (on average, there were 9.7, 20.1 and 21.6 alleles per gene for two-digit, four-digit and six-digit-level allele information, respectively), those of nonclassical HLA genes showed lower variations (1.4, 3.1 and 4.0 alleles per gene, respectively; Fig. 1a and Supplementary Tables 2 and 3 ). Of these, HLA-B , HLA-DRB1 and MICA had the largest numbers of alleles for class I and II classical HLA", "role": "user" }, { "content": "Although genes are distributed widely across chromosomes, many genes related to the immune system are clustered together on human chromosome 6 in a segment called the major histocompatibility complex (MHC) region. The density of genes there makes it difficult for researchers to characterize them and their effects, but new technologies and large biobanks with data on huge numbers of people have opened the door to deeper insights into this region. In a major new study published in the journal Nature Genetics, researchers at Osaka University and their colleagues have surveyed the MHC region specifically in the Japanese population, revealing the existence of different gene variants and their connections with diseases and other traits. The team based their analyses on three sets of data. One was sequencing information on 33 genes determining white blood cell types in over 1,000 Japanese individuals, obtained by high-throughput sequencing. The second was data from genome-wide association studies looking at links between regions across the whole of the genome and traits and diseases in over 170,000 Japanese individuals. The third set comprised data taken from medical records on over 100 phenotypes reflecting clinical states and other traits. \"Our multiple analyses first revealed the levels of polymorphism in the human leukocyte antigen (HLA) genes, then classified the overall patterns of this polymorphism into 11 distinct groups across the Japanese population using a machine learning approach,\" says lead author Jun Hirata. \"This provided insight into the genetic landscape of the MHC region and showed us that 'non-classical' HLA genes should also be included in efforts to characterize the functional effects of this genomic region.\" The list of the phenotypes associated with the genetic variants in the MHC region. Credit: Osaka University After surveying the full complement of variation across the MHC region in the Japanese individuals, the team then focused on clarifying the associations of these variants with different traits and diseases. For this, they used data from medical records on 106 different phenotypes, including 46 complex diseases, from over 170,000 Japanese individuals. About half of these phenotypes showed significant associations with the studied genes. The findings revealed that it is common for a single gene in the MHC region to influence multiple traits, a phenomenon known as \"pleiotropy.\" \"Our work shows the importance of differences in white blood cell type for health in Japanese people,\" senior author Yukinori Okada says. \"The cross-phenotype networks that we constructed also showed correlations between health conditions that were not previously known to be related.\" The key findings of this work, including the clinical importance of non-classical HLA genes and the effects of gene variants within MHC haplotypes, should provide a solid foundation for future studies on risk factors associated with this part of the genome. ", "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 To perform detailed fine-mapping of the major-histocompatibility-complex region, we conducted next-generation sequencing (NGS)-based typing of the 33 human leukocyte antigen (HLA) genes in 1,120 individuals of Japanese ancestry, providing a high-resolution allele catalog and linkage-disequilibrium structure of both classical and nonclassical HLA genes. Together with population-specific deep-whole-genome-sequencing data ( n = 1,276), we conducted NGS-based HLA, single-nucleotide-variant and indel imputation of large-scale genome-wide-association-study data from 166,190 Japanese individuals. A phenome-wide association study assessing 106 clinical phenotypes identified abundant, significant genotype–phenotype associations across 52 phenotypes. Fine-mapping highlighted multiple association patterns conferring independent risks from classical HLA genes. Region-wide heritability estimates and genetic-correlation network analysis elucidated the polygenic architecture shared across the phenotypes. Main Genetic variants of the major histocompatibilty complex (MHC) region at 6p21.3 confer the largest number of associations that explain substantial phenotypic variations of a wide range of complex human diseases and quantitative traits 1 . The MHC region is one of the most polymorphic sites in the human genome and is characterized by population-specific complex linkage disequilibrium (LD) structure and long-range haplotypes 2 , 3 , 4 , 5 . Among the >200 genes densely contained in the MHC region 6 , 7 , human leukocyte antigen (HLA) genes are considered to explain most of the genetic risk of MHC. Fine-mapping efforts to identity causal variants within the MHC region reported many HLA alleles and amino acid polymorphisms associated with complex human traits 8 . In particular, development of the HLA imputation method and construction of population-specific reference panels have successfully accelerated the identification of causal variants that should be useful for personalized medicine 9 , 10 , 11 , 12 . However, several points have yet to be implemented in genetic and phenotypic studies of MHC. The first point is the use of NGS for fine-mapping MHC risk. Compared with traditional HLA typing methods, such as sequence-specific oligonucleotide hybridization (SSO) and sequencing-based typing, HLA typing by NGS could provide higher resolution of alleles for a wider spectrum of HLA and HLA-related genes beyond a limited number of classical HLA genes 13 , 14 , 15 , 16 . Population-specific whole-genome sequencing (WGS) data contribute to imputing functional rare variants with high accuracy 17 . Given that variants of the nonclassical HLA genes are responsible for disease risk, as well as those of the classical HLA genes, and that functional variants of non-HLA genes within the MHC region affect clinical phenotypes 18 , 19 , MHC risk analyses using the NGS-based reference panel are warranted to achieve more accurate fine-mapping of the causal variants. The second point is the application of the HLA imputation method to large-scale genome-wide association study (GWAS) data that represent all the participants of population-level cohorts. Many nation-wide biobanks have recently been launched to capture the genetic and phenotypic variation of these populations. To date, large-scale GWAS data from >100,000 samples have been publicly released from several biobanks (for example, >500,000 from UK Biobank 17 , 20 and >170,000 from BioBank Japan Project (BBJ) 21 , 22 ). Although HLA imputation of such big genotype data needs further tuning in the analytic pipeline, achievement of this task should enhance the knowledge of the genetic landscape of MHC in these populations. The third point is a phenome-wide assessment of risk variants in the MHC region. Cross-phenotype analysis has identified shared genetic correlations among human traits, which are represented as pleiotropic associations of the variants and cross-phenotype network that are linked to disease biology 23 , 24 , 25 , 26 . Phenome-wide association studies (PheWASs) that use electronic medical records or medical information collected throughout a cohort have successfully identified clinically useful genotype–phenotype correlations 27 , 28 . MHC is one of the most pleiotropic sites in the genome 1 , and thus application of the PheWAS approach should elucidate the phenotypic landscape of the MHC variants as well 29 . Here we report a comprehensive analysis that characterizes the genetic and phenotypic landscape of MHC in the Japanese population. We newly constructed an HLA imputation reference panel of Japanese individuals ( n = 1,120) through high-resolution NGS typing of both classical and nonclassical HLA genes ( n = 33). Together with accurate imputation of single-nucleotide variants (SNVs) and indels in a broad allele-frequency spectrum by using the population-specific deep-WGS reference data ( n = 1,276) 30 , HLA imputation of the 166,190 Japanese individuals from the BBJ genotype data was conducted to apply a PheWAS of 106 complex human diseases and quantitative traits extracted from clinical records. Results NGS typing of HLA genes in the Japanese population For the 1,120 unrelated Japanese individuals, we conducted high-resolution typing of 33 HLA-related genes with up to six-digit-level allele information (study design in Supplementary Fig. 1 ). We adopted target-capture technique and sequencing with relatively longer read lengths (350 base pairs (bp) and 250 bp for paired-end, an average depth of 260.1×) 31 , 32 . By conducting validation with the traditional SSO method for some individuals ( n = 182), we observed higher accuracy in classical HLA allele typing than that in previous NGS-based reports (<0.56% potentially inaccurate typing). NGS-based HLA typing was able to update allele information that was incorrectly assigned by traditional typing methods (for example, HLA-DRB1*14:01 by SSO was corrected as HLA-DRB1*14:54 by NGS 33 ; details in Supplementary Table 1 ). Among the 33 sequenced HLA genes, 9 are classical HLA genes (3 for class I and 6 for class II), and 24 are nonclassical HLA genes (Supplementary Table 2 ; HLA gene classification criteria in Methods ). Whereas alleles of classical HLA genes were highly polymorphic (on average, there were 9.7, 20.1 and 21.6 alleles per gene for two-digit, four-digit and six-digit-level allele information, respectively), those of nonclassical HLA genes showed lower variations (1.4, 3.1 and 4.0 alleles per gene, respectively; Fig. 1a and Supplementary Tables 2 and 3 ). Of these, HLA-B , HLA-DRB1 and MICA had the largest numbers of alleles for class I and II classical HLA<|im_end|> <|im_start|>assistant Although genes are distributed widely across chromosomes, many genes related to the immune system are clustered together on human chromosome 6 in a segment called the major histocompatibility complex (MHC) region. The density of genes there makes it difficult for researchers to characterize them and their effects, but new technologies and large biobanks with data on huge numbers of people have opened the door to deeper insights into this region. In a major new study published in the journal Nature Genetics, researchers at Osaka University and their colleagues have surveyed the MHC region specifically in the Japanese population, revealing the existence of different gene variants and their connections with diseases and other traits. The team based their analyses on three sets of data. One was sequencing information on 33 genes determining white blood cell types in over 1,000 Japanese individuals, obtained by high-throughput sequencing. The second was data from genome-wide association studies looking at links between regions across the whole of the genome and traits and diseases in over 170,000 Japanese individuals. The third set comprised data taken from medical records on over 100 phenotypes reflecting clinical states and other traits. "Our multiple analyses first revealed the levels of polymorphism in the human leukocyte antigen (HLA) genes, then classified the overall patterns of this polymorphism into 11 distinct groups across the Japanese population using a machine learning approach," says lead author Jun Hirata. "This provided insight into the genetic landscape of the MHC region and showed us that 'non-classical' HLA genes should also be included in efforts to characterize the functional effects of this genomic region." The list of the phenotypes associated with the genetic variants in the MHC region. Credit: Osaka University After surveying the full complement of variation across the MHC region in the Japanese individuals, the team then focused on clarifying the associations of these variants with different traits and diseases. For this, they used data from medical records on 106 different phenotypes, including 46 complex diseases, from over 170,000 Japanese individuals. About half of these phenotypes showed significant associations with the studied genes. The findings revealed that it is common for a single gene in the MHC region to influence multiple traits, a phenomenon known as "pleiotropy." "Our work shows the importance of differences in white blood cell type for health in Japanese people," senior author Yukinori Okada says. "The cross-phenotype networks that we constructed also showed correlations between health conditions that were not previously known to be related." The key findings of this work, including the clinical importance of non-classical HLA genes and the effects of gene variants within MHC haplotypes, should provide a solid foundation for future studies on risk factors associated with this part of the genome. <|im_end|>
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2,068
[ { "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 Phase transitions can be used to alter the properties of a material without adding any additional atoms and are therefore of significant technological value. In a solid, phase transitions involve collective atomic displacements, but such atomic processes have so far only been investigated using macroscopic approaches. Here, we show that in situ scanning transmission electron microscopy can be used to follow the structural transformation between semiconducting (2H) and metallic (1T) phases in single-layered MoS 2 , with atomic resolution. The 2H/1T phase transition involves gliding atomic planes of sulphur and/or molybdenum and requires an intermediate phase (α-phase) as a precursor. The migration of two kinds of boundaries (β- and γ-boundaries) is also found to be responsible for the growth of the second phase. Furthermore, we show that areas of the 1T phase can be controllably grown in a layer of the 2H phase using an electron beam. Main For several centuries, molybdenum disulphide (MoS 2 ) has been widely used as a practical solid lubricant 1 , 2 . MoS 2 crystal is composed of stacks of atomic layers bound by van der Waals forces, with each layer constructed from S–Mo–S′ triple atomic planes with strong in-plane bonding. Recently, single-layered MoS 2 , a direct-bandgap quasi-two-dimensional semiconductor, has shown its great potential for applications in electrical and optoelectronic devices 3 , 4 , 5 . Interestingly, one of the unique features of MoS 2 is polymorphism, with its distinct electronic characteristics. Depending on the arrangement of its S atoms, single-layered MoS 2 appears in two distinct symmetries: the 2H (trigonal prismatic D 3h ) and 1T (octahedral O h ) phases ( Fig. 1a,b ). The two phases should exhibit completely different electronic structures, with the 2H phase being semiconducting and the 1T phase metallic 6 , 7 , 8 . The two phases can easily convert one to the other via intralayer atomic plane gliding, which involves a transversal displacement of one of the S planes. The 1T phase was first reported to transform from 2H-MoS 2 by Li and K intercalation 6 , 9 , with restacked 1T phases in LiMoS 2 and KMoS 2 confirmed by electron diffraction 10 , 11 , and it is also known to be stabilized by substitutional doping of Re, Tc and Mn atoms, which serve as electron donors 12 . However, 1T-LiMoS 2 is thermodynamically unfavourable, and has been observed (by Raman spectroscopy 13 ) to gradually transform to the 2H phase at room temperature. The phase transitions between 2H and 1T or 2H′ phases due to atomic plane gliding are presented in Fig. 1c,d . Note that 2H′ is a 60° (or 180°) rotational phase of 2H. Figure 1: Polymorphs of single-layered MoS 2 . a , b , Schematic models of single-layered MoS 2 with 2H ( a ) and 1T ( b ) phases in basal plane and cross-section views. Mo, blue; top S, orange; bottom S′, purple. The incident electron beam transmits from top to bottom. The 2H phase shows a hexagonal lattice with threefold symmetry and the atomic stacking sequence (S–Mo–S′) ABA. The 1T phase shows the atomic stacking sequence (S–Mo–S′) ABC, with the bottom S′ plane occupying the hollow centre (HC) of a 2H hexagonal lattice. c , The S plane glides over a distance equivalent to ( a = 3.16 Å). and occupies the HC site of the 2H hexagon, which results in a 2H → 1T phase transition. d , Gliding of the Mo plane results in a 2H → 2H′ transition. The shadow atomic model shows the original 2H-MoS 2 structure. The three planes (Mo, S and S′) in single-layer MoS 2 can glide individually to give different transitions. Full size image Although the coexistence of metallic and semiconducting phases has indeed been reported in chemically exfoliated MoS 2 by Eda and colleagues 14 , the actual dynamical process of the transformation between 2H and 1T phases involving intralayer atomic plane gliding has never been experimentally proven, nor has the atomic process of the phase transition been investigated in situ . If one is to consider the possibility of intentionally introducing the phase transition in single-layered materials in a controllable manner, the atomic process of this phase transition as well as its boundary structures must be corroborated in order to reliably design future low-dimensional devices. In situ observation of 2H/1T phase transition Here, we provide in situ observations of the transformation process between 2H and 1T phases in single-layered MoS 2 at high temperatures. To monitor the phase transition in situ , we operated an aberration-corrected scanning transmission electron microscope (STEM) at 60 kV to visualize the dynamic process of the atomic motions in single-layered MoS 2 . This technique has already been used and verified while studying another ideal two-dimensional material, graphene, for dislocations 15 , 16 , grain boundaries 17 , 18 , 19 and the dynamics of defect movement 20 , 21 . In the case of MoS 2 , few studies have been carried out, except for those that study defects and the native grain boundary between two MoS 2 domains 22 , 23 , 24 . A MoS 2 specimen doped with 0.6 at% Re was exfoliated and transferred to a microgrid 25 , 26 . To promote the phase transition, the specimen was heated to ∼ 400–700 °C in a microscope to provide thermal activation energy for atom displacement. An example of the phase transition is provided in Fig. 2a–d as sequential annular dark-field (ADF) images, where the step-by-step progress of MoS 2 phase transformation at T = 600 °C is represented (see also Supplementary Movie 1 ). Figure 2e–h presents schematics correlating with the ADF images in Fig. 2a–d to illustrate the structural changes in the MoS 2 lattice. A corresponding model of the atomic movements in the 2H → 1T phase transition is presented in Fig. 2i–k . The Re dopants (indicated by arrowheads in Fig. 2a ) tend to substitute at the", "role": "user" }, { "content": "(Phys.org) —A team of researchers with members from Japan, Taiwan and Switzerland has discovered that it is possible to watch a phase transition occur in a 2D semiconducting material using a scanning transmission electron microscope (STEM). In their paper published in the journal Nature Nanotechnolgy describing their research and results, the team outlines how they used the microscope to watch as a sample of the direct bandgap semiconductor molybdenum sulphide underwent a phase shift. An ability to phase shift between metallic capabilities and a semiconductor is an important feature of a material—one that scientists would like to better understand. Up till now however, researchers had to infer some of what occurs when a material undergoes a phase shift, because they couldn't actually see it as it was happening. In this new effort, the researchers show that it is possible to directly watch a phase shift by doing so with a sample of molybdenum sulphide. In so doing, they have discovered that atom-by-atom movements are part of the shift, rather than complete shifts by a collective. The researchers suggest their observations hint at the prospect of creating layered 2D semiconductors \"in-layer\" rather than as a series of steps where one material is layered over another. That would allow for creating structures with atomic scale precision. Molybdenum sulphide is polymorphic—it can function as either a metal or a semiconductor, depending on how much heat is present. Even better the two phases can be made to interconvert using intralayer atomic plane gliding, (a transversal displacement of one of the materials across the other) though it had never been seen actually doing so. As part of their research, the team performed in situ plane gliding while watching using the STEM, giving them an unprecedented view of what actually occurs as such phase shifting happens. The phase shift with the molybdenum sulphide sample occurred due to the heat exerted by the STEM itself. They suggest such a technique could also be used to induce phase shifting in other 2D materials. The researchers also report that they have already used what they have learned to create several prototype nanodevices—one of which performs the functions of a Schottky diode. ", "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 Phase transitions can be used to alter the properties of a material without adding any additional atoms and are therefore of significant technological value. In a solid, phase transitions involve collective atomic displacements, but such atomic processes have so far only been investigated using macroscopic approaches. Here, we show that in situ scanning transmission electron microscopy can be used to follow the structural transformation between semiconducting (2H) and metallic (1T) phases in single-layered MoS 2 , with atomic resolution. The 2H/1T phase transition involves gliding atomic planes of sulphur and/or molybdenum and requires an intermediate phase (α-phase) as a precursor. The migration of two kinds of boundaries (β- and γ-boundaries) is also found to be responsible for the growth of the second phase. Furthermore, we show that areas of the 1T phase can be controllably grown in a layer of the 2H phase using an electron beam. Main For several centuries, molybdenum disulphide (MoS 2 ) has been widely used as a practical solid lubricant 1 , 2 . MoS 2 crystal is composed of stacks of atomic layers bound by van der Waals forces, with each layer constructed from S–Mo–S′ triple atomic planes with strong in-plane bonding. Recently, single-layered MoS 2 , a direct-bandgap quasi-two-dimensional semiconductor, has shown its great potential for applications in electrical and optoelectronic devices 3 , 4 , 5 . Interestingly, one of the unique features of MoS 2 is polymorphism, with its distinct electronic characteristics. Depending on the arrangement of its S atoms, single-layered MoS 2 appears in two distinct symmetries: the 2H (trigonal prismatic D 3h ) and 1T (octahedral O h ) phases ( Fig. 1a,b ). The two phases should exhibit completely different electronic structures, with the 2H phase being semiconducting and the 1T phase metallic 6 , 7 , 8 . The two phases can easily convert one to the other via intralayer atomic plane gliding, which involves a transversal displacement of one of the S planes. The 1T phase was first reported to transform from 2H-MoS 2 by Li and K intercalation 6 , 9 , with restacked 1T phases in LiMoS 2 and KMoS 2 confirmed by electron diffraction 10 , 11 , and it is also known to be stabilized by substitutional doping of Re, Tc and Mn atoms, which serve as electron donors 12 . However, 1T-LiMoS 2 is thermodynamically unfavourable, and has been observed (by Raman spectroscopy 13 ) to gradually transform to the 2H phase at room temperature. The phase transitions between 2H and 1T or 2H′ phases due to atomic plane gliding are presented in Fig. 1c,d . Note that 2H′ is a 60° (or 180°) rotational phase of 2H. Figure 1: Polymorphs of single-layered MoS 2 . a , b , Schematic models of single-layered MoS 2 with 2H ( a ) and 1T ( b ) phases in basal plane and cross-section views. Mo, blue; top S, orange; bottom S′, purple. The incident electron beam transmits from top to bottom. The 2H phase shows a hexagonal lattice with threefold symmetry and the atomic stacking sequence (S–Mo–S′) ABA. The 1T phase shows the atomic stacking sequence (S–Mo–S′) ABC, with the bottom S′ plane occupying the hollow centre (HC) of a 2H hexagonal lattice. c , The S plane glides over a distance equivalent to ( a = 3.16 Å). and occupies the HC site of the 2H hexagon, which results in a 2H → 1T phase transition. d , Gliding of the Mo plane results in a 2H → 2H′ transition. The shadow atomic model shows the original 2H-MoS 2 structure. The three planes (Mo, S and S′) in single-layer MoS 2 can glide individually to give different transitions. Full size image Although the coexistence of metallic and semiconducting phases has indeed been reported in chemically exfoliated MoS 2 by Eda and colleagues 14 , the actual dynamical process of the transformation between 2H and 1T phases involving intralayer atomic plane gliding has never been experimentally proven, nor has the atomic process of the phase transition been investigated in situ . If one is to consider the possibility of intentionally introducing the phase transition in single-layered materials in a controllable manner, the atomic process of this phase transition as well as its boundary structures must be corroborated in order to reliably design future low-dimensional devices. In situ observation of 2H/1T phase transition Here, we provide in situ observations of the transformation process between 2H and 1T phases in single-layered MoS 2 at high temperatures. To monitor the phase transition in situ , we operated an aberration-corrected scanning transmission electron microscope (STEM) at 60 kV to visualize the dynamic process of the atomic motions in single-layered MoS 2 . This technique