Showing papers by "University of Groningen published in 2013"
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University of North Carolina at Chapel Hill1, University of Birmingham2, University of Aberdeen3, University of Barcelona4, Cleveland Clinic5, University of Cambridge6, University of Groningen7, University of Lübeck8, University of Oxford9, University of Paris10, Mayo Clinic11, Boston University12, University of Pennsylvania13, Hacettepe University14, Imperial College London15, Statens Serum Institut16, Medical University of Vienna17, Norwich University18, Harvard University19, Toho University20, University of East Anglia21
TL;DR: 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides J. Watts; Arthritis & Rheumatism
Abstract: 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides J. Jennette;R. Falk;P. Bacon;N. Basu;M. Cid;F. Ferrario;L. Flores-Suarez;W. Gross;L. Guillevin;E. Hagen;G. Hoffman;D. Jayne;C. Kallenberg;P. Lamprecht;C. Langford;R. Luqmani;A. Mahr;E. Matteson;P. Merkel;S. Ozen;C. Pusey;N. Rasmussen;A. Rees;D. Scott;U. Specks;J. Stone;K. Takahashi;R. Watts; Arthritis & Rheumatism
4,249 citations
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University of British Columbia1, East Kent Hospitals University Nhs Foundation Trust2, Newcastle University3, Johns Hopkins University4, University of Groningen5, University of York6, University of Calgary7, University of the Ryukyus8, Tufts University9, University of California, San Francisco10, Peking University11, University of Oxford12
3,645 citations
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Woolcock Institute of Medical Research1, University of Otago2, University of Cape Town3, Boston University4, University of California, San Francisco5, University of Wisconsin-Madison6, Creighton University7, University of Arizona8, University of Newcastle9, Erasmus University Rotterdam10, University of Groningen11, University of Edinburgh12, McMaster University13, Imperial College London14, University of Leicester15, University of Amsterdam16, University of Nevada, Reno17, University of Washington18, University of Aberdeen19, University of Pittsburgh20
TL;DR: This update is a supplement to the previous 2002 IIP classification document and outlines advances in the past decade and potential areas for future investigation.
Abstract: Background: In 2002 the American Thoracic Society/European Respiratory Society (ATS/ERS) classification of idiopathic interstitial pneumonias (IIPs) defined seven specific entities, and provided standardized terminology and diagnostic criteria. In addition, the historical “gold standard” of histologic diagnosis was replaced by a multidisciplinary approach. Since 2002 many publications have provided new information about IIPs.Purpose: The objective of this statement is to update the 2002 ATS/ERS classification of IIPs.Methods: An international multidisciplinary panel was formed and developed key questions that were addressed through a review of the literature published between 2000 and 2011.Results: Substantial progress has been made in IIPs since the previous classification. Nonspecific interstitial pneumonia is now better defined. Respiratory bronchiolitis–interstitial lung disease is now commonly diagnosed without surgical biopsy. The clinical course of idiopathic pulmonary fibrosis and nonspecific inte...
2,931 citations
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Cristen J. Willer1, Ellen M. Schmidt1, Sebanti Sengupta1, Gina M. Peloso2 +316 more•Institutions (87)
TL;DR: It is found that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index.
Abstract: Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.
2,585 citations
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TL;DR: This work proposes an ultrafast bootstrap approximation approach (UFBoot) to compute the support of phylogenetic groups in maximum likelihood (ML) based trees and offers an efficient and easy-to-use software to perform the UFBoot analysis with ML tree inference.
Abstract: Nonparametric bootstrap has been a widely used tool in phylogenetic analysis to assess the clade support of phylogenetic trees. However, with the rapidly growing amount of data, this task remains a computational bottleneck. Recently, approximation methods such as the RAxML rapid bootstrap (RBS) and the Shimodaira-Hasegawa-like approximate likelihood ratio test have been introduced to speed up the bootstrap. Here, we suggest an ultrafast bootstrap approximation approach (UFBoot) to compute the support of phylogenetic groups in maximum likelihood (ML) based trees. To achieve this, we combine the resampling estimated log-likelihood method with a simple but effective collection scheme of candidate trees. We also propose a stopping rule that assesses the convergence of branch support values to automatically determine when to stop collecting candidate trees. UFBoot achieves a median speed up of 3.1 (range: 0.66-33.3) to 10.2 (range: 1.32-41.4) compared with RAxML RBS for real DNA and amino acid alignments, respectively. Moreover, our extensive simulations show that UFBoot is robust against moderate model violations and the support values obtained appear to be relatively unbiased compared with the conservative standard bootstrap. This provides a more direct interpretation of the bootstrap support. We offer an efficient and easy-to-use software (available at http://www.cibiv.at/software/iqtree) to perform the UFBoot analysis with ML tree inference.
