340 research outputs found
Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.
Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (Pâ<â5âĂâ10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and Îł-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition
Cell Specific eQTL Analysis without Sorting Cells
The functional consequences of trait associated SNPs are often investigated using expression quantitative trait locus (eQTL) mapping. While trait-associated variants may operate in a cell-type specific manner, eQTL datasets for such cell-types may not always be available. We performed a genome-environment interaction (GxE) meta-analysis on data from 5,683 samples to infer the cell type specificity of whole blood cis-eQTLs. We demonstrate that this method is able to predict neutrophil and lymphocyte specific cis-eQTLs and replicate these predictions in independent cell-type specific datasets. Finally, we show that SNPs associated with Crohnâs disease preferentially affect gene expression within neutrophils, including the archetypal NOD2 locus
Durvalumab Plus Carboplatin/Paclitaxel Followed by Maintenance Durvalumab With or Without Olaparib as First-Line Treatment for Advanced Endometrial Cancer: The Phase III DUO-E Trial
PURPOSE Immunotherapy and chemotherapy combinations have shown activity in endometrial cancer, with greater benefit in mismatch repair (MMR)-deficient (dMMR) than MMR-proficient (pMMR) disease. Adding a poly(ADP-ribose) polymerase inhibitor may improve outcomes, especially in pMMR disease. METHODS This phase III, global, double-blind, placebo-controlled trial randomly assigned eligible patients with newly diagnosed advanced or recurrent endometrial cancer 1:1:1 to: carboplatin/paclitaxel plus durvalumab placebo followed by placebo maintenance (control arm); carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib placebo (durvalumab arm); or carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib (durvalumab + olaparib arm). The primary end points were progression-free survival (PFS) in the durvalumab arm versus control and the durvalumab + olaparib arm versus control. RESULTS Seven hundred eighteen patients were randomly assigned. In the intention-to-treat population, statistically significant PFS benefit was observed in the durvalumab (hazard ratio [HR], 0.71 [95% CI, 0.57 to 0.89]; P = .003) and durvalumab + olaparib arms (HR, 0.55 [95% CI, 0.43 to 0.69]; P < .0001) versus control. Prespecified, exploratory subgroup analyses showed PFS benefit in dMMR (HR [durvalumab v control], 0.42 [95% CI, 0.22 to 0.80]; HR [durvalumab + olaparib v control], 0.41 [95% CI, 0.21 to 0.75]) and pMMR subgroups (HR [durvalumab v control], 0.77 [95% CI, 0.60 to 0.97]; HR [durvalumab + olaparib v control] 0.57; [95% CI, 0.44 to 0.73]); and in PD-L1-positive subgroups (HR [durvalumab v control], 0.63 [95% CI, 0.48 to 0.83]; HR [durvalumab + olaparib v control], 0.42 [95% CI, 0.31 to 0.57]). Interim overall survival results (maturity approximately 28%) were supportive of the primary outcomes (durvalumab v control: HR, 0.77 [95% CI, 0.56 to 1.07]; P = .120; durvalumab + olaparib v control: HR, 0.59 [95% CI, 0.42 to 0.83]; P = .003). The safety profiles of the experimental arms were generally consistent with individual agents. CONCLUSION Carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab with or without olaparib demonstrated a statistically significant and clinically meaningful PFS benefit in patients with advanced or recurrent endometrial cancer
Les droits disciplinaires des fonctions publiques : « unification », « harmonisation » ou « distanciation ». A propos de la loi du 26 avril 2016 relative à la déontologie et aux droits et obligations des fonctionnaires
The production of tt⟠, W+bb⟠and W+cc⟠is studied in the forward region of protonâproton collisions collected at a centre-of-mass energy of 8 TeV by the LHCb experiment, corresponding to an integrated luminosity of 1.98±0.02 fbâ1 . The W bosons are reconstructed in the decays WââÎœ , where â denotes muon or electron, while the b and c quarks are reconstructed as jets. All measured cross-sections are in agreement with next-to-leading-order Standard Model predictions.The production of , and is studied in the forward region of proton-proton collisions collected at a centre-of-mass energy of 8 TeV by the LHCb experiment, corresponding to an integrated luminosity of 1.98 0.02 \mbox{fb}^{-1}. The bosons are reconstructed in the decays , where denotes muon or electron, while the and quarks are reconstructed as jets. All measured cross-sections are in agreement with next-to-leading-order Standard Model predictions
