Showing papers by "Ludwig Maximilian University of Munich published in 2011"
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TL;DR: A new program called Clustal Omega is described, which can align virtually any number of protein sequences quickly and that delivers accurate alignments, and which outperforms other packages in terms of execution time and quality.
Abstract: Multiple sequence alignments are fundamental to many sequence analysis methods. Most alignments are computed using the progressive alignment heuristic. These methods are starting to become a bottleneck in some analysis pipelines when faced with data sets of the size of many thousands of sequences. Some methods allow computation of larger data sets while sacrificing quality, and others produce high-quality alignments, but scale badly with the number of sequences. In this paper, we describe a new program called Clustal Omega, which can align virtually any number of protein sequences quickly and that delivers accurate alignments. The accuracy of the package on smaller test cases is similar to that of the high-quality aligners. On larger data sets, Clustal Omega outperforms other packages in terms of execution time and quality. Clustal Omega also has powerful features for adding sequences to and exploiting information in existing alignments, making use of the vast amount of precomputed information in public databases like Pfam.
12,489 citations
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TL;DR: The authors conclude that PLS-SEM path modeling, if appropriately applied, is indeed a "silver bullet" for estimating causal models in many theoretical models and empirical data situations.
Abstract: Structural equation modeling (SEM) has become a quasi-standard in marketing and management research when it comes to analyzing the cause-effect relations between latent constructs. For most researchers, SEM is equivalent to carrying out covariance-based SEM (CB-SEM). While marketing researchers have a basic understanding of CB-SEM, most of them are only barely familiar with the other useful approach to SEM-partial least squares SEM (PLS-SEM). The current paper reviews PLS-SEM and its algorithm, and provides an overview of when it can be most appropriately applied, indicating its potential and limitations for future research. The authors conclude that PLS-SEM path modeling, if appropriately applied, is indeed a "silver bullet" for estimating causal models in many theoretical models and empirical data situations.
11,624 citations
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TL;DR: The density matrix renormalization group method (DMRG) has established itself over the last decade as the leading method for the simulation of the statics and dynamics of one-dimensional strongly correlated quantum lattice systems as mentioned in this paper.
2,940 citations
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Stephen Sawcer1, Garrett Hellenthal2, Matti Pirinen2, Chris C. A. Spencer2 +262 more•Institutions (67)
TL;DR: In this article, a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, they have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci.
Abstract: Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
2,511 citations
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The Catholic University of America1, Albert Einstein College of Medicine2, University of Oviedo3, Favaloro University4, University of Groningen5, Ludwig Maximilian University of Munich6, Mental Health Foundation7, Washington University in St. Louis8, Nnamdi Azikiwe University9, Technische Universität München10
TL;DR: Prevalence rates of different physical illnesses as well as important individual lifestyle choices, side effects of psychotropic treatment and disparities in health care access, utilization and provision that contribute to these poor physical health outcomes are reported.
1,895 citations
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31 Mar 2011TL;DR: In this paper, a framework for function spaces is presented, which includes variable exponent Lebesgue spaces, the maximal operator, the generalized Muckenhoupt condition, and transfer techniques.
Abstract: 1 Introduction.- 2 A framework for function spaces.- 3 Variable exponent Lebesgue spaces.- 4 The maximal operator.- 5 The generalized Muckenhoupt condition*.- 6 Classical operators.- 7 Transfer techniques.- 8 Introduction to Sobolev spaces.- 9. Density of regular functions.- 10. Capacities.- 11 Fine properties of Sobolev functions.- 12 Other spaces of differentiable functions.- 13 Dirichlet energy integral and Laplace equation.- 14 PDEs and fluid dynamics
1,894 citations
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Seattle Children's1, National Health Service2, Beaumont Hospital3, University of Toronto4, University of Queensland5, Charles University in Prague6, Ludwig Maximilian University of Munich7, University College Dublin8, Case Western Reserve University9, Stanford University10, University of Paris11, University of Alabama at Birmingham12, Vertex Pharmaceuticals13, Queen's University Belfast14
TL;DR: Ivacaftor was associated with improvements in lung function at 2 weeks that were sustained through 48 weeks and substantial improvements were also observed in the risk of pulmonary exacerbations, patient-reported respiratory symptoms, weight, and concentration of sweat chloride.