has already been used and verified while studying another ideal two-dimensional material, graphene, for dislocations 15 , 16 , grain boundaries 17 , 18 , 19 and the dynamics of defect movement 20 , 21 . In the case of MoS 2 , few studies have been carried out, except for those that study defects and the native grain boundary between two MoS 2 domains 22 , 23 , 24 . A MoS 2 specimen doped with 0.6 at% Re was exfoliated and transferred to a microgrid 25 , 26 . To promote the phase transition, the specimen was heated to ∼ 400–700 °C in a microscope to provide thermal activation energy for atom displacement. An example of the phase transition is provided in Fig. 2a–d as sequential annular dark-field (ADF) images, where the step-by-step progress of MoS 2 phase transformation at T = 600 °C is represented (see also Supplementary Movie 1 ). Figure 2e–h presents schematics correlating with the ADF images in Fig. 2a–d to illustrate the structural changes in the MoS 2 lattice. A corresponding model of the atomic movements in the 2H → 1T phase transition is presented in Fig. 2i–k . The Re dopants (indicated by arrowheads in Fig. 2a ) tend to substitute at the<|im_end|> <|im_start|>assistant (Phys.org) —A team of researchers with members from Japan, Taiwan and Switzerland has discovered that it is possible to watch a phase transition occur in a 2D semiconducting material using a scanning transmission electron microscope (STEM). In their paper published in the journal Nature Nanotechnolgy describing their research and results, the team outlines how they used the microscope to watch as a sample of the direct bandgap semiconductor molybdenum sulphide underwent a phase shift. An ability to phase shift between metallic capabilities and a semiconductor is an important feature of a material—one that scientists would like to better understand. Up till now however, researchers had to infer some of what occurs when a material undergoes a phase shift, because they couldn't actually see it as it was happening. In this new effort, the researchers show that it is possible to directly watch a phase shift by doing so with a sample of molybdenum sulphide. In so doing, they have discovered that atom-by-atom movements are part of the shift, rather than complete shifts by a collective. The researchers suggest their observations hint at the prospect of creating layered 2D semiconductors "in-layer" rather than as a series of steps where one material is layered over another. That would allow for creating structures with atomic scale precision. Molybdenum sulphide is polymorphic—it can function as either a metal or a semiconductor, depending on how much heat is present. Even better the two phases can be made to interconvert using intralayer atomic plane gliding, (a transversal displacement of one of the materials across the other) though it had never been seen actually doing so. As part of their research, the team performed in situ plane gliding while watching using the STEM, giving them an unprecedented view of what actually occurs as such phase shifting happens. The phase shift with the molybdenum sulphide sample occurred due to the heat exerted by the STEM itself. They suggest such a technique could also be used to induce phase shifting in other 2D materials. The researchers also report that they have already used what they have learned to create several prototype nanodevices—one of which performs the functions of a Schottky diode. <|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 central nervous system (CNS) requires a tightly controlled environment free of toxins and pathogens to provide the proper chemical composition for neural function. This environment is maintained by the ‘blood–brain barrier’ (BBB), which is composed of blood vessels whose endothelial cells display specialized tight junctions and extremely low rates of transcellular vesicular transport (transcytosis) 1 , 2 , 3 . In concert with pericytes and astrocytes, this unique brain endothelial physiological barrier seals the CNS and controls substance influx and efflux 4 , 5 , 6 . Although BBB breakdown has recently been associated with initiation and perpetuation of various neurological disorders, an intact BBB is a major obstacle for drug delivery to the CNS 7 , 8 , 9 , 10 . A limited understanding of the molecular mechanisms that control BBB formation has hindered our ability to manipulate the BBB in disease and therapy. Here we identify mechanisms governing the establishment of a functional BBB. First, using a novel tracer-injection method for embryos, we demonstrate spatiotemporal developmental profiles of BBB functionality and find that the mouse BBB becomes functional at embryonic day 15.5 (E15.5). We then screen for BBB-specific genes expressed during BBB formation, and find that major facilitator super family domain containing 2a ( Mfsd2a ) is selectively expressed in BBB-containing blood vessels in the CNS. Genetic ablation of Mfsd2a results in a leaky BBB from embryonic stages through to adulthood, but the normal patterning of vascular networks is maintained. Electron microscopy examination reveals a dramatic increase in CNS-endothelial-cell vesicular transcytosis in Mfsd2a −/− mice, without obvious tight-junction defects. Finally we show that Mfsd2a endothelial expression is regulated by pericytes to facilitate BBB integrity. These findings identify Mfsd2a as a key regulator of BBB function that may act by suppressing transcytosis in CNS endothelial cells. Furthermore, our findings may aid in efforts to develop therapeutic approaches for CNS drug delivery. Main Two unique features of the CNS endothelium determine BBB integrity ( Extended Data Fig. 1 ) 2 . One is specialized tight junctions between a single endothelial cell layer lining the CNS capillaries, which form the physical seal between the blood and brain parenchyma 2 . In addition, CNS endothelial cells have lower rates of transcytosis than endothelial cells in other organs 3 . Peripheral endothelial cells display active vesicle trafficking to deliver nutrients to peripheral tissues, whereas CNS endothelial cells express transporters to selectively traffic nutrients across the BBB 1 , 3 , 11 . However, it is not clear when and how these properties are acquired. Furthermore, the molecular mechanisms that give rise to the unique properties of the CNS endothelium have not been identified. Although recent studies revealed molecular pathways involved in the development of the embryonic BBB 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , disruption of some of these genes affect vascular network development, making it difficult to determine whether barrier defects are primary or secondary to a broader vascular effect. We aimed to first identify the developmental time-point when the BBB gains functional integrity, and then use that time window to profile BBB-specific genes when the BBB is actively forming, to maximize the chance of identifying key regulators. The prevailing view has been that the embryonic and perinatal BBB are not yet functional 1 . However, previous embryonic BBB functionality studies were primarily performed by trans-cardiac tracer perfusion, which may dramatically affect blood pressure, cause bursting of CNS capillaries, and artificially produce leakiness phenotypes 1 , 20 . To circumvent these obstacles, we developed a method to assess BBB integrity during mouse development, in which a small volume of tracer is injected into embryonic liver to minimize changes in blood pressure ( Fig. 1a , see Supplementary Information for the method). Figure 1: A novel tracer-injection method reveals a temporal profile of functional BBB formation in the embryonic cortex. a , In utero embryonic liver tracer injection method; fenestrated liver vasculature enabled rapid tracer uptake into the embryonic circulation. b , Dextran-tracer injection revealed a temporal profile of functional cortical BBB formation. Representative images of dorsal cortical plates from injected embryos after capillary labelling with lectin (green, lectin; red, 10-kDa tracer). Top panel (E13.5), tracer leaked out of capillaries and was subsequently taken up by non-vascular parenchyma cells (arrowheads), with little tracer left inside capillaries (arrow). Middle panel (E14.5), tracer was primarily restricted to capillaries (arrow), with diffused tracer detectable in the parenchyma (arrowheads). Bottom panel (E15.5), tracer was confined to capillaries (arrow). n = 6 embryos (3 litters per age). PowerPoint slide Full size image Using this method, we identified the timing of BBB formation in the developing mouse brain and observed a spatial and temporal pattern of ‘functional-barrier genesis’ ( Fig. 1b ). We found that in E13.5 cortex a 10-kDa dextran tracer leaked out of capillaries and was taken up by non-vascular brain parenchyma cells ( Fig. 1b , top panel). At E14.5, the tracer was primarily restricted to capillaries, but tracer was still detected outside vessels ( Fig. 1b , middle panel). In contrast, at E15.5, the tracer was confined to vessels with no detectable signal in the surrounding brain parenchyma, similar to the mature BBB ( Fig. 1b , bottom panel). The development of BBB functionality differed across brain regions ( Supplementary Information and Extended Data Fig. 2 ). These data demonstrate that following vessel ingression into the neural tube, the BBB gradually becomes functional as early as E15.5. Based on the temporal profile of BBB formation, we compared expression profiles of BBB (cortex) and non-BBB (lung) endothelium at E13.5, using an Affymetrix array ( Supplementary Information ), and identified transcripts with significantly higher representation in cortical than lung endothelium ( Fig. 2 ). These transcripts included transporters, transcription factors, and secreted and transmembrane proteins ( Fig. 2c ). We were particularly interested in transmembrane proteins, owing to their potential involvement in cell–cell interactions that regulate BBB formation. Figure 2: Expression profiling identifies genes involved", "role": "user" }, { "content": "Like a bouncer at an exclusive nightclub, the blood-brain barrier allows only select molecules to pass from the bloodstream into the fluid that bathes the brain. Vital nutrients get in; toxins and pathogens are blocked. The barrier also ensures that waste products are filtered out of the brain and whisked away. The blood-brain barrier helps maintain the delicate environment that allows the human brain to thrive. There's just one problem: The barrier is so discerning, it won't let medicines pass through. Researchers haven't been able to coax it to open up because they don't know enough about how the barrier forms or functions. Now, a team from Harvard Medical School has identified a gene in mice, Mfsd2a, that may beresponsible for limiting the barrier's permeability—and the molecule it produces, Mfsd2a, works in a way few researchers expected. \"Right now, 98 percent of small-molecule drugs and 100 percent of large-molecule drugs and antibodies can't get through the blood-brain barrier,\" said Chenghua Gu, associate professor of neurobiology at HMS and senior author of the study. \"Less than 1 percent of pharmaceuticals even try to target the barrier, because we don't know what the targets are. Mfsd2a could be one.\" Most attempts to understand and manipulate blood-brain barrier function have focused on tight junctions, seals that prevent all but a few substances from squeezing between barrier cells. Gu and her team discovered that Mfsd2a appears to instead affect a second barrier-crossing mechanism that has received much less attention, transcytosis, a process in which substances are transported through the barrier cells in bubbles called vesicles. Transcytosis occurs frequently at other sites in the body but is normally suppressed at the blood-brain barrier. Mfsd2a may be one of the suppressors. \"It's exciting because this is the first molecule identified that inhibits transcytosis,\" said Gu. \"It opens up a new way of thinking about how to design strategies to deliver drugs to the central nervous system.\" Because Mfsd2a has a human equivalent, blocking its activity in people could allow doctors to open the blood-brain barrier briefly and selectively to let in drugs to treat life-threatening conditions such as brain tumors and infections. Conversely, because researchers have begun to link blood-brain barrier degradation to several brain diseases, boosting Mfsd2a or Mfsd2a could allow doctors to strengthen the barrier and perhaps alleviate diseases such as Alzheimer's, amyotrophic lateral sclerosis (ALS) and multiple sclerosis. The findings may also have implications for other areas of the body that rely on transcytosis, such as the retina and kidney. The study was published May 14 in Nature. Back to the beginning As developmental biologists, Gu and her colleagues believed watching the barrier develop in young organisms would reveal molecules important for its formation and function. The team introduced a small amount of dye into the blood of embryonic mice at different stages of development and watched whether it leaked through the walls of the tiny capillaries of the mice's brains, suggesting that the blood-brain barrier hadn't formed yet, or stayed contained within the capillaries, indicating that the barrier was doing its job. This allowed them to define a time window during which the barrier was being built. The team was able to do this by devising a new dye injection technique. Researchers studying blood-brain barrier leakage in adult organisms can inject dye directly into blood vessels, but the capillaries of embryos are too small and delicate. Instead, researchers typically inject dye into the heart. However, according to Gu, this can raise blood pressure and burst brain capillaries, making it difficult to tell whether leakage is due to blood-brain barrier immaturity or the dye procedure itself. She and her team used theirvascular biology expertise to identify an alternate injection site that would avoid such artifacts: the liver. \"This allowed us to provide definitive evidence that the blood-brain barrier comes into play during embryonic development,\" said Ayal Ben-Zvi, a postdoctoral researcher in the Gu lab and first author of the study. \"That changes our understanding of the development of the brain itself.\" Telltale pattern Now that they knew when the barrier formed in the mice, the team compared endothelial cells—the cells that line blood vessel walls and help form the blood-brain barrier—from peripheral blood vessels and cortical (brain) vessels and looked for differences in gene expression. They made a list of genes that were expressed only in the cortical endothelial cells. From thatlist, they validated about a dozen invivo. The team could have studied any of the genes first, but they were most intrigued by Mfsd2a because of its expression pattern. In addition to being switched on in brain vessels, it was active in the placenta and testis, two other organs that have barrier-type functions. Also, the gene is shared across vertebrate organisms that have blood-brain barriers, including humans. Gu and the team then conducted experiments in mice that lacked the Mfsd2a gene. They found that without Mfsd2a, the blood-brain barrier leaked (although it didn't prevent the blood vessels themselves from forming in the first place). The next question was why. \"We focused on two basic characteristics: tight junctions between cells, which prohibit passage of water-soluble molecules, and transcytosis, which happens all the time in peripheral vessels but very little in the cortical vessels,\" said Gu. \"We found the surprising result that Mfsd2a regulates transcytosis without affecting tight junctions. This is exciting because conceptually it says this previously unappreciated feature may be even more important than tight junctions.\" \"At first we were looking at tight junctions, because we were also biased by the field,\" said Ben-Zvi, who will be starting his own lab later this year at The Hebrew University of Jerusalem. \"We weren't finding anything on the electron micrographs even though we knew the vessels leaked. Then we noticed there were tons of vesicles. \"It really shows that if you do systematic science and see something strange, you shouldn't dismiss it, because maybe that's what you're looking for.\" Next steps The team also began to study the relationship between the cortical endothelial cells and another contributor to the blood-brain barrier, cells called pericytes. So far, they have found that pericytes regulate Mfsd2a. Next, they want to learn what exactly the pericytes are telling the endothelial cells to do. Other future work in the Gu lab includes testing the dozen other potential molecular players and trying to piece together the entire network that regulates transcytosis in the blood-brain barrier. \"In addition to Mfsd2a, there may be several other molecules on the list that will be good drug targets,\" said Gu. \"The key here is we are gaining tools to manipulate transcytosis either way: opening or tightening.\" As important as the molecules themselves, she added, is the concept. \"I personally hope people in the blood-brain barrier field will consider the mind-shifting paradigm that transcytosis could be targeted or modulated,\" said Ben-Zvi. Better understanding—and potentially being able to manipulate—the molecular underpinnings of transcytosis could aid in the study and treatment of diseases in tissues beyond the brain, from the intestines absorbing nutrients to the kidneys filtering waste. Being able to open and close the blood-brain barrier also promises to benefit basic research, enabling scientists to investigate how abnormal barrier formation affects brain development and what the relationship may be between barrier deterioration 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 The central nervous system (CNS) requires a tightly controlled environment free of toxins and pathogens to provide the proper chemical composition for neural function. This environment is maintained by the ‘blood–brain barrier’ (BBB), which is composed of blood vessels whose endothelial cells display specialized tight junctions and extremely low rates of transcellular vesicular transport (transcytosis) 1 , 2 , 3 . In concert with pericytes and astrocytes, this unique brain endothelial physiological barrier seals the CNS and controls substance influx and efflux 4 , 5 , 6 . Although BBB breakdown has recently been associated with initiation and perpetuation of various neurological disorders, an intact BBB is a major obstacle for drug delivery to the CNS 7 , 8 , 9 , 10 . A limited understanding of the molecular mechanisms that control BBB formation has hindered our ability to manipulate the BBB in disease and therapy. Here we identify mechanisms governing the establishment of a functional BBB. First, using a novel tracer-injection method for embryos, we demonstrate spatiotemporal developmental profiles of BBB functionality and find that the mouse BBB becomes functional at embryonic day 15.5 (E15.5). We then screen for BBB-specific genes expressed during BBB formation, and find that major facilitator super family domain containing 2a ( Mfsd2a ) is selectively expressed in BBB-containing blood vessels in the CNS. Genetic ablation of Mfsd2a results in a leaky BBB from embryonic stages through to adulthood, but the normal patterning of vascular networks is maintained. Electron microscopy examination reveals a dramatic increase in CNS-endothelial-cell vesicular transcytosis in Mfsd2a −/− mice, without obvious tight-junction defects. Finally we show that Mfsd2a endothelial expression is regulated by pericytes to facilitate BBB integrity. These findings identify Mfsd2a as a key regulator of BBB function that may act by suppressing transcytosis in CNS endothelial cells. Furthermore, our findings may aid in efforts to develop therapeutic approaches for CNS drug delivery. Main Two unique features of the CNS endothelium determine BBB integrity ( Extended Data Fig. 1 ) 2 . One is specialized tight junctions between a single endothelial cell layer lining the CNS capillaries, which form the physical seal between the blood and brain parenchyma 2 . In addition, CNS endothelial cells have lower rates of transcytosis than endothelial cells in other organs 3 . Peripheral endothelial cells display active vesicle trafficking to deliver nutrients to peripheral tissues, whereas CNS endothelial cells express transporters to selectively traffic nutrients across the BBB 1 , 3 , 11 . However, it is not clear when and how these properties are acquired. Furthermore, the molecular mechanisms that give rise to the unique properties of the CNS endothelium have not been identified. Although recent studies revealed molecular pathways involved in the development of the embryonic BBB 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , disruption of some of these genes affect vascular network development, making it difficult to determine whether barrier defects are primary or secondary to a broader vascular effect. We aimed to first identify the developmental time-point when the BBB gains functional integrity, and then use that time window to profile BBB-specific genes when the BBB is actively forming, to maximize the chance of identifying key regulators. The prevailing view has been that the embryonic and perinatal BBB are not yet functional 1 . However, previous embryonic BBB functionality studies were primarily performed by trans-cardiac tracer perfusion, which may dramatically affect blood pressure, cause bursting of CNS capillaries, and artificially produce leakiness phenotypes 1 , 20 . To circumvent these obstacles, we developed a method to assess BBB integrity during mouse development, in which a small volume of tracer is injected into embryonic liver to minimize changes in blood pressure ( Fig. 1a , see Supplementary Information for the method). Figure 1: A novel tracer-injection method reveals a temporal profile of functional BBB formation in the embryonic cortex. a , In utero embryonic liver tracer injection method; fenestrated liver vasculature enabled rapid tracer uptake into the embryonic circulation. b , Dextran-tracer injection revealed a temporal profile of functional cortical BBB formation. Representative images of dorsal cortical plates from injected embryos after capillary labelling with lectin (green, lectin; red, 10-kDa tracer). Top panel (E13.5), tracer leaked out of capillaries and was subsequently taken up by non-vascular parenchyma cells (arrowheads), with little tracer left inside capillaries (arrow). Middle panel (E14.5), tracer was primarily restricted to capillaries (arrow), with diffused tracer detectable in the parenchyma (arrowheads). Bottom panel (E15.5), tracer was confined to capillaries (arrow). n = 6 embryos (3 litters per age). PowerPoint slide Full size image Using this method, we identified the timing of BBB formation in the developing mouse brain and observed a spatial and temporal pattern of ‘functional-barrier genesis’ ( Fig. 1b ). We found that in E13.5 cortex a 10-kDa dextran tracer leaked out of capillaries and was taken up by non-vascular brain parenchyma cells ( Fig. 1b , top panel). At E14.5, the tracer was primarily restricted to capillaries, but tracer was still detected outside vessels ( Fig. 1b , middle panel). In contrast, at E15.5, the tracer was confined to vessels with no detectable signal in the surrounding brain parenchyma, similar to the mature BBB ( Fig. 1b , bottom panel). The development of BBB functionality differed across brain regions ( Supplementary Information and Extended Data Fig. 2 ). These data demonstrate that following vessel ingression into the neural tube, the BBB gradually becomes functional as early as E15.5. Based on the temporal profile of BBB formation, we compared expression profiles of BBB (cortex) and non-BBB (lung) endothelium at E13.5, using an Affymetrix array ( Supplementary Information ), and identified transcripts with significantly higher representation in cortical than lung endothelium ( Fig. 2 ). These transcripts included transporters, transcription factors, and secreted and transmembrane proteins ( Fig. 2c ). We were particularly interested in transmembrane proteins, owing to their potential involvement in cell–cell interactions that regulate BBB formation. Figure 2: Expression profiling identifies genes involved<|im_end|> <|im_start|>assistant Like a bouncer at an exclusive nightclub, the blood-brain barrier allows only select molecules to pass from the bloodstream into the fluid that bathes the brain. Vital nutrients get in; toxins and pathogens are blocked. The barrier also ensures that waste products are filtered out of the brain and whisked away. The blood-brain barrier helps maintain the delicate environment that allows the human brain to thrive. There's just one problem: The barrier is so discerning, it won't let medicines pass through. Researchers haven't been able to coax it to open up because they don't know enough about how the barrier forms or functions. Now, a team from Harvard Medical School has identified a gene in mice, Mfsd2a, that may beresponsible for limiting the barrier's permeability—and the molecule it produces, Mfsd2a, works in a way few researchers expected. "Right now, 98 percent of small-molecule drugs and 100 percent of large-molecule drugs and antibodies can't get through the blood-brain barrier," said Chenghua Gu, associate professor of neurobiology at HMS and senior author of the study. "Less than 1 percent of pharmaceuticals even try to target the barrier, because we don't know what the targets are. Mfsd2a could be one." Most attempts to understand and manipulate blood-brain barrier function have focused on tight junctions, seals that prevent all but a few substances from squeezing between barrier cells. Gu and her team discovered that Mfsd2a appears to instead affect a second barrier-crossing mechanism that has received much less attention, transcytosis, a process in which substances are