2,469 citations
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TL;DR: Empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.
Abstract: Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.
2,058 citations
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Copenhagen University Hospital1, French Institute of Health and Medical Research2, University College London3, Columbia University4, University of Gothenburg5, University of Western Ontario6, University of the Witwatersrand7, University of Amsterdam8, University of São Paulo9, University of Western Australia10, Ludwig Maximilian University of Munich11, University of Palermo12, University of Milan13, University of Groningen14, University Medical Center15, University of California, Los Angeles16, University of London17, Radboud University Nijmegen18, University of Helsinki19, University of Copenhagen20
TL;DR: There is an urgent worldwide need for diagnostic screening together with early and aggressive treatment of this extremely high-risk condition, familial hypercholesterolaemia.
Abstract: Aims The first aim was to critically evaluate the extent to which familial hypercholesterolaemia (FH) is underdiagnosed and undertreated. The second aim was to provide guidance for screening and treatment of FH, in order to prevent coronary heart disease (CHD).
Methods and results Of the theoretical estimated prevalence of 1/500 for heterozygous FH, <1% are diagnosed in most countries. Recently, direct screening in a Northern European general population diagnosed approximately 1/200 with heterozygous FH. All reported studies document failure to achieve recommended LDL cholesterol targets in a large proportion of individuals with FH, and up to 13-fold increased risk of CHD. Based on prevalences between 1/500 and 1/200, between 14 and 34 million individuals worldwide have FH. We recommend that children, adults, and families should be screened for FH if a person or family member presents with FH, a plasma cholesterol level in an adult ≥8 mmol/L(≥310 mg/dL) or a child ≥6 mmol/L(≥230 mg/dL), premature CHD, tendon xanthomas, or sudden premature cardiac death. In FH, low-density lipoprotein cholesterol targets are <3.5 mmol/L(<135 mg/dL) for children, <2.5 mmol/L(<100 mg/dL) for adults, and <1.8 mmol/L(<70 mg/dL) for adults with known CHD or diabetes. In addition to lifestyle and dietary counselling, treatment priorities are (i) in children, statins, ezetimibe, and bile acid binding resins, and (ii) in adults, maximal potent statin dose, ezetimibe, and bile acid binding resins. Lipoprotein apheresis can be offered in homozygotes and in treatment-resistant heterozygotes with CHD.
Conclusion Owing to severe underdiagnosis and undertreatment of FH, there is an urgent worldwide need for diagnostic screening together with early and aggressive treatment of this extremely high-risk condition.
2,039 citations
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University Medical Center Groningen1, University of Tartu2, University of Exeter3, Greifswald University Hospital4, National Institute for Health and Welfare5, University of Washington6, Churchill Hospital7, Technische Universität München8, University of Queensland9, University Medical Center Utrecht10, Erasmus University Rotterdam11, Leiden University Medical Center12, National Institutes of Health13, University College London14, University of Auckland15, QIMR Berghofer Medical Research Institute16, Wellcome Trust Centre for Human Genetics17, University of Düsseldorf18, Ludwig Maximilian University of Munich19, University of Groningen20, Group Health Cooperative21, Wellcome Trust Sanger Institute22, University of Helsinki23
TL;DR: Variants associated with cholesterol metabolism and type 1 diabetes showed similar phenomena, indicating that large-scale eQTL mapping provides insight into the downstream effects of many trait-associated variants.
Abstract: Identifying the downstream effects of disease-associated SNPs is challenging. To help overcome this problem, we performed expression quantitative trait locus (eQTL) meta-analysis in non-transformed peripheral blood samples from 5,311 individuals with replication in 2,775 individuals. We identified and replicated trans eQTLs for 233 SNPs (reflecting 103 independent loci) that were previously associated with complex traits at genome-wide significance. Some of these SNPs affect multiple genes in trans that are known to be altered in individuals with disease: rs4917014, previously associated with systemic lupus erythematosus (SLE), altered gene expression of C1QB and five type I interferon response genes, both hallmarks of SLE. DeepSAGE RNA sequencing showed that rs4917014 strongly alters the 3' UTR levels of IKZF1 in cis, and chromatin immunoprecipitation and sequencing analysis of the trans-regulated genes implicated IKZF1 as the causal gene. Variants associated with cholesterol metabolism and type 1 diabetes showed similar phenomena, indicating that large-scale eQTL mapping provides insight into the downstream effects of many trait-associated variants.