Abstract: Background Increasing the activity of defective cystic fibrosis transmembrane conductance regulator (CFTR) protein is a potential treatment for cystic fibrosis. Methods We conducted a randomized, double-blind, placebo-controlled trial to evaluate ivacaftor (VX-770), a CFTR potentiator, in subjects 12 years of age or older with cystic fibrosis and at least one G551D-CFTR mutation. Subjects were randomly assigned to receive 150 mg of ivacaftor every 12 hours (84 subjects, of whom 83 received at least one dose) or placebo (83, of whom 78 received at least one dose) for 48 weeks. The primary end point was the estimated mean change from baseline through week 24 in the percent of predicted forced expiratory volume in 1 second (FEV1). Results The change from baseline through week 24 in the percent of predicted FEV1 was greater by 10.6 percentage points in the ivacaftor group than in the placebo group (P<0.001). Effects on pulmonary function were noted by 2 weeks, and a significant treatment effect was maintained...
1,835 citations
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TL;DR: This work aims to systematically survey recently identified molecular mechanisms, translational developments and clinical strategies for targeting lipid-related inflammation in atherosclerosis and CAD.
Abstract: Coronary artery disease (CAD) arising from atherosclerosis is a leading cause of death and morbidity worldwide. The underlying pathogenesis involves an imbalanced lipid metabolism and a maladaptive immune response entailing a chronic inflammation of the arterial wall. The disturbed equilibrium of lipid accumulation, immune responses and their clearance is shaped by leukocyte trafficking and homeostasis governed by chemokines and their receptors. New pro- and anti-inflammatory pathways linking lipid and inflammation biology have been discovered, and genetic profiling studies have unveiled variations involved in human CAD. The growing understanding of the inflammatory processes and mediators has uncovered an intriguing diversity of targetable mechanisms that can be exploited to complement lipid-lowering therapies. Here we aim to systematically survey recently identified molecular mechanisms, translational developments and clinical strategies for targeting lipid-related inflammation in atherosclerosis and CAD.
1,834 citations
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TL;DR: A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function, and these findings suggest potential novel therapeutic pathways for cardiovascular disease prevention.
Abstract: Blood pressure is a heritable trait(1) influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (>= 140 mm Hg systolic blood pressure or >= 90 mm Hg diastolic blood pressure)(2). Even small increments in blood pressure are associated with an increased risk of cardiovascular events(3). This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.
1,829 citations
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TL;DR: Meta-analyses of all data provided compelling evidence that ABCA7 and the MS4A gene cluster are new Alzheimer's disease susceptibility loci and independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance.
Abstract: We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10−5. We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10−17; including ADGC data, meta P = 5.0 × 10−21) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10−14; including ADGC data, meta P = 1.2 × 10−16) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10−4; including ADGC data, meta P = 8.6 × 10−9), CD33 (GERAD+, P = 2.2 × 10−4; including ADGC data, meta P = 1.6 × 10−9) and EPHA1 (GERAD+, P = 3.4 × 10−4; including ADGC data, meta P = 6.0 × 10−10).
1,771 citations
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Heribert Schunkert1, Inke R. König1, Sekar Kathiresan2, Muredach P. Reilly3 +163 more•Institutions (59)
TL;DR: This paper performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals.
Abstract: We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 - 10'8 and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci showed significant association with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.
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Stephan Ripke1, Alan R. Sanders2, Kenneth S. Kendler3, Douglas F. Levinson4 +207 more•Institutions (71)
TL;DR: The authors examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects.
Abstract: We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated (6p21.32-p22.1 and 18q21.2). The strongest new finding (P = 1.6 x 10(-11)) was with rs1625579 within an intron of a putative primary transcript for MIR137 (microRNA 137), a known regulator of neuronal development. Four other schizophrenia loci achieving genome-wide significance contain predicted targets of MIR137, suggesting MIR137-mediated dysregulation as a previously unknown etiologic mechanism in schizophrenia. In a joint analysis with a bipolar disorder sample (16,374 affected individuals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 x 10(-9)), ANK3 (rs10994359, P = 2.5 x 10(-8)) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 x 10(-9)).