transported through the barrier cells in bubbles called vesicles. Transcytosis occurs frequently at other sites in the body but is normally suppressed at the blood-brain barrier. Mfsd2a may be one of the suppressors. "It's exciting because this is the first molecule identified that inhibits transcytosis," said Gu. "It opens up a new way of thinking about how to design strategies to deliver drugs to the central nervous system." Because Mfsd2a has a human equivalent, blocking its activity in people could allow doctors to open the blood-brain barrier briefly and selectively to let in drugs to treat life-threatening conditions such as brain tumors and infections. Conversely, because researchers have begun to link blood-brain barrier degradation to several brain diseases, boosting Mfsd2a or Mfsd2a could allow doctors to strengthen the barrier and perhaps alleviate diseases such as Alzheimer's, amyotrophic lateral sclerosis (ALS) and multiple sclerosis. The findings may also have implications for other areas of the body that rely on transcytosis, such as the retina and kidney. The study was published May 14 in Nature. Back to the beginning As developmental biologists, Gu and her colleagues believed watching the barrier develop in young organisms would reveal molecules important for its formation and function. The team introduced a small amount of dye into the blood of embryonic mice at different stages of development and watched whether it leaked through the walls of the tiny capillaries of the mice's brains, suggesting that the blood-brain barrier hadn't formed yet, or stayed contained within the capillaries, indicating that the barrier was doing its job. This allowed them to define a time window during which the barrier was being built. The team was able to do this by devising a new dye injection technique. Researchers studying blood-brain barrier leakage in adult organisms can inject dye directly into blood vessels, but the capillaries of embryos are too small and delicate. Instead, researchers typically inject dye into the heart. However, according to Gu, this can raise blood pressure and burst brain capillaries, making it difficult to tell whether leakage is due to blood-brain barrier immaturity or the dye procedure itself. She and her team used theirvascular biology expertise to identify an alternate injection site that would avoid such artifacts: the liver. "This allowed us to provide definitive evidence that the blood-brain barrier comes into play during embryonic development," said Ayal Ben-Zvi, a postdoctoral researcher in the Gu lab and first author of the study. "That changes our understanding of the development of the brain itself." Telltale pattern Now that they knew when the barrier formed in the mice, the team compared endothelial cells—the cells that line blood vessel walls and help form the blood-brain barrier—from peripheral blood vessels and cortical (brain) vessels and looked for differences in gene expression. They made a list of genes that were expressed only in the cortical endothelial cells. From thatlist, they validated about a dozen invivo. The team could have studied any of the genes first, but they were most intrigued by Mfsd2a because of its expression pattern. In addition to being switched on in brain vessels, it was active in the placenta and testis, two other organs that have barrier-type functions. Also, the gene is shared across vertebrate organisms that have blood-brain barriers, including humans. Gu and the team then conducted experiments in mice that lacked the Mfsd2a gene. They found that without Mfsd2a, the blood-brain barrier leaked (although it didn't prevent the blood vessels themselves from forming in the first place). The next question was why. "We focused on two basic characteristics: tight junctions between cells, which prohibit passage of water-soluble molecules, and transcytosis, which happens all the time in peripheral vessels but very little in the cortical vessels," said Gu. "We found the surprising result that Mfsd2a regulates transcytosis without affecting tight junctions. This is exciting because conceptually it says this previously unappreciated feature may be even more important than tight junctions." "At first we were looking at tight junctions, because we were also biased by the field," said Ben-Zvi, who will be starting his own lab later this year at The Hebrew University of Jerusalem. "We weren't finding anything on the electron micrographs even though we knew the vessels leaked. Then we noticed there were tons of vesicles. "It really shows that if you do systematic science and see something strange, you shouldn't dismiss it, because maybe that's what you're looking for." Next steps The team also began to study the relationship between the cortical endothelial cells and another contributor to the blood-brain barrier, cells called pericytes. So far, they have found that pericytes regulate Mfsd2a. Next, they want to learn what exactly the pericytes are telling the endothelial cells to do. Other future work in the Gu lab includes testing the dozen other potential molecular players and trying to piece together the entire network that regulates transcytosis in the blood-brain barrier. "In addition to Mfsd2a, there may be several other molecules on the list that will be good drug targets," said Gu. "The key here is we are gaining tools to manipulate transcytosis either way: opening or tightening." As important as the molecules themselves, she added, is the concept. "I personally hope people in the blood-brain barrier field will consider the mind-shifting paradigm that transcytosis could be targeted or modulated," said Ben-Zvi. Better understanding—and potentially being able to manipulate—the molecular underpinnings of transcytosis could aid in the study and treatment of diseases in tissues beyond the brain, from the intestines absorbing nutrients to the kidneys filtering waste. Being able to open and close the blood-brain barrier also promises to benefit basic research, enabling scientists to investigate how abnormal barrier formation affects brain development and what the relationship may be between barrier deterioration and disease. <|im_end|>
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2,993
[ { "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 Ionic liquid (IL)-water mixtures can exhibit a lower critical solution temperature (LCST) transition, but changes in long-range order and local molecular environment during this transition are not comprehensively understood. Here we show that in IL-H 2 O LCST mixtures, the IL forms loosely held aggregate structures that grow in size leading up to a critical temperature, whereas the aggregation of a fully miscible aqueous mixture, obtained by minor chemical modification of the anion, decreases with increasing temperature. Radial distribution functions from molecular dynamics simulations support the observation of aggregation phenomena in the IL-H 2 O mixtures. A local molecular structure of the ions is derived from multi-dimensional NMR experiments in conjunction with reported molecular dynamics simulations. In addition to considerable shifts of water’s hydrogen bonding network in the fully miscible phase, by NMR we observe the anion’s protons response to the intermolecular thermal environment and the intramolecular environment and find that the responses are determined by the sulfonate ionic functional group. Introduction Room temperature ILs (RTILs) are ionic materials with a melting point below 100 °C due to functional groups introducing steric hindrance and preventing closed packing structures. Owing to their ionic character, ILs have a number of desirable attributes, such as negligible vapor pressure, high ionic conductance, and often high thermal and chemical stability 1 , 2 , 3 , 4 . The physicochemical properties of ionic liquids can be tailored by chemical modification of the cation and/or anion, leading to a vast number (>10 14 ) of distinct ionic liquid combinations 5 . This presents an enormous library of ionic liquids to fully explore. To date, much of the fundamental and applied studies have focused on the imidazolium cation-based ILs 6 , 7 , 8 , 9 . A subclass of ionic liquids undergoes a thermoresponsive liquid–liquid phase transition of either an upper critical solution temperature (UCST) or lower critical solution temperature (LCST). Such thermoresponsive IL-based mixtures have opened up new potential applications such as protein extraction 10 , 11 , 12 , metal ion extraction 13 , and forward osmosis draw solutes for water purification 14 , 15 , 16 , 17 , 18 . In liquid–liquid mixtures with a LCST transition, a single and miscible phase appears at lower temperatures. However, upon heating above a critical temperature T c , the single-phase liquid–liquid mixture separates into two immiscible phases. From a thermodynamic view, this behavior is understood in the framework of equation (1), where ΔG mix is the free energy of mixing, ΔH mix is the enthalpy of mixing, and ΔS mix is the entropy of mixing. $${\\it{\\Delta }}G_{{{mix}}} = {\\it{\\Delta }}H_{{{mix}}} - T\\Delta S_{{{mix}}}$$ (1) At lower temperatures, strong intermolecular interactions, such as hydrogen bonding, lead to a negative enthalpy of mixing and formation of a miscible phase between the two components. These intermolecular interactions are often highly directional and come at an entropic cost. Upon heating above T c , the entropic term dominates as intermolecular interactions are broken, and the system entropy can increase by phase separation due to increased degrees of freedom from the broken intermolecular interactions 19 , 20 or if dispersion forces between two like components (A–A) and (B–B) is greater than between unlike components (A–B) 21 . While this type of behavior has been observed for many polymer-solvent systems, there are fewer cases of small molecule LCST mixtures. Ionic liquids exhibiting a LCST in aqueous mixtures have been developed by Ohno and coworkers 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 . Their argument for the physicochemical conditions necessary for LCST behavior between an ionic liquid and water mixtures is the balance between the hydrophilic and hydrophobic character of the component positive and negative ions 26 . If both the anion and cation are too hydrophobic, aqueous mixtures will be immiscible over the whole temperature range, and conversely, if both components are too hydrophilic, aqueous mixtures will remain fully miscible independent of temperature. In studying related protonated tertiary amines, our team has found that is not the total organic content of the molecular ions that drive this phenomena but the proximity of the organic content to the charged center 30 . Recent studies have attempted to understand the molecular interactions responsible for the IL-water LCST transition. FT-IR spectroscopic probing of tetrabutylphosphonium [P 4444 ] 4-vinylbenezenesulfonate-water mixtures concluded that the C–H functional groups of the cation responded first to a temperature perturbation, followed by the sulfonate group of the anion. The mechanism proposed that the cation initiates conformational changes (due to greater hydrophobic interaction with water) forming single cation–anion ion pair aggregates due to strong coulombic forces 31 . A different IL-H 2 O LCST mixture obtained by replacing the 4-vinylbenezenesulfonate anion with trifluoroacetate ([P 4444 ][CF 3 COO]) was studied to examine the hydrophilic nature of the ions using 1-propanol probing methodology. The results found that [P 4444 ] showed equally strong hydrophilic and hydrophobic character, whereas the anion exhibited slightly hydrophobic character. The number of water molecules hydrating the cation was 10 times that of the anion and this large hydration shell of the cation results in an unfavorable entropy of mixing 32 . Cations are known to require greater hydration than anions 33 , and the largely neutral polarity (neither polar nor non-polar) of the [P 4444 ] further explains why to date many of the observed IL-H 2 O LCST mixtures are based on quaternary ammonium and phosphonium cations 34 . MD simulations demonstrated that the LCST transition of [P 6668 ] and amino acid anions in aqueous solutions occurs by temperature-dependent changes in intermolecular interactions between the anion, cation, and water 35 . Specifically, the anion’s functional groups, –NH 2 and –COOH, are able to form a hydrogen bond to the carboxylate group of another anion. Similar interactions between anions are believed to play a role in the self-assembly of tertiary amine bicarbonates 30 . With increasing temperature, the anion-water and cation–anion interactions weaken, whereas anion–anion interactions", "role": "user" }, { "content": "As populations boom and chronic droughts persist, coastal cities like Carlsbad in Southern California have increasingly turned to ocean desalination to supplement a dwindling fresh water supply. Now scientists at the Department of Energy's Lawrence Berkeley National Laboratory (Berkeley Lab) investigating how to make desalination less expensive have hit on promising design rules for making so-called \"thermally responsive\" ionic liquids to separate water from salt. Ionic liquids are a liquid salt that binds to water, making them useful in forward osmosis to separate contaminants from water. (See Berkeley Lab Q&A, \"Moving Forward on Desalination\") Even better are thermally responsive ionic liquids as they use thermal energy rather than electricity, which is required by conventional reverse osmosis (RO) desalination for the separation. The new Berkeley Lab study, published recently in the journal Nature Communications Chemistry, studied the chemical structures of several types of ionic liquid/water to determine what \"recipe\" would work best. \"The current state-of-the-art in RO desalination works very well, but the cost of RO desalination driven by electricity is prohibitive,\" said Robert Kostecki, co-corresponding author of the study. \"Our study shows that the use of low-cost \"free\" heat—such as geothermal or solar heat or industrial waste heat generated by machines—combined with thermally responsive ionic liquids could offset a large fraction of costs that goes into current RO desalination technologies that solely rely on electricity.\" Kostecki, deputy director of the Energy Storage and Distributed Resources (ESDR) Division in Berkeley Lab's Energy Technologies Area, partnered with co-corresponding author Jeff Urban, a staff scientist in Berkeley Lab's Molecular Foundry, to investigate the behavior of ionic liquids in water at the molecular level. Using nuclear magnetic resonance spectroscopy and dynamic light scattering provided by researchers in the ESDR Division, as well as molecular dynamics simulation techniques at the Molecular Foundry, the team made an unexpected finding. Berkeley Lab scientists investigating how to make desalination less expensive have hit on promising design rules for making so-called \"thermally responsive\" ionic liquids to separate water from salt. Credit: Berkeley Lab It was long thought that an effective ionic liquid separation relied on the overall ratio of organic components (parts of the ionic liquid that are neither positively or negatively charged) to its positively charged ions, explained Urban. But the Berkeley Lab team learned that the number of water molecules an ionic liquid can separate from seawater depends on the proximity of its organic components to its positively charged ions. \"This result was completely unexpected,\" Urban said. \"With it, we now have rules of design for which atoms in ionic liquids are doing the hard work in desalination.\" A decades-old membrane-based reverse osmosis technology originally developed at UCLA in the 1950s, is experiencing a resurgence—currently there are 11 desalination plants in California, and more have been proposed. Berkeley Lab scientists, through the Water-Energy Resilience Research Institute, are pursuing a range of technologies for improving the reliability of the U.S. water system, including advanced water treatments technologies such as desalination. Because forward osmosis uses heat instead of electricity, the thermal energy can be provided by renewable sources such as geothermal and solar or industrial low-grade heat. \"Our study is an important step toward lowering the cost of desalination,\" added Kostecki. \"It's also a great example of what's possible in the national lab system, where interdisciplinary collaborations between the basic sciences and applied sciences can lead to creative solutions to hard problems benefiting generations to come.\" Also contributing to the study were researchers from UC Berkeley and Idaho National Laboratory. The Molecular Foundry is a DOE Office of Science User Facility that specializes in nanoscale science. This work was supported by the U.S. Department of Energy's Office of Energy Efficiency and Renewable Energy. ", "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 Ionic liquid (IL)-water mixtures can exhibit a lower critical solution temperature (LCST) transition, but changes in long-range order and local molecular environment during this transition are not comprehensively understood. Here we show that in IL-H 2 O LCST mixtures, the IL forms loosely held aggregate structures that grow in size leading up to a critical temperature, whereas the aggregation of a fully miscible aqueous mixture, obtained by minor chemical modification of the anion, decreases with increasing temperature. Radial distribution functions from molecular dynamics simulations support the observation of aggregation phenomena in the IL-H 2 O mixtures. A local molecular structure of the ions is derived from multi-dimensional NMR experiments in conjunction with reported molecular dynamics simulations. In addition to considerable shifts of water’s hydrogen bonding network in the fully miscible phase, by NMR we observe the anion’s protons response to the intermolecular thermal environment and the intramolecular environment and find that the responses are determined by the sulfonate ionic functional group. Introduction Room temperature ILs (RTILs) are ionic materials with a melting point below 100 °C due to functional groups introducing steric hindrance and preventing closed packing structures. Owing to their ionic character, ILs have a number of desirable attributes, such as negligible vapor pressure, high ionic conductance, and often high thermal and chemical stability 1 , 2 , 3 , 4 . The physicochemical properties of ionic liquids can be tailored by chemical modification of the cation and/or anion, leading to a vast number (>10 14 ) of distinct ionic liquid combinations 5 . This presents an enormous library of ionic liquids to fully explore. To date, much of the fundamental and applied studies have focused on the imidazolium cation-based ILs 6 , 7 , 8 , 9 . A subclass of ionic liquids undergoes a thermoresponsive liquid–liquid phase transition of either an upper critical solution temperature (UCST) or lower critical solution temperature (LCST). Such thermoresponsive IL-based mixtures have opened up new potential applications such as protein extraction 10 , 11 , 12 , metal ion extraction 13 , and forward osmosis draw solutes for water purification 14 , 15 , 16 , 17 , 18 . In liquid–liquid mixtures with a LCST transition, a single and miscible phase appears at lower temperatures. However, upon heating above a critical temperature T c , the single-phase liquid–liquid mixture separates into two immiscible phases. From a thermodynamic view, this behavior is understood in the framework of equation (1), where ΔG mix is the free energy of mixing, ΔH mix is the enthalpy of mixing, and ΔS mix is the entropy of mixing. $${\it{\Delta }}G_{{{mix}}} = {\it{\Delta }}H_{{{mix}}} - T\Delta S_{{{mix}}}$$ (1) At lower temperatures, strong intermolecular interactions, such as hydrogen bonding, lead to a negative enthalpy of mixing and formation of a miscible phase between the two components. These intermolecular interactions are often highly directional and come at an entropic cost. Upon heating above T c , the entropic term dominates as intermolecular interactions are broken, and the system entropy can increase by phase separation due to increased degrees of freedom from the broken intermolecular interactions 19 , 20 or if dispersion forces between two like components (A–A) and (B–B) is greater than between unlike components (A–B) 21 . While this type of behavior has been observed for many polymer-solvent systems, there are fewer cases of small molecule LCST mixtures. Ionic liquids exhibiting a LCST in aqueous mixtures have been developed by Ohno and coworkers 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 . Their argument for the physicochemical conditions necessary for LCST behavior between an ionic liquid and water mixtures is the balance between the hydrophilic and hydrophobic character of the component positive and negative ions 26 . If both the anion and cation are too hydrophobic, aqueous mixtures will be immiscible over the whole temperature range, and conversely, if both components are too hydrophilic, aqueous mixtures will remain fully miscible independent of temperature. In studying related protonated tertiary amines, our team has found that is not the total organic content of the molecular ions that drive this phenomena but the proximity of the organic content to the charged center 30 . Recent studies have attempted to understand the molecular interactions responsible for the IL-water LCST transition. FT-IR spectroscopic probing of tetrabutylphosphonium [P 4444 ] 4-vinylbenezenesulfonate-water mixtures concluded that the C–H functional groups of the cation responded first to a temperature perturbation, followed by the sulfonate group of the anion. The mechanism proposed that the cation initiates conformational changes (due to greater hydrophobic interaction with water) forming single cation–anion ion pair aggregates due to strong coulombic forces 31 . A different IL-H 2 O LCST mixture obtained by replacing the 4-vinylbenezenesulfonate anion with trifluoroacetate ([P 4444 ][CF 3 COO]) was studied to examine the hydrophilic nature of the ions using 1-propanol probing methodology. The results found that [P 4444 ] showed equally strong hydrophilic and hydrophobic character, whereas the anion exhibited slightly hydrophobic character. The number of water molecules hydrating the cation was 10 times that of the anion and this large hydration shell of the cation results in an unfavorable entropy of mixing 32 . Cations are known to require greater hydration than anions 33 , and the largely neutral polarity (neither polar nor non-polar) of the [P 4444 ] further explains why to date many of the observed IL-H 2 O LCST mixtures are based on quaternary ammonium and phosphonium cations 34 . MD simulations demonstrated that the LCST transition of [P 6668 ] and amino acid anions in aqueous solutions occurs by temperature-dependent changes in intermolecular interactions between the anion, cation, and water 35 . Specifically, the anion’s functional groups, –NH 2 and –COOH, are able to form a hydrogen bond to the carboxylate group of another anion. Similar interactions between anions are believed to play a role in the self-assembly of tertiary amine bicarbonates 30 . With increasing temperature, the anion-water and cation–anion interactions weaken, whereas anion–anion interactions<|im_end|> <|im_start|>assistant As populations boom and chronic droughts persist, coastal cities like Carlsbad in Southern California have increasingly turned to ocean desalination to supplement a dwindling fresh water supply. Now scientists at the Department of Energy's Lawrence Berkeley National Laboratory (Berkeley Lab) investigating how to make desalination less expensive have hit on promising design rules for making so-called "thermally responsive" ionic liquids to separate water from salt. Ionic liquids are a liquid salt that binds to water, making them useful in forward osmosis to separate contaminants from water. (See Berkeley Lab Q&A, "Moving Forward on Desalination") Even better are thermally responsive ionic liquids as they use thermal energy rather than electricity, which is required by conventional reverse osmosis (RO) desalination for the separation. The new Berkeley Lab study, published recently in the journal Nature Communications Chemistry, studied the chemical structures of several types of ionic liquid/water to determine what "recipe" would work best. "The current state-of-the-art in RO desalination works very well, but the cost of RO desalination driven by electricity is prohibitive," said Robert Kostecki, co-corresponding author of the study. "Our study shows that the use of low-cost "free" heat—such as geothermal or solar heat or industrial waste heat generated by machines—combined with thermally responsive ionic liquids could offset a large fraction of costs that goes into current RO desalination technologies that solely rely on electricity." Kostecki, deputy director of the Energy Storage and Distributed Resources (ESDR) Division in Berkeley Lab's Energy Technologies Area, partnered with co-corresponding author Jeff Urban, a staff scientist in Berkeley Lab's Molecular Foundry, to investigate the behavior of ionic liquids in water at the molecular level. Using nuclear magnetic resonance spectroscopy and dynamic light scattering provided by researchers in the ESDR Division, as well as molecular dynamics simulation techniques at the Molecular Foundry, the team made an unexpected finding. Berkeley Lab scientists investigating how to make desalination less expensive have hit on promising design rules for making so-called "thermally responsive" ionic liquids to separate water from salt. Credit: Berkeley Lab It was long thought that an effective ionic liquid separation relied on the overall ratio of organic components (parts of the ionic liquid that are neither positively or negatively charged) to its positively charged ions, explained Urban. But the Berkeley Lab team learned that the number of water molecules an ionic liquid can separate from seawater depends on the proximity of its organic components to its positively charged ions. "This result was completely unexpected," Urban said. "With it, we now have rules of design for which atoms in ionic liquids are doing the hard work in desalination." A decades-old membrane-based reverse osmosis technology originally developed at UCLA in the 1950s, is experiencing a resurgence—currently there are 11 desalination plants in California, and more have been proposed. Berkeley Lab scientists, through the Water-Energy Resilience Research Institute, are pursuing a range of technologies for improving the reliability of the U.S. water system, including advanced water treatments technologies such as desalination. Because forward osmosis uses heat instead of electricity, the thermal energy can be provided by renewable sources such as geothermal and solar or industrial low-grade heat. "Our study is an important step toward lowering the cost of desalination," added Kostecki. "It's also a great example of what's possible in the national lab system, where interdisciplinary collaborations between the basic sciences and applied sciences can lead to creative solutions to hard problems benefiting generations to come." Also contributing to the study were researchers from UC Berkeley and Idaho National Laboratory. The Molecular Foundry is a DOE Office of Science User Facility that specializes in nanoscale science. This work was supported by the U.S. Department of Energy's Office of Energy Efficiency and Renewable Energy. <|im_end|>