1,627 citations
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TL;DR: The epidemiology and pathophysiological mechanisms of cardiovascular risk in patients with chronic kidney disease are discussed, and methods of prevention are discussed.
1,566 citations
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Alternatives1, John Innes Centre2, University of Bonn3, University of North Carolina at Chapel Hill4, University of Wisconsin-Madison5, University of Utah6, University of Southern California7, University of Edinburgh8, University of Warwick9, Harvard University10, University College Cork11, University of Queensland12, University of Hertfordshire13, University of Potsdam14, University of California, San Diego15, Goethe University Frankfurt16, University of California, San Francisco17, University of Delaware18, Uppsala University19, Medical University of Vienna20, J. Craig Venter Institute21, University of Hawaii at Manoa22, Leibniz Association23, University of Iowa24, University of Aberdeen25, Georgia Institute of Technology26, University of California, Berkeley27, University of Groningen28, Princeton University29, University of Marburg30, University of Illinois at Urbana–Champaign31, Saarland University32, Norwegian University of Life Sciences33, Massey University34, Toyama Prefectural University35, ETH Zurich36, University of Saskatchewan37, Rutgers University38, Scripps Research Institute39, University of Helsinki40, Texas A&M University41, National Institutes of Health42, Technical University of Berlin43, University of Otago44, University of Cambridge45, University of Alberta46, Michigan State University47, Hofstra University48
TL;DR: This review presents recommended nomenclature for the biosynthesis of ribosomally synthesized and post-translationally modified peptides (RiPPs), a rapidly growing class of natural products.
1,560 citations
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TL;DR: Improve some of the bonded terms in the Martini protein force field that lead to a more realistic length of α-helices and to improved numerical stability for polyalanine and glycine repeats.
Abstract: The Martini coarse-grained force field has been successfully used for simulating a wide range of (bio)molecular systems. Recent progress in our ability to test the model against fully atomistic force fields, however, has revealed some shortcomings. Most notable, phenylalanine and proline were too hydrophobic, and dimers formed by polar residues in apolar solvents did not bind strongly enough. Here, we reparametrize these residues either through reassignment of particle types or by introducing embedded charges. The new parameters are tested with respect to partitioning across a lipid bilayer, membrane binding of Wimley–White peptides, and dimerization free energy in solvents of different polarity. In addition, we improve some of the bonded terms in the Martini protein force field that lead to a more realistic length of α-helices and to improved numerical stability for polyalanine and glycine repeats. The new parameter set is denoted Martini version 2.2.
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University of Düsseldorf1, Goethe University Frankfurt2, Vrije Universiteit Brussel3, University of Freiburg4, Leipzig University5, Dow Chemical Company6, University of Tübingen7, Durham University8, University of Turin9, Seoul National University10, University of Jena11, Charité12, University of Valencia13, Heidelberg University14, French Institute for Research in Computer Science and Automation15, University of Paris16, University of Liverpool17, University of Groningen18, Lund University19, University of Manchester20, South Valley University21, University Hospital Regensburg22, Merck KGaA23, Musashino University24, University of Kansas25, Ludwig Maximilian University of Munich26, Fresenius Medical Care27, University of Regensburg28, Merck & Co.29
TL;DR: This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro and how closely hepatoma, stem cell and iPS cell–derived hepatocyte-like-cells resemble real hepatocytes.
Abstract: This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro. In a complex architecture of nested, zonated lobules, the liver consists of approximately 80 % hepatocytes and 20 % non-parenchymal cells, the latter being involved in a secondary phase that may dramatically aggravate the initial damage. Hepatotoxicity, as well as hepatic metabolism, is controlled by a set of nuclear receptors (including PXR, CAR, HNF-4α, FXR, LXR, SHP, VDR and PPAR) and signaling pathways. When isolating liver cells, some pathways are activated, e.g., the RAS/MEK/ERK pathway, whereas others are silenced (e.g. HNF-4α), resulting in up- and downregulation of hundreds of genes. An understanding of these changes is crucial for a correct interpretation of in vitro data. The possibilities and limitations of the most useful liver in vitro systems are summarized, including three-dimensional culture techniques, co-cultures with non-parenchymal cells, hepatospheres, precision cut liver slices and the isolated perfused liver. Also discussed is how closely hepatoma, stem cell and iPS cell-derived hepatocyte-like-cells resemble real hepatocytes. Finally, a summary is given of the state of the art of liver in vitro and mathematical modeling systems that are currently used in the pharmaceutical industry with an emphasis on drug metabolism, prediction of clearance, drug interaction, transporter studies and hepatotoxicity. One key message is that despite our enthusiasm for in vitro systems, we must never lose sight of the in vivo situation. Although hepatocytes have been isolated for decades, the hunt for relevant alternative systems has only just begun.
