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[ "The purpose of this study was to examine differences in resting, submaximal, and maximal (VO2max) oxygen consumption (VO2) in African-American (n = 44) and Caucasian (n = 31) prepubertal children aged 5-10 yr.", "Resting VO2 was measured via indirect calorimetry in the fasted state.", "Submaximal VO2 and VO2max were determined during an all out, progressive treadmill exercise test appropriate for children.", "Dual-energy X-ray absorptiometry was used to determine total fat mass (FM), soft lean tissue mass (LTM), and leg soft LTM.", "Doubly labeled water was used to determine total energy expenditure (TEE) and activity energy expenditure (AEE).", "A significant effect of ethnicity (P < 0.01) was found for VO2max but not resting or submaximal VO2, with African-American children having absolute VO2max approximately 15% lower than Caucasian children (1.21 +/- 0.032 vs. 1.43 +/-", "0.031 l/min, respectively).", "The lower VO2max persisted in African-American children after adjustment for soft LTM (1.23 +/- 0.025 vs. 1.39 +/-", "0.031 l/min; P < 0.01), leg soft LTM (1.20 +/-", "0.031 vs. 1.43 +/-", "0.042 l/min; P < 0.01), and soft LTM and FM (1.23 +/-", "0.025 vs. 1.39 +/-", "0.031 l/min; P < 0.01).", "The lower VO2max persisted also after adjustment for TEE (1.20 +/-", "0.02 vs. 1.38 +/-", "0.0028 l/min P < 0.001) and AEE (1.20 +/- 0.024 vs. 1.38 +/-", "0.028 l/min; P < 0.001).", "In conclusion, our data indicate that African-American and Caucasian children have similar rates of VO2 at rest and during submaximal exercise, but VO2max is approximately 15% lower in African-American children, independent of soft LTM, FM, leg LTM, TEE, and AEE." ]

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[ "BACKGROUND Little is known about how the intensity of exercise influences cardiovascular fitness and body composition, especially in obese adolescents.", "OBJECTIVE Our goal was to determine the effects of physical training intensity on the cardiovascular fitness, percentage of body fat (%BF), and visceral adipose tissue (VAT) of obese adolescents.", "DESIGN Obese 13-16-y-olds (n = 80) were assigned to 1) biweekly lifestyle education (LSE), 2) LSE + moderate-intensity physical training, or 3) LSE + high-intensity physical training.", "The intervention lasted 8 mo.", "Physical training was offered 5 d/wk, and the target energy expenditure for all subjects in physical training groups was 1047 kJ (250 kcal)/session.", "Cardiovascular fitness was measured with a multistage treadmill test, %BF with dual-energy X-ray absorptiometry, and VAT with magnetic resonance imaging.", "RESULTS The increase in cardiovascular fitness in the high-intensity physical training group, but not in the moderate-intensity group, was significantly greater than that in the LSE alone group (P = 0.009); no other comparisons of the 3 groups were significant.", "Compared with the LSE alone group, a group composed of subjects in both physical training groups combined who attended training sessions >or=2 d/wk showed favorable changes in cardiovascular fitness (P < 0.001), %BF (P = 0.001), and VAT (P = 0.029).", "We found no evidence that the high-intensity physical training was more effective than the moderate-intensity physical training in enhancing body composition.", "CONCLUSIONS The cardiovascular fitness of obese adolescents was significantly improved by physical training, especially high-intensity physical training.", "The physical training also reduced both visceral and total-body adiposity, but there was no clear effect of the intensity of physical training." ]

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[ "OBJECTIVES Despite recognition of the important influence of environmental determinants on physical activity patterns, minimal empirical research has been done to assess the impact of environmental/contextual determinants of physical activity.", "This article aims to investigate environmental and sociodemographic determinants of physical activity and inactivity patterns among subpopulations of US adolescents.", "We define environmental determinants as modifiable factors in the physical environment that impose a direct influence on the opportunity to engage in physical activity.", "The present research examines environmental and sociodemographic determinants of physical activity and inactivity with the implication that these findings can point toward societal-level intervention strategies for increasing physical activity and decreasing inactivity among adolescents.", "STUDY DESIGN AND METHODOLOGY The study population consists of nationally representative data from the 1996 National Longitudinal Study of Adolescent Health on 17 766 US adolescents enrolled in US middle and high schools (including 3933 non-Hispanic blacks, 3148 Hispanics, and 1337 Asians).", "Hours/week of inactivity (TV/video viewing and video/computer games) and times/week of moderate to vigorous physical activity were collected by questionnaire.", "Outcome variables were moderate to vigorous physical activity and inactivity, which were broken into categories (physical activity: 0-2 times/week, 3-4 times/week, and >/=5 times/week; inactivity: 0-10 hours/week, 11-24 hours/week, and >/=25 hours/week).", "Sociodemographic and environmental correlates of physical activity and inactivity were used as exposure and control variables and included sex, age, urban residence, participation in school physical education program, use of community recreation center, total reported incidents of serious crime in neighborhood, socioeconomic status, ethnicity, generation of residence in the United States, presence of mother/father in household, pregnancy status, work status, in-school status, region, and month of interview.", "Logistic regression models of high versus low and medium physical activity and inactivity were used to investigate sex and ethnic interactions in relation to environmental and sociodemographic factors to examine evidence for the potential impact of physical education and recreation programs and sociodemographic factors on physical activity and inactivity patterns.", "RESULTS Moderate to vigorous physical activity was lower and inactivity higher for non-Hispanic black and Hispanic adolescents.", "Participation in school physical education programs was considerably low for these adolescents and decreased with age.", "Participation in daily school physical education (PE) program classes (adjusted odds ratio [AOR]: 2.21; confidence interval [CI]: 1.82-2.68) and use of a community recreation center (AOR: 1.75; CI: 1.56-1.96) were associated with an increased likelihood of engaging in high level moderate to vigorous physical activity.", "Maternal education was inversely associated with high inactivity patterns; for example, having a mother with a graduate or professional degree was associated with an AOR of.61 (CI:.48-.76) for high inactivity.", "High family income was associated with increased moderate to vigorous physical activity (AOR: 1.43; CI: 1.22-1.67) and decreased inactivity (AOR:.70; CI:.59-.82).", "High neighborhood serious crime level was associated with a decreased likelihood of falling in the highest category of moderate to vigorous physical activity (AOR:.77; CI:.66-.91).", "CONCLUSIONS These results show important associations between modifiable environmental factors, such as participation in school PE and community recreation programs, with activity patterns of adolescents.", "Despite the marked and significant impact of participation in school PE programs on physical activity patterns of US adolescents, few adolescents participated in such school PE programs; only 21.3% of all adolescents" ]

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[ "Human transglutaminase 2 (TG2), a member of a large family of enzymes that catalyze protein crosslinking, plays an important role in the extracellular matrix biology of many tissues and is implicated in the gluten-induced pathogenesis of celiac sprue.", "Although vertebrate transglutaminases have been studied extensively, thus far all structurally characterized members of this family have been crystallized in conformations with inaccessible active sites.", "We have trapped human TG2 in complex with an inhibitor that mimics inflammatory gluten peptide substrates and have solved, at 2-A resolution, its x-ray crystal structure.", "The inhibitor stabilizes TG2 in an extended conformation that is dramatically different from earlier transglutaminase structures.", "The active site is exposed, revealing that catalysis takes place in a tunnel, bridged by two tryptophan residues that separate acyl-donor from acyl-acceptor and stabilize the tetrahedral reaction intermediates.", "Site-directed mutagenesis was used to investigate the acyl-acceptor side of the tunnel, yielding mutants with a marked increase in preference for hydrolysis over transamidation.", "By providing the ability to visualize this activated conformer, our results create a foundation for understanding the catalytic as well as the non-catalytic roles of TG2 in biology, and for dissecting the process by which the autoantibody response to TG2 is induced in celiac sprue patients." ]

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[ "Trefoil factor family 1 (TFF1) is a member of the TFF-domain peptide family involved in epithelial restitution and cell motility.", "Recently, we screened Piezo1 as a candidate TFF1-binding protein.", "We aimed to confirm Piezo1 as a novel TFF1 binding protein and to assess the role of this interaction in mediating gastric cancer cell mobility.", "This interaction was confirmed by co-immunoprecipitation and co-localisation of TFF1 and Piezo1 in GES-1 cells.", "We used stable RNA interference to knockdown Piezo1 protein expression and restored the expression of TFF1 in the gastric cancer cell lines SGC-7901 and BGC-823.", "Cell motility was evaluated using invasion assay and migration assay in vitro.", "The expression levels of the integrin subunits β1, β5, α1 as well as the expression of β-catenin and E-cadherin were detected by Western blot.", "We demonstrate that TFF1, but not TFF2 or TFF3, bind to and co-localize with Piezo1 in the cytoplasm in vitro.", "TFF1 interacts with the C-terminal portion of the Piezo1 protein.", "Wound healing and trans-well assays demonstrated that the restored expression of TFF1 promoted cell mobility in gastric cancer cells, and this effect was attenuated by the knockdown of Piezo1.", "Western blots demonstrated the decreased expression of integrin β1 in Piezo1-knockdown cells.", "Our data demonstrate that Piezo1 is a novel TFF1 binding protein that is important for TFF1-mediated cell migration and suggest that this interaction may be a therapeutic target in the invasion and metastasis of gastric cancer." ]

[ 3, 7, 8, 11 ]

[ "IMPORTANCE Studies suggest pioglitazone use may increase risk of cancers.", "OBJECTIVE To examine whether pioglitazone use for diabetes is associated with risk of bladder and 10 additional cancers.", "DESIGN, SETTING, AND PARTICIPANTS Cohort and nested case-control analyses among persons with diabetes.", "A bladder cancer cohort followed 193,099 persons aged 40 years or older in 1997-2002 until December 2012; 464 case patients and 464 matched controls were surveyed about additional confounders.", "A cohort analysis of 10 additional cancers included 236,507 persons aged 40 years or older in 1997-2005 and followed until June 2012.", "Cohorts were from Kaiser Permanente Northern California.", "EXPOSURES Ever use, duration, cumulative dose, and time since initiation of pioglitazone as time dependent.", "MAIN OUTCOMES AND MEASURES Incident cancer, including bladder, prostate, female breast, lung/bronchus, endometrial, colon, non-Hodgkin lymphoma, pancreas, kidney/renal pelvis, rectum, and melanoma.", "RESULTS Among 193,099 persons in the bladder cancer cohort, 34,181 (18%) received pioglitazone (median duration, 2.8 years; range, 0.2-13.2 years) and 1261 had incident bladder cancer.", "Crude incidences of bladder cancer in pioglitazone users and nonusers were 89.8 and 75.9 per 100,000 person-years, respectively.", "Ever use of pioglitazone was not associated with bladder cancer risk (adjusted hazard ratio [HR], 1.06; 95% CI, 0.89-1.26).", "Results were similar in case-control analyses (pioglitazone use: 19.6% among case patients and 17.5% among controls; adjusted odds ratio, 1.18; 95% CI, 0.78-1.80).", "In adjusted analyses, there was no association with 8 of the 10 additional cancers; ever use of pioglitazone was associated with increased risk of prostate cancer (HR, 1.13; 95% CI, 1.02-1.26) and pancreatic cancer (HR, 1.41; 95% CI, 1.16-1.71).", "Crude incidences of prostate and pancreatic cancer in pioglitazone users vs nonusers were 453.3 vs 449.3 and 81.1 vs 48.4 per 100,000 person-years, respectively.", "No clear patterns of risk for any cancer were observed for time since initiation, duration, or dose.", "CONCLUSIONS AND RELEVANCE Pioglitazone use was not associated with a statistically significant increased risk of bladder cancer, although an increased risk, as previously observed, could not be excluded.", "The increased prostate and pancreatic cancer risks associated with ever use of pioglitazone merit further investigation to assess whether they are causal or are due to chance, residual confounding, or reverse causality." ]

[ 12, 16 ]

[ "IMPORTANCE Studies suggest pioglitazone use may increase risk of cancers.", "OBJECTIVE To examine whether pioglitazone use for diabetes is associated with risk of bladder and 10 additional cancers.", "DESIGN, SETTING, AND PARTICIPANTS Cohort and nested case-control analyses among persons with diabetes.", "A bladder cancer cohort followed 193,099 persons aged 40 years or older in 1997-2002 until December 2012; 464 case patients and 464 matched controls were surveyed about additional confounders.", "A cohort analysis of 10 additional cancers included 236,507 persons aged 40 years or older in 1997-2005 and followed until June 2012.", "Cohorts were from Kaiser Permanente Northern California.", "EXPOSURES Ever use, duration, cumulative dose, and time since initiation of pioglitazone as time dependent.", "MAIN OUTCOMES AND MEASURES Incident cancer, including bladder, prostate, female breast, lung/bronchus, endometrial, colon, non-Hodgkin lymphoma, pancreas, kidney/renal pelvis, rectum, and melanoma.", "RESULTS Among 193,099 persons in the bladder cancer cohort, 34,181 (18%) received pioglitazone (median duration, 2.8 years; range, 0.2-13.2 years) and 1261 had incident bladder cancer.", "Crude incidences of bladder cancer in pioglitazone users and nonusers were 89.8 and 75.9 per 100,000 person-years, respectively.", "Ever use of pioglitazone was not associated with bladder cancer risk (adjusted hazard ratio [HR], 1.06; 95% CI, 0.89-1.26).", "Results were similar in case-control analyses (pioglitazone use: 19.6% among case patients and 17.5% among controls; adjusted odds ratio, 1.18; 95% CI, 0.78-1.80).", "In adjusted analyses, there was no association with 8 of the 10 additional cancers; ever use of pioglitazone was associated with increased risk of prostate cancer (HR, 1.13; 95% CI, 1.02-1.26) and pancreatic cancer (HR, 1.41; 95% CI, 1.16-1.71).", "Crude incidences of prostate and pancreatic cancer in pioglitazone users vs nonusers were 453.3 vs 449.3 and 81.1 vs 48.4 per 100,000 person-years, respectively.", "No clear patterns of risk for any cancer were observed for time since initiation, duration, or dose.", "CONCLUSIONS AND RELEVANCE Pioglitazone use was not associated with a statistically significant increased risk of bladder cancer, although an increased risk, as previously observed, could not be excluded.", "The increased prostate and pancreatic cancer risks associated with ever use of pioglitazone merit further investigation to assess whether they are causal or are due to chance, residual confounding, or reverse causality." ]

[ 12, 13, 16 ]

[ "IMPORTANCE Studies suggest pioglitazone use may increase risk of cancers.", "OBJECTIVE To examine whether pioglitazone use for diabetes is associated with risk of bladder and 10 additional cancers.", "DESIGN, SETTING, AND PARTICIPANTS Cohort and nested case-control analyses among persons with diabetes.", "A bladder cancer cohort followed 193,099 persons aged 40 years or older in 1997-2002 until December 2012; 464 case patients and 464 matched controls were surveyed about additional confounders.", "A cohort analysis of 10 additional cancers included 236,507 persons aged 40 years or older in 1997-2005 and followed until June 2012.", "Cohorts were from Kaiser Permanente Northern California.", "EXPOSURES Ever use, duration, cumulative dose, and time since initiation of pioglitazone as time dependent.", "MAIN OUTCOMES AND MEASURES Incident cancer, including bladder, prostate, female breast, lung/bronchus, endometrial, colon, non-Hodgkin lymphoma, pancreas, kidney/renal pelvis, rectum, and melanoma.", "RESULTS Among 193,099 persons in the bladder cancer cohort, 34,181 (18%) received pioglitazone (median duration, 2.8 years; range, 0.2-13.2 years) and 1261 had incident bladder cancer.", "Crude incidences of bladder cancer in pioglitazone users and nonusers were 89.8 and 75.9 per 100,000 person-years, respectively.", "Ever use of pioglitazone was not associated with bladder cancer risk (adjusted hazard ratio [HR], 1.06; 95% CI, 0.89-1.26).", "Results were similar in case-control analyses (pioglitazone use: 19.6% among case patients and 17.5% among controls; adjusted odds ratio, 1.18; 95% CI, 0.78-1.80).", "In adjusted analyses, there was no association with 8 of the 10 additional cancers; ever use of pioglitazone was associated with increased risk of prostate cancer (HR, 1.13; 95% CI, 1.02-1.26) and pancreatic cancer (HR, 1.41; 95% CI, 1.16-1.71).", "Crude incidences of prostate and pancreatic cancer in pioglitazone users vs nonusers were 453.3 vs 449.3 and 81.1 vs 48.4 per 100,000 person-years, respectively.", "No clear patterns of risk for any cancer were observed for time since initiation, duration, or dose.", "CONCLUSIONS AND RELEVANCE Pioglitazone use was not associated with a statistically significant increased risk of bladder cancer, although an increased risk, as previously observed, could not be excluded.", "The increased prostate and pancreatic cancer risks associated with ever use of pioglitazone merit further investigation to assess whether they are causal or are due to chance, residual confounding, or reverse causality." ]

[ 12, 16 ]

[ "Oct4 is a well-known transcription factor that plays fundamental roles in stem cell self-renewal, pluripotency, and somatic cell reprogramming.", "However, limited information is available on Oct4-associated protein complexes and their intrinsic protein-protein interactions that dictate Oct4's critical regulatory activities.", "Here we employed an improved affinity purification approach combined with mass spectrometry to purify Oct4 protein complexes in mouse embryonic stem cells (mESCs), and discovered many novel Oct4 partners important for self-renewal and pluripotency of mESCs.", "Notably, we found that Oct4 is associated with multiple chromatin-modifying complexes with documented as well as newly proved functional significance in stem cell maintenance and somatic cell reprogramming.", "Our study establishes a solid biochemical basis for genetic and epigenetic regulation of stem cell pluripotency and provides a framework for exploring alternative factor-based reprogramming strategies." ]

