Showing papers by "University of Tübingen published in 2013"
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TL;DR: Despite the high accuracy of GBDP-based DDH prediction, inferences from limited empirical data are always associated with a certain degree of uncertainty, so it is crucial to enrich in-silico DDH replacements with confidence-interval estimation, enabling the user to statistically evaluate the outcomes.
Abstract: For the last 25 years species delimitation in prokaryotes (Archaea and Bacteria) was to a large extent based on DNA-DNA hybridization (DDH), a tedious lab procedure designed in the early 1970s that served its purpose astonishingly well in the absence of deciphered genome sequences. With the rapid progress in genome sequencing time has come to directly use the now available and easy to generate genome sequences for delimitation of species. GBDP (Genome Blast Distance Phylogeny) infers genome-to-genome distances between pairs of entirely or partially sequenced genomes, a digital, highly reliable estimator for the relatedness of genomes. Its application as an in-silico replacement for DDH was recently introduced. The main challenge in the implementation of such an application is to produce digital DDH values that must mimic the wet-lab DDH values as close as possible to ensure consistency in the Prokaryotic species concept. Correlation and regression analyses were used to determine the best-performing methods and the most influential parameters. GBDP was further enriched with a set of new features such as confidence intervals for intergenomic distances obtained via resampling or via the statistical models for DDH prediction and an additional family of distance functions. As in previous analyses, GBDP obtained the highest agreement with wet-lab DDH among all tested methods, but improved models led to a further increase in the accuracy of DDH prediction. Confidence intervals yielded stable results when inferred from the statistical models, whereas those obtained via resampling showed marked differences between the underlying distance functions. Despite the high accuracy of GBDP-based DDH prediction, inferences from limited empirical data are always associated with a certain degree of uncertainty. It is thus crucial to enrich in-silico DDH replacements with confidence-interval estimation, enabling the user to statistically evaluate the outcomes. Such methodological advancements, easily accessible through the web service at http://ggdc.dsmz.de
, are crucial steps towards a consistent and truly genome sequence-based classification of microorganisms.
4,411 citations
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TL;DR: Recent progress on drug metabolism activity profiles, interindividual variability and regulation of expression, and the functional and clinical impact of genetic variation in drug metabolizing P450s are reviewed.
2,832 citations
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University of Tartu1, American Museum of Natural History2, University of Gothenburg3, University of Aberdeen4, James Hutton Institute5, Cooperative Institute for Research in Environmental Sciences6, University of California, Berkeley7, Aberystwyth University8, Estonian University of Life Sciences9, Spanish National Research Council10, Royal Botanic Gardens11, Academy of Sciences of the Czech Republic12, Swedish University of Agricultural Sciences13, University of Tennessee14, University of Helsinki15, Stanford University16, Ludwig Maximilian University of Munich17, University of Toronto18, University of Florida19, University of New Mexico20, University of Tübingen21
TL;DR: All fungal species represented by at least two ITS sequences in the international nucleotide sequence databases are now given a unique, stable name of the accession number type, and the term ‘species hypothesis’ (SH) is introduced for the taxa discovered in clustering on different similarity thresholds.
Abstract: The nuclear ribosomal internal transcribed spacer (ITS) region is the formal fungal barcode and in most cases the marker of choice for the exploration of fungal diversity in environmental samples. Two problems are particularly acute in the pursuit of satisfactory taxonomic assignment of newly generated ITS sequences: (i) the lack of an inclusive, reliable public reference data set and (ii) the lack of means to refer to fungal species, for which no Latin name is available in a standardized stable way. Here, we report on progress in these regards through further development of the UNITE database (http://unite.ut.ee) for molecular identification of fungi. All fungal species represented by at least two ITS sequences in the international nucleotide sequence databases are now given a unique, stable name of the accession number type (e.g. Hymenoscyphus pseudoalbidus|GU586904|SH133781.05FU), and their taxonomic and ecological annotations were corrected as far as possible through a distributed, third-party annotation effort. We introduce the term ‘species hypothesis’ (SH) for the taxa discovered in clustering on different similarity thresholds (97–99%). An automatically or manually designated sequence is chosen to represent each such SH. These reference sequences are released (http://unite.ut.ee/repository.php) for use by the scientific community in, for example, local sequence similarity searches and in the QIIME pipeline. The system and the data will be updated automatically as the number of public fungal ITS sequences grows. We invite everybody in the position to improve the annotation or metadata associated with their particular fungal lineages of expertise to do so through the new Web-based sequence management system in UNITE.
2,605 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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TL;DR: This review aims to comprehensively cover the field of "sleep and memory" research by providing a historical perspective on concepts and a discussion of more recent key findings.