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TL;DR: The Martini model, a coarse-grained force field for biomolecular simulations, has found a broad range of applications since its release a decade ago and is described as a building block principle model that combines speed and versatility while maintaining chemical specificity.
Abstract: The Martini model, a coarse-grained force field for biomolecular simulations, has found a broad range of applications since its release a decade ago. Based on a building block principle, the model combines speed and versatility while maintaining chemical specificity. Here we review the current state of the model. We describe recent highlights as well as shortcomings, and our ideas on the further development of the model.
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San Francisco VA Medical Center1, Durham University2, Duke University3, Athens State University4, University of California, San Diego5, University of Groningen6, University of North Carolina at Chapel Hill7, University of Buenos Aires8, University of Paris9, University of Barcelona10, Northwestern University11, Martin Luther University of Halle-Wittenberg12, Novartis13, University of Brescia14
TL;DR: Treatment of acute heart failure with serelaxin was associated with dyspnoea relief and improvement in other clinical outcomes, but had no effect on readmission to hospital.
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University of Groningen1, Showa University2, University of Chicago3, AbbVie4, University of Glasgow5, University of Copenhagen6, Mario Negri Institute for Pharmacological Research7, University of Texas Southwestern Medical Center8, University of California, Irvine9, University of Würzburg10, Stanford University11
TL;DR: Among patients with type 2 diabetes mellitus and stage 4 chronic kidney disease, bardoxolone methyl did not reduce the risk of end-stage renal disease (ESRD) or death from cardiovascular causes and was terminated on the recommendation of the independent data and safety monitoring committee.
Abstract: BACKGROUND: Although inhibitors of the renin-angiotensin-aldosterone system can slow the progression of diabetic kidney disease, the residual risk is high. Whether nuclear 1 factor (erythroid-derived 2)-related factor 2 activators further reduce this risk is unknown. METHODS: We randomly assigned 2185 patients with type 2 diabetes mellitus and stage 4 chronic kidney disease (estimated glomerular filtration rate [GFR], 15 to <30 ml per minute per 1.73 m(2) of body-surface area) to bardoxolone methyl, at a daily dose of 20 mg, or placebo. The primary composite outcome was end-stage renal disease (ESRD) or death from cardiovascular causes. RESULTS: The sponsor and the steering committee terminated the trial on the recommendation of the independent data and safety monitoring committee; the median follow-up was 9 months. A total of 69 of 1088 patients (6%) randomly assigned to bardoxolone methyl and 69 of 1097 (6%) randomly assigned to placebo had a primary composite outcome (hazard ratio in the bardoxolone methyl group vs. the placebo group, 0.98; 95% confidence interval [CI], 0.70 to 1.37; P=0.92). In the bardoxolone methyl group, ESRD developed in 43 patients, and 27 patients died from cardiovascular causes; in the placebo group, ESRD developed in 51 patients, and 19 patients died from cardiovascular causes. A total of 96 patients in the bardoxolone methyl group were hospitalized for heart failure or died from heart failure, as compared with 55 in the placebo group (hazard ratio, 1.83; 95% CI, 1.32 to 2.55; P<0.001). Estimated GFR, blood pressure, and the urinary albumin-to-creatinine ratio increased significantly and body weight decreased significantly in the bardoxolone methyl group, as compared with the placebo group. CONCLUSIONS: Among patients with type 2 diabetes mellitus and stage 4 chronic kidney disease, bardoxolone methyl did not reduce the risk of ESRD or death from cardiovascular causes. A higher rate of cardiovascular events with bardoxolone methyl than with placebo prompted termination of the trial. (Funded by Reata Pharmaceuticals; BEACON ClinicalTrials.gov number, NCT01351675.).