[ 3 ]

[ "Transcription factors, such as Oct4, are critical for establishing and maintaining pluripotent cell identity.", "Whereas the genomic locations of several pluripotency transcription factors have been reported, the spectrum of their interaction partners is underexplored.", "Here, we use an improved affinity protocol to purify Oct4-interacting proteins from mouse embryonic stem cells (ESCs).", "Subsequent purification of Oct4 partners Sall4, Tcfcp2l1, Dax1, and Esrrb resulted in an Oct4 interactome of 166 proteins, including transcription factors and chromatin-modifying complexes with documented roles in self-renewal, but also many factors not previously associated with the ESC network.", "We find that Esrrb associated with the basal transcription machinery and also detect interactions between transcription factors and components of the TGF-beta, Notch, and Wnt signaling pathways.", "Acute depletion of Oct4 reduced binding of Tcfcp2l1, Dax1, and Esrrb to several target genes.", "In conclusion, our purification protocol allowed us to bring greater definition to the circuitry controlling pluripotent cell identity." ]

[ 3 ]

[ "OBJECTIVE Although the Polypill concept (proposed in 2003) is promising in terms of benefits for cardiovascular risk management, the potential costs and adverse effects are its main pitfalls.", "The objective of this study was to identify a tastier and safer alternative to the Polypill: the Polymeal.", "METHODS Data on the ingredients of the Polymeal were taken from the literature.", "The evidence based recipe included wine, fish, dark chocolate, fruits, vegetables, garlic, and almonds.", "Data from the Framingham heart study and the Framingham offspring study were used to build life tables to model the benefits of the Polymeal in the general population from age 50, assuming multiplicative correlations.", "RESULTS Combining the ingredients of the Polymeal would reduce cardiovascular disease events by 76%.", "For men, taking the Polymeal daily represented an increase in total life expectancy of 6.6 years, an increase in life expectancy free from cardiovascular disease of 9.0 years, and a decrease in life expectancy with cardiovascular disease of 2.4 years.", "The corresponding differences for women were 4.8, 8.1, and 3.3 years.", "CONCLUSION The Polymeal promises to be an effective, non-pharmacological, safe, cheap, and tasty alternative to reduce cardiovascular morbidity and increase life expectancy in the general population." ]

[ 6, 8 ]

[ "Various specialized domains have been described in the cytosol and the nucleus; however, little is known about compartmentalization within the mitochondrial matrix.", "GRSF1 (G-rich sequence factor 1) is an RNA binding protein that was previously reported to localize in the cytosol.", "We found that an isoform of GRSF1 accumulates in discrete foci in the mitochondrial matrix.", "These foci are composed of nascent mitochondrial RNA and also contain RNase P, an enzyme that participates in mitochondrial RNA processing.", "GRSF1 was found to interact with RNase P and to be required for processing of both classical and tRNA-less RNA precursors.", "In its absence, cleavage of primary RNA transcripts is abnormal, leading to decreased expression of mitochondrially encoded proteins and mitochondrial dysfunction.", "Our findings suggest that the foci containing GRSF1 and RNase P correspond to sites where primary RNA transcripts converge to be processed.", "We have termed these large ribonucleoprotein structures \"mitochondrial RNA granules.", "\"" ]

[ 6 ]

[ "RNA-binding proteins are at the heart of posttranscriptional gene regulation, coordinating the processing, storage, and handling of cellular RNAs.", "We show here that GRSF1, previously implicated in the binding and selective translation of influenza mRNAs, is targeted to mitochondria where it forms granules that colocalize with foci of newly synthesized mtRNA next to mitochondrial nucleoids.", "GRSF1 preferentially binds RNAs transcribed from three contiguous genes on the light strand of mtDNA, the ND6 mRNA, and the long noncoding RNAs for cytb and ND5, each of which contains multiple consensus binding sequences.", "RNAi-mediated knockdown of GRSF1 leads to alterations in mitochondrial RNA stability, abnormal loading of mRNAs and lncRNAs on the mitochondrial ribosome, and impaired ribosome assembly.", "This results in a specific protein synthesis defect and a failure to assemble normal amounts of the oxidative phosphorylation complexes.", "These data implicate GRSF1 as a key regulator of posttranscriptional mitochondrial gene expression." ]

[ 1, 5 ]

[ "Human mitochondrial ribosomes are specialized in the synthesis of 13 proteins, which are fundamental components of the oxidative phosphorylation system.", "The pathway of mitoribosome biogenesis, the compartmentalization of the process, and factors involved remain largely unknown.", "Here, we have identified the DEAD-box protein DDX28 as an RNA granule component essential for the biogenesis of the mitoribosome large subunit (mt-LSU).", "DDX28 interacts with the 16S rRNA and the mt-LSU.", "RNAi-mediated DDX28 silencing in HEK293T cells does not affect mitochondrial mRNA stability or 16S rRNA processing or modification.", "However, it leads to reduced levels of 16S rRNA and mt-LSU proteins, impaired mt-LSU assembly, deeply attenuated mitochondrial protein synthesis, and consequent failure to assemble oxidative phosphorylation complexes.", "Our findings identify DDX28 as essential during the early stages of mitoribosome mt-LSU biogenesis, a process that takes place mainly near the mitochondrial nucleoids, in the compartment defined by the RNA granules." ]

[ 2, 6 ]

[ "RNA processing is carried out in close proximity to the site of transcription, suggesting a regulatory link between transcription and pre-mRNA splicing.", "Using an in vitro transcription/splicing assay, we demonstrate that an association of RNA polymerase II (Pol II) transcription and pre-mRNA splicing is required for efficient gene expression.", "Pol II-synthesized RNAs containing functional splice sites are protected from nuclear degradation, presumably because the local concentration of the splicing machinery is sufficiently high to ensure its association over interactions with nucleases.", "Furthermore, the process of transcription influences alternative splicing of newly synthesized pre-mRNAs.", "Because other RNA polymerases do not provide similar protection from nucleases, and their RNA products display altered splicing patterns, the link between transcription and RNA processing is RNA Pol II-specific.", "We propose that the connection between transcription by Pol II and pre-mRNA splicing guarantees an extended half-life and proper processing of nascent pre-mRNAs." ]

[ 5 ]

[ "The development of in vitro assays to analyze pre-mRNA splicing resulted in the discovery of many fundamental features characterizing splicing signals and the machinery that completes this process.", "Because in vitro assays can be manipulated by various biochemical approaches, the versatility of investigating alternative pre-mRNA splicing in the test tube appears endless.", "Importantly, modifications in reaction conditions can lead to the accumulation, isolation, and characterization of reaction intermediates, a prerequisite for gaining mechanistic insights into how the spliceosome carries out intron removal, and how regulatory elements assist the general splicing machinery in defining splice sites and alternative exons.", "These considerable experimental advantages have made the in vitro splicing system a standard assay, even though this approach is independent from RNA transcription and other RNA processing events, and in some respects deviates from the natural process of mRNA biogenesis.", "Here, we describe the tools and techniques necessary to carry out in vitro splicing assays.", "Analyses of various experimental designs are presented to highlight the approaches taken to gain insights into the mechanisms by which splice site recognition and activation are communicated with the general splicing machinery.", "Methods to measure the kinetics of splicing, to observe the formation of the pre-spliceosomal complexes, and to manipulate and modify the in vitro system to resolve the regulatory influences in alternative splicing are presented." ]

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[ "RNA processing is carried out in close proximity to the site of transcription, suggesting a regulatory link between transcription and pre-mRNA splicing.", "Using an in vitro transcription/splicing assay, we demonstrate that an association of RNA polymerase II (Pol II) transcription and pre-mRNA splicing is required for efficient gene expression.", "Pol II-synthesized RNAs containing functional splice sites are protected from nuclear degradation, presumably because the local concentration of the splicing machinery is sufficiently high to ensure its association over interactions with nucleases.", "Furthermore, the process of transcription influences alternative splicing of newly synthesized pre-mRNAs.", "Because other RNA polymerases do not provide similar protection from nucleases, and their RNA products display altered splicing patterns, the link between transcription and RNA processing is RNA Pol II-specific.", "We propose that the connection between transcription by Pol II and pre-mRNA splicing guarantees an extended half-life and proper processing of nascent pre-mRNAs." ]

[ 5 ]

[ "The development of in vitro assays to analyze pre-mRNA splicing resulted in the discovery of many fundamental features characterizing splicing signals and the machinery that completes this process.", "Because in vitro assays can be manipulated by various biochemical approaches, the versatility of investigating alternative pre-mRNA splicing in the test tube appears endless.", "Importantly, modifications in reaction conditions can lead to the accumulation, isolation, and characterization of reaction intermediates, a prerequisite for gaining mechanistic insights into how the spliceosome carries out intron removal, and how regulatory elements assist the general splicing machinery in defining splice sites and alternative exons.", "These considerable experimental advantages have made the in vitro splicing system a standard assay, even though this approach is independent from RNA transcription and other RNA processing events, and in some respects deviates from the natural process of mRNA biogenesis.", "Here, we describe the tools and techniques necessary to carry out in vitro splicing assays.", "Analyses of various experimental designs are presented to highlight the approaches taken to gain insights into the mechanisms by which splice site recognition and activation are communicated with the general splicing machinery.", "Methods to measure the kinetics of splicing, to observe the formation of the pre-spliceosomal complexes, and to manipulate and modify the in vitro system to resolve the regulatory influences in alternative splicing are presented." ]

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[ "CONTEXT Findings from previous studies of the effects of exercise training on patient-reported health status have been inconsistent.", "OBJECTIVE To test the effects of exercise training on health status among patients with heart failure.", "DESIGN, SETTING, AND PATIENTS Multicenter, randomized controlled trial among 2331 medically stable outpatients with heart failure with left ventricular ejection fraction of 35% or less.", "Patients were randomized from April 2003 through February 2007.", "INTERVENTIONS Usual care plus aerobic exercise training (n = 1172), consisting of 36 supervised sessions followed by home-based training, vs usual care alone (n = 1159).", "Randomization was stratified by heart failure etiology, which was a covariate in all models.", "MAIN OUTCOME MEASURES Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary scale and key subscales at baseline, every 3 months for 12 months, and annually thereafter for up to 4 years.", "The KCCQ is scored from 0 to 100 with higher scores corresponding to better health status.", "Treatment group effects were estimated using linear mixed models according to the intention-to-treat principle.", "RESULTS Median follow-up was 2.5 years.", "At 3 months, usual care plus exercise training led to greater improvement in the KCCQ overall summary score (mean, 5.21; 95% confidence interval, 4.42 to 6.00) compared with usual care alone (3.28; 95% confidence interval, 2.48 to 4.09).", "The additional 1.93-point increase (95% confidence interval, 0.84 to 3.01) in the exercise training group was statistically significant (P < .001).", "After 3 months, there were no further significant changes in KCCQ score for either group (P = .85 for the difference between slopes), resulting in a sustained, greater improvement overall for the exercise group (P < .001).", "Results were similar on the KCCQ subscales, and no subgroup interactions were detected.", "CONCLUSIONS Exercise training conferred modest but statistically significant improvements in self-reported health status compared with usual care without training.", "Improvements occurred early and persisted over time.", "TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00047437." ]

[ 10, 12, 14 ]

[ "Prim-pol is a recently identified DNA primase-polymerase belonging to the archaeao-eukaryotic primase (AEP) superfamily.", "Here, we characterize a previously unrecognized prim-pol in human cells, which we designate hPrimpol1 (human primase-polymerase 1).", "hPrimpol1 possesses primase and DNA polymerase activities in vitro, interacts directly with RPA1 and is recruited to sites of DNA damage and stalled replication forks in an RPA1-dependent manner.", "Cells depleted of hPrimpol1 display increased spontaneous DNA damage and defects in the restart of stalled replication forks.", "Both RPA1 binding and the primase activity of hPrimpol1 are required for its cellular function during DNA replication.", "Our results indicate that hPrimpol1 is a novel factor involved in the response to DNA replication stress." ]

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[ "We describe a second primase in human cells, PrimPol, which has the ability to start DNA chains with deoxynucleotides unlike regular primases, which use exclusively ribonucleotides.", "Moreover, PrimPol is also a DNA polymerase tailored to bypass the most common oxidative lesions in DNA, such as abasic sites and 8-oxoguanine.", "Subcellular fractionation and immunodetection studies indicated that PrimPol is present in both nuclear and mitochondrial DNA compartments.", "PrimPol activity is detectable in mitochondrial lysates from human and mouse cells but is absent from mitochondria derived from PRIMPOL knockout mice.", "PRIMPOL gene silencing or ablation in human and mouse cells impaired mitochondrial DNA replication.", "On the basis of the synergy observed with replicative DNA polymerases Polγ and Polε, PrimPol is proposed to facilitate replication fork progression by acting as a translesion DNA polymerase or as a specific DNA primase reinitiating downstream of lesions that block synthesis during both mitochondrial and nuclear DNA replication." ]

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[ "Prim-pol is a recently identified DNA primase-polymerase belonging to the archaeao-eukaryotic primase (AEP) superfamily.", "Here, we characterize a previously unrecognized prim-pol in human cells, which we designate hPrimpol1 (human primase-polymerase 1).", "hPrimpol1 possesses primase and DNA polymerase activities in vitro, interacts directly with RPA1 and is recruited to sites of DNA damage and stalled replication forks in an RPA1-dependent manner.", "Cells depleted of hPrimpol1 display increased spontaneous DNA damage and defects in the restart of stalled replication forks.", "Both RPA1 binding and the primase activity of hPrimpol1 are required for its cellular function during DNA replication.", "Our results indicate that hPrimpol1 is a novel factor involved in the response to DNA replication stress." ]

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[ "We describe a second primase in human cells, PrimPol, which has the ability to start DNA chains with deoxynucleotides unlike regular primases, which use exclusively ribonucleotides.", "Moreover, PrimPol is also a DNA polymerase tailored to bypass the most common oxidative lesions in DNA, such as abasic sites and 8-oxoguanine.", "Subcellular fractionation and immunodetection studies indicated that PrimPol is present in both nuclear and mitochondrial DNA compartments.", "PrimPol activity is detectable in mitochondrial lysates from human and mouse cells but is absent from mitochondria derived from PRIMPOL knockout mice.", "PRIMPOL gene silencing or ablation in human and mouse cells impaired mitochondrial DNA replication.", "On the basis of the synergy observed with replicative DNA polymerases Polγ and Polε, PrimPol is proposed to facilitate replication fork progression by acting as a translesion DNA polymerase or as a specific DNA primase reinitiating downstream of lesions that block synthesis during both mitochondrial and nuclear DNA replication." ]

[]

[ "BACKGROUND Screening for cervical cancer based on testing for human papillomavirus (HPV) increases the sensitivity of detection of high-grade (grade 2 or 3) cervical intraepithelial neoplasia, but whether this gain represents overdiagnosis or protection against future high-grade cervical epithelial neoplasia or cervical cancer is unknown.", "METHODS In a population-based screening program in Sweden, 12,527 women 32 to 38 years of age were randomly assigned at a 1:1 ratio to have an HPV test plus a Papanicolaou (Pap) test (intervention group) or a Pap test alone (control group).", "Women with a positive HPV test and a normal Pap test result were offered a second HPV test at least 1 year later, and those who were found to be persistently infected with the same high-risk type of HPV were then offered colposcopy with cervical biopsy.", "A similar number of double-blinded Pap smears and colposcopies with biopsy were performed in randomly selected women in the control group.", "Comprehensive registry data were used to follow the women for a mean of 4.1 years.", "The relative rates of grade 2 or 3 cervical intraepithelial neoplasia or cancer detected at enrollment and at subsequent screening examinations were calculated.", "RESULTS At enrollment, the proportion of women in the intervention group who were found to have lesions of grade 2 or 3 cervical intraepithelial neoplasia or cancer was 51% greater (95% confidence interval [CI], 13 to 102) than the proportion of women in the control group who were found to have such lesions.", "At subsequent screening examinations, the proportion of women in the intervention group who were found to have grade 2 or 3 lesions or cancer was 42% less (95% CI, 4 to 64) and the proportion with grade 3 lesions or cancer was 47% less (95% CI, 2 to 71) than the proportions of control women who were found to have such lesions.", "Women with persistent HPV infection remained at high risk for grade 2 or 3 lesions or cancer after referral for colposcopy.", "CONCLUSIONS The addition of an HPV test to the Pap test to screen women in their mid-30s for cervical cancer reduces the incidence of grade 2 or 3 cervical intraepithelial neoplasia or cancer detected by subsequent screening examinations.", "(ClinicalTrials.gov number, NCT00479375 [ClinicalTrials.gov].)." ]

[ 0, 9 ]