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Wellcome Trust Sanger Institute1, Université de Montréal2, University of Edinburgh3, University of Kiel4, Karolinska Institutet5, Cedars-Sinai Medical Center6, University of Cambridge7, University of Pennsylvania8, Casa Sollievo della Sofferenza9, University of Pittsburgh10, Université libre de Bruxelles11, University of Otago12, Johns Hopkins University13, Ludwig Maximilian University of Munich14, Charité15, Lille University of Science and Technology16, Cincinnati Children's Hospital Medical Center17, Ghent University18, Torbay Hospital19, University of Groningen20, Mater Health Services21, University of Liège22, University of Washington23, University of Utah24, QIMR Berghofer Medical Research Institute25, University of Paris26, University of Western Australia27, Tel Aviv University28, University of Dundee29, Harvard University30, University of Manchester31, Utrecht University32, University of Florence33, King's College London34, Yale University35, Royal Hospital for Sick Children36, Katholieke Universiteit Leuven37, Guy's and St Thomas' NHS Foundation Trust38, University of Barcelona39, University of Chicago40, University of Bern41, University of California, San Francisco42, Agency for Science, Technology and Research43, University of Toronto44, University of Oslo45, Leiden University46, University of Amsterdam47, Aarhus University48, National and Kapodistrian University of Athens49, Lithuanian University of Health Sciences50, Newcastle University51, Emory University52, Örebro University53, French Institute of Health and Medical Research54, Center for Applied Genomics55
TL;DR: A meta-analysis of six ulcerative colitis genome-wide association study datasets found many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1.
Abstract: Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 × 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis.
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Indiana University1, University of Notre Dame2, Utah State University3, University of New Hampshire4, University of California, Santa Barbara5, University of Tokyo6, United States Department of Energy7, Ludwig Maximilian University of Munich8, J. Craig Venter Institute9, National Institutes of Health10, University of Illinois at Urbana–Champaign11, Hebrew University of Jerusalem12, University of North Texas13, Harvard University14, Research Institute of Molecular Pathology15, University of Geneva16, Oregon State University17, Utrecht University18, University of California, Davis19, University of Iowa20, Hoffmann-La Roche21, University of Strasbourg22, University of Washington23, University of Texas at Arlington24, University of California, Santa Cruz25, Life Technologies26, New York University27, University of Guelph28, Imperial College London29, University of California, Berkeley30
TL;DR: The Daphnia genome reveals a multitude of genes and shows adaptation through gene family expansions, and the coexpansion of gene families interacting within metabolic pathways suggests that the maintenance of duplicated genes is not random.
Abstract: We describe the draft genome of the microcrustacean Daphnia pulex, which is only 200 megabases and contains at least 30,907 genes. The high gene count is a consequence of an elevated rate of gene duplication resulting in tandem gene clusters. More than a third of Daphnia's genes have no detectable homologs in any other available proteome, and the most amplified gene families are specific to the Daphnia lineage. The coexpansion of gene families interacting within metabolic pathways suggests that the maintenance of duplicated genes is not random, and the analysis of gene expression under different environmental conditions reveals that numerous paralogs acquire divergent expression patterns soon after duplication. Daphnia-specific genes, including many additional loci within sequenced regions that are otherwise devoid of annotations, are the most responsive genes to ecological challenges.
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TL;DR: In this paper, the authors report on the construction, reliability, internal validity, and external validity of the Achievement Emotions Questionnaire (AEQ) which is designed to assess various achievement emotions experienced by students in academic settings.
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TL;DR: The current understanding of the pathophysiology underlying keloid and hypertrophic scar formation is summarized and established treatments and novel therapeutic strategies are discussed.
Abstract: Excessive scars form as a result of aberrations of physiologic wound healing and may arise following any Insult to the deep dermis. By causing pain, pruritus and contractures, excessive scarring significantly affects the patient’s quality of life, both physically and psychologically. Multiple studies on hypertrophic scar and keloid formation have been conducted for decades and have led to a plethora of therapeutic strategies to prevent or attenuate excessive scar formation. However, most therapeutic approaches remain clinically unsatisfactory, most likely owing to poor understanding of the complex mechanisms underlying the processes of scarring and wound contraction. In this review we summarize the current understanding of the pathophysiology underlying keloid and hypertrophic scar formation and discuss established treatments and novel therapeutic strategies.