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TL;DR: It is suggested that triglyceride-rich lipoproteins causally influence risk for CAD, and the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk.
Abstract: Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
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TL;DR: In this article, a genome-wide association study of educational attainment was conducted in a discovery sample of 101,069 individuals and a replication sample of 25,490 individuals, and three independent SNPs are genome wide significant (rs9320913, rs11584700, rs4851266).
Abstract: A genome-wide association study of educational attainment was conducted in a discovery sample of 101,069 individuals and a replication sample of 25,490. Three independent SNPs are genome-wide significant (rs9320913, rs11584700, rs4851266), and all three replicate. Estimated effects sizes are small (R2 ≈ 0.02%), approximately 1 month of schooling per allele. A linear polygenic score from all measured SNPs accounts for ≈ 2% of the variance in both educational attainment and cognitive function. Genes in the region of the loci have previously been associated with health, cognitive, and central nervous system phenotypes, and bioinformatics analyses suggest the involvement of the anterior caudate nucleus. These findings provide promising candidate SNPs for follow-up work, and our effect size estimates can anchor power analyses in social-science genetics.
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TL;DR: The highly improved antiSMASH 2.0 now supports input of multiple related sequences simultaneously (multi-FASTA/GenBank/EMBL), which allows the analysis of draft genomes comprising multiple contigs, and direct analysis of protein sequences is now possible.
Abstract: Microbial secondary metabolites are a potent source of antibiotics and other pharmaceuticals. Genome mining of their biosynthetic gene clusters has become a key method to accelerate their identification and characterization. In 2011, we developed antiSMASH, a web-based analysis platform that automates this process. Here, we present the highly improved antiSMASH 2.0 release, available at http://antismash.secondarymetabolites.org/. For the new version, antiSMASH was entirely re-designed using a plug-and-play concept that allows easy integration of novel predictor or output modules. antiSMASH 2.0 now supports input of multiple related sequences simultaneously (multi-FASTA/GenBank/EMBL), which allows the analysis of draft genomes comprising multiple contigs. Moreover, direct analysis of protein sequences is now possible. antiSMASH 2.0 has also been equipped with the capacity to detect additional classes of secondary metabolites, including oligosaccharide antibiotics, phenazines, thiopeptides, homo-serine lactones, phosphonates and furans. The algorithm for predicting the core structure of the cluster end product is now also covering lantipeptides, in addition to polyketides and non-ribosomal peptides. The antiSMASH ClusterBlast functionality has been extended to identify sub-clusters involved in the biosynthesis of specific chemical building blocks. The new features currently make antiSMASH 2.0 the most comprehensive resource for identifying and analyzing novel secondary metabolite biosynthetic pathways in microorganisms.
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TL;DR: In this article, the suitability of low frequency (LF) heart rate variability (HRV) as an index of sympathetic cardiac control and the LF/high frequency (HF) ratio was evaluated.
Abstract: This article evaluates the suitability of low frequency (LF) heart rate variability (HRV) as an index of sympathetic cardiac control and the LF/high frequency (HF) ratio as an index of autonomic balance. It includes a comprehensive literature review and a reanalysis of some previous studies on autonomic cardiovascular regulation. The following sources of evidence are addressed: effects of manipulations affecting sympathetic and vagal activity on HRV, predictions of group differences in cardiac autonomic regulation from HRV, relationships between HRV and other cardiac parameters, and the theoretical and mathematical bases of the concept of autonomic balance. Available data challenge the interpretation of the LF and LF/HF ratio as indices of sympathetic cardiac control and autonomic balance, respectively, and suggest that the HRV power spectrum, including its LF component, is mainly determined by the parasympathetic system.
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University of Leicester1, King's College London2, Leiden University3, Imperial College London4, VU University Amsterdam5, University of Tartu6, University of Helsinki7, QIMR Berghofer Medical Research Institute8, University of Groningen9, Karolinska Institutet10, University College London11, University of Cambridge12, Erasmus University Rotterdam13, University of Leeds14, University of Georgia15, University of Oulu16, University of Oxford17, University of Washington18, National Institutes of Health19, National Institute for Health and Welfare20, Wellcome Trust Centre for Human Genetics21, National Institute for Health Research22, Prevention Institute23, Georgia Regents University24, Ludwig Maximilian University of Munich25, University of North Carolina at Chapel Hill26, University of Texas MD Anderson Cancer Center27, University of Milan28, University of Pennsylvania29, Harvard University30, Broad Institute31, Glenfield Hospital32
TL;DR: In this paper, a genome-wide meta-analysis of 37,684 individuals with replication of selected variants in an additional 10,739 individuals was carried out to identify seven loci, including five new loci associated with mean leukocyte telomere length (LTL) (P < 5 × 10−8).