[ "BACKGROUND Human papillomavirus (HPV) testing is known to be more sensitive, but less specific than cytology for detecting cervical intraepithelial neoplasia (CIN).", "We assessed the efficacy of cervical-cancer screening policies that are based on HPV testing.", "METHODS Between March, 2004, and December, 2004, in two separate recruitment phases, women aged 25-60 years were randomly assigned to conventional cytology or to HPV testing in combination with liquid-based cytology (first phase) or alone (second phase).", "Randomisation was done by computer in two screening centres and by sequential opening of numbered sealed envelopes in the remaining seven centres.", "During phase one, women who were HPV-positive and aged 35-60 years were referred to colposcopy, whereas women aged 25-34 years were referred to colposcopy only if cytology was also abnormal or HPV testing was persistently positive.", "During phase two, women in the HPV group were referred for colposcopy if the HPV test was positive.", "Two rounds of screening occurred in each phase, and all women had cytology testing only at the second round.", "The primary endpoint was the detection of grade 2 and 3 CIN, and of invasive cervical cancers during the first and second screening rounds.", "Analysis was done by intention to screen.", "This trial is registered, number ISRCTN81678807.", "FINDINGS In total for both phases, 47,001 women were randomly assigned to the cytology group and 47,369 to HPV testing.", "33,851 women from the cytology group and 32,998 from the HPV-testing group had a second round of screening.", "We also retrieved the histological diagnoses from screening done elsewhere.", "The detection of invasive cervical cancers was similar for the two groups in the first round of screening (nine in the cytology group vs seven in the HPV group, p=0.62); no cases were detected in the HPV group during round two, compared with nine in the cytology group (p=0.004).", "Overall, in the two rounds of screening, 18 invasive cancers were detected in the cytology group versus seven in the HPV group (p=0.028).", "Among women aged 35-60 years, at round one the relative detection (HPV vs cytology) was 2.00 (95% CI 1.44-2.77) for CIN2, 2.08 (1.47-2.95) for CIN3, and 2.03 (1.60-2.57) for CIN2 and 3 together.", "At round two the relative detection was 0.54 (0.23-1.28) for CIN2, 0.48 (0.21-1.11) for CIN3, and 0.51 (0.28-0.93) for CIN2 and 3 together.", "Among women aged 25-34 years, there was significant heterogeneity between phases in the relative detection of CIN3.", "At round one the relative detection was 0.93 (0.52-1.64) in phase one and 3.91 (2.02-7.57) in phase two.", "At round two the relative detection was 1.34 (0.46-3.84) in phase one and 0.20 (0.04-0.93) in phase two.", "Pooling both phases, the detection ratio of CIN2 for women aged 25-34 years was 4.09 (2.24-7.48) at round one and 0.64 (0.23-1.27) at round two.", "INTERPRETATION HPV-based screening is more effective than cytology in preventing invasive cervical cancer, by detecting persistent high-grade lesions earlier and providing a longer low-risk period.", "However, in younger women, HPV screening leads to over-diagnosis of regressive CIN2.", "FUNDING European Union, Italian Ministry of Health, Regional Health Administrations of Piemonte, Tuscany, Veneto and Emilia-Romagna, and Public Health Agency of Lazio." ]

[ 0, 15, 21 ]

[ "More than ever, clinicians need regularly updated reviews given the continuously increasing amount of new information regarding innovative cervical cancer prevention methods.", "A summary is given from recent meta-analyses and systematic reviews on 3 possible clinical applications of human papillomavirus (HPV) testing: triage of women with equivocal or low-grade cytologic abnormalities; prediction of the therapeutic outcome after treatment of cervical intraepithelial neoplasia (CIN) lesions, and last not but not least, primary screening for cervical cancer and pre-cancer.", "Consistent evidence is available indicating that HPV-triage with the Hybrid Capture(®) 2 assay (Qiagen Gaithersburg, Inc., MD, USA [previously Digene Corp.] (HC2) is more accurate (higher sensitivity, similar specificity) than repeat cytology to triage women with equivocal Pap smear results.", "Several other tests show at least similar accuracy but mRNA testing with the APTIMA(®) (Gen-Probe Inc., San Diego, CA, USA) test is similarly sensitive but more specific compared to HC2.", "In triage of low-grade squamous intraepithelial lesions (LSIL), HC2 is more sensitive but its specificity is substantially lower compared to repeat cytology.", "The APTIMA(®) test is more specific than HC2 without showing a loss in sensitivity.", "Identification of DNA of HPV types 16 and/or 18, or RNA from the five most carcinogenic HPV types allow selecting women at highest risk for CIN3+ but the sensitivity and negative predictive value of these markers are lower than full-range high-risk HPV (hrHPV) testing.", "After conservative treatment of cervical pre-cancer, HPV testing picks up more quickly, with higher sensitivity and not lower specificity, residual or recurrent high-grade CIN than follow-up cytology.", "Primary screening for hrHPV generally detects more CIN2, CIN3 or cancer compared to cytology at cut-off atypical squamous cells of undetermined significance (ASC-US) or LSIL, but is less specific.", "Combined HPV and cytology screening provides a further small gain in sensitivity at the expense of a considerable loss in specificity if positive by either test is referred to colposcopy, in comparison with HPV testing only.", "Randomised trials and follow-up of cohort studies consistently demonstrate a significantly lower cumulative incidence of CIN3+ and even of cancer, in women aged 30 years or older, who were at enrollment hrHPV DNA negative compared to those who were cytologically negative.", "The difference in cumulative risk of CIN3+ or cancer for double negative (cytology & HPV) versus only HPV-negative women is small.", "HC2, GP5+/6+ PCR (polymerase chain reaction), cobas(®) 4800 PCR (Roche Molecular Systems Inc., Alameda, CA, USA) and Real Time PCR (Abbott Molecular, Des Plaines, IL, USA) can be considered as clinically validated for use in primary screening.", "The loss in specificity associated with primary HPV-based screening can be compensated by appropriate algorithms involving reflex cytology and/or HPV genotyping for HPV16 or 18.", "There exists a substantial evidence base to support that HPV testing is advantageous both in triage of women with equivocal abnormal cytology, in surveillance after treatment of CIN lesions and in primary screening of women aged 30 years or older.", "However, the possible advantages offered by HPV-based screening require a well organised program with good compliance with screening and triage policies.", "This article forms part of a special supplement entitled \"Comprehensive Control of HPV Infections and Related Diseases\" Vaccine Volume 30, Supplement 5, 2012." ]

[ 8 ]

[ "BACKGROUND Human papillomavirus (HPV) testing is more sensitive for the detection of high-grade cervical lesions than is cytology, but detection of HPV by DNA screening in two screening rounds 5 years apart has not been assessed.", "The aim of this study was to assess whether HPV DNA testing in the first screen decreases detection of cervical intraepithelial neoplasia (CIN) grade 3 or worse, CIN grade 2 or worse, and cervical cancer in the second screening.", "METHODS In this randomised trial, women aged 29-56 years participating in the cervical screening programme in the Netherlands were randomly assigned to receive HPV DNA (GP5+/6+-PCR method) and cytology co-testing or cytology testing alone, from January, 1999, to September, 2002.", "Randomisation (in a 1:1 ratio) was done with computer-generated random numbers after the cervical specimen had been taken.", "At the second screening 5 years later, HPV DNA and cytology co-testing was done in both groups; researchers were masked to the patient's assignment.", "The primary endpoint was the number of CIN grade 3 or worse detected.", "Analysis was done by intention to screen.", "The trial is now finished and is registered, number ISRCTN20781131.", "FINDINGS 22,420 women were randomly assigned to the intervention group and 22 518 to the control group; 19 999 in the intervention group and 20,106 in the control group were eligible for analysis at the first screen.", "At the second screen, 19 579 women in the intervention group and 19,731 in the control group were eligible, of whom 16,750 and 16,743, respectively, attended the second screen.", "In the second round, CIN grade 3 or worse was less common in the intervention group than in the control group (88 of 19 579 in the intervention group vs 122 of 19,731 in the control group; relative risk 0·73, 95% CI 0·55-0·96; p=0·023).", "Cervical cancer was also less common in the intervention group than in the control group (four of 19 579 in the intervention group vs 14 of 19,731; 0·29, 0·10-0·87; p=0·031).", "In the baseline round, detection of CIN grade 3 or worse did not differ significantly between groups (171 of 19 999 vs 150 of 20,106; 1·15, 0·92-1·43; p=0·239) but was significantly more common in women with normal cytology (34 of 19,286 vs 12 of 19,373; 2·85, 1·47-5·49; p=0·001).", "Furthermore, significantly more cases of CIN grade 2 or worse were detected in the intervention group than in the control group (267 of 19 999 vs 215 of 20,106; 1·25, 1·05-1·50; p=0·015).", "In the second screen, fewer HPV16-positive CIN grade 3 or worse were detected in the intervention group than in the control group (17 of 9481 vs 35 of 9354; 0·48, 0·27-0·85; p=0·012); detection of non-HPV16-positive CIN grade 3 or worse did not differ between groups (25 of 9481 vs 25 of 9354; 0·99, 0·57-1·72; p=1·00).", "The cumulative detection of CIN grade 3 or worse and CIN grade 2 or worse did not differ significantly between study arms, neither for the whole study group (CIN grade 3 or worse: 259 of 19 999 vs 272 of 20,106; 0·96, 0·81-1·14, p=0·631; CIN grade 2 or worse: 427 of 19 999 vs 399 of 20,106; 1·08, 0·94-1·24; p=0·292), nor for subgroups of women invited for the first time (CIN grade 3 or worse in women aged 29-33 years: 102 of 3139 vs 105 of 3128; 0·97, 0·74-1·27; CIN grade 2 or worse in women aged 29-33 years: 153 of 3139 vs 151 of 3128; 1·01, 0·81-1·26; CIN grade 3 or worse in women aged 34-56 years: 157 of 16,860 vs 167 of 16 978; 0·95, 0·76-1·18; CIN grade 2 or worse in women aged 34-56 years: 274 of 16,860 vs 248 of 16 978; 1·11, 0·94-1·32).", "INTERPRETATION Implementation of HPV DNA testing in cervical screening leads to earlier detection of clinically relevant CIN grade 2 or worse, which when adequately treated, improves protection against CIN grade 3 or worse and cervical cancer.", "Early detection of high-grade cervical legions caused by HPV16 was a major component of this benefit.", "Our results lend support to the use of HPV DNA testing for all women aged 29 years and older.", "FUNDING Zorg Onderzoek Nederland (Netherlands Organisation for Health Research and Development)." ]

[ 13 ]

[ "OBJECTIVE To assess the performance and impact of primary human papillomavirus (HPV) DNA screening with cytology triage compared with conventional cytology on cervical cancer and severe pre-cancerous lesions.", "DESIGN Randomised trial.", "SETTING Population based screening programme for cervical cancer in southern Finland in 2003-5.", "PARTICIPANTS 58 076 women, aged 30-60, invited to the routine population based screening programme for cervical cancer.", "INTERVENTIONS Primary HPV DNA test (hybrid capture II) with cytology triage if the result was positive or conventional cytological screening (reference).", "MAIN OUTCOME MEASURES Rate of cervical cancer, cervical intraepithelial neoplasia (CIN) grade III, and adenocarcinoma in situ (as a composite outcome referred to as CIN III+) during 2003-7 through record linkage between files from the screening registry and the national cancer registry.", "RESULTS In the HPV and conventional arms there were 95 600 and 95 700 woman years of follow-up and 76 and 53 cases of CIN III+, respectively (of which six and eight were cervical cancers).", "The relative rate of CIN III+ in the HPV arm versus the conventional arm was 1.44 (95% confidence interval 1.01 to 2.05) among all women invited for screening and 1.77 (1.16 to 2.74) among those who attended.", "Among women with a normal or negative test result, the relative rate of subsequent CIN III+ was 0.28 (0.04 to 1.17).", "The rate of cervical cancer between arms was 0.75 (0.25 to 2.16) among women invited for screening and 1.98 (0.52 to 9.38) among those who attended.", "CONCLUSIONS When incorporated into a well established organised screening programme, primary HPV screening with cytology triage was more sensitive than conventional cytology in detecting CIN III+ lesions.", "The number of cases of cervical cancer was small, but considering the high probability of progression of CIN III the findings are of importance regarding cancer prevention.", "TRIAL REGISTRATION Current Controlled Trials ISRCTN23885553." ]

[ 7, 10 ]

[ "BACKGROUND Human papillomavirus (HPV) testing is known to be more sensitive, but less specific than cytology for detecting cervical intraepithelial neoplasia (CIN).", "We assessed the efficacy of cervical-cancer screening policies that are based on HPV testing.", "METHODS Between March, 2004, and December, 2004, in two separate recruitment phases, women aged 25-60 years were randomly assigned to conventional cytology or to HPV testing in combination with liquid-based cytology (first phase) or alone (second phase).", "Randomisation was done by computer in two screening centres and by sequential opening of numbered sealed envelopes in the remaining seven centres.", "During phase one, women who were HPV-positive and aged 35-60 years were referred to colposcopy, whereas women aged 25-34 years were referred to colposcopy only if cytology was also abnormal or HPV testing was persistently positive.", "During phase two, women in the HPV group were referred for colposcopy if the HPV test was positive.", "Two rounds of screening occurred in each phase, and all women had cytology testing only at the second round.", "The primary endpoint was the detection of grade 2 and 3 CIN, and of invasive cervical cancers during the first and second screening rounds.", "Analysis was done by intention to screen.", "This trial is registered, number ISRCTN81678807.", "FINDINGS In total for both phases, 47,001 women were randomly assigned to the cytology group and 47,369 to HPV testing.", "33,851 women from the cytology group and 32,998 from the HPV-testing group had a second round of screening.", "We also retrieved the histological diagnoses from screening done elsewhere.", "The detection of invasive cervical cancers was similar for the two groups in the first round of screening (nine in the cytology group vs seven in the HPV group, p=0.62); no cases were detected in the HPV group during round two, compared with nine in the cytology group (p=0.004).", "Overall, in the two rounds of screening, 18 invasive cancers were detected in the cytology group versus seven in the HPV group (p=0.028).", "Among women aged 35-60 years, at round one the relative detection (HPV vs cytology) was 2.00 (95% CI 1.44-2.77) for CIN2, 2.08 (1.47-2.95) for CIN3, and 2.03 (1.60-2.57) for CIN2 and 3 together.", "At round two the relative detection was 0.54 (0.23-1.28) for CIN2, 0.48 (0.21-1.11) for CIN3, and 0.51 (0.28-0.93) for CIN2 and 3 together.", "Among women aged 25-34 years, there was significant heterogeneity between phases in the relative detection of CIN3.", "At round one the relative detection was 0.93 (0.52-1.64) in phase one and 3.91 (2.02-7.57) in phase two.", "At round two the relative detection was 1.34 (0.46-3.84) in phase one and 0.20 (0.04-0.93) in phase two.", "Pooling both phases, the detection ratio of CIN2 for women aged 25-34 years was 4.09 (2.24-7.48) at round one and 0.64 (0.23-1.27) at round two.", "INTERPRETATION HPV-based screening is more effective than cytology in preventing invasive cervical cancer, by detecting persistent high-grade lesions earlier and providing a longer low-risk period.", "However, in younger women, HPV screening leads to over-diagnosis of regressive CIN2.", "FUNDING European Union, Italian Ministry of Health, Regional Health Administrations of Piemonte, Tuscany, Veneto and Emilia-Romagna, and Public Health Agency of Lazio." ]

[ 0, 21 ]

[ "More than ever, clinicians need regularly updated reviews given the continuously increasing amount of new information regarding innovative cervical cancer prevention methods.", "A summary is given from recent meta-analyses and systematic reviews on 3 possible clinical applications of human papillomavirus (HPV) testing: triage of women with equivocal or low-grade cytologic abnormalities; prediction of the therapeutic outcome after treatment of cervical intraepithelial neoplasia (CIN) lesions, and last not but not least, primary screening for cervical cancer and pre-cancer.", "Consistent evidence is available indicating that HPV-triage with the Hybrid Capture(®) 2 assay (Qiagen Gaithersburg, Inc., MD, USA [previously Digene Corp.] (HC2) is more accurate (higher sensitivity, similar specificity) than repeat cytology to triage women with equivocal Pap smear results.", "Several other tests show at least similar accuracy but mRNA testing with the APTIMA(®) (Gen-Probe Inc., San Diego, CA, USA) test is similarly sensitive but more specific compared to HC2.", "In triage of low-grade squamous intraepithelial lesions (LSIL), HC2 is more sensitive but its specificity is substantially lower compared to repeat cytology.", "The APTIMA(®) test is more specific than HC2 without showing a loss in sensitivity.", "Identification of DNA of HPV types 16 and/or 18, or RNA from the five most carcinogenic HPV types allow selecting women at highest risk for CIN3+ but the sensitivity and negative predictive value of these markers are lower than full-range high-risk HPV (hrHPV) testing.", "After conservative treatment of cervical pre-cancer, HPV testing picks up more quickly, with higher sensitivity and not lower specificity, residual or recurrent high-grade CIN than follow-up cytology.", "Primary screening for hrHPV generally detects more CIN2, CIN3 or cancer compared to cytology at cut-off atypical squamous cells of undetermined significance (ASC-US) or LSIL, but is less specific.", "Combined HPV and cytology screening provides a further small gain in sensitivity at the expense of a considerable loss in specificity if positive by either test is referred to colposcopy, in comparison with HPV testing only.", "Randomised trials and follow-up of cohort studies consistently demonstrate a significantly lower cumulative incidence of CIN3+ and even of cancer, in women aged 30 years or older, who were at enrollment hrHPV DNA negative compared to those who were cytologically negative.", "The difference in cumulative risk of CIN3+ or cancer for double negative (cytology & HPV) versus only HPV-negative women is small.", "HC2, GP5+/6+ PCR (polymerase chain reaction), cobas(®) 4800 PCR (Roche Molecular Systems Inc., Alameda, CA, USA) and Real Time PCR (Abbott Molecular, Des Plaines, IL, USA) can be considered as clinically validated for use in primary screening.", "The loss in specificity associated with primary HPV-based screening can be compensated by appropriate algorithms involving reflex cytology and/or HPV genotyping for HPV16 or 18.", "There exists a substantial evidence base to support that HPV testing is advantageous both in triage of women with equivocal abnormal cytology, in surveillance after treatment of CIN lesions and in primary screening of women aged 30 years or older.", "However, the possible advantages offered by HPV-based screening require a well organised program with good compliance with screening and triage policies.", "This article forms part of a special supplement entitled \"Comprehensive Control of HPV Infections and Related Diseases\" Vaccine Volume 30, Supplement 5, 2012." ]