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2,279
[ { "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 Memory impairment following West Nile virus neuroinvasive disease (WNND) is associated with loss of hippocampal synapses with lack of recovery. Adult neurogenesis and synaptogenesis are fundamental features of hippocampal repair, which suggests that viruses affect these processes. Here, in an established model of WNND-induced cognitive dysfunction, transcriptional profiling revealed alterations in the expression of genes encoding molecules that limit adult neurogenesis, including interleukin 1 (IL-1). Mice that had recovered from WNND exhibited fewer neuroblasts and increased astrogenesis without recovery of hippocampal neurogenesis at 30 d. Analysis of cytokine production in microglia and astrocytes isolated ex vivo revealed that the latter were the predominant source of IL-1. Mice deficient in the IL-1 receptor IL-1R1 and that had recovered from WNND exhibited normal neurogenesis, recovery of presynaptic termini and resistance to spatial learning defects, the last of which likewise occurred after treatment with an IL-1R1 antagonist. Thus, ‘preferential’ generation of proinflammatory astrocytes impaired the homeostasis of neuronal progenitor cells via expression of IL-1; this might underlie the long-term cognitive consequences of WNND but also provides a therapeutic target. Main Members of the Flavivirus genus, which include West Nile virus (WNV), Japanese encephalitis virus and Zika virus, are the most important arthropod-borne viruses that cause encephalitis in humans 1 . Acutely, patients suffering from WNV neuroinvasive disease (WNND) can experience confusion, fatigue, loss of motor control, memory loss and coma, and acute WNND has a mortality rate of 5–10% (ref. 1 ). WNV is a (+)-sense single-stranded RNA virus that targets fully differentiated neurons but can be cleared by immune-system-mediated processes, even after infection of the central nervous system (CNS) 2 . However, approximately half of the survivors of WNND experience debilitating, long-term cognitive sequelae, including defects in verbal and visuospatial learning, for months to years beyond the acute infectious event 3 , 4 . Animal studies have identified multiple cytokines with critical roles in cell-mediated antiviral immunity, including tumor-necrosis factor (TNF) 5 , type I, II and III interferons 6 , 7 , 8 , 9 and interleukin 1 (IL-1) 10 , 11 , that improve survival. Published studies have determined that human and mouse neurons are the target of WNV in vivo 12 , 13 , 14 . Notably, studies in which critical cytokines have been deleted via genetic approaches have not led to expanded tropism of WNV to non-neuronal cells within the CNS 10 , 15 . While neuronal death is associated with high mortality of WNV encephalitis in humans and mice 16 , survivors may exhibit limited neuronal loss 14 , 17 , which suggests that inflammatory processes triggered acutely contribute to long-term memory dysfunction. The fact that many patients recovering from WNND experience memory impairments for months to years beyond viral clearance indeed suggests a chronic condition with either sustained damage or limited repair. In a mouse model of recovery from WNND in which intracranial inoculation of an attenuated mutant WNV (WNV-NS5-E218A) leads to high survival rates with visuospatial learning defects, hippocampi exhibit upregulation of genes encoding molecules involved in microglia-mediated synaptic remodeling, including drivers of phagocytosis and the classical complement pathway, and decreased expression of genes encoding synaptic scaffolding proteins and glutamate receptors 14 . Complement-mediated elimination of synapses has been reported to occur in numerous neuroinflammatory diseases, including multiple sclerosis 18 , Alzheimer’s disease 19 and schizophrenia 20 , which suggests that this might be a general mechanism underlying inflammation-associated disruption of neural circuitry. The hippocampus, which is essential for spatial and contextual memory formation, receives input from the entorhinal cortex, which relays through the dentate gyrus (DG) and regions CA3 and CA1 21 . Mice that have recovered from WNV-NS5-E218A infection with poor spatial learning show persistence of phagocytic microglia engulfing presynaptic terminals within hippocampal region CA3 both acutely and during recovery 14 . While this provides a molecular explanation for the poor spatial learning in mice that have recovered from WNV infection, it does not explain why other hippocampal correlates of learning, such as adult neurogenesis, are not able to restore spatial learning. Adult neurogenesis occurs within the hippocampal DG and the subventricular zone (SVZ) 22 . Within the DG, adult neural stem cells give rise to astrocytes and intermediate neuronal progenitor cells, the latter of which proliferate and differentiate into neuroblasts that mature into granule-cell neurons and integrate into the hippocampal circuit over the course of a few weeks 23 . This process is regulated by intrinsic and extrinsic factors, including local signaling molecules, exercise, aging and inflammation 24 . A variety of endogenous factors have critical roles in the generation and integration of newly generated neurons in the adult hippocampus. These include morphogens, such as neurogenic Notch proteins, Shh, Wnts and BMPs, and neurotrophic factors, such as BDNF, CNTF, IGF-1 and VEGF 25 . Proinflammatory pathways, including those triggered by systemic accumulation of TNF, IL-1β and IL-6, and microglial activation have been linked to the regulation of neural correlates of memory, including adult neurogenesis, synaptic plasticity and modulation of long-term potentiation 14 , 26 , 27 , 28 , 29 . IL-1, in particular, has gained attention for its effect on cognitive function in the context of neuroinflammation. IL-1 signaling is mediated by a family of proteins comprising IL-1α, the anti-neurogenic cytokine IL-1β and IL-1 receptor antagonist, mainly through the type I IL-1 receptor (IL-1R1). IL-1β is generated via proteolytic cleavage of pro-IL-1β by caspase-1 during inflammasome activation 30 . IL-1 has high expression in vivo by infiltrating myeloid cells during WNV encephalitis, during which it critically regulates antiviral effector T cell responses 10 , 11 . While IL-1 is a key player in the orchestration of CNS immune responses, including the onset of fever 27 , it also has a role in spatial learning and memory-related behavior 28 . Indeed, injection of IL-1β into the brain impairs spatial learning, contextual fear memory and adult neurogenesis 29 , 30 , 31 . Although several studies have investigated the effects of IL-1 on hippocampus-based learning and behavior in neurologic diseases 31 ,", "role": "user" }, { "content": "More than 10,000 people in the United States are living with memory loss and other persistent neurological problems that occur after West Nile virus infects the brain. Now, a new study in mice suggests that such ongoing neurological deficits may be due to unresolved inflammation that hinders the brain's ability to repair damaged neurons and grow new ones. When the inflammation was reduced by treatment with an arthritis drug, the animals' ability to learn and remember remained sharp after West Nile disease. \"These memory disturbances make it hard for people to hold down a job, to drive, to take care of all the duties of everyday life,\" said senior author Robyn Klein, MD, Ph.D., a professor of medicine at Washington University School of Medicine in St. Louis. \"We found that targeting the inflammation with the arthritis drug could prevent some of these problems with memory.\" The findings are available online in Nature Immunology. Spread by the bite of a mosquito, West Nile virus can cause fever and sometimes life-threatening brain infections known as West Nile encephalitis. About half the people who survive the encephalitis are left with permanent neurological problems such as disabling fatigue, weakness, difficulty walking and memory loss. These problems not only persist but often worsen with time. Klein and colleagues previously had shown that during West Nile encephalitis, the patient's own immune system destroys parts of neurons, leading to memory problems. \"We started wondering why the damage isn't repaired after the virus is cleared from the brain,\" said Klein, vice provost and associate dean for graduate education for the Division of Biology & Biomedical Sciences. \"We know that neurons are produced in the part of the brain involved in learning and memory, so why weren't new neurons being made after West Nile infection?\" To find out, Klein; co-first authors Michael Vasek, a postdoc researcher, and graduate research assistant Charise Garber; and colleagues injected mice with West Nile virus or saltwater. During the acute infection, the mice received several doses of a chemical compound that tags neural cells as they are formed. Forty-five days after infection, the researchers isolated the tagged cells from the mice's brains and assessed how many and what kinds of cells had been formed during the first week of infection. Mice ill with West Nile disease produced fewer neurons and more astrocytes – a star-shaped neural cell – than uninfected mice. Astrocytes normally provide nutrition for neurons, but the ones formed during West Nile infection behaved like immune cells, churning out an inflammatory protein known as IL-1. IL-1 is an indispensable part of the body's immune system. It is produced by immune cells that swarm into the brain to fight invading viruses. Once the battle is won, the immune cells depart and IL-1 levels in the brain fall. But in mice recovering from West Nile infection, astrocytes continue to produce IL-1 even after the virus is gone. Since IL-1 guides precursor cells down the path toward becoming astrocytes and away from developing into neurons, a vicious cycle emerges: Astrocytes produce IL-1, which leads to more astrocytes while also preventing new neurons from arising. Hampered by an inability to grow new neurons, the brain fails to repair the neurological damage sustained during infection, the researchers said. \"It's almost like the brain gets caught in a loop that keeps IL-1 levels high and prevents it from repairing itself,\" said Klein, who is also a professor of neuroscience and of pathology and immunology. To see whether the cycle could be broken, Klein and colleagues infected mice with either West Nile virus or saltwater as a mock infection. Ten days later, they treated both groups of mice with a placebo or with anakinra, an FDA-approved arthritis drug that interferes with IL-1. After giving the mice a month to recover, they tested the animals' ability to learn and remember by placing them inside a maze. Mice that had been infected with West Nile virus and treated with a placebo took longer to learn the maze than mock-infected mice. Mice that were infected and treated with the IL-1 blocker learned just as quickly as mock-infected mice, indicating that blocking IL-1 protected the mice from memory problems. \"When we treated the mice during the acute phase with a drug that blocks IL-1 signaling, we prevented the memory disturbance,\" Klein said. \"The cycle gets reversed back: They stop making astrocytes, they start making new neurons, and they repair the damaged connections between neurons.\" But, Klein cautions, IL-1 itself may not be a good drug target for people because of the important role it plays in fighting viruses. Suppressing IL-1 while the virus is still in the brain could exacerbate encephalitis, already a potentially lethal condition. \"This is a proof of concept that a drug can prevent cognitive impairments caused by viral encephalitis,\" Klein said. \"This study sheds light on not just post-viral memory disturbances but other types of memory disorders as well. It may turn out that IL-1 is not a feasible target during viral infections, but these findings could lead to new therapeutic targets that are less problematic for clearing virus or to therapies for neurologic diseases of memory impairment that are not caused by viruses.\" ", "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 Memory impairment following West Nile virus neuroinvasive disease (WNND) is associated with loss of hippocampal synapses with lack of recovery. Adult neurogenesis and synaptogenesis are fundamental features of hippocampal repair, which suggests that viruses affect these processes. Here, in an established model of WNND-induced cognitive dysfunction, transcriptional profiling revealed alterations in the expression of genes encoding molecules that limit adult neurogenesis, including interleukin 1 (IL-1). Mice that had recovered from WNND exhibited fewer neuroblasts and increased astrogenesis without recovery of hippocampal neurogenesis at 30 d. Analysis of cytokine production in microglia and astrocytes isolated ex vivo revealed that the latter were the predominant source of IL-1. Mice deficient in the IL-1 receptor IL-1R1 and that had recovered from WNND exhibited normal neurogenesis, recovery of presynaptic termini and resistance to spatial learning defects, the last of which likewise occurred after treatment with an IL-1R1 antagonist. Thus, ‘preferential’ generation of proinflammatory astrocytes impaired the homeostasis of neuronal progenitor cells via expression of IL-1; this might underlie the long-term cognitive consequences of WNND but also provides a therapeutic target. Main Members of the Flavivirus genus, which include West Nile virus (WNV), Japanese encephalitis virus and Zika virus, are the most important arthropod-borne viruses that cause encephalitis in humans 1 . Acutely, patients suffering from WNV neuroinvasive disease (WNND) can experience confusion, fatigue, loss of motor control, memory loss and coma, and acute WNND has a mortality rate of 5–10% (ref. 1 ). WNV is a (+)-sense single-stranded RNA virus that targets fully differentiated neurons but can be cleared by immune-system-mediated processes, even after infection of the central nervous system (CNS) 2 . However, approximately half of the survivors of WNND experience debilitating, long-term cognitive sequelae, including defects in verbal and visuospatial learning, for months to years beyond the acute infectious event 3 , 4 . Animal studies have identified multiple cytokines with critical roles in cell-mediated antiviral immunity, including tumor-necrosis factor (TNF) 5 , type I, II and III interferons 6 , 7 , 8 , 9 and interleukin 1 (IL-1) 10 , 11 , that improve survival. Published studies have determined that human and mouse neurons are the target of WNV in vivo 12 , 13 , 14 . Notably, studies in which critical cytokines have been deleted via genetic approaches have not led to expanded tropism of WNV to non-neuronal cells within the CNS 10 , 15 . While neuronal death is associated with high mortality of WNV encephalitis in humans and mice 16 , survivors may exhibit limited neuronal loss 14 , 17 , which suggests that inflammatory processes triggered acutely contribute to long-term memory dysfunction. The fact that many patients recovering from WNND experience memory impairments for months to years beyond viral clearance indeed suggests a chronic condition with either sustained damage or limited repair. In a mouse model of recovery from WNND in which intracranial inoculation of an attenuated mutant WNV (WNV-NS5-E218A) leads to high survival rates with visuospatial learning defects, hippocampi exhibit upregulation of genes encoding molecules involved in microglia-mediated synaptic remodeling, including drivers of phagocytosis and the classical complement pathway, and decreased expression of genes encoding synaptic scaffolding proteins and glutamate receptors 14 . Complement-mediated elimination of synapses has been reported to occur in numerous neuroinflammatory diseases, including multiple sclerosis 18 , Alzheimer’s disease 19 and schizophrenia 20 , which suggests that this might be a general mechanism underlying inflammation-associated disruption of neural circuitry. The hippocampus, which is essential for spatial and contextual memory formation, receives input from the entorhinal cortex, which relays through the dentate gyrus (DG) and regions CA3 and CA1 21 . Mice that have recovered from WNV-NS5-E218A infection with poor spatial learning show persistence of phagocytic microglia engulfing presynaptic terminals within hippocampal region CA3 both acutely and during recovery 14 . While this provides a molecular explanation for the poor spatial learning in mice that have recovered from WNV infection, it does not explain why other hippocampal correlates of learning, such as adult neurogenesis, are not able to restore spatial learning. Adult neurogenesis occurs within the hippocampal DG and the subventricular zone (SVZ) 22 . Within the DG, adult neural stem cells give rise to astrocytes and intermediate neuronal progenitor cells, the latter of which proliferate and differentiate into neuroblasts that mature into granule-cell neurons and integrate into the hippocampal circuit over the course of a few weeks 23 . This process is regulated by intrinsic and extrinsic factors, including local signaling molecules, exercise, aging and inflammation 24 . A variety of endogenous factors have critical roles in the generation and integration of newly generated neurons in the adult hippocampus. These include morphogens, such as neurogenic Notch proteins, Shh, Wnts and BMPs, and neurotrophic factors, such as BDNF, CNTF, IGF-1 and VEGF 25 . Proinflammatory pathways, including those triggered by systemic accumulation of TNF, IL-1β and IL-6, and microglial activation have been linked to the regulation of neural correlates of memory, including adult neurogenesis, synaptic plasticity and modulation of long-term potentiation 14 , 26 , 27 , 28 , 29 . IL-1, in particular, has gained attention for its effect on cognitive function in the context of neuroinflammation. IL-1 signaling is mediated by a family of proteins comprising IL-1α, the anti-neurogenic cytokine IL-1β and IL-1 receptor antagonist, mainly through the type I IL-1 receptor (IL-1R1). IL-1β is generated via proteolytic cleavage of pro-IL-1β by caspase-1 during inflammasome activation 30 . IL-1 has high expression in vivo by infiltrating myeloid cells during WNV encephalitis, during which it critically regulates antiviral effector T cell responses 10 , 11 . While IL-1 is a key player in the orchestration of CNS immune responses, including the onset of fever 27 , it also has a role in spatial learning and memory-related behavior 28 . Indeed, injection of IL-1β into the brain impairs spatial learning, contextual fear memory and adult neurogenesis 29 , 30 , 31 . Although several studies have investigated the effects of IL-1 on hippocampus-based learning and behavior in neurologic diseases 31 ,<|im_end|> <|im_start|>assistant More than 10,000 people in the United States are living with memory loss and other persistent neurological problems that occur after West Nile virus infects the brain. Now, a new study in mice suggests that such ongoing neurological deficits may be due to unresolved inflammation that hinders the brain's ability to repair damaged neurons and grow new ones. When the inflammation was reduced by treatment with an arthritis drug, the animals' ability to learn and remember remained sharp after West Nile disease. "These memory disturbances make it hard for people to hold down a job, to drive, to take care of all the duties of everyday life," said senior author Robyn Klein, MD, Ph.D., a professor of medicine at Washington University School of Medicine in St. Louis. "We found that targeting the inflammation with the arthritis drug could prevent some of these problems with memory." The findings are available online in Nature Immunology. Spread by the bite of a mosquito, West Nile virus can cause fever and sometimes life-threatening brain infections known as West Nile encephalitis. About half the people who survive the encephalitis are left with permanent neurological problems such as disabling fatigue, weakness, difficulty walking and memory loss. These problems not only persist but often worsen with time. Klein and colleagues previously had shown that during West Nile encephalitis, the patient's own immune system destroys parts of neurons, leading to memory problems. "We started wondering why the damage isn't repaired after the virus is cleared from the brain," said Klein, vice provost and associate dean for graduate education for the Division of Biology & Biomedical Sciences. "We know that neurons are produced in the part of the brain involved in learning and memory, so why weren't new neurons being made after West Nile infection?" To find out, Klein; co-first authors Michael Vasek, a postdoc researcher, and graduate research assistant Charise Garber; and colleagues injected mice with West Nile virus or saltwater. During the acute infection, the mice received several doses of a chemical compound that tags neural cells as they are formed. Forty-five days after infection, the researchers isolated the tagged cells from the mice's brains and assessed how many and what kinds of cells had been formed during the first week of infection. Mice ill with West Nile disease produced fewer neurons and more astrocytes – a star-shaped neural cell – than uninfected mice. Astrocytes normally provide nutrition for neurons, but the ones formed during West Nile infection behaved like immune cells, churning out an inflammatory protein known as IL-1. IL-1 is an indispensable part of the body's immune system. It is produced by immune cells that swarm into the brain to fight invading viruses. Once the battle is won, the immune cells depart and IL-1 levels in the brain fall. But in mice recovering from West Nile infection, astrocytes continue to produce IL-1 even after the virus is gone. Since IL-1 guides precursor cells down the path toward becoming astrocytes and away from developing into neurons, a vicious cycle emerges: Astrocytes produce IL-1, which leads to more astrocytes while also preventing new neurons from arising. Hampered by an inability to grow new neurons, the brain fails to repair the neurological damage sustained during infection, the researchers said. "It's almost like the brain gets caught in a loop that keeps IL-1 levels high and prevents it from repairing itself," said Klein, who is also a professor of neuroscience and of pathology and immunology. To see whether the cycle could be broken, Klein and colleagues infected mice with either West Nile virus or saltwater as a mock infection. Ten days later, they treated both groups of mice with a placebo or with anakinra, an FDA-approved arthritis drug that interferes with IL-1. After giving the mice a month to recover, they tested the animals' ability to learn and remember by placing them inside a maze. Mice that had been infected with West Nile virus and treated with a placebo took longer to learn the maze than mock-infected mice. Mice that were infected and treated with the IL-1 blocker learned just as quickly as mock-infected mice, indicating that blocking IL-1 protected the mice from memory problems. "When we treated the mice during the acute phase with a drug that blocks IL-1 signaling, we prevented the memory disturbance," Klein said. "The cycle gets reversed back: They stop making astrocytes, they start making new neurons, and they repair the damaged connections between neurons." But, Klein cautions, IL-1 itself may not be a good drug target for people because of the important role it plays in fighting viruses. Suppressing IL-1 while the virus is still in the brain could exacerbate encephalitis, already a potentially lethal condition. "This is a proof of concept that a drug can prevent cognitive impairments caused by viral encephalitis," Klein said. "This study sheds light on not just post-viral memory disturbances but other types of memory disorders as well. It may turn out that IL-1 is not a feasible target during viral infections, but these findings could lead to new therapeutic targets that are less problematic for clearing virus or to therapies for neurologic diseases of memory impairment that are not caused by viruses." <|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 Rising air temperatures threaten the snow reliability of ski resorts. Most resorts rely on technical snowmaking to compensate lacking natural snow. But