Abstract: Interindividual variation in mean leukocyte telomere length (LTL) is associated with cancer and several age-associated diseases. We report here a genome-wide meta-analysis of 37,684 individuals with replication of selected variants in an additional 10,739 individuals. We identified seven loci, including five new loci, associated with mean LTL (P < 5 × 10(-8)). Five of the loci contain candidate genes (TERC, TERT, NAF1, OBFC1 and RTEL1) that are known to be involved in telomere biology. Lead SNPs at two loci (TERC and TERT) associate with several cancers and other diseases, including idiopathic pulmonary fibrosis. Moreover, a genetic risk score analysis combining lead variants at all 7 loci in 22,233 coronary artery disease cases and 64,762 controls showed an association of the alleles associated with shorter LTL with increased risk of coronary artery disease (21% (95% confidence interval, 5-35%) per standard deviation in LTL, P = 0.014). Our findings support a causal role of telomere-length variation in some age-related diseases.
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TL;DR: In this paper, the authors generalize this class of superconformal inflationary models by introducing a parameter α inversely proportional to the curvature of the inflaton Kahler manifold.
Abstract: Recently a broad class of superconformal inflationary models was found leading to a universal observational prediction $ {n_s}=1-\frac{2}{N} $
and $ r=\frac{12 }{{{N^2}}} $
[1, 2]. Here we generalize this class of models by introducing a parameter α inversely proportional to the curvature of the inflaton Kahler manifold. In the small curvature (large α) limit, the observational predictions of this class of models coincide with the predictions of generic chaotic inflation models. However, for sufficiently large curvature (small α), the predictions converge to the universal attractor regime with $ {n_s}=1-\frac{2}{N} $
and $ r=\alpha \frac{12 }{{{N^2}}} $
, which corresponds to the part of the n
s − r plane favored by the Planck data.
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TL;DR: The use of cystatin C alone or in combination with creatinine strengthens the association between the eGFR and the risks of death and end-stage renal disease across diverse populations.
Abstract: BACKGROUND Adding the measurement of cystatin C to that of serum creatinine to determine the estimated glomerular filtration rate (eGFR) improves accuracy, but the effect on detection, staging, and risk classification of chronic kidney disease across diverse populations has not been determined. METHODS We performed a meta-analysis of 11 general-population studies (with 90,750 participants) and 5 studies of cohorts with chronic kidney disease (2960 participants) for whom standardized measurements of serum creatinine and cystatin C were available. We compared the association of the eGFR, as calculated by the measurement of creatinine or cystatin C alone or in combination with creatinine, with the rates of death (13,202 deaths in 15 cohorts), death from cardiovascular causes (3471 in 12 cohorts), and end-stage renal disease (1654 cases in 7 cohorts) and assessed improvement in reclassification with the use of cystatin C. RESULTS In the general-population cohorts, the prevalence of an eGFR of less than 60 ml per minute per 1.73 m(2) of body-surface area was higher with the cystatin C-based eGFR than with the creatinine-based eGFR (13.7% vs. 9.7%). Across all eGFR categories, the reclassification of the eGFR to a higher value with the measurement of cystatin C, as compared with creatinine, was associated with a reduced risk of all three study outcomes, and reclassification to a lower eGFR was associated with an increased risk. The net reclassification improvement with the measurement of cystatin C, as compared with creatinine, was 0.23 (95% confidence interval [CI], 0.18 to 0.28) for death and 0.10 (95% CI, 0.00 to 0.21) for end-stage renal disease. Results were generally similar for the five cohorts with chronic kidney disease and when both creatinine and cystatin C were used to calculate the eGFR. CONCLUSIONS The use of cystatin C alone or in combination with creatinine strengthens the association between the eGFR and the risks of death and end-stage renal disease across diverse populations.
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TL;DR: In this article, the process e(+)e(-) -> pi(+)pi(-) J/psi at a center-of-mass energy of 4.260 GeV using a 525 pb(-1) data sample collected with the BESIII detector operating at the Beijing Electron Positron Collider was studied.