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University of Bologna1, University of Copenhagen2, Imperial College London3, University of Bergen4, University of Trieste5, Ludwig Maximilian University of Munich6, University of Paris7, University of Verona8, Sapienza University of Rome9, University of Regensburg10, Innsbruck Medical University11, Institut Gustave Roussy12, Hai phong University Of Medicine and Pharmacy13, University of Cambridge14, The Royal Marsden NHS Foundation Trust15, Katholieke Universiteit Leuven16
TL;DR: Authors F. Piscaglia, C. Nolsøe, M. M. Gilja, and H. P. Weskott review the manuscript and suggest ways in which the manuscript could have been improved.
Abstract: Authors F. Piscaglia1, C. Nolsøe2, C. F. Dietrich3, D. O. Cosgrove4, O. H. Gilja5, M. Bachmann Nielsen6, T. Albrecht7, L. Barozzi8, M. Bertolotto9, O. Catalano10, M. Claudon11, D. A. Clevert12, J. M. Correas13, M. D’Onofrio14, F. M. Drudi15, J. Eyding16, M. Giovannini17, M. Hocke18, A. Ignee19, E. M. Jung20, A. S. Klauser21, N. Lassau22, E. Leen23, G. Mathis24, A. Saftoiu25, G. Seidel26, P. S. Sidhu27, G. ter. Haar28, D. Timmerman29, H. P. Weskott30
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TL;DR: Three recent large-scale phylogenomics studies, which deal with the early diversification of animals, produced highly incongruent findings despite the use of considerable sequence data, suggesting that merely adding more sequences is not enough to resolve the inconsistencies.
Abstract: In the quest to reconstruct the Tree of Life, researchers have increasingly turned to phylogenomics, the inference of phylogenetic relationships using genome-scale data (Box 1). Mesmerized by the sustained increase in sequencing throughput, many phylogeneticists entertained the hope that the incongruence frequently observed in studies using single or a few genes [1] would come to an end with the generation of large multigene datasets. Yet, as so often happens, reality has turned out to be far more complex, as three recent large-scale analyses, one published in PLoS Biology [2]–[4], make clear. The studies, which deal with the early diversification of animals, produced highly incongruent (Box 2) findings despite the use of considerable sequence data (see Figure 1). Clearly, merely adding more sequences is not enough to resolve the inconsistencies.
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TL;DR: A comprehensive analysis of genotype-dependent metabolic phenotypes using a genome-wide association study with non-targeted metabolomics to identify genetic loci associated with blood metabolite concentrations and generates many new hypotheses for biomedical and pharmaceutical research.
Abstract: Genome-wide association studies (GWAS) have identified many risk loci for complex diseases, but effect sizes are typically small and information on the underlying biological processes is often lacking. Associations with metabolic traits as functional intermediates can overcome these problems and potentially inform individualized therapy. Here we report a comprehensive analysis of genotype-dependent metabolic phenotypes using a GWAS with non-targeted metabolomics. We identified 37 genetic loci associated with blood metabolite concentrations, of which 25 show effect sizes that are unusually high for GWAS and account for 10-60% differences in metabolite levels per allele copy. Our associations provide new functional insights for many disease-related associations that have been reported in previous studies, including those for cardiovascular and kidney disorders, type 2 diabetes, cancer, gout, venous thromboembolism and Crohn's disease. The study advances our knowledge of the genetic basis of metabolic individuality in humans and generates many new hypotheses for biomedical and pharmaceutical research.
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TL;DR: It is shown that acute myeloid leukemia (AML) follows a CSC model on the basis of sorting multiple populations from each of 16 primary human AML samples and identifying which contain leukemia stem cells (LSCs) using a sensitive xenograft assay, establishing that LSCs are clinically relevant and not artifacts of xenotransplantation.
Abstract: Xenograft studies indicate that some solid tumors and leukemias are organized as cellular hierarchies sustained by cancer stem cells (CSCs). Despite the promise of the CSC model, its relevance in humans remains uncertain. Here we show that acute myeloid leukemia (AML) follows a CSC model on the basis of sorting multiple populations from each of 16 primary human AML samples and identifying which contain leukemia stem cells (LSCs) using a sensitive xenograft assay. Analysis of gene expression from all functionally validated populations yielded an LSC-specific signature. Similarly, a hematopoietic stem cell (HSC) gene signature was established. Bioinformatic analysis identified a core transcriptional program shared by LSCs and HSCs, revealing the molecular machinery underlying 'stemness' properties. Both stem cell programs were highly significant independent predictors of patient survival and were found in existing prognostic signatures. Thus, determinants of stemness influence the clinical outcome of AML, establishing that LSCs are clinically relevant and not artifacts of xenotransplantation.