Abstract: Over more than a century of research has established the fact that sleep benefits the retention of memory. In this review we aim to comprehensively cover the field of "sleep and memory" research by providing a historical perspective on concepts and a discussion of more recent key findings. Whereas initial theories posed a passive role for sleep enhancing memories by protecting them from interfering stimuli, current theories highlight an active role for sleep in which memories undergo a process of system consolidation during sleep. Whereas older research concentrated on the role of rapid-eye-movement (REM) sleep, recent work has revealed the importance of slow-wave sleep (SWS) for memory consolidation and also enlightened some of the underlying electrophysiological, neurochemical, and genetic mechanisms, as well as developmental aspects in these processes. Specifically, newer findings characterize sleep as a brain state optimizing memory consolidation, in opposition to the waking brain being optimized for encoding of memories. Consolidation originates from reactivation of recently encoded neuronal memory representations, which occur during SWS and transform respective representations for integration into long-term memory. Ensuing REM sleep may stabilize transformed memories. While elaborated with respect to hippocampus-dependent memories, the concept of an active redistribution of memory representations from networks serving as temporary store into long-term stores might hold also for non-hippocampus-dependent memory, and even for nonneuronal, i.e., immunological memories, giving rise to the idea that the offline consolidation of memory during sleep represents a principle of long-term memory formation established in quite different physiological systems.
1,964 citations
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23 Sep 2013TL;DR: This work presents a simple but effective gradient-based approach that can be exploited to systematically assess the security of several, widely-used classification algorithms against evasion attacks.
Abstract: In security-sensitive applications, the success of machine learning depends on a thorough vetting of their resistance to adversarial data. In one pertinent, well-motivated attack scenario, an adversary may attempt to evade a deployed system at test time by carefully manipulating attack samples. In this work, we present a simple but effective gradient-based approach that can be exploited to systematically assess the security of several, widely-used classification algorithms against evasion attacks. Following a recently proposed framework for security evaluation, we simulate attack scenarios that exhibit different risk levels for the classifier by increasing the attacker's knowledge of the system and her ability to manipulate attack samples. This gives the classifier designer a better picture of the classifier performance under evasion attacks, and allows him to perform a more informed model selection (or parameter setting). We evaluate our approach on the relevant security task of malware detection in PDF files, and show that such systems can be easily evaded. We also sketch some countermeasures suggested by our analysis.
1,667 citations
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TL;DR: It is demonstrated that the SASP can cause paracrine senescence and impact on tumour suppression andSenescence in vivo and TGF-β ligands play a major role by regulating p15INK4b and p21CIP1.
Abstract: Oncogene-induced senescence (OIS) is crucial for tumour suppression. Senescent cells implement a complex pro-inflammatory response termed the senescence-associated secretory phenotype (SASP). The SASP reinforces senescence, activates immune surveillance and paradoxically also has pro-tumorigenic properties. Here, we present evidence that the SASP can also induce paracrine senescence in normal cells both in culture and in human and mouse models of OIS in vivo. Coupling quantitative proteomics with small-molecule screens, we identified multiple SASP components mediating paracrine senescence, including TGF-β family ligands, VEGF, CCL2 and CCL20. Amongst them, TGF-β ligands play a major role by regulating p15(INK4b) and p21(CIP1). Expression of the SASP is controlled by inflammasome-mediated IL-1 signalling. The inflammasome and IL-1 signalling are activated in senescent cells and IL-1α expression can reproduce SASP activation, resulting in senescence. Our results demonstrate that the SASP can cause paracrine senescence and impact on tumour suppression and senescence in vivo.
1,468 citations
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TL;DR: As a unifying pathogenic principle, the prion paradigm suggests broadly relevant therapeutic directions for a large class of currently intractable diseases.
Abstract: For several decades scientists have speculated that the key to understanding age-related neurodegenerative disorders may be found in the unusual biology of the prion diseases. Recently, owing largely to the advent of new disease models, this hypothesis has gained experimental momentum. In a remarkable variety of diseases, specific proteins have been found to misfold and aggregate into seeds that structurally corrupt like proteins, causing them to aggregate and form pathogenic assemblies ranging from small oligomers to large masses of amyloid. Proteinaceous seeds can therefore serve as self-propagating agents for the instigation and progression of disease. Alzheimer's disease and other cerebral proteopathies seem to arise from the de novo misfolding and sustained corruption of endogenous proteins, whereas prion diseases can also be infectious in origin. However, the outcome in all cases is the functional compromise of the nervous system, because the aggregated proteins gain a toxic function and/or lose their normal function. As a unifying pathogenic principle, the prion paradigm suggests broadly relevant therapeutic directions for a large class of currently intractable diseases.
1,318 citations
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TL;DR: Although in theory every CpG can change its methylation state, the results suggest that only a fraction does so as part of coordinated regulatory programs, which highlights the general inefficiency of whole-genome bisulphite sequencing.