increased water consumption for snowmaking may cause conflicts with other sectors’ water uses such as hydropower production or the hotel industry. We assessed the future snow reliability (likelihood of a continuous 100-day skiing season and of operable Christmas holidays) of the Swiss resort Andermatt-Sedrun-Disentis throughout the twenty-first century, where 65% of the area is currently equipped for snowmaking. Our projections are based on the most recent climate change scenarios for Switzerland (CH2018) and the model SkiSim 2.0 including a snowmaking module. Unabated greenhouse gas emissions (scenario RCP8.5) will cause a lack of natural snow at areas below 1800–2000 m asl by the mid-twenty-first century. Initially, this can be fully compensated by snowmaking, but by the end of the century, the results become more nuanced. While snowmaking can provide a continuous 100-day season throughout the twenty-first century, the economically important Christmas holidays are increasingly at risk under the high-emission scenario in the late twenty-first century. The overall high snow reliability of the resort comes at the cost of an increased water demand. The total water consumption of the resort will rise by 79% by the end of the century (2070–2099 compared to 1981–2010; scenario RCP8.5), implying that new water sources will have to be exploited. Future water management plans at the catchment level, embracing the stakeholders, could help to solve future claims for water in the region. Working on a manuscript? Avoid the common mistakes Introduction Winter tourism is an important economic sector in mountain regions. Globally, the European Alps are the number one destination for skiing, with 43% of all skier days worldwide. With 24.9 Mio registered skier days in 2018/19, Switzerland ranks as number six in the world (Vanat 2021 ). In the winter season 2018/19, the Swiss cable cars yielded revenues of 758 Mio CHF (transport only; SBS 2019 ), underpinning the substantial economic value. Rising temperatures due to ongoing and future climate change (Rebetez and Reinhard 2008 ; IPCC 2018 ) entail severe reductions in the snow cover (Marty 2008 ; Klein et al. 2016 ; NCCS 2018 ; Hock et al. 2019 ). For the Swiss Alps, winter and spring temperatures are projected to increase by 1.8 K by the end of the twenty-first century if we drastically reduce greenhouse gas emissions, or even up to 3.9 K without any abatement measures (high-emission scenario). Winter precipitation will progressively fall as rain instead of snow and may increase by 12%. However, the projections for the precipitation increase are less clear than for air temperature (NCCS 2018 ). Winter runoff will increase and the peak runoff will occur earlier because of earlier snowmelt (Haeberli and Weingartner 2020 ).The operators of ski areas are thus confronted with major challenges for the future. The snow reliability of resorts has often been assessed by means of the 100-day rule (Witmer 1986 , for instance used by Abegg et al. 2007 ; Scott et al. 2008 ; Steiger and Abegg 2013 ), stating that a resort requires at least 100 consecutive days with a sufficient snow cover (≥ 30 cm). However, snow reliability does not necessarily result in economic profitability. Another indicator is the Christmas rule introduced by Scott et al. ( 2008 ), specifying that the 2 weeks over the Christmas and New Year’s break are a crucial time period for the operators, as these holidays can yield around one quarter of the revenues (Abegg 1996 ). The dominant adaptation strategy of operators to cope with climate change and variability is technical snowmaking (OECD 2007 ; Gonseth and Vielle 2019 ; Spandre et al. 2019b ; Steiger et al. 2019 ). Currently, the majority of ski slopes in the European Alps are equipped for snowmaking. According to SBS ( 2021 ), the area covered with snowmaking in Switzerland massively increased from 14% (2004) to 48% (2014). Today (2020), 53% of all slopes can be snowed-in technically. This is still markedly less than in Italy (90%) and in Austria (70%), but more than in France (37%). The costs for snowmaking, including the water consumption, are substantial. In Switzerland, these amount to 17% of the daily operating expenses (average for resorts with > 25 Mio CHF revenue; SBS 2021 ). Surveys among stakeholders in the skiing industry have shown that the operators of ski resorts are very aware of climate change (Abegg et al. 2008 ). Nevertheless, many do not perceive it as an immediate threat and empathise the high priority of economic competition and short-term weather variability as a major cause for revenue fluctuations (Saarinen and Tervo 2006 ; Hopkins 2015 ; Abegg et al. 2017 ). The adaptation strategy to these more short-term challenges is often also technical snowmaking (Trawöger 2014 ). A study in Austria highlighted a high confidence in snowmaking facilities, even in low-elevation resorts (Wolfsegger et al. 2008 ). However, increasing temperatures will reduce the snowmaking potential, as high temperatures and/or high relative humidity inhibit the snow production (Willibald et al. 2021 ). From 1961 to 2020, the number of hours allowing for snowmaking decreased on average by 26% in Austria, with more pronounced reductions at elevations between 1000 and 1500 m asl (Olefs et al. 2020 ). Nonetheless, water demand is expected to markedly increase by 50% to 110% across the Alps, according to Steiger et al. ( 2019 ). These higher water demands for snowmaking must be put in perspective to water uses in other sectors, such as hydropower production, agriculture, and tourism infrastructures, as well as their future demands under a warmer climate. The ski resort Andermatt-Sedrun-Disentis has recently expanded the ski area with roughly 68 ha of new slopes and with new snowmaking facilities. Such major interventions in the landscape become more and more controversial, especially in times of climate change and a declining demand for ski tickets. Moreover, the short planning horizon of operators does not account for the rising", "role": "user" }, { "content": "For many people, holidays in the snow are as much a part of the end of the year as Christmas trees and fireworks. As global warming progresses, however, white slopes are becoming increasingly rare. Researchers at the University of Basel have calculated how well one of Switzerland's largest ski resorts will remain snow reliable with technical snowmaking by the year 2100, and how much water this snow will consume. The future for ski sports in Switzerland looks anything but rosy—or rather white. Current climate models predict that there will be more precipitation in winter in the coming decades, but that it will fall as rain instead of snow. Despite this, one investor recently spent several million Swiss francs on expanding the Andermatt-Sedrun-Disentis ski resort. A short-sighted decision they will regret in future? A research team led by Dr. Erika Hiltbrunner from the Department of Environmental Sciences at the University of Basel has now calculated the extent to which this ski resort can maintain its economically important Christmas holidays and a ski season of at least 100 days with and without snowmaking. The team collected data on the aspects of the slopes, where and when the snow is produced at the ski resort and with how much water. They then applied the latest climate change scenarios (CH2018) in combination with the SkiSim 2.0 simulation software for projections of snow conditions with and without technical snowmaking. The results of their investigations were recently published in the International Journal of Biometeorology. No guarantee of a white Christmas According to the results, the use of technical snow can indeed guarantee a 100-day ski season—in the higher parts of the ski resort (at 1,800 meters and above), at least. But business is likely to be tight during the Christmas holidays in coming decades, with the weather often not cold enough at this time and in the weeks before. In the scenario with unabated greenhouse gas emissions, the Sedrun region in particular will no longer be able to offer guaranteed snow over Christmas in the longer term. New snow guns may alleviate the situation to a certain extent, say the researchers, but will not resolve the issue completely. \"Many people don't realize that you also need certain weather conditions for snowmaking,\" explains Hiltbrunner. \"It must not be too warm or too humid, otherwise there will not be enough evaporation cooling for the sprayed water to freeze in the air and come down as snow.\" Warm air absorbs more moisture and so, as winters become warmer, it also gets increasingly difficult or impossible to produce snow technically. In other words: \"Here, the laws of physics set clear limits for snowmaking.\" Technical snowmaking requires certain weather conditions. Credit: Erika Hiltbrunner, University of Basel 540 million liters The skiing will still go on, however, because technical snowmaking at least enables resort operators to keep the higher ski runs open for 100 consecutive days—even up until the end of the century and with climate change continuing unabated. But there is a high price to be paid for this. The researchers' calculations show that water consumption for snowmaking will increase significantly, by about 80% for the resort as a whole. In an average winter toward the end of the century, consumption would thus amount to about 540 million liters of water, compared with 300 million liters today. But this increase in water demand is still relatively moderate compared with other ski resorts, the researchers emphasize. Earlier studies had shown that water consumption for snowmaking in the Scuol ski resort, for example, would increase by a factor of 2.4 to 5, because the area covered with snow there will have to be largely expanded in order to guarantee snow reliability. For their analysis, the researchers considered periods of 30 years. However, there are large annual fluctuations: In addition, extreme events are not depicted in the climate scenarios. In the winter of 2017 with low levels of snow, water consumption for snowmaking in one of the three sub-areas of Andermatt-Sedrun-Disentis tripled. Conflicts over water use Today, some of the water used for snowmaking in the largest sub-area of Andermatt-Sedrun-Disentis comes from the Oberalpsee. A maximum of 200 million liters may be withdrawn annually for this purpose. If climate change continues unabated, this source of water will last until the middle of the century, at which point new sources will have to be exploited. \"The Oberalpsee is also used to produce hydroelectric power,\" says Dr. Maria Vorkauf, lead author of the study, who now works at the Agroscope research station. \"Here, we are likely to see a conflict between the water demands for the ski resort and those for hydropower generation.\" At first, this ski resort may even benefit from climate change—if lower-lying and smaller ski resorts are obliged to close, tourists will move to larger resorts at higher altitude, one of which is Andermatt-Sedrun-Disentis. What is certain is that increased snowmaking will drive up costs and thus also the price of ski holidays. \"Sooner or later, people with average incomes will simply no longer be able to afford them,\" says Hiltbrunner. ", "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 Rising air temperatures threaten the snow reliability of ski resorts. Most resorts rely on technical snowmaking to compensate lacking natural snow. But increased water consumption for snowmaking may cause conflicts with other sectors’ water uses such as hydropower production or the hotel industry. We assessed the future snow reliability (likelihood of a continuous 100-day skiing season and of operable Christmas holidays) of the Swiss resort Andermatt-Sedrun-Disentis throughout the twenty-first century, where 65% of the area is currently equipped for snowmaking. Our projections are based on the most recent climate change scenarios for Switzerland (CH2018) and the model SkiSim 2.0 including a snowmaking module. Unabated greenhouse gas emissions (scenario RCP8.5) will cause a lack of natural snow at areas below 1800–2000 m asl by the mid-twenty-first century. Initially, this can be fully compensated by snowmaking, but by the end of the century, the results become more nuanced. While snowmaking can provide a continuous 100-day season throughout the twenty-first century, the economically important Christmas holidays are increasingly at risk under the high-emission scenario in the late twenty-first century. The overall high snow reliability of the resort comes at the cost of an increased water demand. The total water consumption of the resort will rise by 79% by the end of the century (2070–2099 compared to 1981–2010; scenario RCP8.5), implying that new water sources will have to be exploited. Future water management plans at the catchment level, embracing the stakeholders, could help to solve future claims for water in the region. Working on a manuscript? Avoid the common mistakes Introduction Winter tourism is an important economic sector in mountain regions. Globally, the European Alps are the number one destination for skiing, with 43% of all skier days worldwide. With 24.9 Mio registered skier days in 2018/19, Switzerland ranks as number six in the world (Vanat 2021 ). In the winter season 2018/19, the Swiss cable cars yielded revenues of 758 Mio CHF (transport only; SBS 2019 ), underpinning the substantial economic value. Rising temperatures due to ongoing and future climate change (Rebetez and Reinhard 2008 ; IPCC 2018 ) entail severe reductions in the snow cover (Marty 2008 ; Klein et al. 2016 ; NCCS 2018 ; Hock et al. 2019 ). For the Swiss Alps, winter and spring temperatures are projected to increase by 1.8 K by the end of the twenty-first century if we drastically reduce greenhouse gas emissions, or even up to 3.9 K without any abatement measures (high-emission scenario). Winter precipitation will progressively fall as rain instead of snow and may increase by 12%. However, the projections for the precipitation increase are less clear than for air temperature (NCCS 2018 ). Winter runoff will increase and the peak runoff will occur earlier because of earlier snowmelt (Haeberli and Weingartner 2020 ).The operators of ski areas are thus confronted with major challenges for the future. The snow reliability of resorts has often been assessed by means of the 100-day rule (Witmer 1986 , for instance used by Abegg et al. 2007 ; Scott et al. 2008 ; Steiger and Abegg 2013 ), stating that a resort requires at least 100 consecutive days with a sufficient snow cover (≥ 30 cm). However, snow reliability does not necessarily result in economic profitability. Another indicator is the Christmas rule introduced by Scott et al. ( 2008 ), specifying that the 2 weeks over the Christmas and New Year’s break are a crucial time period for the operators, as these holidays can yield around one quarter of the revenues (Abegg 1996 ). The dominant adaptation strategy of operators to cope with climate change and variability is technical snowmaking (OECD 2007 ; Gonseth and Vielle 2019 ; Spandre et al. 2019b ; Steiger et al. 2019 ). Currently, the majority of ski slopes in the European Alps are equipped for snowmaking. According to SBS ( 2021 ), the area covered with snowmaking in Switzerland massively increased from 14% (2004) to 48% (2014). Today (2020), 53% of all slopes can be snowed-in technically. This is still markedly less than in Italy (90%) and in Austria (70%), but more than in France (37%). The costs for snowmaking, including the water consumption, are substantial. In Switzerland, these amount to 17% of the daily operating expenses (average for resorts with > 25 Mio CHF revenue; SBS 2021 ). Surveys among stakeholders in the skiing industry have shown that the operators of ski resorts are very aware of climate change (Abegg et al. 2008 ). Nevertheless, many do not perceive it as an immediate threat and empathise the high priority of economic competition and short-term weather variability as a major cause for revenue fluctuations (Saarinen and Tervo 2006 ; Hopkins 2015 ; Abegg et al. 2017 ). The adaptation strategy to these more short-term challenges is often also technical snowmaking (Trawöger 2014 ). A study in Austria highlighted a high confidence in snowmaking facilities, even in low-elevation resorts (Wolfsegger et al. 2008 ). However, increasing temperatures will reduce the snowmaking potential, as high temperatures and/or high relative humidity inhibit the snow production (Willibald et al. 2021 ). From 1961 to 2020, the number of hours allowing for snowmaking decreased on average by 26% in Austria, with more pronounced reductions at elevations between 1000 and 1500 m asl (Olefs et al. 2020 ). Nonetheless, water demand is expected to markedly increase by 50% to 110% across the Alps, according to Steiger et al. ( 2019 ). These higher water demands for snowmaking must be put in perspective to water uses in other sectors, such as hydropower production, agriculture, and tourism infrastructures, as well as their future demands under a warmer climate. The ski resort Andermatt-Sedrun-Disentis has recently expanded the ski area with roughly 68 ha of new slopes and with new snowmaking facilities. Such major interventions in the landscape become more and more controversial, especially in times of climate change and a declining demand for ski tickets. Moreover, the short planning horizon of operators does not account for the rising<|im_end|> <|im_start|>assistant For many people, holidays in the snow are as much a part of the end of the year as Christmas trees and fireworks. As global warming progresses, however, white slopes are becoming increasingly rare. Researchers at the University of Basel have calculated how well one of Switzerland's largest ski resorts will remain snow reliable with technical snowmaking by the year 2100, and how much water this snow will consume. The future for ski sports in Switzerland looks anything but rosy—or rather white. Current climate models predict that there will be more precipitation in winter in the coming decades, but that it will fall as rain instead of snow. Despite this, one investor recently spent several million Swiss francs on expanding the Andermatt-Sedrun-Disentis ski resort. A short-sighted decision they will regret in future? A research team led by Dr. Erika Hiltbrunner from the Department of Environmental Sciences at the University of Basel has now calculated the extent to which this ski resort can maintain its economically important Christmas holidays and a ski season of at least 100 days with and without snowmaking. The team collected data on the aspects of the slopes, where and when the snow is produced at the ski resort and with how much water. They then applied the latest climate change scenarios (CH2018) in combination with the SkiSim 2.0 simulation software for projections of snow conditions with and without technical snowmaking. The results of their investigations were recently published in the International Journal of Biometeorology. No guarantee of a white Christmas According to the results, the use of technical snow can indeed guarantee a 100-day ski season—in the higher parts of the ski resort (at 1,800 meters and above), at least. But business is likely to be tight during the Christmas holidays in coming decades, with the weather often not cold enough at this time and in the weeks before. In the scenario with unabated greenhouse gas emissions, the Sedrun region in particular will no longer be able to offer guaranteed snow over Christmas in the longer term. New snow guns may alleviate the situation to a certain extent, say the researchers, but will not resolve the issue completely. "Many people don't realize that you also need certain weather conditions for snowmaking," explains Hiltbrunner. "It must not be too warm or too humid, otherwise there will not be enough evaporation cooling for the sprayed water to freeze in the air and come down as snow." Warm air absorbs more moisture and so, as winters become warmer, it also gets increasingly difficult or impossible to produce snow technically. In other words: "Here, the laws of physics set clear limits for snowmaking." Technical snowmaking requires certain weather conditions. Credit: Erika Hiltbrunner, University of Basel 540 million liters The skiing will still go on, however, because technical snowmaking at least enables resort operators to keep the higher ski runs open for 100 consecutive days—even up until the end of the century and with climate change continuing unabated. But there is a high price to be paid for this. The researchers' calculations show that water consumption for snowmaking will increase significantly, by about 80% for the resort as a whole. In an average winter toward the end of the century, consumption would thus amount to about 540 million liters of water, compared with 300 million liters today. But this increase in water demand is still relatively moderate compared with other ski resorts, the researchers emphasize. Earlier studies had shown that water consumption for snowmaking in the Scuol ski resort, for example, would increase by a factor of 2.4 to 5, because the area covered with snow there will have to be largely expanded in order to guarantee snow reliability. For their analysis, the researchers considered periods of 30 years. However, there are large annual fluctuations: In addition, extreme events are not depicted in the climate scenarios. In the winter of 2017 with low levels of snow, water consumption for snowmaking in one of the three sub-areas of Andermatt-Sedrun-Disentis tripled. Conflicts over water use Today, some of the water used for snowmaking in the largest sub-area of Andermatt-Sedrun-Disentis comes from the Oberalpsee. A maximum of 200 million liters may be withdrawn annually for this purpose. If climate change continues unabated, this source of water will last until the middle of the century, at which point new sources will have to be exploited. "The Oberalpsee is also used to produce hydroelectric power," says Dr. Maria Vorkauf, lead author of the study, who now works at the Agroscope research station. "Here, we are likely to see a conflict between the water demands for the ski resort and those for hydropower generation." At first, this ski resort may even benefit from climate change—if lower-lying and smaller ski resorts are obliged to close, tourists will move to larger resorts at higher altitude, one of which is Andermatt-Sedrun-Disentis. What is certain is that increased snowmaking will drive up costs and thus also the price of ski holidays. "Sooner or later, people with average incomes will simply no longer be able to afford them," says Hiltbrunner. <|im_end|>
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2,515