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TL;DR: The combination of high nuclease activity with reduced cytotoxicity and the simple design process marks TALENs as a key technology platform for targeted modifications of complex genomes.
Abstract: Sequence-specific nucleases represent valuable tools for precision genome engineering. Traditionally, zinc-finger nucleases (ZFNs) and meganucleases have been used to specifically edit complex genomes. Recently, the DNA binding domains of transcription activator-like effectors (TALEs) from the bacterial pathogen Xanthomonas have been harnessed to direct nuclease domains to desired genomic loci. In this study, we tested a panel of truncation variants based on the TALE protein AvrBs4 to identify TALE nucleases (TALENs) with high DNA cleavage activity. The most favorable parameters for efficient DNA cleavage were determined in vitro and in cellular reporter assays. TALENs were designed to disrupt an EGFP marker gene and the human loci CCR5 and IL2RG. Gene editing was achieved in up to 45% of transfected cells. A side-by-side comparison with ZFNs showed similar gene disruption activities by TALENs but significantly reduced nucleaseassociated cytotoxicities. Moreover, the CCR5specific TALEN revealed only minimal off-target activity at the CCR2 locus as compared to the corresponding ZFN, suggesting that the TALEN platform enables the design of nucleases with single-nucleotide specificity. The combination of high nuclease activity with reduced cytotoxicity and the simple design process marks TALENs as a key technology platform for targeted modifications of complex genomes.
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TL;DR: It is shown that RAN translation across human spinocerebellar ataxia type 8 (SCA8) and myotonic dystrophy type 1 (DM1) CAG expansion transcripts results in the accumulation of SCA8 polyalanine and DM1 polyglutamine expansion proteins in previously established mouse models and human tissue.
Abstract: Trinucleotide expansions cause disease by both protein- and RNA-mediated mechanisms. Unexpectedly, we discovered that CAG expansion constructs express homopolymeric polyglutamine, polyalanine, and polyserine proteins in the absence of an ATG start codon. This repeat-associated non-ATG translation (RAN translation) occurs across long, hairpin-forming repeats in transfected cells or when expansion constructs are integrated into the genome in lentiviral-transduced cells and brains. Additionally, we show that RAN translation across human spinocerebellar ataxia type 8 (SCA8) and myotonic dystrophy type 1 (DM1) CAG expansion transcripts results in the accumulation of SCA8 polyalanine and DM1 polyglutamine expansion proteins in previously established SCA8 and DM1 mouse models and human tissue. These results have implications for understanding fundamental mechanisms of gene expression. Moreover, these toxic, unexpected, homopolymeric proteins now should be considered in pathogenic models of microsatellite disorders.
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TL;DR: The KKR-GF method as mentioned in this paper represents the electronic structure of a system directly and efficiently in terms of its single-particle Green's function (GF), which is in contrast to its original version and many other traditional wave-function-based all-electron band structure methods dealing with periodically ordered solids.
Abstract: The modern version of the KKR (Korringa–Kohn–Rostoker) method represents the electronic structure of a system directly and efficiently in terms of its single-particle Green's function (GF). This is in contrast to its original version and many other traditional wave-function-based all-electron band structure methods dealing with periodically ordered solids. Direct access to the GF results in several appealing features. In addition, a wide applicability of the method is achieved by employing multiple scattering theory. The basic ideas behind the resulting KKR-GF method are outlined and the different techniques to deal with the underlying multiple scattering problem are reviewed. Furthermore, various applications of the KKR-GF method are reviewed in some detail to demonstrate the remarkable flexibility of the approach. Special attention is devoted to the numerous developments of the KKR-GF method, that have been contributed in recent years by a number of work groups, in particular in the following fields: embedding schemes for atoms, clusters and surfaces, magnetic response functions and anisotropy, electronic and spin-dependent transport, dynamical mean field theory, various kinds of spectroscopies, as well as first-principles determination of model parameters.
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TL;DR: The data suggest an important role of 5hmC and Tet3 for DNA methylation reprogramming processes in the mammalian zygote, as detected in mouse, bovine and rabbit zygotes.