[ 7, 8 ]

[ "BACKGROUND Human papillomavirus (HPV) testing is more sensitive for the detection of high-grade cervical lesions than is cytology, but detection of HPV by DNA screening in two screening rounds 5 years apart has not been assessed.", "The aim of this study was to assess whether HPV DNA testing in the first screen decreases detection of cervical intraepithelial neoplasia (CIN) grade 3 or worse, CIN grade 2 or worse, and cervical cancer in the second screening.", "METHODS In this randomised trial, women aged 29-56 years participating in the cervical screening programme in the Netherlands were randomly assigned to receive HPV DNA (GP5+/6+-PCR method) and cytology co-testing or cytology testing alone, from January, 1999, to September, 2002.", "Randomisation (in a 1:1 ratio) was done with computer-generated random numbers after the cervical specimen had been taken.", "At the second screening 5 years later, HPV DNA and cytology co-testing was done in both groups; researchers were masked to the patient's assignment.", "The primary endpoint was the number of CIN grade 3 or worse detected.", "Analysis was done by intention to screen.", "The trial is now finished and is registered, number ISRCTN20781131.", "FINDINGS 22,420 women were randomly assigned to the intervention group and 22 518 to the control group; 19 999 in the intervention group and 20,106 in the control group were eligible for analysis at the first screen.", "At the second screen, 19 579 women in the intervention group and 19,731 in the control group were eligible, of whom 16,750 and 16,743, respectively, attended the second screen.", "In the second round, CIN grade 3 or worse was less common in the intervention group than in the control group (88 of 19 579 in the intervention group vs 122 of 19,731 in the control group; relative risk 0·73, 95% CI 0·55-0·96; p=0·023).", "Cervical cancer was also less common in the intervention group than in the control group (four of 19 579 in the intervention group vs 14 of 19,731; 0·29, 0·10-0·87; p=0·031).", "In the baseline round, detection of CIN grade 3 or worse did not differ significantly between groups (171 of 19 999 vs 150 of 20,106; 1·15, 0·92-1·43; p=0·239) but was significantly more common in women with normal cytology (34 of 19,286 vs 12 of 19,373; 2·85, 1·47-5·49; p=0·001).", "Furthermore, significantly more cases of CIN grade 2 or worse were detected in the intervention group than in the control group (267 of 19 999 vs 215 of 20,106; 1·25, 1·05-1·50; p=0·015).", "In the second screen, fewer HPV16-positive CIN grade 3 or worse were detected in the intervention group than in the control group (17 of 9481 vs 35 of 9354; 0·48, 0·27-0·85; p=0·012); detection of non-HPV16-positive CIN grade 3 or worse did not differ between groups (25 of 9481 vs 25 of 9354; 0·99, 0·57-1·72; p=1·00).", "The cumulative detection of CIN grade 3 or worse and CIN grade 2 or worse did not differ significantly between study arms, neither for the whole study group (CIN grade 3 or worse: 259 of 19 999 vs 272 of 20,106; 0·96, 0·81-1·14, p=0·631; CIN grade 2 or worse: 427 of 19 999 vs 399 of 20,106; 1·08, 0·94-1·24; p=0·292), nor for subgroups of women invited for the first time (CIN grade 3 or worse in women aged 29-33 years: 102 of 3139 vs 105 of 3128; 0·97, 0·74-1·27; CIN grade 2 or worse in women aged 29-33 years: 153 of 3139 vs 151 of 3128; 1·01, 0·81-1·26; CIN grade 3 or worse in women aged 34-56 years: 157 of 16,860 vs 167 of 16 978; 0·95, 0·76-1·18; CIN grade 2 or worse in women aged 34-56 years: 274 of 16,860 vs 248 of 16 978; 1·11, 0·94-1·32).", "INTERPRETATION Implementation of HPV DNA testing in cervical screening leads to earlier detection of clinically relevant CIN grade 2 or worse, which when adequately treated, improves protection against CIN grade 3 or worse and cervical cancer.", "Early detection of high-grade cervical legions caused by HPV16 was a major component of this benefit.", "Our results lend support to the use of HPV DNA testing for all women aged 29 years and older.", "FUNDING Zorg Onderzoek Nederland (Netherlands Organisation for Health Research and Development)." ]

[ 13, 16 ]

[ "Little is known about the inter-individual variation of cytokine responses to different pathogens in healthy individuals.", "To systematically describe cytokine responses elicited by distinct pathogens and to determine the effect of genetic variation on cytokine production, we profiled cytokines produced by peripheral blood mononuclear cells from 197 individuals of European origin from the 200 Functional Genomics (200FG) cohort in the Human Functional Genomics Project (http://www.humanfunctionalgenomics.org), obtained over three different years.", "We compared bacteria- and fungi-induced cytokine profiles and found that most cytokine responses were organized around a physiological response to specific pathogens, rather than around a particular immune pathway or cytokine.", "We then correlated genome-wide single-nucleotide polymorphism (SNP) genotypes with cytokine abundance and identified six cytokine quantitative trait loci (QTLs).", "Among them, a cytokine QTL at the NAA35-GOLM1 locus markedly modulated interleukin (IL)-6 production in response to multiple pathogens and was associated with susceptibility to candidemia.", "Furthermore, the cytokine QTLs that we identified were enriched among SNPs previously associated with infectious diseases and heart diseases.", "These data reveal and begin to explain the variability in cytokine production by human immune cells in response to pathogens." ]

[]

[ "Paraneoplastic thrombocytosis is associated with many solid tumors and often correlates with reduced survival.", "Recent studies suggest that a pathogenic feed back loop may be operative between platelets and tumor cells, with reciprocal interactions between tumor growth/metastasis and thrombocytosis/platelet activation.", "Specific molecular pathways have been identified in which tumors can stimulate platelet production and activation; activated platelets can, in turn, promote tumor growth and metastasis.", "Taken together, these findings provide exciting new potential targets for therapeutic intervention." ]

[]

[ "OBJECTIVES We investigated the role of cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in cachexia development in newly diagnosed nonsmall cell lung cancer (NSCLC) patients.", "METHODS : We evaluated 44 (M/F:41/3) NSCLC patients and 12 (M/F:10/2) age matched healthy smokers.", "NSCLC cases with a weight loss of > or =10% consisted the cachectic group (n:23, M/F:21/2) and the ones with <10% weight loss consisted the noncachectic group (n:21, M/F:19/2).", "RESULTS Body mass index (BMI) of cachectics was significantly lower than that of noncachectics (21.0 +/- 2.9 versus 24.5 +/-", "3.6, P = 0.02) and controls (21.0 +/- 2.9 versus 25.5 +/- 2.6, P = 0.01).", "Serum TNF-alpha level did not differ between cachectic and noncachectics (37.3 +/-", "39.1 and 51.6 +/-", "84.2 pg/mL, respectively).", "However, it was significantly higher in NSCLC patients compared with controls (44.1 +/- 64.3 and 15.1 +/-", "14.3 pg/mL, P = 0.03).", "Serum IL-6 level was not different between 3 groups (6.4 +/- 4.1, 8.9 +/-", "16.3, and 4.1 +/-", "3.5 pg/mL, respectively)", "but it correlated significantly with TNF-alpha (r = 0.4, P = 0.006) and BMI (r = -0.3, P = 0.03).", "Erythrocyte sedimentation rate (ESR) correlated significantly with TNF-alpha (r = 0.4, P = 0.003) and BMI (r = -0.3, P = 0.03).", "Among 44 cases, survival of 12 and 17 patients was recorded in cachectics and noncachectics, with no statistical difference (12.2 +/- 3.7 and 11.2 +/-", "1.0 months, respectively).", "CONCLUSIONS TNF-alpha and IL-6 levels did not differ significantly between cachectics and noncachectics.", "However, significant correlations between IL-6, BMI, and TNF-alpha suggested that these cytokines acted as cofactors in weight loss.", "Survival was neither influenced by BMI, nor the cytokine levels in the present study.", "The significant correlation of ESR with TNF-alpha suggested that ESR could provide valuable clue for considerable weight loss in the follow-up of NSCLC patients." ]

[ 8, 9 ]

[ "Paraneoplastic thrombocytosis is associated with many solid tumors and often correlates with reduced survival.", "Recent studies suggest that a pathogenic feed back loop may be operative between platelets and tumor cells, with reciprocal interactions between tumor growth/metastasis and thrombocytosis/platelet activation.", "Specific molecular pathways have been identified in which tumors can stimulate platelet production and activation; activated platelets can, in turn, promote tumor growth and metastasis.", "Taken together, these findings provide exciting new potential targets for therapeutic intervention." ]

[]

[ "Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) resets their identity back to an embryonic age and, thus, presents a significant hurdle for modeling late-onset disorders.", "In this study, we describe a strategy for inducing aging-related features in human iPSC-derived lineages and apply it to the modeling of Parkinson's disease (PD).", "Our approach involves expression of progerin, a truncated form of lamin A associated with premature aging.", "We found that expression of progerin in iPSC-derived fibroblasts and neurons induces multiple aging-related markers and characteristics, including dopamine-specific phenotypes such as neuromelanin accumulation.", "Induced aging in PD iPSC-derived dopamine neurons revealed disease phenotypes that require both aging and genetic susceptibility, such as pronounced dendrite degeneration, progressive loss of tyrosine hydroxylase (TH) expression, and enlarged mitochondria or Lewy-body-precursor inclusions.", "Thus, our study suggests that progerin-induced aging can be used to reveal late-onset age-related disease features in hiPSC-based disease models." ]

[ 3, 5 ]

[ "Spinal cord injuries (SCIs) in humans and experimental animals are often associated with varying degrees of spontaneous functional recovery during the first months after injury.", "Such recovery is widely attributed to axons spared from injury that descend from the brain and bypass incomplete lesions, but its mechanisms are uncertain.", "To investigate the neural basis of spontaneous recovery, we used kinematic, physiological and anatomical analyses to evaluate mice with various combinations of spatially and temporally separated lateral hemisections with or without the excitotoxic ablation of intrinsic spinal cord neurons.", "We show that propriospinal relay connections that bypass one or more injury sites are able to mediate spontaneous functional recovery and supraspinal control of stepping, even when there has been essentially total and irreversible interruption of long descending supraspinal pathways in mice.", "Our findings show that pronounced functional recovery can occur after severe SCI without the maintenance or regeneration of direct projections from the brain past the lesion and can be mediated by the reorganization of descending and propriospinal connections.", "Targeting interventions toward augmenting the remodeling of relay connections may provide new therapeutic strategies to bypass lesions and restore function after SCI and in other conditions such as stroke and multiple sclerosis." ]

[ 3, 4 ]

[ "The canonical role of messenger RNA (mRNA) is to deliver protein-coding information to sites of protein synthesis.", "However, given that microRNAs bind to RNAs, we hypothesized that RNAs could possess a regulatory role that relies on their ability to compete for microRNA binding, independently of their protein-coding function.", "As a model for the protein-coding-independent role of RNAs, we describe the functional relationship between the mRNAs produced by the PTEN tumour suppressor gene and its pseudogene PTENP1 and the critical consequences of this interaction.", "We find that PTENP1 is biologically active as it can regulate cellular levels of PTEN and exert a growth-suppressive role.", "We also show that the PTENP1 locus is selectively lost in human cancer.", "We extended our analysis to other cancer-related genes that possess pseudogenes, such as oncogenic KRAS.", "We also demonstrate that the transcripts of protein-coding genes such as PTEN are biologically active.", "These findings attribute a novel biological role to expressed pseudogenes, as they can regulate coding gene expression, and reveal a non-coding function for mRNAs." ]

[ 3 ]

[ "RNases P and MRP are ribonucleoprotein complexes involved in tRNA and rRNA processing, respectively.", "The RNA subunits of these two enzymes are structurally related to each other and play an essential role in the enzymatic reaction.", "Both of the RNAs have a highly conserved helical region, P4, which is important in the catalytic reaction.", "We have used a bioinformatics approach based on conserved elements to computationally analyze available genomic sequences of eukaryotic organisms and have identified a large number of novel nuclear RNase P and MRP RNA genes.", "For MRP RNA for instance, this investigation increases the number of known sequences by a factor of three.", "We present secondary structure models of many of the predicted RNAs.", "Although all sequences are able to fold into the consensus secondary structure of P and MRP RNAs, a striking variation in size is observed, ranging from a Nosema locustae MRP RNA of 160 nt to much larger RNAs, e.g. a Plasmodium knowlesi P RNA of 696 nt.", "The P and MRP RNA genes appear in tandem in some protists, further emphasizing the close evolutionary relationship of these RNAs." ]

[]

[ "Pluripotent mouse embryonic stem (ES) cells multiply in simple monoculture by symmetrical divisions.", "In vivo, however, stem cells are generally thought to depend on specialised cellular microenvironments and to undergo predominantly asymmetric divisions.", "Ex vivo expansion of pure populations of tissue stem cells has proven elusive.", "Neural progenitor cells are propagated in combination with differentiating progeny in floating clusters called neurospheres.", "The proportion of stem cells in neurospheres is low, however, and they cannot be directly observed or interrogated.", "Here we demonstrate that the complex neurosphere environment is dispensable for stem cell maintenance, and that the combination of fibroblast growth factor 2 (FGF-2) and epidermal growth factor (EGF) is sufficient for derivation and continuous expansion by symmetrical division of pure cultures of neural stem (NS) cells.", "NS cells were derived first from mouse ES cells.", "Neural lineage induction was followed by growth factor addition in basal culture media.", "In the presence of only EGF and FGF-2, resulting NS cells proliferate continuously, are diploid, and clonogenic.", "After prolonged expansion, they remain able to differentiate efficiently into neurons and astrocytes in vitro and upon transplantation into the adult brain.", "Colonies generated from single NS cells all produce neurons upon growth factor withdrawal.", "NS cells uniformly express morphological, cell biological, and molecular features of radial glia, developmental precursors of neurons and glia.", "Consistent with this profile, adherent NS cell lines can readily be established from foetal mouse brain.", "Similar NS cells can be generated from human ES cells and human foetal brain.", "The extrinsic factors EGF plus FGF-2 are sufficient to sustain pure symmetrical self-renewing divisions of NS cells.", "The resultant cultures constitute the first known example of tissue-specific stem cells that can be propagated without accompanying differentiation.", "These homogenous cultures will enable delineation of molecular mechanisms that define a tissue-specific stem cell and allow direct comparison with pluripotent ES cells." ]

[]

[ "G-quadruplex (G4)-forming genomic sequences, including telomeres, represent natural replication fork barriers.", "Stalled replication forks can be stabilized and restarted by homologous recombination (HR), which also repairs DNA double-strand breaks (DSBs) arising at collapsed forks.", "We have previously shown that HR facilitates telomere replication.", "Here, we demonstrate that the replication efficiency of guanine-rich (G-rich) telomeric repeats is decreased significantly in cells lacking HR.", "Treatment with the G4-stabilizing compound pyridostatin (PDS) increases telomere fragility in BRCA2-deficient cells, suggesting that G4 formation drives telomere instability.", "Remarkably, PDS reduces proliferation of HR-defective cells by inducing DSB accumulation, checkpoint activation, and deregulated G2/M progression and by enhancing the replication defect intrinsic to HR deficiency.", "PDS toxicity extends to HR-defective cells that have acquired olaparib resistance through loss of 53BP1 or REV7.", "Altogether, these results highlight the therapeutic potential of G4-stabilizing drugs to selectively eliminate HR-compromised cells and tumors, including those resistant to PARP inhibition." ]

[ 4 ]

[ "G-quadruplex (G4)-forming genomic sequences, including telomeres, represent natural replication fork barriers.", "Stalled replication forks can be stabilized and restarted by homologous recombination (HR), which also repairs DNA double-strand breaks (DSBs) arising at collapsed forks.", "We have previously shown that HR facilitates telomere replication.", "Here, we demonstrate that the replication efficiency of guanine-rich (G-rich) telomeric repeats is decreased significantly in cells lacking HR.", "Treatment with the G4-stabilizing compound pyridostatin (PDS) increases telomere fragility in BRCA2-deficient cells, suggesting that G4 formation drives telomere instability.", "Remarkably, PDS reduces proliferation of HR-defective cells by inducing DSB accumulation, checkpoint activation, and deregulated G2/M progression and by enhancing the replication defect intrinsic to HR deficiency.", "PDS toxicity extends to HR-defective cells that have acquired olaparib resistance through loss of 53BP1 or REV7.", "Altogether, these results highlight the therapeutic potential of G4-stabilizing drugs to selectively eliminate HR-compromised cells and tumors, including those resistant to PARP inhibition." ]

[ 5 ]

[ "G-quadruplex (G4)-forming genomic sequences, including telomeres, represent natural replication fork barriers.", "Stalled replication forks can be stabilized and restarted by homologous recombination (HR), which also repairs DNA double-strand breaks (DSBs) arising at collapsed forks.", "We have previously shown that HR facilitates telomere replication.", "Here, we demonstrate that the replication efficiency of guanine-rich (G-rich) telomeric repeats is decreased significantly in cells lacking HR.", "Treatment with the G4-stabilizing compound pyridostatin (PDS) increases telomere fragility in BRCA2-deficient cells, suggesting that G4 formation drives telomere instability.", "Remarkably, PDS reduces proliferation of HR-defective cells by inducing DSB accumulation, checkpoint activation, and deregulated G2/M progression and by enhancing the replication defect intrinsic to HR deficiency.", "PDS toxicity extends to HR-defective cells that have acquired olaparib resistance through loss of 53BP1 or REV7.", "Altogether, these results highlight the therapeutic potential of G4-stabilizing drugs to selectively eliminate HR-compromised cells and tumors, including those resistant to PARP inhibition." ]