[ { "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 Limited research exists on carbohydrate intake and oral microbiome diversity and composition assessed with next-generation sequencing. We aimed to better understand the association between habitual carbohydrate intake and the oral microbiome, as the oral microbiome has been associated with caries, periodontal disease, and systemic diseases. We investigated if total carbohydrates, starch, monosaccharides, disaccharides, fiber, or glycemic load (GL) were associated with the diversity and composition of oral bacteria in subgingival plaque samples of 1204 post-menopausal women. Carbohydrate intake and GL were assessed from a food frequency questionnaire, and adjusted for energy intake. The V3–V4 region of the 16S rRNA gene from subgingival plaque samples were sequenced to identify the relative abundance of microbiome compositional data expressed as operational taxonomic units (OTUs). The abundance of OTUs were centered log(2)-ratio transformed to account for the compositional data structure. Associations between carbohydrate/GL intake and microbiome alpha-diversity measures were examined using linear regression. PERMANOVA analyses were conducted to examine microbiome beta-diversity measures across quartiles of carbohydrate/GL intake. Associations between intake of carbohydrates and GL and the abundance of the 245 identified OTUs were examined by using linear regression. Total carbohydrates, GL, starch, lactose, and sucrose intake were inversely associated with alpha-diversity measures. Beta-diversity across quartiles of total carbohydrates, fiber, GL, sucrose, and galactose, were all statistically significant (p for PERMANOVA p < 0.05). Positive associations were observed between total carbohydrates, GL, sucrose and Streptococcus mutans; GL and both Sphingomonas HOT 006 and Scardovia wiggsiae; and sucrose and Streptococcus lactarius. A negative association was observed between lactose and Aggregatibacter segnis, and between sucrose and both TM7_[G-1] HOT 346 and Leptotrichia HOT 223 . Intake of total carbohydrate, GL, and sucrose were inversely associated with subgingival bacteria alpha-diversity, the microbial beta-diversity varied by their intake, and they were associated with the relative abundance of specific OTUs. Higher intake of sucrose, or high GL foods, may influence poor oral health outcomes (and perhaps systemic health outcomes) in older women via their influence on the oral microbiome. Introduction The human microbiome plays a critical role in human health and disease 1 . In particular, the oral microbiome is associated with not only the health of the mouth, but also risk of other chronic diseases (e.g., cardiovascular disease 2 , 3 hypertension 4 , type 2 diabetes 5 , and cancer 6 , 7 ). Understanding of the factors (e.g., dietary intake, smoking behavior, medication use, etc.) affecting the composition of the oral microbiome is critical to understanding these observed associations with disease outcomes. Over 700 different species of bacteria have been identified in the oral cavity 8 with, on average, more than 250 different species in any one individual mouth 9 . The diversity of the oral microbiome in relation to oral health is complex. For example, previous data shows that the alpha-diversity of the microbiome in supragingival plaque samples (where cariogenic pathogens reside), decreases with the severity of caries 10 . Differently, the alpha-diversity in subgingival plaque samples, (where periodontal pathogens reside), increases with increasing severity of periodontal disease 11 , 12 , and such a relationship was observed in this cohort with the microbiome of our subgingival plaque samples 13 . Diet has been shown to be associated with both caries and periodontal disease 14 and hypothesized to influence the microbial composition and diversity of the saliva and gingival crevicular fluid 15 . Fermentable carbohydrates (simple sugars and starch) are significant sources of bacterial energy metabolism and are broken down by both bacterial enzymes and by endogenous processes in the oral cavity 15 . There is evidence that fermentable carbohydrates are essential to development of dental caries 16 . However, the association of carbohydrate intake with periodontal disease is less well studied 17 , 18 , 19 , 20 , 21 . Few studies have examining habitual intake of dietary carbohydrates in relation to the diversity and composition of the oral microbiome 22 , 23 , 24 . We studied the association between habitual dietary carbohydrate intake and the subgingival plaque oral microbiome in a cohort of 1204 postmenopausal women, using data from the Buffalo Osteoporosis and Periodontal Disease (OsteoPerio) Study, a cohort study ancillary to the Women’s Health Initiative (WHI) Observational Study (OS) 25 . The OsteoPerio Study used 16S rRNA gene sequencing of oral plaque samples to identify and measure the relative abundance of the oral bacteria found 26 . We hypothesized that the alpha-diversity (within-subject diversity [number of species]) of the oral microbiome would be associated with intake of total carbohydrates, GL, starch, disaccharides (lactose, maltose, sucrose) and monosaccharides (fructose, galactose, and glucose) and that the beta-diversity (between group diversity) of the oral microbiome would differ across quartiles of intake in all carbohydrates and glycemic load (GL). Methods Study design The OsteoPerio Study is an ongoing prospective cohort 26 , and ancillary to the WHI, a national study focused on health outcomes of postmenopausal women 25 . The OsteoPerio study was originated to examine the association between osteoporosis and loss of bone in the oral cavity 27 . Study participants were recruited from the WHI clinical center in Buffalo, NY between 1997 and 2001; 1,342 women participated in the baseline exam (Supplemental Fig. 1 ) 26 . Women were excluded if they had fewer than 6 teeth, bilateral hip replacement, a history of non-osteoporotic bone disease, a recent 10 years history of cancer, or if they were treated for serious diseases 26 . There were 1222 women with sequenced subgingival microbiome and dietary data at baseline, and of these, 18 women were excluded because their self-reported energy intakes were > 5000 or < 600 kcals, leaving a sample of 1204 women. All participants provided informed consent, and the study protocol was approved by the University at Buffalo’s Health Sciences Institutional Review Board. All experiments were in agreement with relevant guidelines regarding Human Subjects Research. Assessment of dietary carbohydrate intake Dietary intake was assessed as part of the WHI OS participant’s year 3 visit, which coincided with the OsteoPerio baseline exam 26 .", "role": "user" }, { "content": "The foods we eat on a regular basis influence the makeup of the bacteria—both good and bad—in our mouths. And researchers are finding that this collective of bacteria known as the oral microbiome likely plays a large role in our overall health, in addition to its previously known associations with tooth decay and periodontal disease. Scientists from the University at Buffalo have shown how eating certain types of foods impacts the oral microbiome of postmenopausal women. They found that higher intake of sugary and high glycemic load foods—like doughnuts and other baked goods, regular soft drinks, breads and non-fat yogurts—may influence poor oral health and, perhaps, systemic health outcomes in older women due to the influence these foods have on the oral microbiome. In a study in Scientific Reports, an open access journal from the publishers of Nature, the UB-led team investigated whether carbohydrates and sucrose, or table sugar, were associated with the diversity and composition of oral bacteria in a sample of 1,204 postmenopausal women using data from the Women's Health Initiative. It is the first study to examine carbohydrate intake and the subgingival microbiome in a sample consisting exclusively of postmenopausal women. The study was unique in that the samples were taken from subgingival plaque, which occurs under the gums, rather than salivary bacteria. \"This is important because the oral bacteria involved in periodontal disease are primarily residing in the subgingival plaque,\" said study first author Amy Millen, Ph.D., associate professor of epidemiology and environmental health in UB's School of Public Health and Health Professions. \"Looking at measures of salivary bacteria might not tell us how oral bacteria relate to periodontal disease because we are not looking in the right environment within the mouth,\" she added. The research team reported positive associations between total carbohydrates, glycemic load and sucrose and Streptococcus mutans, a contributor to tooth decay and some types of cardiovascular disease, a finding that confirms previous observations. But they also observed associations between carbohydrates and the oral microbiome that are not as well established. The researchers observed Leptotrichia spp., which has been associated with gingivitis, a common gum disease, in some studies, to be positively associated with sugar intake. The other bacteria they identified as associated with carbohydrate intake or glycemic load have not been previously appreciated as contributing to periodontal disease in the literature or in this cohort of women, according to Millen. \"We examined these bacteria in relation to usual carbohydrate consumption in postmenopausal women across a wide variety of carbohydrate types: total carbohydrate intake, fiber intake, disaccharide intake, to simple sugar intake,\" Millen said. \"No other study had examined the oral bacteria in relation to such a broad array of carbohydrate types in one cohort. We also looked at associations with glycemic load, which is not well studied in relation to the oral microbiome.\" The key question now is what this all means for overall health, and that's not as easily understood just yet. \"As more studies are conducted looking at the oral microbiome using similar sequencing techniques and progression or development of periodontal disease over time, we might begin to make better inferences about how diet relates to the oral microbiome and periodontal disease,\" Millen 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 Limited research exists on carbohydrate intake and oral microbiome diversity and composition assessed with next-generation sequencing. We aimed to better understand the association between habitual carbohydrate intake and the oral microbiome, as the oral microbiome has been associated with caries, periodontal disease, and systemic diseases. We investigated if total carbohydrates, starch, monosaccharides, disaccharides, fiber, or glycemic load (GL) were associated with the diversity and composition of oral bacteria in subgingival plaque samples of 1204 post-menopausal women. Carbohydrate intake and GL were assessed from a food frequency questionnaire, and adjusted for energy intake. The V3–V4 region of the 16S rRNA gene from subgingival plaque samples were sequenced to identify the relative abundance of microbiome compositional data expressed as operational taxonomic units (OTUs). The abundance of OTUs were centered log(2)-ratio transformed to account for the compositional data structure. Associations between carbohydrate/GL intake and microbiome alpha-diversity measures were examined using linear regression. PERMANOVA analyses were conducted to examine microbiome beta-diversity measures across quartiles of carbohydrate/GL intake. Associations between intake of carbohydrates and GL and the abundance of the 245 identified OTUs were examined by using linear regression. Total carbohydrates, GL, starch, lactose, and sucrose intake were inversely associated with alpha-diversity measures. Beta-diversity across quartiles of total carbohydrates, fiber, GL, sucrose, and galactose, were all statistically significant (p for PERMANOVA p < 0.05). Positive associations were observed between total carbohydrates, GL, sucrose and Streptococcus mutans; GL and both Sphingomonas HOT 006 and Scardovia wiggsiae; and sucrose and Streptococcus lactarius. A negative association was observed between lactose and Aggregatibacter segnis, and between sucrose and both TM7_[G-1] HOT 346 and Leptotrichia HOT 223 . Intake of total carbohydrate, GL, and sucrose were inversely associated with subgingival bacteria alpha-diversity, the microbial beta-diversity varied by their intake, and they were associated with the relative abundance of specific OTUs. Higher intake of sucrose, or high GL foods, may influence poor oral health outcomes (and perhaps systemic health outcomes) in older women via their influence on the oral microbiome. Introduction The human microbiome plays a critical role in human health and disease 1 . In particular, the oral microbiome is associated with not only the health of the mouth, but also risk of other chronic diseases (e.g., cardiovascular disease 2 , 3 hypertension 4 , type 2 diabetes 5 , and cancer 6 , 7 ). Understanding of the factors (e.g., dietary intake, smoking behavior, medication use, etc.) affecting the composition of the oral microbiome is critical to understanding these observed associations with disease outcomes. Over 700 different species of bacteria have been identified in the oral cavity 8 with, on average, more than 250 different species in any one individual mouth 9 . The diversity of the oral microbiome in relation to oral health is complex. For example, previous data shows that the alpha-diversity of the microbiome in supragingival plaque samples (where cariogenic pathogens reside), decreases with the severity of caries 10 . Differently, the alpha-diversity in subgingival plaque samples, (where periodontal pathogens reside), increases with increasing severity of periodontal disease 11 , 12 , and such a relationship was observed in this cohort with the microbiome of our subgingival plaque samples 13 . Diet has been shown to be associated with both caries and periodontal disease 14 and hypothesized to influence the microbial composition and diversity of the saliva and gingival crevicular fluid 15 . Fermentable carbohydrates (simple sugars and starch) are significant sources of bacterial energy metabolism and are broken down by both bacterial enzymes and by endogenous processes in the oral cavity 15 . There is evidence that fermentable carbohydrates are essential to development of dental caries 16 . However, the association of carbohydrate intake with periodontal disease is less well studied 17 , 18 , 19 , 20 , 21 . Few studies have examining habitual intake of dietary carbohydrates in relation to the diversity and composition of the oral microbiome 22 , 23 , 24 . We studied the association between habitual dietary carbohydrate intake and the subgingival plaque oral microbiome in a cohort of 1204 postmenopausal women, using data from the Buffalo Osteoporosis and Periodontal Disease (OsteoPerio) Study, a cohort study ancillary to the Women’s Health Initiative (WHI) Observational Study (OS) 25 . The OsteoPerio Study used 16S rRNA gene sequencing of oral plaque samples to identify and measure the relative abundance of the oral bacteria found 26 . We hypothesized that the alpha-diversity (within-subject diversity [number of species]) of the oral microbiome would be associated with intake of total carbohydrates, GL, starch, disaccharides (lactose, maltose, sucrose) and monosaccharides (fructose, galactose, and glucose) and that the beta-diversity (between group diversity) of the oral microbiome would differ across quartiles of intake in all carbohydrates and glycemic load (GL). Methods Study design The OsteoPerio Study is an ongoing prospective cohort 26 , and ancillary to the WHI, a national study focused on health outcomes of postmenopausal women 25 . The OsteoPerio study was originated to examine the association between osteoporosis and loss of bone in the oral cavity 27 . Study participants were recruited from the WHI clinical center in Buffalo, NY between 1997 and 2001; 1,342 women participated in the baseline exam (Supplemental Fig. 1 ) 26 . Women were excluded if they had fewer than 6 teeth, bilateral hip replacement, a history of non-osteoporotic bone disease, a recent 10 years history of cancer, or if they were treated for serious diseases 26 . There were 1222 women with sequenced subgingival microbiome and dietary data at baseline, and of these, 18 women were excluded because their self-reported energy intakes were > 5000 or < 600 kcals, leaving a sample of 1204 women. All participants provided informed consent, and the study protocol was approved by the University at Buffalo’s Health Sciences Institutional Review Board. All experiments were in agreement with relevant guidelines regarding Human Subjects Research. Assessment of dietary carbohydrate intake Dietary intake was assessed as part of the WHI OS participant’s year 3 visit, which coincided with the OsteoPerio baseline exam 26 .<|im_end|> <|im_start|>assistant The foods we eat on a regular basis influence the makeup of the bacteria—both good and bad—in our mouths. And researchers are finding that this collective of bacteria known as the oral microbiome likely plays a large role in our overall health, in addition to its previously known associations with tooth decay and periodontal disease. Scientists from the University at Buffalo have shown how eating certain types of foods impacts the oral microbiome of postmenopausal women. They found that higher intake of sugary and high glycemic load foods—like doughnuts and other baked goods, regular soft drinks, breads and non-fat yogurts—may influence poor oral health and, perhaps, systemic health outcomes in older women due to the influence these foods have on the oral microbiome. In a study in Scientific Reports, an open access journal from the publishers of Nature, the UB-led team investigated whether carbohydrates and sucrose, or table sugar, were associated with the diversity and composition of oral bacteria in a sample of 1,204 postmenopausal women using data from the Women's Health Initiative. It is the first study to examine carbohydrate intake and the subgingival microbiome in a sample consisting exclusively of postmenopausal women. The study was unique in that the samples were taken from subgingival plaque, which occurs under the gums, rather than salivary bacteria. "This is important because the oral bacteria involved in periodontal disease are primarily residing in the subgingival plaque," said study first author Amy Millen, Ph.D., associate professor of epidemiology and environmental health in UB's School of Public Health and Health Professions. "Looking at measures of salivary bacteria might not tell us how oral bacteria relate to periodontal disease because we are not looking in the right environment within the mouth," she added. The research team reported positive associations between total carbohydrates, glycemic load and sucrose and Streptococcus mutans, a contributor to tooth decay and some types of cardiovascular disease, a finding that confirms previous observations. But they also observed associations between carbohydrates and the oral microbiome that are not as well established. The researchers observed Leptotrichia spp., which has been associated with gingivitis, a common gum disease, in some studies, to be positively associated with sugar intake. The other bacteria they identified as associated with carbohydrate intake or glycemic load have not been previously appreciated as contributing to periodontal disease in the literature or in this cohort of women, according to Millen. "We examined these bacteria in relation to usual carbohydrate consumption in postmenopausal women across a wide variety of carbohydrate types: total carbohydrate intake, fiber intake, disaccharide intake, to simple sugar intake," Millen said. "No other study had examined the oral bacteria in relation to such a broad array of carbohydrate types in one cohort. We also looked at associations with glycemic load, which is not well studied in relation to the oral microbiome." The key question now is what this all means for overall health, and that's not as easily understood just yet. "As more studies are conducted looking at the oral microbiome using similar sequencing techniques and progression or development of periodontal disease over time, we might begin to make better inferences about how diet relates to the oral microbiome and periodontal disease," Millen said. <|im_end|>
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2,159
[ { "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 A fundamental step of tumour single cell mRNA analysis is separating cancer and non-cancer cells. We show that the common approach to separation, using shifts in average expression, can lead to erroneous biological conclusions. By contrast, allelic imbalances representing copy number changes directly detect the cancer genotype and accurately separate cancer from non-cancer cells. Our findings provide a definitive approach to identifying cancer cells from single cell mRNA sequencing data. Introduction Single cell mRNA sequencing has enabled transcriptomic profiling of tumours and their environment with data being generated across the entire spectrum of human cancer. Studying the cancer transcriptomes depends on accurate identification of cancer cells. Therefore, the foundational step of tumour single cell analyses is separating cancer from non-cancer cells. The simplest approach to identifying cancer cells is to use expression of cancer specific marker genes. However, such genes do not always exist and are generally insufficiently precise, especially without corroborating readouts such as cellular morphology. Another approach is to infer the presence of tumour-defining somatic copy-number changes from shifts in average expression 1 , 2 . The idea here is that gains or losses of genomic regions will generally increase or decrease the expression level of genes in these regions respectively. Challenges with this approach include smoothing and denoising expression changes, establishing a baseline against which to measure shifts in expression, segmenting the genome, and identifying changes in expression not due to copy-number changes. Despite these challenges, both marker genes and shifts in average expression, which we collectively refer to as “expression-based annotation”, may accurately identify cancer cells in certain circumstances. However, if there is any novelty or ambiguity in the identity of cancer cells, then these two approaches are inherently fallible as they are both based on expression and not direct evidence that a cell is cancerous, i.e. that it carries the somatic cancer genome. For example, there has been historical controversy about what cell types are malignant in neuroblastoma, a childhood cancer that arises from peripheral nervous sympathetic lineages. In addition to unambiguous cancer cells, neuroblastomas often harbour stromal cells, composed of Schwannian stroma or mesenchymal cells. It has been suggested that these stromal cell types represent cancer lineages, although a rich body of evidence, including cytogenetic investigations, have not supported this proposition 3 . Recent single cell mRNA studies of neuroblastoma have rekindled the debate on the basis of expression-based cancer cell identification 4 . Although neuroblastoma is an exemplar of the difficulties in annotating single cell tumour transcriptomes, the same problems are common to tumours with complex histology or unresolved origins. Even among tumours with well-defined origins, the variability inherent to all cancer can make annotation challenging. The alternative to expression-based annotation is direct detection of either cancer-defining (i.e. somatic) point mutations or copy-number aberrations from the nucleic acid sequences of each transcriptome, which we pursued here. Such approaches utilise additional information from whole genome/exome sequencing of tumour DNA to detect the altered genotype or the allelic imbalance it creates. More specifically, sequencing of tumour DNA is used to identify regions of copy-number change shared by all cancer cells. Within these regions the B-allele frequency or BAF, defined as the fraction of reads from the non-reference allele, will differ from the value of 0.5 that characterises normal cells (Fig. 1a ). The altered BAF is then used to phase together heterozygous bases across the altered region and the nucleotide sequences underlying single transcriptomes can be interrogated for these cancer-defining shifts. The principle of using shifts in BAF to detect copy-number changes has been previously used to detect de novo copy-number changes in single cell data 5 , 6 . Here we leverage the extra information provided by tumour DNA sequencing to use shifts in BAF to precisely identify single cancer cell transcriptomes. Fig. 1: Overview of different approaches to identifying cancer-derived cells. a Genomic changes present in cancer genomes. b Number of cells (y-axis) with N reads covering point mutations (x-axis), separated by low (NB neuroblastoma) and high (RCC renal cell carcinoma) mutation burden. c Number of cells (y-axis) with N reads covering heterozygous single nucleotide polymorphisms (SNP) (x-axis). d Overview of using allelic shifts representing copy-number changes to detect cancer cells. Full size image Results Briefly, our method, which we call alleleIntegrator, works as follows. Firstly, whole genome or exome sequencing is performed on tumour DNA. From this, regions of copy-number change are identified, using established methods such as ASCAT 7 , along with germline heterozygous single nucleotide polymorphisms (SNPs) within altered regions. The alleles with frequency significantly greater than 0.5 (binomial test) are phased together and collectively designated the “major allele”. The allele frequency of all phased heterozygous SNPs within copy-number altered regions is then measured in each single cell transcriptome. Finally, the posterior probability of both the normal genotype (where all alleles have BAF 0.5) and the cancer genotype (where the BAF of each allele matches that implied by the copy-number status of the cancer) are calculated. It is possible that allelic shifts may result from allele-specific expression rather than copy-number change. To control for this, we exclude genes known to be imprinted or have allele-biased expression (e.g. HLA genes), model any residual allele-specific expression using the data, and only consider large regions spanning multiple genes. Those cells with a posterior probability exceeding some threshold (set to 99% throughout this paper) are designated as cancer or normal cells, with all other cells designated as unassigned. To test approaches used to identify cancer cells, we generated or downloaded single cell droplet-based 3′ single cell transcriptomes from 13 individuals and 5 tumour types: renal cell carcinoma (RCC), neuroblastoma, Wilms tumour, Ewing’s sarcoma, and atypical teratoid rhabdoid tumour (AT/RT) 8 , 9 , 10 (Supplementary Table 1 ). We first tested if detection of cancer specific point mutations would identify cancer transcriptomes. Across all samples, the majority of cells had no reads covering a point mutation (Fig. 1b ), with on average 9.7 reads per ten thousand point mutations per cell (range 0", "role": "user" }, { "content": "A new method of separating cancer cells from non-cancer cells has been developed by researchers at the Wellcome Sanger Institute, in a boost for those working to better understand cancer biology using single-cell mRNA sequencing. The study, published today in Communications Biology, improves on existing methods to identify which cells in a sample are cancerous and provides crucial data on the microenvironment of tumors. The software is openly available for researchers around the world to apply to their own data, advancing the effectiveness of single-cell sequencing to understand cancer. Single cell mRNA analysis of cancer cells is one of the leading edge techniques being used to better understand cancer biology. The data generated can be used to try to disrupt cancers with drugs or work out how cancers arise in the first place. A fundamental step in this process is separating cancer and non-cancer cells, but this isn't always an easy task. As well as the many types of cancer, there will also be molecular differences between cancer cells of the same type within a single tumor. Currently, the best method of doing this is to measure the average gene expression of cells in the sample, with higher or lower expression used to distinguish cancer cells from healthy cells. But this method can lead to false conclusions. In this new study, researchers at the Wellcome Sanger Institute performed whole genome sequencing and single-cell mRNA sequencing on samples collected by Great Ormond Street Hospital (GOSH). By locating imbalances of alleles in these data, which indicate copy number changes in the genome, the team was able to identify cancer cells more reliably than with previous methods. This approach will primarily be useful for validating new cancer cell types and better understanding the microenvironment of tumor tissue. \"Being able to know how the transcriptome is different