Abstract: The epigenomes of early mammalian embryos are extensively reprogrammed to acquire a totipotent developmental potential. A major initial event in this reprogramming is the active loss/demethylation of 5-methylcytosine (5mC) in the zygote. Here, we report on findings that link this active demethylation to molecular mechanisms. We detect 5-hydroxymethylcytosine (5hmC) as a novel modification in mouse, bovine and rabbit zygotes. On zygotic development 5hmC accumulates in the paternal pronucleus along with a reduction of 5mC. A knockdown of the 5hmC generating dioxygenase Tet3 simultaneously affects the patterns of 5hmC and 5mC in the paternal pronucleus. This finding links the loss of 5mC to its conversion into 5hmC. The maternal pronucleus seems to be largely protected against this mechanism by PGC7/Dppa3/Stella, as in PGC7 knockout zygotes 5mC also becomes accessible to oxidation into 5hmC. In summary, our data suggest an important role of 5hmC and Tet3 for DNA methylation reprogramming processes in the mammalian zygote.
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TL;DR: It is reported that peripheral vision is limited with regard to pattern categorization by a distinctly lower representational complexity and processing speed than those imposed on low-level functions and by way of crowding.
Abstract: We summarize the various strands of research on peripheral vision and relate them to theories of form perception. After a historical overview, we describe quantifications of the cortical magnification hypothesis, including an extension of Schwartz's cortical mapping function. The merits of this concept are considered across a wide range of psychophysical tasks, followed by a discussion of its limitations and the need for non-spatial scaling. We also review the eccentricity dependence of other low-level functions including reaction time, temporal resolution, and spatial summation, as well as perimetric methods. A central topic is then the recognition of characters in peripheral vision, both at low and high levels of contrast, and the impact of surrounding contours known as crowding. We demonstrate how Bouma's law, specifying the critical distance for the onset of crowding, can be stated in terms of the retinocortical mapping. The recognition of more complex stimuli, like textures, faces, and scenes, reveals a substantial impact of mid-level vision and cognitive factors. We further consider eccentricity-dependent limitations of learning, both at the level of perceptual learning and pattern category learning. Generic limitations of extrafoveal vision are observed for the latter in categorization tasks involving multiple stimulus classes. Finally, models of peripheral form vision are discussed. We report that peripheral vision is limited with regard to pattern categorization by a distinctly lower representational complexity and processing speed. Taken together, the limitations of cognitive processing in peripheral vision appear to be as significant as those imposed on low-level functions and by way of crowding.
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French Institute of Health and Medical Research1, Rockefeller University2, Paris Descartes University3, University of Debrecen4, Academy of Medical Sciences, United Kingdom5, Charité6, University of Zurich7, Ludwig Maximilian University of Munich8, Rappaport Faculty of Medicine9, Hiroshima University10, Uludağ University11, Boston Children's Hospital12
TL;DR: Whole-exome sequencing reveals activating STAT1 mutations in some patients with autosomal dominant chronic mucocutaneous candidiasis disease.
Abstract: Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD. Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-γ. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-α/β, IFN-γ, IFN-λ, and IL-27. In contrast, the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21. All of these mutations affect the coiled-coil domain and impair the nuclear dephosphorylation of activated STAT1, accounting for their gain-of-function and dominance. Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/β, IFN-γ, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22. Gain-of-function STAT1 alleles therefore cause AD CMCD by impairing IL-17 immunity.
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The Catholic University of America1, University of Groningen2, University of Oviedo3, Favaloro University4, Technische Universität München5, Mental Health Foundation6, Washington University in St. Louis7, Nnamdi Azikiwe University8, Ludwig Maximilian University of Munich9, Albert Einstein College of Medicine10
TL;DR: The adoption of the recommendations presented in this paper across health care systems throughout the world will contribute to a significant improvement in the medical and related psychiatric health outcomes of patients with SMI.
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TL;DR: This meta-analysis integrates the bystander literature from the 1960s to 2010, provides statistical tests of potential moderators, and presents new theoretical and empirical perspectives on the novel finding of non-negative bystander effects in certain dangerous emergencies as well as situations where bystanders are a source of physical support for the potentially intervening individual.