[ 5 ]

[ "G-quadruplex (G4)-forming genomic sequences, including telomeres, represent natural replication fork barriers.", "Stalled replication forks can be stabilized and restarted by homologous recombination (HR), which also repairs DNA double-strand breaks (DSBs) arising at collapsed forks.", "We have previously shown that HR facilitates telomere replication.", "Here, we demonstrate that the replication efficiency of guanine-rich (G-rich) telomeric repeats is decreased significantly in cells lacking HR.", "Treatment with the G4-stabilizing compound pyridostatin (PDS) increases telomere fragility in BRCA2-deficient cells, suggesting that G4 formation drives telomere instability.", "Remarkably, PDS reduces proliferation of HR-defective cells by inducing DSB accumulation, checkpoint activation, and deregulated G2/M progression and by enhancing the replication defect intrinsic to HR deficiency.", "PDS toxicity extends to HR-defective cells that have acquired olaparib resistance through loss of 53BP1 or REV7.", "Altogether, these results highlight the therapeutic potential of G4-stabilizing drugs to selectively eliminate HR-compromised cells and tumors, including those resistant to PARP inhibition." ]

[ 5 ]

[ "G-quadruplex (G4)-forming genomic sequences, including telomeres, represent natural replication fork barriers.", "Stalled replication forks can be stabilized and restarted by homologous recombination (HR), which also repairs DNA double-strand breaks (DSBs) arising at collapsed forks.", "We have previously shown that HR facilitates telomere replication.", "Here, we demonstrate that the replication efficiency of guanine-rich (G-rich) telomeric repeats is decreased significantly in cells lacking HR.", "Treatment with the G4-stabilizing compound pyridostatin (PDS) increases telomere fragility in BRCA2-deficient cells, suggesting that G4 formation drives telomere instability.", "Remarkably, PDS reduces proliferation of HR-defective cells by inducing DSB accumulation, checkpoint activation, and deregulated G2/M progression and by enhancing the replication defect intrinsic to HR deficiency.", "PDS toxicity extends to HR-defective cells that have acquired olaparib resistance through loss of 53BP1 or REV7.", "Altogether, these results highlight the therapeutic potential of G4-stabilizing drugs to selectively eliminate HR-compromised cells and tumors, including those resistant to PARP inhibition." ]

[ 5 ]

[ "G-quadruplex (G4)-forming genomic sequences, including telomeres, represent natural replication fork barriers.", "Stalled replication forks can be stabilized and restarted by homologous recombination (HR), which also repairs DNA double-strand breaks (DSBs) arising at collapsed forks.", "We have previously shown that HR facilitates telomere replication.", "Here, we demonstrate that the replication efficiency of guanine-rich (G-rich) telomeric repeats is decreased significantly in cells lacking HR.", "Treatment with the G4-stabilizing compound pyridostatin (PDS) increases telomere fragility in BRCA2-deficient cells, suggesting that G4 formation drives telomere instability.", "Remarkably, PDS reduces proliferation of HR-defective cells by inducing DSB accumulation, checkpoint activation, and deregulated G2/M progression and by enhancing the replication defect intrinsic to HR deficiency.", "PDS toxicity extends to HR-defective cells that have acquired olaparib resistance through loss of 53BP1 or REV7.", "Altogether, these results highlight the therapeutic potential of G4-stabilizing drugs to selectively eliminate HR-compromised cells and tumors, including those resistant to PARP inhibition." ]

[ 5 ]

[ "G-quadruplex (G4)-forming genomic sequences, including telomeres, represent natural replication fork barriers.", "Stalled replication forks can be stabilized and restarted by homologous recombination (HR), which also repairs DNA double-strand breaks (DSBs) arising at collapsed forks.", "We have previously shown that HR facilitates telomere replication.", "Here, we demonstrate that the replication efficiency of guanine-rich (G-rich) telomeric repeats is decreased significantly in cells lacking HR.", "Treatment with the G4-stabilizing compound pyridostatin (PDS) increases telomere fragility in BRCA2-deficient cells, suggesting that G4 formation drives telomere instability.", "Remarkably, PDS reduces proliferation of HR-defective cells by inducing DSB accumulation, checkpoint activation, and deregulated G2/M progression and by enhancing the replication defect intrinsic to HR deficiency.", "PDS toxicity extends to HR-defective cells that have acquired olaparib resistance through loss of 53BP1 or REV7.", "Altogether, these results highlight the therapeutic potential of G4-stabilizing drugs to selectively eliminate HR-compromised cells and tumors, including those resistant to PARP inhibition." ]

[ 5 ]

[ "G-quadruplex (G4)-forming genomic sequences, including telomeres, represent natural replication fork barriers.", "Stalled replication forks can be stabilized and restarted by homologous recombination (HR), which also repairs DNA double-strand breaks (DSBs) arising at collapsed forks.", "We have previously shown that HR facilitates telomere replication.", "Here, we demonstrate that the replication efficiency of guanine-rich (G-rich) telomeric repeats is decreased significantly in cells lacking HR.", "Treatment with the G4-stabilizing compound pyridostatin (PDS) increases telomere fragility in BRCA2-deficient cells, suggesting that G4 formation drives telomere instability.", "Remarkably, PDS reduces proliferation of HR-defective cells by inducing DSB accumulation, checkpoint activation, and deregulated G2/M progression and by enhancing the replication defect intrinsic to HR deficiency.", "PDS toxicity extends to HR-defective cells that have acquired olaparib resistance through loss of 53BP1 or REV7.", "Altogether, these results highlight the therapeutic potential of G4-stabilizing drugs to selectively eliminate HR-compromised cells and tumors, including those resistant to PARP inhibition." ]

[ 4 ]

[ "Drosophila Dicer-2 generates small interfering RNAs (siRNAs) from long double-stranded RNA (dsRNA), whereas Dicer-1 produces microRNAs (miRNAs) from pre-miRNA.", "What makes the two Dicers specific for their biological substrates?", "We find that purified Dicer-2 can efficiently cleave pre-miRNA, but that inorganic phosphate and the Dicer-2 partner protein R2D2 inhibit pre-miRNA cleavage.", "Dicer-2 contains C-terminal RNase III domains that mediate RNA cleavage and an N-terminal helicase motif, whose function is unclear.", "We show that Dicer-2 is a dsRNA-stimulated ATPase that hydrolyzes ATP to ADP; ATP hydrolysis is required for Dicer-2 to process long dsRNA, but not pre-miRNA.", "Wild-type Dicer-2, but not a mutant defective in ATP hydrolysis, can generate siRNAs faster than it can dissociate from a long dsRNA substrate.", "We propose that the Dicer-2 helicase domain uses ATP to generate many siRNAs from a single molecule of dsRNA before dissociating from its substrate." ]

[]

[ "Nuclear receptors undergo ligand-dependent conformational changes that are required for corepressor-coactivator exchange, but whether there is an actual requirement for specific epigenetic landmarks to impose ligand dependency for gene activation remains unknown.", "Here we report an unexpected and general strategy that is based on the requirement for specific cohorts of inhibitory histone methyltransferases (HMTs) to impose gene-specific gatekeeper functions that prevent unliganded nuclear receptors and other classes of regulated transcription factors from binding to their target gene promoters and causing constitutive gene activation in the absence of stimulating signals.", "This strategy, based at least in part on an HMT-dependent inhibitory histone code, imposes a requirement for specific histone demethylases, including LSD1, to permit ligand- and signal-dependent activation of regulated gene expression.", "These events link an inhibitory methylation component of the histone code to a broadly used strategy that circumvents pathological constitutive gene induction by physiologically regulated transcription factors." ]

[]

[ "Human cancers are characterized by the presence of oncogene-induced DNA replication stress (DRS), making them dependent on repair pathways such as break-induced replication (BIR) for damaged DNA replication forks.", "To better understand BIR, we performed a targeted siRNA screen for genes whose depletion inhibited G1 to S phase progression when oncogenic cyclin E was overexpressed.", "RAD52, a gene dispensable for normal development in mice, was among the top hits.", "In cells in which fork collapse was induced by oncogenes or chemicals, the Rad52 protein localized to DRS foci.", "Depletion of Rad52 by siRNA or knockout of the gene by CRISPR/Cas9 compromised restart of collapsed forks and led to DNA damage in cells experiencing DRS.", "Furthermore, in cancer-prone, heterozygous APC mutant mice, homozygous deletion of the Rad52 gene suppressed tumor growth and prolonged lifespan.", "We therefore propose that mammalian RAD52 facilitates repair of collapsed DNA replication forks in cancer cells." ]

[ 6 ]

[ "Alternative lengthening of telomeres (ALT) is a telomerase-independent telomere maintenance mechanism that occurs in a subset of cancers.", "By analyzing telomerase-positive cells and their human TERC knockout-derived ALT human cell lines, we show that ALT cells harbor more fragile telomeres representing telomere replication problems.", "ALT-associated replication defects trigger mitotic DNA synthesis (MiDAS) at telomeres in a RAD52-dependent, but RAD51-independent, manner.", "Telomeric MiDAS is a conservative DNA synthesis process, potentially mediated by break-induced replication, similar to type II ALT survivors in Saccharomyces cerevisiae Replication stresses induced by ectopic oncogenic expression of cyclin E, G-quadruplexes, or R-loop formation facilitate the ALT pathway and lead to telomere clustering, a hallmark of ALT cancers.", "The TIMELESS/TIPIN complex suppresses telomere clustering and telomeric MiDAS, whereas the SMC5/6 complex promotes them.", "In summary, ALT cells exhibit more telomere replication defects that result in persistent DNA damage responses at telomeres, leading to the engagement of telomeric MiDAS (spontaneous mitotic telomere synthesis) that is triggered by DNA replication stress, a potential driver of genomic duplications in cancer." ]

[ 2 ]

[ "Telomeres resemble common fragile sites (CFSs) in that they are difficult-to-replicate and exhibit fragility in mitosis in response to DNA replication stress.", "At CFSs, this fragility is associated with a delay in the completion of DNA replication until early mitosis, whereupon cells are proposed to switch to a RAD52-dependent form of break-induced replication.", "Here, we show that this mitotic DNA synthesis (MiDAS) is also a feature of human telomeres.", "Telomeric MiDAS is not restricted to those telomeres displaying overt fragility, and is a feature of a wide range of cell lines irrespective of whether their telomeres are maintained by telomerase or by the alternative lengthening of telomeres (ALT) mechanism.", "MiDAS at telomeres requires RAD52, and is mechanistically similar to CFS-associated MiDAS, with the notable exception that telomeric MiDAS does not require the MUS81-EME1 endonuclease.", "We propose a model whereby replication stress initiates a RAD52-dependent form of break-induced replication that bypasses a requirement for MUS81-EME1 to complete DNA synthesis in mitosis." ]

[ 1, 5 ]

[ "The thymic medulla provides a specialized microenvironment for the negative selection of T cells, with the presence of autoimmune regulator (Aire)-expressing medullary thymic epithelial cells (mTECs) during the embryonic-neonatal period being both necessary and sufficient to establish long-lasting tolerance.", "Here we showed that emergence of the first cohorts of Aire(+) mTECs at this key developmental stage, prior to αβ T cell repertoire selection, was jointly directed by Rankl(+) lymphoid tissue inducer cells and invariant Vγ5(+) dendritic epidermal T cell (DETC) progenitors that are the first thymocytes to express the products of gene rearrangement.", "In turn, generation of Aire(+) mTECs then fostered Skint-1-dependent, but Aire-independent, DETC progenitor maturation and the emergence of an invariant DETC repertoire.", "Hence, our data attributed a functional importance to the temporal development of Vγ5(+) γδ T cells during thymus medulla formation for αβ T cell tolerance induction and demonstrated a Rank-mediated reciprocal link between DETC and Aire(+) mTEC maturation." ]

[ 1, 3 ]

[ "Medullary thymic epithelial cells (mTECs) establish T cell self-tolerance through the expression of autoimmune regulator (Aire) and peripheral tissue-specific self-antigens.", "However, signals underlying mTEC development remain largely unclear.", "Here, we demonstrate crucial regulation of mTEC development by receptor activator of NF-kappaB (RANK) and CD40 signals.", "Whereas only RANK signaling was essential for mTEC development during embryogenesis, in postnatal mice, cooperation between CD40 and RANK signals was required for mTEC development to successfully establish the medullary microenvironment.", "Ligation of RANK or CD40 on fetal thymic stroma in vitro induced mTEC development in a tumor necrosis factor-associated factor 6 (TRAF6)-, NF-kappaB inducing kinase (NIK)-, and IkappaB kinase beta (IKKbeta)-dependent manner.", "These results show that developmental-stage-dependent cooperation between RANK and CD40 promotes mTEC development, thereby establishing self-tolerance." ]

[ 2, 3, 4, 5 ]

[ "Aire-expressing medullary thymic epithelial cells (mTECs) play a key role in preventing autoimmunity by expressing tissue-restricted antigens to help purge the emerging T cell receptor repertoire of self-reactive specificities.", "Here we demonstrate a novel role for a CD4+3− inducer cell population, previously linked to development of organized secondary lymphoid structures and maintenance of T cell memory in the functional regulation of Aire-mediated promiscuous gene expression in the thymus.", "CD4+3− cells are closely associated with mTECs in adult thymus, and in fetal thymus their appearance is temporally linked with the appearance of Aire+ mTECs.", "We show that RANKL signals from this cell promote the maturation of RANK-expressing CD80−Aire− mTEC progenitors into CD80+Aire+ mTECs, and that transplantation of RANK-deficient thymic stroma into immunodeficient hosts induces autoimmunity.", "Collectively, our data reveal cellular and molecular mechanisms leading to the generation of Aire+ mTECs and highlight a previously unrecognized role for CD4+3−RANKL+ inducer cells in intrathymic self-tolerance." ]

[ 3, 4 ]

[ "The thymic medulla provides a specialized microenvironment for the negative selection of T cells, with the presence of autoimmune regulator (Aire)-expressing medullary thymic epithelial cells (mTECs) during the embryonic-neonatal period being both necessary and sufficient to establish long-lasting tolerance.", "Here we showed that emergence of the first cohorts of Aire(+) mTECs at this key developmental stage, prior to αβ T cell repertoire selection, was jointly directed by Rankl(+) lymphoid tissue inducer cells and invariant Vγ5(+) dendritic epidermal T cell (DETC) progenitors that are the first thymocytes to express the products of gene rearrangement.", "In turn, generation of Aire(+) mTECs then fostered Skint-1-dependent, but Aire-independent, DETC progenitor maturation and the emergence of an invariant DETC repertoire.", "Hence, our data attributed a functional importance to the temporal development of Vγ5(+) γδ T cells during thymus medulla formation for αβ T cell tolerance induction and demonstrated a Rank-mediated reciprocal link between DETC and Aire(+) mTEC maturation." ]

[ 1, 3 ]

[ "Medullary thymic epithelial cells (mTECs) establish T cell self-tolerance through the expression of autoimmune regulator (Aire) and peripheral tissue-specific self-antigens.", "However, signals underlying mTEC development remain largely unclear.", "Here, we demonstrate crucial regulation of mTEC development by receptor activator of NF-kappaB (RANK) and CD40 signals.", "Whereas only RANK signaling was essential for mTEC development during embryogenesis, in postnatal mice, cooperation between CD40 and RANK signals was required for mTEC development to successfully establish the medullary microenvironment.", "Ligation of RANK or CD40 on fetal thymic stroma in vitro induced mTEC development in a tumor necrosis factor-associated factor 6 (TRAF6)-, NF-kappaB inducing kinase (NIK)-, and IkappaB kinase beta (IKKbeta)-dependent manner.", "These results show that developmental-stage-dependent cooperation between RANK and CD40 promotes mTEC development, thereby establishing self-tolerance." ]

[ 2, 3, 4, 5 ]

[ "Aire-expressing medullary thymic epithelial cells (mTECs) play a key role in preventing autoimmunity by expressing tissue-restricted antigens to help purge the emerging T cell receptor repertoire of self-reactive specificities.", "Here we demonstrate a novel role for a CD4+3− inducer cell population, previously linked to development of organized secondary lymphoid structures and maintenance of T cell memory in the functional regulation of Aire-mediated promiscuous gene expression in the thymus.", "CD4+3− cells are closely associated with mTECs in adult thymus, and in fetal thymus their appearance is temporally linked with the appearance of Aire+ mTECs.", "We show that RANKL signals from this cell promote the maturation of RANK-expressing CD80−Aire− mTEC progenitors into CD80+Aire+ mTECs, and that transplantation of RANK-deficient thymic stroma into immunodeficient hosts induces autoimmunity.", "Collectively, our data reveal cellular and molecular mechanisms leading to the generation of Aire+ mTECs and highlight a previously unrecognized role for CD4+3−RANKL+ inducer cells in intrathymic self-tolerance." ]

[ 3, 4 ]

