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Showing papers by "University of Groningen published in 2013"


Journal ArticleDOI
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



Journal ArticleDOI
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


Journal ArticleDOI
Cristen J. Willer1, Ellen M. Schmidt1, Sebanti Sengupta1, Gina M. Peloso2  +316 moreInstitutions (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


Journal ArticleDOI
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


Journal ArticleDOI
S. Hong Lee1, Stephan Ripke2, Stephan Ripke3, Benjamin M. Neale3  +402 moreInstitutions (124)
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


Journal ArticleDOI
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


Journal ArticleDOI
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


Journal ArticleDOI
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


Journal ArticleDOI
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


Journal ArticleDOI
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.

Journal ArticleDOI
Patricio Godoy, Nicola J. Hewitt, Ute Albrecht1, Melvin E. Andersen, Nariman Ansari2, Sudin Bhattacharya, Johannes G. Bode1, Jennifer Bolleyn3, Christoph Borner4, J Böttger5, Albert Braeuning, Robert A. Budinsky6, Britta Burkhardt7, Neil R. Cameron8, Giovanni Camussi9, Chong Su Cho10, Yun Jaie Choi10, J. Craig Rowlands6, Uta Dahmen11, Georg Damm12, Olaf Dirsch11, María Teresa Donato13, Jian Dong, Steven Dooley14, Dirk Drasdo15, Dirk Drasdo5, Dirk Drasdo16, Rowena Eakins17, Karine Sá Ferreira4, Valentina Fonsato9, Joanna Fraczek3, Rolf Gebhardt5, Andrew Gibson17, Matthias Glanemann12, Christopher E. Goldring17, María José Gómez-Lechón, Geny M. M. Groothuis18, Lena Gustavsson19, Christelle Guyot, David Hallifax20, Seddik Hammad21, Adam S. Hayward8, Dieter Häussinger1, Claus Hellerbrand22, Philip Hewitt23, Stefan Hoehme5, Hermann-Georg Holzhütter12, J. Brian Houston20, Jens Hrach, Kiyomi Ito24, Hartmut Jaeschke25, Verena Keitel1, Jens M. Kelm, B. Kevin Park17, Claus Kordes1, Gerd A. Kullak-Ublick, Edward L. LeCluyse, Peng Lu, Jennifer Luebke-Wheeler, Anna Lutz4, Daniel J. Maltman, Madlen Matz-Soja5, Patrick D. McMullen, Irmgard Merfort4, Simon Messner, Christoph Meyer14, Jessica Mwinyi, Dean J. Naisbitt17, Andreas K. Nussler7, Peter Olinga18, Francesco Pampaloni2, Jingbo Pi, Linda J. Pluta, Stefan Przyborski8, Anup Ramachandran25, Vera Rogiers3, Cliff Rowe17, Celine Schelcher26, Kathrin Schmich4, Michael Schwarz, Bijay Singh10, Ernst H. K. Stelzer2, Bruno Stieger, Regina Stöber, Yuichi Sugiyama, Ciro Tetta27, Wolfgang E. Thasler26, Tamara Vanhaecke3, Mathieu Vinken3, Thomas S. Weiss28, Agata Widera, Courtney G. Woods, Jinghai James Xu29, Kathy Yarborough, Jan G. Hengstler 
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.

Journal ArticleDOI
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.



Journal ArticleDOI
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.).

Journal ArticleDOI
Ron Do1, Cristen J. Willer2, Ellen M. Schmidt2, Sebanti Sengupta2  +263 moreInstitutions (83)
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.

Journal ArticleDOI
Cornelius A. Rietveld1, Sarah E. Medland2, Jaime Derringer3, Jian Yang4  +227 moreInstitutions (62)
21 Jun 2013-Science
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.

Journal ArticleDOI
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.

Journal ArticleDOI
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.

Journal ArticleDOI
Veryan Codd1, Christopher P. Nelson1, Eva Albrecht, Massimo Mangino2, Joris Deelen3, Jessica L. Buxton4, Jouke-Jan Hottenga5, Krista Fischer6, Tõnu Esko6, Ida Surakka7, Linda Broer, Dale R. Nyholt8, Irene Mateo Leach9, Perttu Salo, Sara Hägg10, Mary K. Matthews1, Jutta Palmen11, Giuseppe Danilo Norata, Paul F. O'Reilly4, Danish Saleheen12, Najaf Amin13, Anthony J. Balmforth14, Marian Beekman3, Rudolf A. de Boer9, Stefan Böhringer3, Peter S. Braund1, Paul Burton1, Anton J. M. de Craen3, Matthew Denniff1, Yanbin Dong15, Konstantinos Douroudis6, Elena Dubinina1, Johan G. Eriksson, Katia Garlaschelli, Dehuang Guo15, Anna-Liisa Hartikainen16, Anjali K. Henders8, Jeanine J. Houwing-Duistermaat3, Laura Kananen7, Lennart C. Karssen13, Johannes Kettunen7, Norman Klopp, Vasiliki Lagou17, Elisabeth M. van Leeuwen13, Pamela A. F. Madden18, Reedik Mägi6, Patrik K. E. Magnusson10, Satu Männistö19, Satu Männistö20, Mark I. McCarthy21, Mark I. McCarthy17, Mark I. McCarthy22, Sarah E. Medland8, Evelin Mihailov6, Grant W. Montgomery8, Ben A. Oostra13, Aarno Palotie, Annette Peters, Helen Pollard1, Anneli Pouta16, Anneli Pouta20, Inga Prokopenko17, Samuli Ripatti, Veikko Salomaa20, Veikko Salomaa19, H. Eka D. Suchiman3, Ana M. Valdes2, Niek Verweij9, Ana Viñuela2, Xiaoling Wang23, Xiaoling Wang24, H-Erich Wichmann25, Elisabeth Widen7, Gonneke Willemsen5, Margaret J. Wright8, Kai Xia26, Xiangjun Xiao27, Dirk J. van Veldhuisen9, Alberico L. Catapano28, Martin D. Tobin1, Alistair S. Hall14, Alexandra I. F. Blakemore4, Wiek H. van Gilst9, Haidong Zhu23, Haidong Zhu24, Jeanette Erdmann, Muredach P. Reilly29, Sekar Kathiresan30, Sekar Kathiresan31, Heribert Schunkert, Philippa J. Talmud11, Nancy L. Pedersen10, Markus Perola6, Markus Perola20, Markus Perola7, Willem H. Ouwehand, Jaakko Kaprio, Nicholas G. Martin8, Cornelia M. van Duijn, Iiris Hovatta7, Iiris Hovatta20, Christian Gieger11, Andres Metspalu6, Dorret I. Boomsma5, Marjo-Riitta Järvelin, P. Eline Slagboom3, John R Thompson1, Tim D. Spector2, Pim van der Harst1, Nilesh J. Samani1, Nilesh J. Samani32 
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.

Journal ArticleDOI
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.

Journal ArticleDOI
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.

Journal ArticleDOI
M. Ablikim, M. N. Achasov1, Xiaocong Ai, O. Albayrak2  +365 moreInstitutions (50)
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.

Journal ArticleDOI
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.

Journal ArticleDOI
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.

Journal ArticleDOI
Anna Köttgen1, Anna Köttgen2, Eva Albrecht, Alexander Teumer3  +247 moreInstitutions (64)
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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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.)

Journal ArticleDOI
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.