in cells with aberrant genomes, such as those found in cancers, is valuable knowledge and will expand the questions that we can answer using single-cell sequencing,\" says Dr. Matt Young. The method, named alleleIntegrator, is available as a software package for researchers across the world to use. ", "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 A fundamental step of tumour single cell mRNA analysis is separating cancer and non-cancer cells. We show that the common approach to separation, using shifts in average expression, can lead to erroneous biological conclusions. By contrast, allelic imbalances representing copy number changes directly detect the cancer genotype and accurately separate cancer from non-cancer cells. Our findings provide a definitive approach to identifying cancer cells from single cell mRNA sequencing data. Introduction Single cell mRNA sequencing has enabled transcriptomic profiling of tumours and their environment with data being generated across the entire spectrum of human cancer. Studying the cancer transcriptomes depends on accurate identification of cancer cells. Therefore, the foundational step of tumour single cell analyses is separating cancer from non-cancer cells. The simplest approach to identifying cancer cells is to use expression of cancer specific marker genes. However, such genes do not always exist and are generally insufficiently precise, especially without corroborating readouts such as cellular morphology. Another approach is to infer the presence of tumour-defining somatic copy-number changes from shifts in average expression 1 , 2 . The idea here is that gains or losses of genomic regions will generally increase or decrease the expression level of genes in these regions respectively. Challenges with this approach include smoothing and denoising expression changes, establishing a baseline against which to measure shifts in expression, segmenting the genome, and identifying changes in expression not due to copy-number changes. Despite these challenges, both marker genes and shifts in average expression, which we collectively refer to as “expression-based annotation”, may accurately identify cancer cells in certain circumstances. However, if there is any novelty or ambiguity in the identity of cancer cells, then these two approaches are inherently fallible as they are both based on expression and not direct evidence that a cell is cancerous, i.e. that it carries the somatic cancer genome. For example, there has been historical controversy about what cell types are malignant in neuroblastoma, a childhood cancer that arises from peripheral nervous sympathetic lineages. In addition to unambiguous cancer cells, neuroblastomas often harbour stromal cells, composed of Schwannian stroma or mesenchymal cells. It has been suggested that these stromal cell types represent cancer lineages, although a rich body of evidence, including cytogenetic investigations, have not supported this proposition 3 . Recent single cell mRNA studies of neuroblastoma have rekindled the debate on the basis of expression-based cancer cell identification 4 . Although neuroblastoma is an exemplar of the difficulties in annotating single cell tumour transcriptomes, the same problems are common to tumours with complex histology or unresolved origins. Even among tumours with well-defined origins, the variability inherent to all cancer can make annotation challenging. The alternative to expression-based annotation is direct detection of either cancer-defining (i.e. somatic) point mutations or copy-number aberrations from the nucleic acid sequences of each transcriptome, which we pursued here. Such approaches utilise additional information from whole genome/exome sequencing of tumour DNA to detect the altered genotype or the allelic imbalance it creates. More specifically, sequencing of tumour DNA is used to identify regions of copy-number change shared by all cancer cells. Within these regions the B-allele frequency or BAF, defined as the fraction of reads from the non-reference allele, will differ from the value of 0.5 that characterises normal cells (Fig. 1a ). The altered BAF is then used to phase together heterozygous bases across the altered region and the nucleotide sequences underlying single transcriptomes can be interrogated for these cancer-defining shifts. The principle of using shifts in BAF to detect copy-number changes has been previously used to detect de novo copy-number changes in single cell data 5 , 6 . Here we leverage the extra information provided by tumour DNA sequencing to use shifts in BAF to precisely identify single cancer cell transcriptomes. Fig. 1: Overview of different approaches to identifying cancer-derived cells. a Genomic changes present in cancer genomes. b Number of cells (y-axis) with N reads covering point mutations (x-axis), separated by low (NB neuroblastoma) and high (RCC renal cell carcinoma) mutation burden. c Number of cells (y-axis) with N reads covering heterozygous single nucleotide polymorphisms (SNP) (x-axis). d Overview of using allelic shifts representing copy-number changes to detect cancer cells. Full size image Results Briefly, our method, which we call alleleIntegrator, works as follows. Firstly, whole genome or exome sequencing is performed on tumour DNA. From this, regions of copy-number change are identified, using established methods such as ASCAT 7 , along with germline heterozygous single nucleotide polymorphisms (SNPs) within altered regions. The alleles with frequency significantly greater than 0.5 (binomial test) are phased together and collectively designated the “major allele”. The allele frequency of all phased heterozygous SNPs within copy-number altered regions is then measured in each single cell transcriptome. Finally, the posterior probability of both the normal genotype (where all alleles have BAF 0.5) and the cancer genotype (where the BAF of each allele matches that implied by the copy-number status of the cancer) are calculated. It is possible that allelic shifts may result from allele-specific expression rather than copy-number change. To control for this, we exclude genes known to be imprinted or have allele-biased expression (e.g. HLA genes), model any residual allele-specific expression using the data, and only consider large regions spanning multiple genes. Those cells with a posterior probability exceeding some threshold (set to 99% throughout this paper) are designated as cancer or normal cells, with all other cells designated as unassigned. To test approaches used to identify cancer cells, we generated or downloaded single cell droplet-based 3′ single cell transcriptomes from 13 individuals and 5 tumour types: renal cell carcinoma (RCC), neuroblastoma, Wilms tumour, Ewing’s sarcoma, and atypical teratoid rhabdoid tumour (AT/RT) 8 , 9 , 10 (Supplementary Table 1 ). We first tested if detection of cancer specific point mutations would identify cancer transcriptomes. Across all samples, the majority of cells had no reads covering a point mutation (Fig. 1b ), with on average 9.7 reads per ten thousand point mutations per cell (range 0<|im_end|> <|im_start|>assistant A new method of separating cancer cells from non-cancer cells has been developed by researchers at the Wellcome Sanger Institute, in a boost for those working to better understand cancer biology using single-cell mRNA sequencing. The study, published today in Communications Biology, improves on existing methods to identify which cells in a sample are cancerous and provides crucial data on the microenvironment of tumors. The software is openly available for researchers around the world to apply to their own data, advancing the effectiveness of single-cell sequencing to understand cancer. Single cell mRNA analysis of cancer cells is one of the leading edge techniques being used to better understand cancer biology. The data generated can be used to try to disrupt cancers with drugs or work out how cancers arise in the first place. A fundamental step in this process is separating cancer and non-cancer cells, but this isn't always an easy task. As well as the many types of cancer, there will also be molecular differences between cancer cells of the same type within a single tumor. Currently, the best method of doing this is to measure the average gene expression of cells in the sample, with higher or lower expression used to distinguish cancer cells from healthy cells. But this method can lead to false conclusions. In this new study, researchers at the Wellcome Sanger Institute performed whole genome sequencing and single-cell mRNA sequencing on samples collected by Great Ormond Street Hospital (GOSH). By locating imbalances of alleles in these data, which indicate copy number changes in the genome, the team was able to identify cancer cells more reliably than with previous methods. This approach will primarily be useful for validating new cancer cell types and better understanding the microenvironment of tumor tissue. "Being able to know how the transcriptome is different in cells with aberrant genomes, such as those found in cancers, is valuable knowledge and will expand the questions that we can answer using single-cell sequencing," says Dr. Matt Young. The method, named alleleIntegrator, is available as a software package for researchers across the world to use. <|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 Background Since the onset of the SARS-CoV-2 pandemic, most clinical testing has focused on RT-PCR 1 . Host epigenome manipulation post coronavirus infection 2 , 3 , 4 suggests that DNA methylation signatures may differentiate patients with SARS-CoV-2 infection from uninfected individuals, and help predict COVID-19 disease severity, even at initial presentation. Methods We customized Illumina’s Infinium MethylationEPIC array to enhance immune response detection and profiled peripheral blood samples from 164 COVID-19 patients with longitudinal measurements of disease severity and 296 patient controls. Results Epigenome-wide association analysis revealed 13,033 genome-wide significant methylation sites for case-vs-control status. Genes and pathways involved in interferon signaling and viral response were significantly enriched among differentially methylated sites. We observe highly significant associations at genes previously reported in genetic association studies ( e.g. IRF7 , OAS1 ). Using machine learning techniques, models built using sparse regression yielded highly predictive findings: cross-validated best fit AUC was 93.6% for case-vs-control status, and 79.1%, 80.8%, and 84.4% for hospitalization, ICU admission, and progression to death, respectively. Conclusions In summary, the strong COVID-19-specific epigenetic signature in peripheral blood driven by key immune-related pathways related to infection status, disease severity, and clinical deterioration provides insights useful for diagnosis and prognosis of patients with viral infections. Plain language summary Viral infections affect the body in many ways, including via changes to the epigenome, the sum of chemical modifications to an individual’s collection of genes that affect gene activity. Here, we analyzed the epigenome in blood samples from people with and without COVID-19 to determine whether we could find changes consistent with SARS-CoV-2 infection. Using a combination of statistical and machine learning techniques, we identify markers of SARS-CoV-2 infection as well as of severity and progression of COVID-19 disease. These signals of disease progression were present from the initial blood draw when first walking into the hospital. Together, these approaches demonstrate the potential of measuring the epigenome for monitoring SARS-CoV-2 status and severity. Introduction Coronaviruses (CoV) comprise a large group of human and animal pathogens, including the novel enveloped RNA betacoronavirus referred to as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 5 . This pathogen is associated with coronavirus disease 2019 (COVID-19) first identified in Wuhan, China in 2019 6 and declared a pandemic on March 11, 2020 7 . Since the onset of the pandemic, multiple tests for diagnosing COVID-19 have been launched, including real-time reverse transcriptase–polymerase chain reaction (RT-PCR), specific antibody detection, and next-generation sequencing assays that query for current or past infections 1 . With the exception of next-generation sequencing, which can discern viral subtypes, most diagnostic tests are viral strain dependent, can carry a high false negative rate, do not discern if the virus is viable and replicating, and do not predict clinical outcomes of infection 1 , 8 , 9 . For example, pre-symptomatic patients may test negative 10 , 11 while patients who have recovered may continue to test positive though they are no longer infectious 12 . Accurate diagnostics are urgently required to control continued communal spread, to better understand host response, and for the development of vaccines and antivirals 13 . Individuals infected with SARS-CoV-2 have a variable course of infection, ranging from asymptomatic to death. Although the fatality rate varies tremendously according to demographic characteristics and co-morbidities 14 , the U.S. ranks as one of the countries with the highest COVID-19 mortality rates 15 . Identification of which SARS-CoV-2-infected patients are most likely to develop severe disease would enable clinicians to triage patients via augmented clinical decision support. Having more information on disease severity has recently become critical due to widespread lack of hospital and intensive care unit (ICU) capacity, necessitating difficult decisions about resource triage. To our knowledge, no test can predict COVID-19 clinical course or severity, although work on cytokine abundance ratios after hospitalization has been proposed as a prognostic indicator of severe outcomes 16 . There is considerable evidence that enveloped RNA viruses such as CoV can manipulate the host’s epigenome via evolved functions that antagonize and regulate the host innate immune antiviral defense processes 2 , 3 , specifically via DNA methylation. Viral-mediated antagonism of antigen-presentation gene expression in the case of Middle East respiratory syndrome coronavirus (MERS-CoV) was shown to occur via DNA methylation 4 . DNA methylation changes at cytosine-phosphate-guanine (CpG) sites have been increasingly leveraged in the emerging field of clinical epigenetics to characterize unique epigenetic signatures that diagnose disease. To date, considerable success has been demonstrated in developing highly accurate and robust machine learning (ML)-based disease classifiers using DNA methylation patterns to differentiate Mendelian disorders 17 , behavior disorders 18 , coronary artery disease 19 , and some cancers 20 , 21 , 22 . Consequently integration of a methylation-based disease classification can result in relevant improvement in clinical practice 23 , 24 . With a goal to leverage Illumina’s Infinium MethylationEPIC Array to classify differential methylation signatures of SARS-CoV-2-positive (hereafter referred to as SARS-CoV-2+, regardless of additional symptoms) and control peripheral blood DNA samples (either confirmed SARS-CoV-2 negative or samples collected prior to the SARS-CoV-2 pandemic), we conducted this study to determine whether DNA methylation patterns could differentiate SARS-CoV-2-infected patients from non-infected patients from whole blood obtained from patients. Our secondary objective was to determine whether DNA methylation patterns could differentiate patients with SARS-CoV-2 infection who go on to develop severe disease. In this study, we identified a strong COVID-19-specific epigenetic signature in peripheral blood driven by key immune-related pathways related to SARS-CoV-2 infection status, disease severity, and clinical deterioration. Methods Source of data This protocol was reviewed and approved by the Colorado Multiple Institutional Review Board (COMIRB) and the research adheres to the ethical principles of research outlined in the U.S. Federal Policy for the Protection of Human Subjects. SARS-CoV-2+ were defined as those patients who tested positive for SARS-CoV-2 infection via a routine diagnostic RT-PCR assay in the Biobank at the Colorado Center for Personalized Medicine (Thermo Fisher Scientific, Waltham, MA) or in the UCHealth University of Colorado Hospital Clinical Laboratory", "role": "user" }, { "content": "Scientists at the University of Colorado School of Medicine, along with colleagues at UCHealth University of Colorado Hospital, have discovered specific genetic biomarkers that not only show who is infected with COVID-19, but offer insights into how severe the disease might be, filling a major diagnostic gap. \"I think this study is a tremendous proof-of-concept in the realm of COVID-19 testing, one that can be applied to other diseases,\" said the study's lead author, Kathleen Barnes, Ph.D., professor at the CU School of Medicine. \"It's a major move forward in the world of precision medicine.\" The study, published Tuesday in the journal Communications Medicine, suggests that specific signals from a process called DNA methylation varies between those infected and those not infected with SARS-CoV-2. And they can indicate the severity of the disease even in the early stages. DNA methylation, critical in how cells function, is an epigenetic signaling tool that cells use to turn genes off. Any mistakes in the process can trigger a variety of disease. Barnes believes that paying attention to these signals could help fill a needed gap in the current world of COVID testing. Most COVID-19 antigen or rapid tests are dependent on viral strains and can carry high false negative rates. They don't predict if the virus is viable and replicating, nor do they predict clinical outcomes, the study said. A pre-symptomatic patient may test negative for the SARS-CoV-2 virus while patients who have recovered may still test positive despite no longer being infectious. \"Accurate diagnostics are urgently required to control continued communal spread, to better understand host response, and for the development of vaccines and antivirals,\" the study said. \"Identification of which SARS-CoV-2 infected patients are most likely to develop severe disease would enable clinicians to triage patients via augmented clinical decision support.\" But the authors said they didn't know of any test that can predict the clinical course of COVID-19. With that in mind, they analyzed the epigenome in blood samples from people with and without COVID-19. They customized a tool from Illumina called the Infinium Methylation EPIC array to enhance immune response detection. Researchers then profiled peripheral blood samples from 164 COVID-19 patients and 296 control patients. The peripheral blood DNA samples were collected from patients seen at UCHealth and tested for SARS-CoV-2 epigenetic signatures starting March 1, 2020. Most blood specimens were collected in the University of Colorado Emergency Medicine Specimen Bank under the direction of study co-author Andrew Monte, MD, Ph.D., and passed on to the Colorado Anschutz Research Genetics Organization (CARGO). Additional specimens were taken from patients consented to the University of Colorado COVID-19 Biorepository. The researchers discovered specific genetic markers of SARS-CoV-2 infection along with indications of how severe the disease might be. \"These signals of disease progression were present from the initial blood draw when first walking into the hospital,\" the study said. \"Together, these approaches demonstrate the potential of measuring the epigenome for monitoring SARS-CoV-2 status and severity.\" According to Barnes, the findings could ultimately lead to a new and more accurate way to test for COVID-19. \"We are exploring how this platform could add value to the COVID diagnostic world,\" she said. \"We think it adds value to knowing what patients develop more serious disease. This could tell you if you could ride out the infection or if it is likely to get worse.\" ", "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 Since the onset of the SARS-CoV-2 pandemic, most clinical testing has focused on RT-PCR 1 . Host epigenome manipulation post coronavirus infection 2 , 3 , 4 suggests that DNA methylation signatures may differentiate patients with SARS-CoV-2 infection from uninfected individuals, and help predict COVID-19 disease severity, even at initial presentation. Methods We customized Illumina’s Infinium MethylationEPIC array to enhance immune response detection and profiled peripheral blood samples from 164 COVID-19 patients with longitudinal measurements of disease severity and 296 patient controls. Results Epigenome-wide association analysis revealed 13,033 genome-wide significant methylation sites for case-vs-control status. Genes and pathways involved in interferon signaling and viral response were significantly enriched among differentially methylated sites. We observe highly significant associations at genes previously reported in genetic association studies ( e.g. IRF7 , OAS1 ). Using machine learning techniques, models built using sparse regression yielded highly predictive findings: cross-validated best fit AUC was 93.6% for case-vs-control status, and 79.1%, 80.8%, and 84.4% for hospitalization, ICU admission, and progression to death, respectively. Conclusions In summary, the strong COVID-19-specific epigenetic signature in peripheral blood driven by key immune-related pathways related to infection status, disease severity, and clinical deterioration provides insights useful for diagnosis and prognosis of patients with viral infections. Plain language summary Viral infections affect the body in many ways, including via changes to the epigenome, the sum of chemical modifications to an individual’s collection of genes that affect gene activity. Here, we analyzed the epigenome in blood samples from people with and without COVID-19 to determine whether we could find changes consistent with SARS-CoV-2 infection. Using a combination of statistical and machine learning techniques, we identify markers of SARS-CoV-2 infection as well as of severity and progression of COVID-19 disease. These signals of disease progression were present from the initial blood draw when first walking into the hospital. Together, these approaches demonstrate the potential of measuring the epigenome for monitoring SARS-CoV-2 status and severity. Introduction Coronaviruses (CoV) comprise a large group of human and animal pathogens, including the novel enveloped RNA betacoronavirus referred to as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 5 . This pathogen is associated with coronavirus disease 2019 (COVID-19) first identified in Wuhan, China in 2019 6 and declared a pandemic on March 11, 2020 7 . Since the onset of the pandemic, multiple tests for diagnosing COVID-19 have been launched, including real-time reverse transcriptase–polymerase chain reaction (RT-PCR), specific antibody detection, and next-generation sequencing assays that query for current or past infections 1 . With the exception of next-generation sequencing, which can discern viral subtypes, most diagnostic tests are viral strain dependent, can carry a high false negative rate, do not discern if the virus is viable and replicating, and do not predict clinical outcomes of infection 1 , 8 , 9 . For example, pre-symptomatic patients may test negative 10 , 11 while patients who have recovered may continue to test positive though they are no longer infectious 12 . Accurate diagnostics are urgently required to control continued communal spread, to better understand host response, and for the development of vaccines and antivirals 13 . Individuals infected with SARS-CoV-2 have a variable course of infection, ranging from asymptomatic to death. Although the fatality rate varies tremendously according to demographic characteristics and co-morbidities 14 , the U.S. ranks as one of the countries with the highest COVID-19 mortality rates 15 . Identification of which SARS-CoV-2-infected patients are most likely to develop severe disease would enable clinicians to triage patients via augmented clinical decision support. Having more information on disease severity has recently become critical due to widespread lack of hospital and intensive care unit (ICU) capacity, necessitating difficult decisions about resource triage. To our knowledge, no test can predict COVID-19 clinical course or severity, although work on cytokine abundance ratios after hospitalization has been proposed as a prognostic indicator of severe outcomes 16 . There is considerable evidence that enveloped RNA viruses such as CoV can manipulate the host’s epigenome via evolved functions that antagonize and regulate the host innate immune antiviral defense processes 2 , 3 , specifically via DNA methylation. Viral-mediated antagonism of antigen-presentation gene expression in the case of Middle East respiratory syndrome coronavirus (MERS-CoV) was shown to occur via DNA methylation 4 . DNA methylation changes at cytosine-phosphate-guanine (CpG) sites have been increasingly leveraged in the emerging field of clinical epigenetics to characterize unique epigenetic signatures that diagnose disease. To date, considerable success has been demonstrated in developing highly accurate and robust machine learning (ML)-based disease classifiers using DNA methylation patterns to differentiate Mendelian disorders 17 , behavior disorders 18 , coronary artery disease 19 , and some cancers 20 , 21 , 22 . Consequently integration of a methylation-based disease classification can result in relevant improvement in clinical practice 23 , 24 . With a goal to leverage Illumina’s Infinium MethylationEPIC Array to classify differential methylation signatures of SARS-CoV-2-positive (hereafter referred to as SARS-CoV-2+, regardless of additional symptoms) and control peripheral blood DNA samples (either confirmed SARS-CoV-2 negative or samples collected prior to the SARS-CoV-2 