[ "The helicase RTEL1 promotes t-loop unwinding and suppresses telomere fragility to maintain the integrity of vertebrate telomeres.", "An interaction between RTEL1 and PCNA is important to prevent telomere fragility, but how RTEL1 engages with the telomere to promote t-loop unwinding is unclear.", "Here, we establish that the shelterin protein TRF2 recruits RTEL1 to telomeres in S phase, which is required to prevent catastrophic t-loop processing by structure-specific nucleases.", "We show that the TRF2-RTEL1 interaction is mediated by a metal-coordinating C4C4 motif in RTEL1, which is compromised by the Hoyeraal-Hreidarsson syndrome (HHS) mutation, RTEL1(R1264H).", "Conversely, we define a TRF2(I124D) substitution mutation within the TRFH domain of TRF2, which eliminates RTEL1 binding and phenocopies the RTEL1(R1264H) mutation, giving rise to aberrant t-loop excision, telomere length heterogeneity, and loss of the telomere as a circle.", "These results implicate TRF2 in the recruitment of RTEL1 to facilitate t-loop disassembly at telomeres in S phase." ]

[ 3 ]

[ "Human skin copes with harmful environmental factors that are circadian in nature, yet how circadian rhythms modulate the function of human epidermal stem cells is mostly unknown.", "Here we show that in human epidermal stem cells and their differentiated counterparts, core clock genes peak in a successive and phased manner, establishing distinct temporal intervals during the 24 hr day period.", "Each of these successive clock waves is associated with a peak in the expression of subsets of transcripts that temporally segregate the predisposition of epidermal stem cells to respond to cues that regulate their proliferation or differentiation, such as TGFβ and calcium.", "Accordingly, circadian arrhythmia profoundly affects stem cell function in culture and in vivo.", "We hypothesize that this intricate mechanism ensures homeostasis by providing epidermal stem cells with environmentally relevant temporal functional cues during the course of the day and that its perturbation may contribute to aging and carcinogenesis." ]

[]

[ "The TLX1 and TLX3 transcription factor oncogenes have a key role in the pathogenesis of T cell acute lymphoblastic leukemia (T-ALL).", "Here we used reverse engineering of global transcriptional networks to decipher the oncogenic regulatory circuit controlled by TLX1 and TLX3.", "This systems biology analysis defined T cell leukemia homeobox 1 (TLX1) and TLX3 as master regulators of an oncogenic transcriptional circuit governing T-ALL.", "Notably, a network structure analysis of this hierarchical network identified RUNX1 as a key mediator of the T-ALL induced by TLX1 and TLX3 and predicted a tumor-suppressor role for RUNX1 in T cell transformation.", "Consistent with these results, we identified recurrent somatic loss-of-function mutations in RUNX1 in human T-ALL.", "Overall, these results place TLX1 and TLX3 at the top of an oncogenic transcriptional network controlling leukemia development, show the power of network analyses to identify key elements in the regulatory circuits governing human cancer and identify RUNX1 as a tumor-suppressor gene in T-ALL." ]

[ 3, 5 ]

[ "OBJECTIVE To investigate the long term effect of radioactive iodine on thyroid function and size in patients with non-toxic multinodular goitre.", "DESIGN Consecutive patients with multinodular non-toxic goitre selected for radioactive iodine treatment and followed for a minimum of 12 months (median 48 months) after an intended dose of 3.7 MBq/g thyroid tissue corrected to a 100% uptake of iodine-131 in 24 hours.", "PATIENTS 69 patients with a growing multinodular non-toxic goitre causing local compression symptoms or cosmetic inconveniences.", "The treatment was chosen because of a high operative risk, previous thyroidectomy, or refusal to be operated on.", "MAIN OUTCOME MEASUREMENTS Standard thyroid function variables and ultrasonically determined thyroid volume before treatment as well as 1, 2, 3, 6, and 12 months after treatment and then once a year.", "RESULTS 56 patients were treated with a single dose of 131I, 12 with two doses, and one with four doses.", "In 45 patients treated with one dose and remaining euthyroid the median thyroid volume was reduced from 73 (interquartile range 50-106) ml to 29 (23-48) ml at 24 months in the 39 patients in whom this was measured during follow up.", "The median reduction was 40 (22-48) ml (60% reduction, p < 0.0001), half of which occurred within three months.", "Patients treated with two doses as well as those developing hypothyroidism and hyperthyroidism had a significant reduction in thyroid volume.", "Eleven patients developed hypothyroidism (cumulative five year risk 22%, 95% confidence interval 4.8% to 38.4%).", "Side effects were few: three cases of hyperthyroidism and two cases of radiation thyroiditis.", "Only one patient was dissatisfied with the result; she was referred for operation six months after treatment.", "CONCLUSIONS A substantial reduction in thyroid volume accompanied by a low incidence of hypothyroidism and few side effects makes the use of radioactive iodine an attractive alternative to surgery in selected cases of non-toxic multinodular goitre." ]

[ 6, 12 ]

[ "The target of rapamycin (TOR) pathway is a major nutrient-sensing pathway that, when genetically downregulated, increases life span in evolutionarily diverse organisms including mammals.", "The central component of this pathway, TOR kinase, is the target of the inhibitory drug rapamycin, a highly specific and well-described drug approved for human use.", "We show here that feeding rapamycin to adult Drosophila produces the life span extension seen in some TOR mutants.", "Increase in life span by rapamycin was associated with increased resistance to both starvation and paraquat.", "Analysis of the underlying mechanisms revealed that rapamycin increased longevity specifically through the TORC1 branch of the TOR pathway, through alterations to both autophagy and translation.", "Rapamycin could increase life span of weak insulin/Igf signaling (IIS) pathway mutants and of flies with life span maximized by dietary restriction, indicating additional mechanisms." ]

[ 2 ]

[ "The target of rapamycin (TOR) pathway is a major nutrient-sensing pathway that, when genetically downregulated, increases life span in evolutionarily diverse organisms including mammals.", "The central component of this pathway, TOR kinase, is the target of the inhibitory drug rapamycin, a highly specific and well-described drug approved for human use.", "We show here that feeding rapamycin to adult Drosophila produces the life span extension seen in some TOR mutants.", "Increase in life span by rapamycin was associated with increased resistance to both starvation and paraquat.", "Analysis of the underlying mechanisms revealed that rapamycin increased longevity specifically through the TORC1 branch of the TOR pathway, through alterations to both autophagy and translation.", "Rapamycin could increase life span of weak insulin/Igf signaling (IIS) pathway mutants and of flies with life span maximized by dietary restriction, indicating additional mechanisms." ]

[]

[ "Two-component signal transduction pathways comprising histidine protein kinases (HPKs) and their response regulators (RRs) are widely used to control bacterial responses to environmental challenges.", "Some bacteria have over 150 different two-component pathways, and the specificity of the phosphotransfer reactions within these systems is tightly controlled to prevent unwanted crosstalk.", "One of the best understood two-component signalling pathways is the chemotaxis pathway.", "Here, we present the 1.40 A crystal structure of the histidine-containing phosphotransfer domain of the chemotaxis HPK, CheA(3), in complex with its cognate RR, CheY(6).", "A methionine finger on CheY(6) that nestles in a hydrophobic pocket in CheA(3) was shown to be important for the interaction and was found to only occur in the cognate RRs of CheA(3), CheY(6), and CheB(2).", "Site-directed mutagenesis of this methionine in combination with two adjacent residues abolished binding, as shown by surface plasmon resonance studies, and phosphotransfer from CheA(3)-P to CheY(6).", "Introduction of this methionine and an adjacent alanine residue into a range of noncognate CheYs, dramatically changed their specificity, allowing protein interaction and rapid phosphotransfer from CheA(3)-P. The structure presented here has allowed us to identify specificity determinants for the CheA-CheY interaction and subsequently to successfully reengineer phosphotransfer signalling.", "In summary, our results provide valuable insight into how cells mediate specificity in one of the most abundant signalling pathways in biology, two-component signal transduction." ]

[ 6 ]

[ "In bacterial translational initiation, three initiation factors (IFs 1-3) enable the selection of initiator tRNA and the start codon in the P site of the 30S ribosomal subunit.", "Here, we report 11 single-particle cryo-electron microscopy (cryoEM) reconstructions of the complex of bacterial 30S subunit with initiator tRNA, mRNA, and IFs 1-3, representing different steps along the initiation pathway.", "IF1 provides key anchoring points for IF2 and IF3, thereby enhancing their activities.", "IF2 positions a domain in an extended conformation appropriate for capturing the formylmethionyl moiety charged on tRNA.", "IF3 and tRNA undergo large conformational changes to facilitate the accommodation of the formylmethionyl-tRNA (fMet-tRNA(fMet)) into the P site for start codon recognition." ]

[ 4 ]

[ "Cigarette smoking promotes body weight reduction in humans while paradoxically also promoting insulin resistance (IR) and hyperinsulinemia.", "However, the mechanisms behind these effects are unclear.", "Here we show that nicotine, a major constituent of cigarette smoke, selectively activates AMP-activated protein kinase α2 (AMPKα2) in adipocytes, which in turn phosphorylates MAP kinase phosphatase-1 (MKP1) at serine 334, initiating its proteasome-dependent degradation.", "The nicotine-dependent reduction of MKP1 induces the aberrant activation of both p38 mitogen-activated protein kinase and c-Jun N-terminal kinase, leading to increased phosphorylation of insulin receptor substrate 1 (IRS1) at serine 307.", "Phosphorylation of IRS1 leads to its degradation, protein kinase B inhibition, and the loss of insulin-mediated inhibition of lipolysis.", "Consequently, nicotine increases lipolysis, which results in body weight reduction, but this increase also elevates the levels of circulating free fatty acids and thus causes IR in insulin-sensitive tissues.", "These results establish AMPKα2 as an essential mediator of nicotine-induced whole-body IR in spite of reductions in adiposity." ]

[]

[ "Ataxia telangiectasia is a neurodegenerative disease caused by mutation of the Atm gene.", "Here we report that ataxia telangiectasia mutated (ATM) deficiency causes nuclear accumulation of histone deacetylase 4 (HDAC4) in neurons and promotes neurodegeneration.", "Nuclear HDAC4 binds to chromatin, as well as to myocyte enhancer factor 2A (MEF2A) and cAMP-responsive element binding protein (CREB), leading to histone deacetylation and altered neuronal gene expression.", "Blocking either HDAC4 activity or its nuclear accumulation blunts these neurodegenerative changes and rescues several behavioral abnormalities of ATM-deficient mice.", "Full rescue of the neurodegeneration, however, also requires the presence of HDAC4 in the cytoplasm, suggesting that the ataxia telangiectasia phenotype results both from a loss of cytoplasmic HDAC4 as well as its nuclear accumulation.", "To remain cytoplasmic, HDAC4 must be phosphorylated.", "The activity of the HDAC4 phosphatase, protein phosphatase 2A (PP2A), is downregulated by ATM-mediated phosphorylation.", "In ATM deficiency, enhanced PP2A activity leads to HDAC4 dephosphorylation and the nuclear accumulation of HDAC4.", "Our results define a crucial role of the cellular localization of HDAC4 in the events leading to ataxia telangiectasia neurodegeneration." ]

[]

[ "Ataxia telangiectasia is a neurodegenerative disease caused by mutation of the Atm gene.", "Here we report that ataxia telangiectasia mutated (ATM) deficiency causes nuclear accumulation of histone deacetylase 4 (HDAC4) in neurons and promotes neurodegeneration.", "Nuclear HDAC4 binds to chromatin, as well as to myocyte enhancer factor 2A (MEF2A) and cAMP-responsive element binding protein (CREB), leading to histone deacetylation and altered neuronal gene expression.", "Blocking either HDAC4 activity or its nuclear accumulation blunts these neurodegenerative changes and rescues several behavioral abnormalities of ATM-deficient mice.", "Full rescue of the neurodegeneration, however, also requires the presence of HDAC4 in the cytoplasm, suggesting that the ataxia telangiectasia phenotype results both from a loss of cytoplasmic HDAC4 as well as its nuclear accumulation.", "To remain cytoplasmic, HDAC4 must be phosphorylated.", "The activity of the HDAC4 phosphatase, protein phosphatase 2A (PP2A), is downregulated by ATM-mediated phosphorylation.", "In ATM deficiency, enhanced PP2A activity leads to HDAC4 dephosphorylation and the nuclear accumulation of HDAC4.", "Our results define a crucial role of the cellular localization of HDAC4 in the events leading to ataxia telangiectasia neurodegeneration." ]

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[ "Autoimmune diseases are thought to result from imbalances in normal immune physiology and regulation.", "Here, we show that autoimmune disease susceptibility and resistance alleles on mouse chromosome 3 (Idd3) correlate with differential expression of the key immunoregulatory cytokine interleukin-2 (IL-2).", "In order to test directly that an approximately twofold reduction in IL-2 underpins the Idd3-linked destabilization of immune homeostasis, we show that engineered haplodeficiency of Il2 gene expression not only reduces T cell IL-2 production by twofold but also mimics the autoimmune dysregulatory effects of the naturally occurring susceptibility alleles of Il2.", "Reduced IL-2 production achieved by either genetic mechanism correlates with reduced function of CD4+ CD25+ regulatory T cells, which are critical for maintaining immune homeostasis." ]

[ 2, 3 ]

[ "Numerous reports have demonstrated that CD4(+)CD25(+) regulatory T cells (Tregs) from individuals with a range of human autoimmune diseases, including type 1 diabetes, are deficient in their ability to control autologous proinflammatory responses when compared with nondiseased, control individuals.", "Treg dysfunction could be a primary, causal event or may result from perturbations in the immune system during disease development.", "Polymorphisms in genes associated with Treg function, such as IL2RA, confer a higher risk of autoimmune disease.", "Although this suggests a primary role for defective Tregs in autoimmunity, a link between IL2RA gene polymorphisms and Treg function has not been examined.", "We addressed this by examining the impact of an IL2RA haplotype associated with type 1 diabetes on Treg fitness and suppressive function.", "Studies were conducted using healthy human subjects to avoid any confounding effects of disease.", "We demonstrated that the presence of an autoimmune disease-associated IL2RA haplotype correlates with diminished IL-2 responsiveness in Ag-experienced CD4(+) T cells, as measured by phosphorylation of STAT5a, and is associated with lower levels of FOXP3 expression by Tregs and a reduction in their ability to suppress proliferation of autologous effector T cells.", "These data offer a rationale that contributes to the molecular and cellular mechanisms through which polymorphisms in the IL-2RA gene affect immune regulation, and consequently upon susceptibility to autoimmune and inflammatory diseases." ]

[ 6 ]

[ "The interconversion between naive and primed pluripotent states is accompanied by drastic epigenetic rearrangements.", "However, it is unclear whether intrinsic epigenetic events can drive reprogramming to naive pluripotency or if distinct chromatin states are instead simply a reflection of discrete pluripotent states.", "Here, we show that blocking histone H3K4 methyltransferase MLL1 activity with the small-molecule inhibitor MM-401 reprograms mouse epiblast stem cells (EpiSCs) to naive pluripotency.", "This reversion is highly efficient and synchronized, with more than 50% of treated EpiSCs exhibiting features of naive embryonic stem cells (ESCs) within 3 days.", "Reverted ESCs reactivate the silenced X chromosome and contribute to embryos following blastocyst injection, generating germline-competent chimeras.", "Importantly, blocking MLL1 leads to global redistribution of H3K4me1 at enhancers and represses lineage determinant factors and EpiSC markers, which indirectly regulate ESC transcription circuitry.", "These findings show that discrete perturbation of H3K4 methylation is sufficient to drive reprogramming to naive pluripotency." ]

[ 2 ]

[ "Historically, the ribosome has been viewed as a complex ribozyme with constitutive rather than regulatory capacity in mRNA translation.", "Here we identify mutations of the Ribosomal Protein L38 (Rpl38) gene in mice exhibiting surprising tissue-specific patterning defects, including pronounced homeotic transformations of the axial skeleton.", "In Rpl38 mutant embryos, global protein synthesis is unchanged; however the translation of a select subset of Homeobox mRNAs is perturbed.", "Our data reveal that RPL38 facilitates 80S complex formation on these mRNAs as a regulatory component of the ribosome to confer transcript-specific translational control.", "We further show that Rpl38 expression is markedly enriched in regions of the embryo where loss-of-function phenotypes occur.", "Unexpectedly, a ribosomal protein (RP) expression screen reveals dynamic regulation of individual RPs within the vertebrate embryo.", "Collectively, these findings suggest that RP activity may be highly regulated to impart a new layer of specificity in the control of gene expression and mammalian development." ]

[ 2 ]

[ "Gram-negative bacteria have an outer membrane (OM) that functions as a barrier to protect the cell from toxic compounds such as antibiotics and detergents.", "The OM is a highly asymmetric bilayer composed of phospholipids, glycolipids, and proteins.", "Assembly of this essential organelle occurs outside the cytoplasm in an environment that lacks obvious energy sources such as ATP, and the mechanisms involved are poorly understood.", "We describe the identification of a multiprotein complex required for the assembly of proteins in the OM of Escherichia coli.", "We also demonstrate genetic interactions between genes encoding components of this protein assembly complex and imp, which encodes a protein involved in the assembly of lipopolysaccharides (LPS) in the OM.", "These genetic interactions suggest a role for YfgL, one of the lipoprotein components of the protein assembly complex, in a homeostatic control mechanism that coordinates the overall OM assembly process." ]

[]

[ "Gram-negative bacteria have an outer membrane (OM) that functions as a barrier to protect the cell from toxic compounds such as antibiotics and detergents.", "The OM is a highly asymmetric bilayer composed of phospholipids, glycolipids, and proteins.", "Assembly of this essential organelle occurs outside the cytoplasm in an environment that lacks obvious energy sources such as ATP, and the mechanisms involved are poorly understood.", "We describe the identification of a multiprotein complex required for the assembly of proteins in the OM of Escherichia coli.", "We also demonstrate genetic interactions between genes encoding components of this protein assembly complex and imp, which encodes a protein involved in the assembly of lipopolysaccharides (LPS) in the OM.", "These genetic interactions suggest a role for YfgL, one of the lipoprotein components of the protein assembly complex, in a homeostatic control mechanism that coordinates the overall OM assembly process." ]