TRY plant trait database â enhanced coverage and open access
Plant traits - the morphological, anatomical, physiological, biochemical and phenological characteristics of plants - determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of traitâbased plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits - almost complete coverage for âplant growth formâ. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and traitâenvironmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives
Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors
Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe
The genetic architecture of the human cerebral cortex
The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder
26th Annual Computational Neuroscience Meeting (CNS*2017): Part 3 - Meeting Abstracts - Antwerp, Belgium. 15â20 July 2017
This work was produced as part of the activities of FAPESP Research,\ud
Disseminations and Innovation Center for Neuromathematics (grant\ud
2013/07699-0, S. Paulo Research Foundation). NLK is supported by a\ud
FAPESP postdoctoral fellowship (grant 2016/03855-5). ACR is partially\ud
supported by a CNPq fellowship (grant 306251/2014-0)
Measurement of the (eta c)(1S) production cross-section in proton-proton collisions via the decay (eta c)(1S) -> p(p)over-bar
The production of the state in proton-proton collisions is probed via its decay to the final state with the LHCb detector, in the rapidity range GeV/c. The cross-section for prompt production of mesons relative to the prompt cross-section is measured, for the first time, to be at a centre-of-mass energy TeV using data corresponding to an integrated luminosity of 0.7 fb, and at TeV using 2.0 fb. The uncertainties quoted are, in order, statistical, systematic, and that on the ratio of branching fractions of the and decays to the final state. In addition, the inclusive branching fraction of -hadron decays into mesons is measured, for the first time, to be , where the third uncertainty includes also the uncertainty on the inclusive branching fraction from -hadron decays. The difference between the and meson masses is determined to be MeV/c.The production of the state in proton-proton collisions is probed via its decay to the final state with the LHCb detector, in the rapidity range . The cross-section for prompt production of mesons relative to the prompt cross-section is measured, for the first time, to be at a centre-of-mass energy using data corresponding to an integrated luminosity of 0.7Â fb , and at using 2.0Â fb . The uncertainties quoted are, in order, statistical, systematic, and that on the ratio of branching fractions of the and decays to the final state. In addition, the inclusive branching fraction of -hadron decays into mesons is measured, for the first time, to be , where the third uncertainty includes also the uncertainty on the inclusive branching fraction from -hadron decays. The difference between the and meson masses is determined to be .The production of the state in proton-proton collisions is probed via its decay to the final state with the LHCb detector, in the rapidity range GeV/c. The cross-section for prompt production of mesons relative to the prompt cross-section is measured, for the first time, to be at a centre-of-mass energy TeV using data corresponding to an integrated luminosity of 0.7 fb, and at TeV using 2.0 fb. The uncertainties quoted are, in order, statistical, systematic, and that on the ratio of branching fractions of the and decays to the final state. In addition, the inclusive branching fraction of -hadron decays into mesons is measured, for the first time, to be , where the third uncertainty includes also the uncertainty on the inclusive branching fraction from -hadron decays. The difference between the and meson masses is determined to be MeV/c
A study of CP violation in B-+/- -> DK +/- and B-+/- -> D pi(+/-) decays with D -> (KSK +/-)-K-0 pi(-/+) final states
A first study of CP violation in the decay modes and , where labels a or meson and labels a or meson, is performed. The analysis uses the LHCb data set collected in collisions, corresponding to an integrated luminosity of 3 fb. The analysis is sensitive to the CP-violating CKM phase through seven observables: one charge asymmetry in each of the four modes and three ratios of the charge-integrated yields. The results are consistent with measurements of using other decay modes
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