Abstract: Research on bystander intervention has produced a great number of studies showing that the presence of other people in a critical situation reduces the likelihood that an individual will help. As the last systematic review of bystander research was published in 1981 and was not a quantitative meta-analysis in the modern sense, the present meta-analysis updates the knowledge about the bystander effect and its potential moderators. The present work (a) integrates the bystander literature from the 1960s to 2010, (b) provides statistical tests of potential moderators, and (c) presents new theoretical and empirical perspectives on the novel finding of non-negative bystander effects in certain dangerous emergencies as well as situations where bystanders are a source of physical support for the potentially intervening individual. In a fixed effects model, data from over 7,700 participants and 105 independent effect sizes revealed an overall effect size of g = -0.35. The bystander effect was attenuated when situations were perceived as dangerous (compared with non-dangerous), perpetrators were present (compared with non-present), and the costs of intervention were physical (compared with non-physical). This pattern of findings is consistent with the arousal-cost-reward model, which proposes that dangerous emergencies are recognized faster and more clearly as real emergencies, thereby inducing higher levels of arousal and hence more helping. We also identified situations where bystanders provide welcome physical support for the potentially intervening individual and thus reduce the bystander effect, such as when the bystanders were exclusively male, when they were naive rather than passive confederates or only virtually present persons, and when the bystanders were not strangers.
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TL;DR: In vivo imaging and pharmacological experiments show that macrophage-derived reactive oxygen and nitrogen species (ROS and RNS) can trigger mitochondrial pathology and initiate FAD, and suggest that inflammatory axon damage might be spontaneously reversible and thus a potential target for therapy.
Abstract: In multiple sclerosis, a common inflammatory disease of the central nervous system, immune-mediated axon damage is responsible for permanent neurological deficits. How axon damage is initiated is not known. Here we use in vivo imaging to identify a previously undescribed variant of axon damage in a mouse model of multiple sclerosis. This process, termed 'focal axonal degeneration' (FAD), is characterized by sequential stages, beginning with focal swellings and progressing to axon fragmentation. Notably, most swollen axons persist unchanged for several days, and some recover spontaneously. Early stages of FAD can be observed in axons with intact myelin sheaths. Thus, contrary to the classical view, demyelination-a hallmark of multiple sclerosis-is not a prerequisite for axon damage. Instead, focal intra-axonal mitochondrial pathology is the earliest ultrastructural sign of damage, and it precedes changes in axon morphology. Molecular imaging and pharmacological experiments show that macrophage-derived reactive oxygen and nitrogen species (ROS and RNS) can trigger mitochondrial pathology and initiate FAD. Indeed, neutralization of ROS and RNS rescues axons that have already entered the degenerative process. Finally, axonal changes consistent with FAD can be detected in acute human multiple sclerosis lesions. In summary, our data suggest that inflammatory axon damage might be spontaneously reversible and thus a potential target for therapy.
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TL;DR: In this article, the authors studied the properties of giant star-forming clumps in five z ~ 2 star forming disks with deep SINFONI AO spectroscopy at the ESO VLT.
Abstract: We have studied the properties of giant star-forming clumps in five z ~ 2 star-forming disks with deep SINFONI AO spectroscopy at the ESO VLT. The clumps reside in disk regions where the Toomre Q-parameter is below unity, consistent with their being bound and having formed from gravitational instability. Broad Hα/[N II] line wings demonstrate that the clumps are launching sites of powerful outflows. The inferred outflow rates are comparable to or exceed the star formation rates, in one case by a factor of eight. Typical clumps may lose a fraction of their original gas by feedback in a few hundred million years, allowing them to migrate into the center. The most active clumps may lose much of their mass and disrupt in the disk. The clumps leave a modest imprint on the gas kinematics. Velocity gradients across the clumps are 10-40 km s–1 kpc–1, similar to the galactic rotation gradients. Given beam smearing and clump sizes, these gradients may be consistent with significant rotational support in typical clumps. Extreme clumps may not be rotationally supported; either they are not virialized or they are predominantly pressure supported. The velocity dispersion is spatially rather constant and increases only weakly with star formation surface density. The large velocity dispersions may be driven by the release of gravitational energy, either at the outer disk/accreting streams interface, and/or by the clump migration within the disk. Spatial variations in the inferred gas phase oxygen abundance are broadly consistent with inside-out growing disks, and/or with inward migration of the clumps.