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[ "Aberrant epigenetic reprogramming often results in developmental defects in somatic cell nuclear transfer (SCNT) embryos during embryonic genome activation (EGA).", "Bovine eight-cell SCNT embryos exhibit global hypermethylation of histone H3 lysine 9 tri- and di-methylation (H3K9me3/2), but the intrinsic reason for this remains elusive.", "Here, we provide evidence that two H3K9 demethylase genes, lysine-specific demethylase 4D (KDM4D) and 4E (KDM4E), are related to active H3K9me3/2 demethylation in in vitro fertilized (IVF) embryos and are deficiently expressed in cloned embryos at the time of EGA.", "Moreover, KDM4E plays a more crucial role in IVF and SCNT embryonic development, and overexpression of KDM4E can restore the global transcriptome, improve blastocyst formation and increase the cloning efficiency of SCNT embryos.", "Our results thereby indicate that KDM4E can function as a crucial epigenetic regulator of EGA and as an internal defective factor responsible for persistent H3K9me3/2 barriers to SCNT-mediated reprogramming.", "Furthermore, we show that interactions between RNA and KDM4E are essential for H3K9 demethylation during EGA.", "These observations advance the understanding of incomplete nuclear reprogramming and are of great importance for transgenic cattle procreation." ]

[ 3 ]

[ "Aberrant epigenetic reprogramming often results in developmental defects in somatic cell nuclear transfer (SCNT) embryos during embryonic genome activation (EGA).", "Bovine eight-cell SCNT embryos exhibit global hypermethylation of histone H3 lysine 9 tri- and di-methylation (H3K9me3/2), but the intrinsic reason for this remains elusive.", "Here, we provide evidence that two H3K9 demethylase genes, lysine-specific demethylase 4D (KDM4D) and 4E (KDM4E), are related to active H3K9me3/2 demethylation in in vitro fertilized (IVF) embryos and are deficiently expressed in cloned embryos at the time of EGA.", "Moreover, KDM4E plays a more crucial role in IVF and SCNT embryonic development, and overexpression of KDM4E can restore the global transcriptome, improve blastocyst formation and increase the cloning efficiency of SCNT embryos.", "Our results thereby indicate that KDM4E can function as a crucial epigenetic regulator of EGA and as an internal defective factor responsible for persistent H3K9me3/2 barriers to SCNT-mediated reprogramming.", "Furthermore, we show that interactions between RNA and KDM4E are essential for H3K9 demethylation during EGA.", "These observations advance the understanding of incomplete nuclear reprogramming and are of great importance for transgenic cattle procreation." ]

[ 3 ]

[ "Aberrant epigenetic reprogramming often results in developmental defects in somatic cell nuclear transfer (SCNT) embryos during embryonic genome activation (EGA).", "Bovine eight-cell SCNT embryos exhibit global hypermethylation of histone H3 lysine 9 tri- and di-methylation (H3K9me3/2), but the intrinsic reason for this remains elusive.", "Here, we provide evidence that two H3K9 demethylase genes, lysine-specific demethylase 4D (KDM4D) and 4E (KDM4E), are related to active H3K9me3/2 demethylation in in vitro fertilized (IVF) embryos and are deficiently expressed in cloned embryos at the time of EGA.", "Moreover, KDM4E plays a more crucial role in IVF and SCNT embryonic development, and overexpression of KDM4E can restore the global transcriptome, improve blastocyst formation and increase the cloning efficiency of SCNT embryos.", "Our results thereby indicate that KDM4E can function as a crucial epigenetic regulator of EGA and as an internal defective factor responsible for persistent H3K9me3/2 barriers to SCNT-mediated reprogramming.", "Furthermore, we show that interactions between RNA and KDM4E are essential for H3K9 demethylation during EGA.", "These observations advance the understanding of incomplete nuclear reprogramming and are of great importance for transgenic cattle procreation." ]

[ 3 ]

[ "Since the initial discovery that OCT4, SOX2, KLF4, and c-MYC overexpression sufficed for the induction of pluripotency in somatic cells, methodologies replacing the original factors have enhanced our understanding of the reprogramming process.", "However, unlike in mouse, OCT4 has not been replaced successfully during reprogramming of human cells.", "Here we report on a strategy to accomplish this replacement.", "Through a combination of transcriptome and bioinformatic analysis we have identified factors previously characterized as being lineage specifiers that are able to replace OCT4 and SOX2 in the reprogramming of human fibroblasts.", "Our results show that it is possible to replace OCT4 and SOX2 simultaneously with alternative lineage specifiers in the reprogramming of human cells.", "At a broader level, they also support a model in which counteracting lineage specification networks underlies the induction of pluripotency." ]

[]

[ "Since the initial discovery that OCT4, SOX2, KLF4, and c-MYC overexpression sufficed for the induction of pluripotency in somatic cells, methodologies replacing the original factors have enhanced our understanding of the reprogramming process.", "However, unlike in mouse, OCT4 has not been replaced successfully during reprogramming of human cells.", "Here we report on a strategy to accomplish this replacement.", "Through a combination of transcriptome and bioinformatic analysis we have identified factors previously characterized as being lineage specifiers that are able to replace OCT4 and SOX2 in the reprogramming of human fibroblasts.", "Our results show that it is possible to replace OCT4 and SOX2 simultaneously with alternative lineage specifiers in the reprogramming of human cells.", "At a broader level, they also support a model in which counteracting lineage specification networks underlies the induction of pluripotency." ]

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[ "Nucleosomes containing the histone variant H3.3 tend to be clustered in vivo in the neighborhood of transcriptionally active genes and over regulatory elements.", "It has not been clear, however, whether H3.3-containing nucleosomes possess unique properties that would affect transcription.", "We report here that H3.3 nucleosomes isolated from vertebrates, regardless of whether they are partnered with H2A or H2A.Z, are unusually sensitive to salt-dependent disruption, losing H2A/H2B or H2A.Z/H2B dimers.", "Immunoprecipitation studies of nucleosome core particles (NCPs) show that NCPs that contain both H3.3 and H2A.Z are even less stable than NCPs containing H3.3 and H2A.", "Intriguingly, NCPs containing H3 and H2A.Z are at least as stable as H3/H2A NCPs.", "These results establish an hierarchy of stabilities for native nucleosomes carrying different complements of variants, and suggest how H2A.Z could play different roles depending on its partners within the NCP.", "They also are consistent with the idea that H3.3 plays an active role in maintaining accessible chromatin structures in enhancer regions and transcribed regions.", "Consistent with this idea, promoters and enhancers at transcriptionally active genes and coding regions at highly expressed genes have nucleosomes that simultaneously carry both H3.3 and H2A.Z, and should therefore be extremely sensitive to disruption." ]

[ 3 ]

[ "Histone variants help specialize chromatin regions; however, their impact on transcriptional regulation is largely unknown.", "Here, we determined the genome-wide localization and dynamics of Htz1, the yeast histone H2A variant.", "Htz1 localizes to hundreds of repressed/basal Pol II promoters and prefers TATA-less promoters.", "Specific Htz1 deposition requires the SWR1 complex, which largely colocalizes with Htz1.", "Htz1 occupancy correlates with particular histone modifications, and Htz1 deposition is partially reliant on Gcn5 (a histone acetyltransferase) and Bdf1, an SWR1 complex member that binds acetylated histones.", "Changes in growth conditions cause a striking redistribution of Htz1 from activated to repressed/basal promoters.", "Furthermore, Htz1 promotes full gene activation but does not generally impact repression.", "Importantly, Htz1 releases from purified chromatin in vitro under conditions where H2A and H3 remain associated.", "We suggest that Htz1-bearing nucleosomes are deposited at repressed/basal promoters but facilitate activation through their susceptibility to loss, thereby helping to expose promoter DNA." ]

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[ "BACKGROUND Interleukin (IL)-18 is a potent proinflammatory cytokine with potential atherogenic properties.", "Its expression and role in atherosclerosis, however, are unknown.", "METHODS AND RESULTS In the present study, we examined stable and unstable human carotid atherosclerotic plaques retrieved by endarterectomy for the presence of IL-18 using reverse transcription-polymerase chain reaction (PCR), Western blot, and immunohistochemical techniques.", "IL-18 was highly expressed in the atherosclerotic plaques compared with control normal arteries and was localized mainly in plaque macrophages.", "IL-18 receptor was also upregulated in plaque macrophages and endothelial cells, suggesting potential biological effects.", "To examine the role of IL-18 in atherosclerosis, we determined the relation between IL-18 mRNA expression and signs of plaque instability using real-time quantitative PCR.", "Interestingly, significantly higher levels of IL-18 mRNA were found in symptomatic (unstable) plaques than asymptomatic (stable) plaques (P<0.01).", "CONCLUSIONS These results suggest, for the first time, a major role for IL-18 in atherosclerotic plaque destabilization leading to acute ischemic syndromes." ]

[ 6, 7 ]

[ "The androgen receptor (AR) is overexpressed and hyperactivated in human castration-resistant prostate cancer (CRPC).", "However, the determinants of AR overexpression in CRPC are poorly defined.", "Here we show that retinoic acid receptor-related orphan receptor γ (ROR-γ) is overexpressed and amplified in metastatic CRPC tumors, and that ROR-γ drives AR expression in the tumors.", "ROR-γ recruits nuclear receptor coactivator 1 and 3 (NCOA1 and NCOA3, also known as SRC-1 and SRC-3) to an AR-ROR response element (RORE) to stimulate AR gene transcription.", "ROR-γ antagonists suppress the expression of both AR and its variant AR-V7 in prostate cancer (PCa) cell lines and tumors.", "ROR-γ antagonists also markedly diminish genome-wide AR binding, H3K27ac abundance and expression of the AR target gene network.", "Finally, ROR-γ antagonists suppressed tumor growth in multiple AR-expressing, but not AR-negative, xenograft PCa models, and they effectively sensitized CRPC tumors to enzalutamide, without overt toxicity, in mice.", "Taken together, these results establish ROR-γ as a key player in CRPC by acting upstream of AR and as a potential therapeutic target for advanced PCa." ]

[ 6, 7 ]

[ "During fasting, mammals maintain normal glucose homeostasis by stimulating hepatic gluconeogenesis.", "Elevations in circulating glucagon and epinephrine, two hormones that activate hepatic gluconeogenesis, trigger the cAMP-mediated phosphorylation of cAMP response element-binding protein (Creb) and dephosphorylation of the Creb-regulated transcription coactivator-2 (Crtc2)--two key transcriptional regulators of this process.", "Although the underlying mechanism is unclear, hepatic gluconeogenesis is also regulated by the circadian clock, which coordinates glucose metabolism with changes in the external environment.", "Circadian control of gene expression is achieved by two transcriptional activators, Clock and Bmal1, which stimulate cryptochrome (Cry1 and Cry2) and Period (Per1, Per2 and Per3) repressors that feed back on Clock-Bmal1 activity.", "Here we show that Creb activity during fasting is modulated by Cry1 and Cry2, which are rhythmically expressed in the liver.", "Cry1 expression was elevated during the night-day transition, when it reduced fasting gluconeogenic gene expression by blocking glucagon-mediated increases in intracellular cAMP concentrations and in the protein kinase A-mediated phosphorylation of Creb.", "In biochemical reconstitution studies, we found that Cry1 inhibited accumulation of cAMP in response to G protein-coupled receptor (GPCR) activation but not to forskolin, a direct activator of adenyl cyclase.", "Cry proteins seemed to modulate GPCR activity directly through interaction with G(s)α.", "As hepatic overexpression of Cry1 lowered blood glucose concentrations and improved insulin sensitivity in insulin-resistant db/db mice, our results suggest that compounds that enhance cryptochrome activity may provide therapeutic benefit to individuals with type 2 diabetes." ]

[ 4, 5 ]

[ "During fasting, mammals maintain normal glucose homeostasis by stimulating hepatic gluconeogenesis.", "Elevations in circulating glucagon and epinephrine, two hormones that activate hepatic gluconeogenesis, trigger the cAMP-mediated phosphorylation of cAMP response element-binding protein (Creb) and dephosphorylation of the Creb-regulated transcription coactivator-2 (Crtc2)--two key transcriptional regulators of this process.", "Although the underlying mechanism is unclear, hepatic gluconeogenesis is also regulated by the circadian clock, which coordinates glucose metabolism with changes in the external environment.", "Circadian control of gene expression is achieved by two transcriptional activators, Clock and Bmal1, which stimulate cryptochrome (Cry1 and Cry2) and Period (Per1, Per2 and Per3) repressors that feed back on Clock-Bmal1 activity.", "Here we show that Creb activity during fasting is modulated by Cry1 and Cry2, which are rhythmically expressed in the liver.", "Cry1 expression was elevated during the night-day transition, when it reduced fasting gluconeogenic gene expression by blocking glucagon-mediated increases in intracellular cAMP concentrations and in the protein kinase A-mediated phosphorylation of Creb.", "In biochemical reconstitution studies, we found that Cry1 inhibited accumulation of cAMP in response to G protein-coupled receptor (GPCR) activation but not to forskolin, a direct activator of adenyl cyclase.", "Cry proteins seemed to modulate GPCR activity directly through interaction with G(s)α.", "As hepatic overexpression of Cry1 lowered blood glucose concentrations and improved insulin sensitivity in insulin-resistant db/db mice, our results suggest that compounds that enhance cryptochrome activity may provide therapeutic benefit to individuals with type 2 diabetes." ]

[ 2, 3, 4, 5 ]

[ "Stressed cells coordinate a multi-faceted response spanning many levels of physiology.", "Yet knowledge of the complete stress-activated regulatory network as well as design principles for signal integration remains incomplete.", "We developed an experimental and computational approach to integrate available protein interaction data with gene fitness contributions, mutant transcriptome profiles, and phospho-proteome changes in cells responding to salt stress, to infer the salt-responsive signaling network in yeast.", "The inferred subnetwork presented many novel predictions by implicating new regulators, uncovering unrecognized crosstalk between known pathways, and pointing to previously unknown 'hubs' of signal integration.", "We exploited these predictions to show that Cdc14 phosphatase is a central hub in the network and that modification of RNA polymerase II coordinates induction of stress-defense genes with reduction of growth-related transcripts.", "We find that the orthologous human network is enriched for cancer-causing genes, underscoring the importance of the subnetwork's predictions in understanding stress biology." ]

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[ "The rapamycin-sensitive TOR signalling pathway in Saccharomyces cerevisiae activates a cell-growth program in response to nutrients such as nitrogen and carbon.", "The TOR1 and TOR2 kinases (TOR) control cytoplasmic protein synthesis and degradation through the conserved TAP42 protein.", "Upon phosphorylation by TOR, TAP42 binds and possibly inhibits type 2A and type-2A-related phosphatases; however, the mechanism by which TOR controls nuclear events such as global repression of starvation-specific transcription is unknown.", "Here we show that TOR prevents transcription of genes expressed upon nitrogen limitation by promoting the association of the GATA transcription factor GLN3 with the cytoplasmic protein URE2.", "The binding of GLN3 to URE2 requires TOR-dependent phosphorylation of GLN3.", "Phosphorylation and cytoplasmic retention of GLN3 are also dependent on the TOR effector TAP42, and are antagonized by the type-2A-related phosphatase SIT4.", "TOR inhibits expression of carbon-source-regulated genes by stimulating the binding of the transcriptional activators MSN2 and MSN4 to the cytoplasmic 14-3-3 protein BMH2.", "Thus, the TOR signalling pathway broadly controls nutrient metabolism by sequestering several transcription factors in the cytoplasm." ]

[]

[ "Healthy cells utilize intricate systems to monitor their environment and mount robust responses in the event of cellular stress.", "Whether stress arises from external insults or defects due to mutation and disease, cells must be able to respond precisely to mount the appropriate defenses.", "Multi-faceted stress responses are generally coupled with arrest of growth and cell-cycle progression, which both limits the transmission of damaged materials and serves to reallocate limited cellular resources toward defense.", "Therefore, stress defense versus rapid growth represent competing interests in the cell.", "How eukaryotic cells set the balance between defense versus proliferation, and in particular knowledge of the regulatory networks that control this decision, are poorly understood.", "In this perspective, we expand upon our recent work inferring the stress-activated signaling network in budding yeast, which captures pathways controlling stress defense and regulators of growth and cell-cycle progression.", "We highlight similarities between the yeast and mammalian stress responses and explore how stress-activated signaling networks in yeast can inform on signaling defects in human cancers." ]

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[ "The multifunctional signaling protein p75 neurotrophin receptor (p75(NTR)) is a central regulator and major contributor to the highly invasive nature of malignant gliomas.", "Here, we show that neurotrophin-dependent regulated intramembrane proteolysis (RIP) of p75(NTR) is required for p75(NTR)-mediated glioma invasion, and identify a previously unnamed process for targeted glioma therapy.", "Expression of cleavage-resistant chimeras of p75(NTR) or treatment of animals bearing p75(NTR)-positive intracranial tumors with clinically applicable gamma-secretase inhibitors resulted in dramatically decreased glioma invasion and prolonged survival.", "Importantly, proteolytic processing of p75(NTR) was observed in p75(NTR)-positive patient tumor specimens and brain tumor initiating cells.", "This work highlights the importance of p75(NTR) as a therapeutic target, suggesting that gamma-secretase inhibitors may have direct clinical application for the treatment of malignant glioma." ]

[]