pandemic), we conducted this study to determine whether DNA methylation patterns could differentiate SARS-CoV-2-infected patients from non-infected patients from whole blood obtained from patients. Our secondary objective was to determine whether DNA methylation patterns could differentiate patients with SARS-CoV-2 infection who go on to develop severe disease. In this study, we identified a strong COVID-19-specific epigenetic signature in peripheral blood driven by key immune-related pathways related to SARS-CoV-2 infection status, disease severity, and clinical deterioration. Methods Source of data This protocol was reviewed and approved by the Colorado Multiple Institutional Review Board (COMIRB) and the research adheres to the ethical principles of research outlined in the U.S. Federal Policy for the Protection of Human Subjects. SARS-CoV-2+ were defined as those patients who tested positive for SARS-CoV-2 infection via a routine diagnostic RT-PCR assay in the Biobank at the Colorado Center for Personalized Medicine (Thermo Fisher Scientific, Waltham, MA) or in the UCHealth University of Colorado Hospital Clinical Laboratory<|im_end|> <|im_start|>assistant Scientists at the University of Colorado School of Medicine, along with colleagues at UCHealth University of Colorado Hospital, have discovered specific genetic biomarkers that not only show who is infected with COVID-19, but offer insights into how severe the disease might be, filling a major diagnostic gap. "I think this study is a tremendous proof-of-concept in the realm of COVID-19 testing, one that can be applied to other diseases," said the study's lead author, Kathleen Barnes, Ph.D., professor at the CU School of Medicine. "It's a major move forward in the world of precision medicine." The study, published Tuesday in the journal Communications Medicine, suggests that specific signals from a process called DNA methylation varies between those infected and those not infected with SARS-CoV-2. And they can indicate the severity of the disease even in the early stages. DNA methylation, critical in how cells function, is an epigenetic signaling tool that cells use to turn genes off. Any mistakes in the process can trigger a variety of disease. Barnes believes that paying attention to these signals could help fill a needed gap in the current world of COVID testing. Most COVID-19 antigen or rapid tests are dependent on viral strains and can carry high false negative rates. They don't predict if the virus is viable and replicating, nor do they predict clinical outcomes, the study said. A pre-symptomatic patient may test negative for the SARS-CoV-2 virus while patients who have recovered may still test positive despite no longer being infectious. "Accurate diagnostics are urgently required to control continued communal spread, to better understand host response, and for the development of vaccines and antivirals," the study said. "Identification of which SARS-CoV-2 infected patients are most likely to develop severe disease would enable clinicians to triage patients via augmented clinical decision support." But the authors said they didn't know of any test that can predict the clinical course of COVID-19. With that in mind, they analyzed the epigenome in blood samples from people with and without COVID-19. They customized a tool from Illumina called the Infinium Methylation EPIC array to enhance immune response detection. Researchers then profiled peripheral blood samples from 164 COVID-19 patients and 296 control patients. The peripheral blood DNA samples were collected from patients seen at UCHealth and tested for SARS-CoV-2 epigenetic signatures starting March 1, 2020. Most blood specimens were collected in the University of Colorado Emergency Medicine Specimen Bank under the direction of study co-author Andrew Monte, MD, Ph.D., and passed on to the Colorado Anschutz Research Genetics Organization (CARGO). Additional specimens were taken from patients consented to the University of Colorado COVID-19 Biorepository. The researchers discovered specific genetic markers of SARS-CoV-2 infection along with indications of how severe the disease might be. "These signals of disease progression were present from the initial blood draw when first walking into the hospital," the study said. "Together, these approaches demonstrate the potential of measuring the epigenome for monitoring SARS-CoV-2 status and severity." According to Barnes, the findings could ultimately lead to a new and more accurate way to test for COVID-19. "We are exploring how this platform could add value to the COVID diagnostic world," she said. "We think it adds value to knowing what patients develop more serious disease. This could tell you if you could ride out the infection or if it is likely to get worse." <|im_end|>
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2,183
[ { "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 Cellular membranes are dynamic structures, continuously adjusting their composition, allowing plants to respond to developmental signals, stresses, and changing environments. To facilitate transmembrane transport of substrates, plant membranes are embedded with both active and passive transporters. Aquaporins (AQPs) constitute a major family of membrane spanning channel proteins that selectively facilitate the passive bidirectional passage of substrates across biological membranes at an astonishing 10 8 molecules per second. AQPs are the most diversified in the plant kingdom, comprising of five major subfamilies that differ in temporal and spatial gene expression, subcellular protein localisation, substrate specificity, and post-translational regulatory mechanisms; collectively providing a dynamic transportation network spanning the entire plant. Plant AQPs can transport a range of solutes essential for numerous plant processes including, water relations, growth and development, stress responses, root nutrient uptake, and photosynthesis. The ability to manipulate AQPs towards improving plant productivity, is reliant on expanding our insight into the diversity and functional roles of AQPs. Results We characterised the AQP family from Nicotiana tabacum (NtAQPs; tobacco), a popular model system capable of scaling from the laboratory to the field. Tobacco is closely related to major economic crops (e.g. tomato, potato, eggplant and peppers) and itself has new commercial applications. Tobacco harbours 76 AQPs making it the second largest characterised AQP family. These fall into five distinct subfamilies, for which we characterised phylogenetic relationships, gene structures, protein sequences, selectivity filter compositions, sub-cellular localisation, and tissue-specific expression. We also identified the AQPs from tobacco’s parental genomes ( N. sylvestris and N. tomentosiformis ), allowing us to characterise the evolutionary history of the NtAQP family. Assigning orthology to tomato and potato AQPs allowed for cross-species comparisons of conservation in protein structures, gene expression, and potential physiological roles. Conclusions This study provides a comprehensive characterisation of the tobacco AQP family, and strengthens the current knowledge of AQP biology. The refined gene/protein models, tissue-specific expression analysis, and cross-species comparisons, provide valuable insight into the evolutionary history and likely physiological roles of NtAQPs and their Solanaceae orthologs. Collectively, these results will support future functional studies and help transfer basic research to applied agriculture. Background Cellular membranes are dynamic structures, continuously adjusting their composition in order to allow plants to respond to developmental signals, stresses, and changing environments [ 1 ]. The biological function of cell membranes is conferred by its protein composition, with the lipid bilayer providing a basic structure and permeability barrier, and integral transmembrane proteins facilitating diffusion of selected substrates [ 1 ]. Cell membrane diffusion is a fundamental process of plant biology and one of the oldest subjects studied in plant physiology [ 2 ]. Diffusional events at the cellular level eventuate in the coordinated transport of substrates throughout the plant to support development and growth. Plant membranes contain three major classes of transport proteins known as ATP-powered pumps, Transporters, and Channel proteins [ 3 ]. Pumps, are active transporters that use the energy of ATP hydrolysis to move substrates across the membrane against a concentration gradient or electrical potential. Transporters move a variety of molecules across a membrane along or against a gradient at rates of 10 2 to 10 4 molecules per second. Unlike the first two classes, channel proteins are bidirectional and increase membrane permeability to a particular molecule. Channel proteins are permeable to a wide range of substrates and can pass up to 10 8 molecules per second. In plants, aquaporins (AQPs) constitute a major family of such channel proteins that facilitate selective transport of substrates for numerous biological processes including, water relations, plant development, stress responses, and photosynthesis [ 4 , 5 ]. The AQP monomer forms a characteristic hour-glass membrane-spanning pore that assembles as tetrameric complexes in cell membranes. The union of the four monomers, creates a fifth pore at the centre of the tetramer which may provide an additional diffusional path [ 6 ]. The substrate specificity of a given AQP is conferred by the complement of pore lining residues which achieve specificity through a combination of size exclusion and biochemical interactions with substrates [ 7 ]. Key identified specificity residues include the dual Asn-Pro-Ala (NPA) motifs, the aromatic/Arginine filter (ar/R filter) and Froger’s positions (P1-P5) [ 8 , 9 , 10 ]. However, other pore-lining residues and lengths of the various transmembrane and loop domains of the AQP monomer are also known to influence substrate specificity through conformational changes of the pore size and accessibility [ 7 , 11 ]. It is likely that other residues that determine specificity and transport efficiency remain to be elucidated. Aquaporins, which are members of the major intrinsic proteins (MIP) superfamily, are found across all taxonomic kingdoms [ 12 ]. While mammals usually have only 15 isoforms, plants have vastly larger AQP families commonly ranging from 30 to 121 members [ 5 , 13 , 14 , 15 ]. This impressive diversification has been facilitated by the propensity of gene duplication events, especially prevalent in the angiosperms, and likely by the adaptive potential provided by AQPs. Based on sequence homology and subcellular localisation, up to thirteen AQP subfamilies are now recognised in the plant kingdom [ 13 , 16 , 17 , 18 , 19 ]. Eight of these AQP subfamilies occur in more ancestral plant lineages and include, the GlpF-like Intrinsic Proteins (GIPs) and Hybrid Intrinsic Proteins (HIPs) in mosses, the MIPs A to E of green algae, and the Large Intrinsic Proteins (LIPs) in diatoms. The remaining five subfamilies are prevalent across higher plants and have extensively diversified into sub-groups and include the Plasma membrane Intrinsic Proteins (PIPs; subgroups PIP1 and PIP2), Tonoplast Intrinsic Proteins (TIPs; subgroups TIP1 to TIP5), Small basic Intrinsic Proteins (SIPs; subgroups SIP1 and SIP2), Nodulin 26-like Intrinsic Proteins (NIPs; subgroups NIP1 to NIP5), and X Intrinsic Proteins (XIPs; subgroups XIP1 to XIP3). The XIPs are present in many eudicot species, but are absent in the Brassicaceae and monocots [ 17 ]. The AQP subfamilies differ to some degree in substrate specificity and integrate into different cellular membranes, providing", "role": "user" }, { "content": "Scientists have shed new light on how the network of gatekeepers that controls the traffic in and out of plant cells works, which researchers believe is key to develop food crops with bigger yields and greater ability to cope with extreme environments. Everything that a plant needs to grow first needs to pass through its cells' membranes, which are guarded by a sieve of microscopic pores called aquaporins. \"Aquaporins (AQPs) are ancient channel proteins that are found in most organisms, from bacteria to humans. In plants, they are vital for numerous plant processes including, water transport, growth and development, stress responses, root nutrient uptake, and photosynthesis,\" says former Ph.D. student Annamaria De Rosa from the ARC Centre of Excellence for Translational Photosynthesis (CoETP) at The Australian National University (ANU). \"We know that if we are able to manipulate aquaporins, it will open numerous useful applications for agriculture, including improving crop productivity, but first we need to know more about their diversity, evolutionary history and the many functional roles they have inside the plant,\" Ms De Rosa says. Their research, published this week in the journal BMC Plant Biology, did just that. They identified all the different types of aquaporins found in tobacco (Nicotiana tabacum), a model plant species closely related to major economic crops such as tomato, potato, eggplant and capsicum. \"We described 76 types of these microscopic hour-glass shape channels based on their gene structures, protein composition, location in the plant cell and in the different organs of the plant and their evolutionary origin. These results are extremely important as they will help us to transfer basic research to applied agriculture,\" says Ms De Rosa, whose Ph.D. project focused on aquaporins. \"The Centre (CoETP) is really interested in understanding aquaporins because we believe they are a key player in energy conversion through photosynthesis and also control how a plant uses water. That is why we think we can use aquaporins to enhance plant performance and crop resilience to environmental changes,\" says lead researcher Dr. Michael Groszmann from the Research School of Biology and the CoETP at ANU. Aquaporins are found everywhere in the plant, from the roots to flowers, transporting very different molecules in each location, at an astonishing 100 million molecules per second. The configuration of an aquaporin channel determines the substrate it transports and therefore its function, from the transport of water and nutrients from roots to shoots, to stress signaling or seed development. \"We focused on tobacco because it is a fast-growing model species that allows us to scale from the lab to the field, allowing us to evaluate performance in real-world scenarios. Tobacco is closely related to several important commercial crops, which means we can easily transfer the knowledge we obtain in tobacco to species like tomato and potato. Tobacco itself has own commercial applications and there is a renewed interest in the biofuel and plant-based pharmaceutical sectors,\" he says. \"This research is extremely exciting because the diversity of aquaporins in terms of their function and the substrates they transport, mean they have many potential applications for crop improvement ranging from improved salt tolerance, more efficient fertilizer use, improved drought tolerance, and even more effective response to disease infection. They are currently being used in water filtration systems and our results could help to expand these applications. The future of aquaporins is full of possibilities,\" says Dr. Groszmann. ", "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 Cellular membranes are dynamic structures, continuously adjusting their composition, allowing plants to respond to developmental signals, stresses, and changing environments. To facilitate transmembrane transport of substrates, plant membranes are embedded with both active and passive transporters. Aquaporins (AQPs) constitute a major family of membrane spanning channel proteins that selectively facilitate the passive bidirectional passage of substrates across biological membranes at an astonishing 10 8 molecules per second. AQPs are the most diversified in the plant kingdom, comprising of five major subfamilies that differ in temporal and spatial gene expression, subcellular protein localisation, substrate specificity, and post-translational regulatory mechanisms; collectively providing a dynamic transportation network spanning the entire plant. Plant AQPs can transport a range of solutes essential for numerous plant processes including, water relations, growth and development, stress responses, root nutrient uptake, and photosynthesis. The ability to manipulate AQPs towards improving plant productivity, is reliant on expanding our insight into the diversity and functional roles of AQPs. Results We characterised the AQP family from Nicotiana tabacum (NtAQPs; tobacco), a popular model system capable of scaling from the laboratory to the field. Tobacco is closely related to major economic crops (e.g. tomato, potato, eggplant and peppers) and itself has new commercial applications. Tobacco harbours 76 AQPs making it the second largest characterised AQP family. These fall into five distinct subfamilies, for which we characterised phylogenetic relationships, gene structures, protein sequences, selectivity filter compositions, sub-cellular localisation, and tissue-specific expression. We also identified the AQPs from tobacco’s parental genomes ( N. sylvestris and N. tomentosiformis ), allowing us to characterise the evolutionary history of the NtAQP family. Assigning orthology to tomato and potato AQPs allowed for cross-species comparisons of conservation in protein structures, gene expression, and potential physiological roles. Conclusions This study provides a comprehensive characterisation of the tobacco AQP family, and strengthens the current knowledge of AQP biology. The refined gene/protein models, tissue-specific expression analysis, and cross-species comparisons, provide valuable insight into the evolutionary history and likely physiological roles of NtAQPs and their Solanaceae orthologs. Collectively, these results will support future functional studies and help transfer basic research to applied agriculture. Background Cellular membranes are dynamic structures, continuously adjusting their composition in order to allow plants to respond to developmental signals, stresses, and changing environments [ 1 ]. The biological function of cell membranes is conferred by its protein composition, with the lipid bilayer providing a basic structure and permeability barrier, and integral transmembrane proteins facilitating diffusion of selected substrates [ 1 ]. Cell membrane diffusion is a fundamental process of plant biology and one of the oldest subjects studied in plant physiology [ 2 ]. Diffusional events at the cellular level eventuate in the coordinated transport of substrates throughout the plant to support development and growth. Plant membranes contain three major classes of transport proteins known as ATP-powered pumps, Transporters, and Channel proteins [ 3 ]. Pumps, are active transporters that use the energy of ATP hydrolysis to move substrates across the membrane against a concentration gradient or electrical potential. Transporters move a variety of molecules across a membrane along or against a gradient at rates of 10 2 to 10 4 molecules per second. Unlike the first two classes, channel proteins are bidirectional and increase membrane permeability to a particular molecule. Channel proteins are permeable to a wide range of substrates and can pass up to 10 8 molecules per second. In plants, aquaporins (AQPs) constitute a major family of such channel proteins that facilitate selective transport of substrates for numerous biological processes including, water relations, plant development, stress responses, and photosynthesis [ 4 , 5 ]. The AQP monomer forms a characteristic hour-glass membrane-spanning pore that assembles as tetrameric complexes in cell membranes. The union of the four monomers, creates a fifth pore at the centre of the tetramer which may provide an additional diffusional path [ 6 ]. The substrate specificity of a given AQP is conferred by the complement of pore lining residues which achieve specificity through a combination of size exclusion and biochemical interactions with substrates [ 7 ]. Key identified specificity residues include the dual Asn-Pro-Ala (NPA) motifs, the aromatic/Arginine filter (ar/R filter) and Froger’s positions (P1-P5) [ 8 , 9 , 10 ]. However, other pore-lining residues and lengths of the various transmembrane and loop domains of the AQP monomer are also known to influence substrate specificity through conformational changes of the pore size and accessibility [ 7 , 11 ]. It is likely that other residues that determine specificity and transport efficiency remain to be elucidated. Aquaporins, which are members of the major intrinsic proteins (MIP) superfamily, are found across all taxonomic kingdoms [ 12 ]. While mammals usually have only 15 isoforms, plants have vastly larger AQP families commonly ranging from 30 to 121 members [ 5 , 13 , 14 , 15 ]. This impressive diversification has been facilitated by the propensity of gene duplication events, especially prevalent in the angiosperms, and likely by the adaptive potential provided by AQPs. Based on sequence homology and subcellular localisation, up to thirteen AQP subfamilies are now recognised in the plant kingdom [ 13 , 16 , 17 , 18 , 19 ]. Eight of these AQP subfamilies occur in more ancestral plant lineages and include, the GlpF-like Intrinsic Proteins (GIPs) and Hybrid Intrinsic Proteins (HIPs) in mosses, the MIPs A to E of green algae, and the Large Intrinsic Proteins (LIPs) in diatoms. The remaining five subfamilies are prevalent across higher plants and have extensively diversified into sub-groups and include the Plasma membrane Intrinsic Proteins (PIPs; subgroups PIP1 and PIP2), Tonoplast Intrinsic Proteins (TIPs; subgroups TIP1 to TIP5), Small basic Intrinsic Proteins (SIPs; subgroups SIP1 and SIP2), Nodulin 26-like Intrinsic Proteins (NIPs; subgroups NIP1 to NIP5), and X Intrinsic Proteins (XIPs; subgroups XIP1 to XIP3). The XIPs are present in many eudicot species, but are absent in the Brassicaceae and monocots [ 17 ]. The AQP subfamilies differ to some degree in substrate specificity and integrate into different cellular membranes, providing<|im_end|> <|im_start|>assistant Scientists have shed new light on how the network of gatekeepers that controls the traffic in and out of plant cells works, which researchers believe is key to develop food crops with bigger yields and greater ability to cope with extreme environments. Everything that a plant needs to grow first needs to pass through its cells' membranes, which are guarded by a sieve of microscopic pores called aquaporins. "Aquaporins (AQPs) are ancient channel proteins that are found in most organisms, from bacteria to humans. In plants, they are vital for numerous plant processes including, water transport, growth and development, stress responses, root nutrient uptake, and photosynthesis," says former Ph.D. student Annamaria De Rosa from the ARC Centre of Excellence for Translational Photosynthesis (CoETP) at The Australian National University (ANU). "We know that if we are able to manipulate aquaporins, it will open numerous useful applications for agriculture, including improving crop productivity, but first we need to know more about their diversity, evolutionary history and the many functional roles they have inside the plant," Ms De Rosa says. Their research, published this week in the journal BMC Plant Biology, did just that. They identified all the different types of aquaporins found in tobacco (Nicotiana tabacum), a model plant species closely related to major economic crops such as tomato, potato, eggplant and capsicum. "We described 76 types of these microscopic hour-glass shape channels based on their gene structures, protein composition, location in the plant cell and in the different organs of the plant and their evolutionary origin. These results are extremely important as they will help us to transfer basic research to applied agriculture," says Ms De Rosa, whose Ph.D. project focused on aquaporins. "The Centre (CoETP) is really interested in understanding aquaporins because we believe they are a key player in energy conversion through photosynthesis and also control how a plant uses water. That is why we think we can use aquaporins to enhance plant performance and crop resilience to environmental changes," says lead researcher Dr. Michael Groszmann from the Research School of Biology and the CoETP at ANU. Aquaporins are found everywhere in the plant, from the roots to flowers, transporting very different molecules in each location, at an astonishing 100 million molecules per second. The configuration of an aquaporin channel determines the substrate it transports and therefore its function, from the transport of water and nutrients from roots to shoots, to stress signaling or seed development. "We focused on tobacco because it is a fast-growing model species that allows us to scale from the lab to the field, allowing us to evaluate performance in real-world scenarios. Tobacco is closely related to several important commercial crops, which means we can easily transfer the knowledge we obtain in tobacco to species like tomato and potato. Tobacco itself has own commercial applications and there is a renewed interest in the biofuel and plant-based pharmaceutical sectors," he says. "This research is extremely exciting because the diversity of aquaporins in terms of their function and the substrates they transport, mean they have many potential applications for crop improvement ranging from improved salt tolerance, more efficient fertilizer use, improved drought tolerance, and even more effective response to disease infection. They are currently being used in water filtration systems and our results could help to expand these applications. The future of aquaporins is full of possibilities," says Dr. Groszmann. <|im_end|>
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