Abstract: We study the process e(+)e(-) -> pi(+)pi(-) J/psi at a center-of-mass energy of 4.260 GeV using a 525 pb(-1) data sample collected with the BESIII detector operating at the Beijing Electron Positron Collider. The Born cross section is measured to be (62.9 +/- 1.9 +/- 3.7) pb, consistent with the production of the Y(4260). We observe a structure at around 3.9 GeV/c(2) in the pi(+/-) J/psi mass spectrum, which we refer to as the Z(c)(3900). If interpreted as a new particle, it is unusual in that it carries an electric charge and couples to charmonium. A fit to the pi(+/-) J/psi invariant mass spectrum, neglecting interference, results in a mass of (3899.0 +/- 3.6 +/- 4.9) MeV/c(2) and a width of (46 +/- 10 +/- 20) MeV. Its production ratio is measured to be R = (sigma(e(+)e(-) -> pi(+/-) Z(c)(3900)(-/+) -> pi(+)pi(-) J/psi)/sigma(e(+)e(-) -> pi(+)pi(-) J/psi)) = (21.5 +/- 3.3 +/- 7.5)%. In all measurements the first errors are statistical and the second are systematic.
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TL;DR: This paper introduces a single-item social identification measure (SISI) that involves rating one's agreement with the statement 'I identify with my group (or category)' followed by a 7-point scale.
Abstract: This paper introduces a single-item social identification measure (SISI) that involves rating one's agreement with the statement 'I identify with my group (or category)' followed by a 7-point scale. Three studies provide evidence of the validity (convergent, divergent, and test-retest) of SISI with a broad range of social groups. Overall, the estimated reliability of SISI is good. To address the broader issue of single-item measure reliability, a meta-analysis of 16 widely used single-item measures is reported. The reliability of single-item scales ranges from low to reasonably high. Compared with this field, reliability of the SISI is high. In general, short measures struggle to achieve acceptable reliability because the constructs they assess are broad and heterogeneous. In the case of social identification, however, the construct appears to be sufficiently homogeneous to be adequately operationalized with a single item.
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TL;DR: Ketamine was associated with a rapid antidepressant effect in TRD that was predictive of a sustained effect and future controlled studies will be required to identify strategies to maintain an antidepressant response among patients who benefit from a course of ketamine.
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TL;DR: New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
Abstract: Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
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University of Groningen1, University of Cambridge2, Queen Mary University of London3, University of Rochester4, University of Navarra5, King Saud University6, Medical University of Vienna7, University of Padua8, Maastricht University9, King Abdulaziz University10, Johns Hopkins University11, National and Kapodistrian University of Athens12, University of Geneva13, University of Amsterdam14
TL;DR: The use of LMWH for VTE prevention in cancer patients undergoing laparoscopic surgery may be recommended as for laparotomy and mechanical methods are not recommended as monotherapy except when pharmacological methods are contraindicated.
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TL;DR: In patients with severe ANCA-associated vasculitis, a single course of rituximab was as effective as continuous conventional immunosuppressive therapy for the induction and maintenance of remissions over the course of 18 months.
Abstract: A total of 197 patients were enrolled. As reported previously, 64% of the patients in the rituximab group, as compared with 53% of the patients in the cyclophosphamide– azathioprine group, had a complete remission by 6 months. At 12 and 18 months, 48% and 39%, respectively, of the patients in the rituximab group had maintained the complete remissions, as compared with 39% and 33%, respectively, in the com parison group. Rituximab met the prespecified criteria for noninferiority (P<0.001, with a noninferiority margin of 20%). There was no significant difference between the groups in any efficacy measure, including the duration of complete remission and the frequency or severity of relapses. Among the 101 patients who had relapsing disease at baseline, rituximab was superior to conventional immunosuppression at 6 months (P = 0.01) and at 12 months (P = 0.009) but not at 18 months (P = 0.06), at which time most patients in the rituximab group had reconstituted B cells. There was no significant between-group difference in adverse events. Conclusions In patients with severe ANCA-associated vasculitis, a single course of rituximab was as effective as continuous conventional immunosuppressive therapy for the induction and maintenance of remissions over the course of 18 months. (Funded by the Na tional Institute of Allergy and Infectious Diseases and others; RAVE ClinicalTrials.gov number, NCT00104299.)
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TL;DR: This review focuses on roles in cancer cell-tumour microenvironment interaction and summarises strategies for treating cancer by disrupting this interaction with special emphasis on the CXCR4/CXCL12 axis.