[ "Historically, the ribosome has been viewed as a complex ribozyme with constitutive rather than regulatory capacity in mRNA translation.", "Here we identify mutations of the Ribosomal Protein L38 (Rpl38) gene in mice exhibiting surprising tissue-specific patterning defects, including pronounced homeotic transformations of the axial skeleton.", "In Rpl38 mutant embryos, global protein synthesis is unchanged; however the translation of a select subset of Homeobox mRNAs is perturbed.", "Our data reveal that RPL38 facilitates 80S complex formation on these mRNAs as a regulatory component of the ribosome to confer transcript-specific translational control.", "We further show that Rpl38 expression is markedly enriched in regions of the embryo where loss-of-function phenotypes occur.", "Unexpectedly, a ribosomal protein (RP) expression screen reveals dynamic regulation of individual RPs within the vertebrate embryo.", "Collectively, these findings suggest that RP activity may be highly regulated to impart a new layer of specificity in the control of gene expression and mammalian development." ]

[ 5, 6 ]

[ "CONTEXT Risedronate, a potent bisphosphonate, has been shown to be effective in the treatment of Paget disease of bone and other metabolic bone diseases but, to our knowledge, it has not been evaluated in the treatment of established postmenopausal osteoporosis.", "OBJECTIVE To test the efficacy and safety of daily treatment with risedronate to reduce the risk of vertebral and other fractures in postmenopausal women with established osteoporosis.", "DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind, placebo-controlled trial of 2458 ambulatory postmenopausal women younger than 85 years with at least 1 vertebral fracture at baseline who were enrolled at 1 of 110 centers in North America conducted between December 1993 and January 1998.", "INTERVENTIONS Subjects were randomly assigned to receive oral treatment for 3 years with risedronate (2.5 or 5 mg/d) or placebo.", "All subjects received calcium, 1000 mg/d.", "Vitamin D (cholecalciferol, up to 500 IU/d) was provided if baseline levels of 25-hydroxyvitamin D were low.", "MAIN OUTCOME MEASURES Incidence of new vertebral fractures as detected by quantitative and semiquantitative assessments of radiographs; incidence of radiographically confirmed nonvertebral fractures and change from baseline in bone mineral density as determined by dual x-ray absorptiometry.", "RESULTS The 2.5 mg/d of risedronate arm was discontinued after 1 year; in the placebo and 5 mg/d of risedronate arms, 450 and 489 subjects, respectively, completed all 3 years of the trial.", "Treatment with 5 mg/d of risedronate, compared with placebo, decreased the cumulative incidence of new vertebral fractures by 41 % (95% confidence interval [CI], 18%-58%) over 3 years (11.3 % vs 16.3%; P= .003).", "A fracture reduction of 65% (95% CI, 38%-81 %) was observed after the first year (2.4% vs 6.4%; P<.001).", "The cumulative incidence of nonvertebral fractures over 3 years was reduced by 39% (95% CI, 6%-61 %) (5.2 % vs 8.4%; P = .02).", "Bone mineral density increased significantly compared with placebo at the lumbar spine (5.4% vs 1.1 %), femoral neck (1.6% vs -1.2%), femoral trochanter (3.3% vs -0.7%), and midshaft of the radius (0.2% vs -1.4%).", "Bone formed during risedronate treatment was histologically normal.", "The overall safety profile of risedronate, including gastrointestinal safety, was similar to that of placebo.", "CONCLUSIONS These data suggest that risedronate therapy is effective and well tolerated in the treatment of women with established postmenopausal osteoporosis." ]

[ 8, 10 ]

[ "BACKGROUND Transmission of dengue viruses (DENV), the leading cause of arboviral disease worldwide, is known to vary through time and space, likely owing to a combination of factors related to the human host, virus, mosquito vector, and environment.", "An improved understanding of variation in transmission patterns is fundamental to conducting surveillance and implementing disease prevention strategies.", "To test the hypothesis that DENV transmission is spatially and temporally focal, we compared geographic and temporal characteristics within Thai villages where DENV are and are not being actively transmitted.", "METHODS AND FINDINGS Cluster investigations were conducted within 100 m of homes where febrile index children with (positive clusters) and without (negative clusters) acute dengue lived during two seasons of peak DENV transmission.", "Data on human infection and mosquito infection/density were examined to precisely (1) define the spatial and temporal dimensions of DENV transmission, (2) correlate these factors with variation in DENV transmission, and (3) determine the burden of inapparent and symptomatic infections.", "Among 556 village children enrolled as neighbors of 12 dengue-positive and 22 dengue-negative index cases, all 27 DENV infections (4.9% of enrollees) occurred in positive clusters (p < 0.01; attributable risk [AR] = 10.4 per 100; 95% confidence interval 1-19.8 per 100].", "In positive clusters, 12.4% of enrollees became infected in a 15-d period and DENV infections were aggregated centrally near homes of index cases.", "As only 1 of 217 pairs of serologic specimens tested in positive clusters revealed a recent DENV infection that occurred prior to cluster initiation, we attribute the observed DENV transmission subsequent to cluster investigation to recent DENV transmission activity.", "Of the 1,022 female adult Ae.", "aegypti collected, all eight (0.8%) dengue-infected mosquitoes came from houses in positive clusters; none from control clusters or schools.", "Distinguishing features between positive and negative clusters were greater availability of piped water in negative clusters (p < 0.01) and greater number of Ae.", "aegypti pupae per person in positive clusters (p = 0.04).", "During primarily DENV-4 transmission seasons, the ratio of inapparent to symptomatic infections was nearly 1:1 among child enrollees.", "Study limitations included inability to sample all children and mosquitoes within each cluster and our reliance on serologic rather than virologic evidence of interval infections in enrollees given restrictions on the frequency of blood collections in children.", "CONCLUSIONS Our data reveal the remarkably focal nature of DENV transmission within a hyperendemic rural area of Thailand.", "These data suggest that active school-based dengue case detection prompting local spraying could contain recent virus introductions and reduce the longitudinal risk of virus spread within rural areas.", "Our results should prompt future cluster studies to explore how host immune and behavioral aspects may impact DENV transmission and prevention strategies.", "Cluster methodology could serve as a useful research tool for investigation of other temporally and spatially clustered infectious diseases." ]

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[ "BACKGROUND Transmission of dengue viruses (DENV), the leading cause of arboviral disease worldwide, is known to vary through time and space, likely owing to a combination of factors related to the human host, virus, mosquito vector, and environment.", "An improved understanding of variation in transmission patterns is fundamental to conducting surveillance and implementing disease prevention strategies.", "To test the hypothesis that DENV transmission is spatially and temporally focal, we compared geographic and temporal characteristics within Thai villages where DENV are and are not being actively transmitted.", "METHODS AND FINDINGS Cluster investigations were conducted within 100 m of homes where febrile index children with (positive clusters) and without (negative clusters) acute dengue lived during two seasons of peak DENV transmission.", "Data on human infection and mosquito infection/density were examined to precisely (1) define the spatial and temporal dimensions of DENV transmission, (2) correlate these factors with variation in DENV transmission, and (3) determine the burden of inapparent and symptomatic infections.", "Among 556 village children enrolled as neighbors of 12 dengue-positive and 22 dengue-negative index cases, all 27 DENV infections (4.9% of enrollees) occurred in positive clusters (p < 0.01; attributable risk [AR] = 10.4 per 100; 95% confidence interval 1-19.8 per 100].", "In positive clusters, 12.4% of enrollees became infected in a 15-d period and DENV infections were aggregated centrally near homes of index cases.", "As only 1 of 217 pairs of serologic specimens tested in positive clusters revealed a recent DENV infection that occurred prior to cluster initiation, we attribute the observed DENV transmission subsequent to cluster investigation to recent DENV transmission activity.", "Of the 1,022 female adult Ae.", "aegypti collected, all eight (0.8%) dengue-infected mosquitoes came from houses in positive clusters; none from control clusters or schools.", "Distinguishing features between positive and negative clusters were greater availability of piped water in negative clusters (p < 0.01) and greater number of Ae.", "aegypti pupae per person in positive clusters (p = 0.04).", "During primarily DENV-4 transmission seasons, the ratio of inapparent to symptomatic infections was nearly 1:1 among child enrollees.", "Study limitations included inability to sample all children and mosquitoes within each cluster and our reliance on serologic rather than virologic evidence of interval infections in enrollees given restrictions on the frequency of blood collections in children.", "CONCLUSIONS Our data reveal the remarkably focal nature of DENV transmission within a hyperendemic rural area of Thailand.", "These data suggest that active school-based dengue case detection prompting local spraying could contain recent virus introductions and reduce the longitudinal risk of virus spread within rural areas.", "Our results should prompt future cluster studies to explore how host immune and behavioral aspects may impact DENV transmission and prevention strategies.", "Cluster methodology could serve as a useful research tool for investigation of other temporally and spatially clustered infectious diseases." ]

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[ "Epidemiological studies demonstrate that a lower blood pressure and decline in blood pressure over months or years are associated with higher mortality in dialysis patients.", "In contrast, randomized, controlled trials lack power to establish benefits of antihypertensive therapy.", "Patients on long-term dialysis participating in randomized, controlled trials and receiving antihypertensive drug therapy were the subject of this meta-analysis.", "Outcomes assessed were the hazard ratio of cardiovascular events and all-cause mortality in treated group compared with controls.", "Among 1202 patients who we identified in 5 studies, the overall benefit of antihypertensive therapy compared with the control or placebo group had a combined hazard ratio for cardiovascular events of 0.69 (95% CI: 0.56 to 0.84) using a fixed-effects model and 0.62 (95% CI: 0.45 to 0.86) using a random-effects model.", "In a sensitivity analysis, we found that the hypertensive group had a pooled hazard ratio of 0.49 (95% CI: 0.35 to 0.67), but when normotensives were included in the trial, lesser cardiovascular protection was seen (pooled hazard ratio of 0.86 [95% CI: 0.67 to 1.12]).", "Test for heterogeneity between hypertensive and \"normotensive-included\" groups was significant (P<0.006).", "Similar results were seen for risk ratio for death and cardiovascular events.", "There was evidence of publication bias based on Egger's test and funnel plot.", "Randomized trials suggested a benefit of antihypertensive therapy among hemodialysis patients.", "Adequately powered randomized trials are required to confirm these observations, especially among those with hypertension." ]

[ 4 ]

[ "Background Extensive debate exists in the healthcare community over whether outcomes of medical care at teaching hospitals and other healthcare units are better or worse than those at the respective nonteaching ones.", "Thus, our goal was to systematically evaluate the evidence pertaining to this question.", "Methods and Findings We reviewed all studies that compared teaching versus nonteaching healthcare structures for mortality or any other patient outcome, regardless of health condition.", "Studies were retrieved from PubMed, contact with experts, and literature cross-referencing.", "Data were extracted on setting, patients, data sources, author affiliations, definition of compared groups, types of diagnoses considered, adjusting covariates, and estimates of effect for mortality and for each other outcome.", "Overall, 132 eligible studies were identified, including 93 on mortality and 61 on other eligible outcomes (22 addressed both).", "Synthesis of the available adjusted estimates on mortality yielded a summary relative risk of 0.96 (95% confidence interval [CI], 0.93–1.00) for teaching versus nonteaching healthcare structures and 1.04 (95% CI, 0.99–1.10) for minor teaching versus nonteaching ones.", "There was considerable heterogeneity between studies (I2 = 72% for the main analysis).", "Results were similar in studies using clinical and those using administrative databases.", "No differences were seen in the 14 studies fully adjusting for volume/experience, severity, and comorbidity (relative risk 1.01).", "Smaller studies did not differ in their results from larger studies.", "Differences were seen for some diagnoses (e.g., significantly better survival for breast cancer and cerebrovascular accidents in teaching hospitals and significantly better survival from cholecystectomy in nonteaching hospitals), but these were small in magnitude.", "Other outcomes were diverse, but typically teaching healthcare structures did not do better than nonteaching ones.", "Conclusions The available data are limited by their nonrandomized design, but overall they do not suggest that a healthcare facility's teaching status on its own markedly improves or worsens patient outcomes.", "Differences for specific diseases cannot be excluded, but are likely to be small." ]

[ 6, 13 ]

[ "OBJECTIVE To evaluate if a specific exercise strategy, targeting the rotator cuff and scapula stabilisers, improves shoulder function and pain more than unspecific exercises in patients with subacromial impingement syndrome, thereby decreasing the need for arthroscopic subacromial decompression.", "DESIGN Randomised, participant and single assessor blinded, controlled study.", "SETTING Department of orthopaedics in a Swedish university hospital.", "PARTICIPANTS 102 patients with long standing (over six months) persistent subacromial impingement syndrome in whom earlier conservative treatment had failed, recruited through orthopaedic specialists.", "INTERVENTIONS The specific exercise strategy consisted of strengthening eccentric exercises for the rotator cuff and concentric/eccentric exercises for the scapula stabilisers in combination with manual mobilisation.", "The control exercise programme consisted of unspecific movement exercises for the neck and shoulder.", "Patients in both groups received five to six individual guided treatment sessions during 12 weeks.", "In between these supervised sessions the participants performed home exercises once or twice a day for 12 weeks.", "MAIN OUTCOME MEASURES The primary outcome was the Constant-Murley shoulder assessment score evaluating shoulder function and pain.", "Secondary outcomes were patients' global impression of change because of treatment and decision regarding surgery.", "RESULTS Most (97, 95%) participants completed the 12 week study.", "There was a significantly greater improvement in the Constant-Murley score in the specific exercise group than in the control exercise group (24 points (95% confidence interval 19 to 28.0) v 9 points (5 to 13); mean difference between group: 15 points (8.5 to 20.6)).", "Significantly more patients in the specific exercise group reported successful outcome (defined as large improvement or recovered) in the patients' global assessment of change because of treatment: 69% (35/51) v 24% (11/46); odds ratio 7.6, 3.1 to 18.9; P<0.001.", "A significantly lower proportion of patients in the specific exercise group subsequently chose to undergo surgery: 20% (10/51) v 63% (29/46); odds ratio 7.7, 3.1 to 19.4; P<0.001).", "CONCLUSION A specific exercise strategy, focusing on strengthening eccentric exercises for the rotator cuff and concentric/eccentric exercises for the scapula stabilisers, is effective in reducing pain and improving shoulder function in patients with persistent subacromial impingement syndrome.", "By extension, this exercise strategy reduces the need for arthroscopic subacromial decompression within the three month timeframe used in the study.", "TRIAL REGISTRATION Clinical trials NCT01037673." ]

[ 11 ]

[ "CONTEXT Chronic pelvic pain is a common condition with a major effect on health-related quality of life, work productivity, and health care use.", "Operative interruption of nerve trunks in the uterosacral ligaments by laparoscopic uterosacral nerve ablation (LUNA) is a treatment option for patients with chronic pelvic pain.", "OBJECTIVE To assess the effectiveness of LUNA in patients with chronic pelvic pain.", "DESIGN, SETTING, AND PARTICIPANTS Randomized controlled trial of 487 women with chronic pelvic pain lasting longer than 6 months without or with minimal endometriosis, adhesions, or pelvic inflammatory disease, who were recruited to the study by consultant gynecological surgeons from 18 UK hospitals between February 1998 and December 2005.", "Follow-up was conducted by questionnaires mailed at 3 and 6 months and at 1, 2, 3, and 5 years.", "INTERVENTION Bilateral LUNA or laparoscopy without pelvic denervation (no LUNA); participants were blinded to the treatment allocation.", "MAIN OUTCOME MEASURES", "The primary outcome was pain, which was assessed by a visual analogue scale.", "Data concerning the 3 types of pain (noncyclical pain, dysmenorrhea, and dyspareunia) were analyzed separately as was the worst pain level experienced from any of these 3 types of pain.", "The secondary outcome was health-related quality of life, which was measured using a generic instrument (EuroQoL EQ-5D and EQ-VAS).", "RESULTS After a median follow-up of 69 months, there were no significant differences reported on the visual analogue pain scales for the worst pain (mean difference between the LUNA group and the no LUNA group, -0.04 cm [95% confidence interval {CI}, -0.33 to 0.25 cm]; P = .80), noncyclical pain (-0.11 cm [95% CI, -0.50 to 0.29 cm]; P = .60), dysmenorrhea (-0.09 cm [95% CI, -0.49 to 0.30 cm]; P = .60), or dyspareunia (0.18 cm [95% CI, -0.22 to 0.62 cm]; P = .40).", "No differences were observed between the LUNA group and the no LUNA group for quality of life.", "CONCLUSION Among women with chronic pelvic pain, LUNA did not result in improvements in pain, dysmenorrhea, dyspareunia, or quality of life compared with laparoscopy without pelvic denervation.", "TRIAL REGISTRATION controlled-trials.com Identifier: ISRCTN41196151." ]

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[ "A key determinant of geriatric frailty is sarcopenia, the age-associated loss of skeletal muscle mass and strength.", "Although the etiology of sarcopenia is unknown, the correlation during aging between the loss of activity of satellite cells, which are endogenous muscle stem cells, and impaired muscle regenerative capacity has led to the hypothesis that the loss of satellite cell activity is also a cause of sarcopenia.", "We tested this hypothesis in male sedentary mice by experimentally depleting satellite cells in young adult animals to a degree sufficient to impair regeneration throughout the rest of their lives.", "A detailed analysis of multiple muscles harvested at various time points during aging in different cohorts of these mice showed that the muscles were of normal size, despite low regenerative capacity, but did have increased fibrosis.", "These results suggest that lifelong reduction of satellite cells neither accelerated nor exacerbated sarcopenia and that satellite cells did not contribute to the maintenance of muscle size or fiber type composition during aging, but that their loss may contribute to age-related muscle fibrosis." ]

[ 3, 4 ]