Abstract: DNA methylation is a defining feature of mammalian cellular identity and essential for normal development 1,2 . Most cell types, except germ cells and pre-implantation embryos 3–5 , display relatively stable DNA methylation patterns with 70–80% of all CpGs being methylated 6 . Despite recent advances we still have a too limited understanding of when, where and how many CpGs participate in genomic regulation. Here we report the in depth analysis of 42 whole genome bisulfite sequencing (WGBS) data sets across 30 diverse human cell and tissue types. We observe dynamic regulation for only 21.8% of autosomal CpGs within a normal developmental context, a majority of which are distal to transcription start sites. These dynamic CpGs co-localize with gene regulatory elements, particularly enhancers and transcription factor binding sites (TFBS), which allow identification of key lineage specific regulators. In addition, differentially methylated
1,185 citations
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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.
1,085 citations
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TL;DR: It is shown that long-term treatment with metformin starting at middle age extends healthspan and lifespan in male mice, while a higher dose (1% w/w) was toxic.
Abstract: Metformin is a drug commonly prescribed to treat patients with type 2 diabetes. Here we show that long-term treatment with metformin (0.1% w/w in diet) starting at middle age extends healthspan and lifespan in male mice, while a higher dose (1% w/w) was toxic. Treatment with metformin mimics some of the benefits of calorie restriction, such as improved physical performance, increased insulin sensitivity, and reduced low-density lipoprotein and cholesterol levels without a decrease in caloric intake. At a molecular level, metformin increases AMP-activated protein kinase activity and increases antioxidant protection, resulting in reductions in both oxidative damage accumulation and chronic inflammation. Our results indicate that these actions may contribute to the beneficial effects of metformin on healthspan and lifespan. These findings are in agreement with current epidemiological data and raise the possibility of metformin-based interventions to promote healthy aging.
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University of Florida1, University of Bonn2, Goddard Institute for Space Studies3, Commonwealth Scientific and Industrial Research Organisation4, Institut national de la recherche agronomique5, Agro ParisTech6, Michigan State University7, Blaise Pascal University8, International Water Management Institute9, CGIAR10, University of Leeds11, Counterintelligence Field Activity12, University of Tübingen13, University of Alberta14, International Atomic Energy Agency15, University of Reading16, University of Guelph17, University of Hohenheim18, Joint Global Change Research Institute19, Potsdam Institute for Climate Impact Research20, Indian Agricultural Research Institute21, Aarhus University22, Rothamsted Research23, Washington State University24, Wageningen University and Research Centre25, Chinese Academy of Sciences26, International Trademark Association27, Texas A&M University28
TL;DR: In this article, the authors present the largest standardized model intercomparison for climate change impacts so far, finding that individual crop models are able to simulate measured wheat grain yields accurately under a range of environments, particularly if the input information is sufficient.
Abstract: Projections of climate change impacts on crop yields are inherently uncertain(1). Uncertainty is often quantified when projecting future greenhouse gas emissions and their influence on climate(2). However, multi-model uncertainty analysis of crop responses to climate change is rare because systematic and objective comparisons among process-based crop simulation models(1,3) are difficult(4). Here we present the largest standardized model intercomparison for climate change impacts so far. We found that individual crop models are able to simulate measured wheat grain yields accurately under a range of environments, particularly if the input information is sufficient. However, simulated climate change impacts vary across models owing to differences in model structures and parameter values. A greater proportion of the uncertainty in climate change impact projections was due to variations among crop models than to variations among downscaled general circulation models. Uncertainties in simulated impacts increased with CO2 concentrations and associated warming. These impact uncertainties can be reduced by improving temperature and CO2 relationships in models and better quantified through use of multi-model ensembles. Less uncertainty in describing how climate change may affect agricultural productivity will aid adaptation strategy development and policymaking.
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TL;DR: A meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, and identified 29,807 SNPs for further genotyping suggests that more than 1,000 additional loci are involved in breast cancer susceptibility.
Abstract: Breast cancer is the most common cancer among women Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ∼9% of the familial risk of the disease We report here a meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping These SNPs were genotyped in 45,290 cases and 41,880 controls of European ancestry from 41 studies in the Breast Cancer Association Consortium (BCAC) The SNPs were genotyped as part of a collaborative genotyping experiment involving four consortia (Collaborative Oncological Gene-environment Study, COGS) and used a custom Illumina iSelect genotyping array, iCOGS, comprising more than 200,000 SNPs We identified SNPs at 41 new breast cancer susceptibility loci at genome-wide significance (P < 5 × 10(-8)) Further analyses suggest that more than 1,000 additional loci are involved in breast cancer susceptibility
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TL;DR: The theoretical background defining its strength and directionality, a systematic analysis of its occurrence and interaction geometries in protein-ligand complexes, and recent examples where halogen bonding has been successfully harnessed for lead identification and optimization are provided.
Abstract: Halogen bonding has been known in material science for decades, but until recently, halogen bonds in protein–ligand interactions were largely the result of serendipitous discovery rather than rational design. In this Perspective, we provide insights into the phenomenon of halogen bonding, with special focus on its role in drug discovery. We summarize the theoretical background defining its strength and directionality, provide a systematic analysis of its occurrence and interaction geometries in protein–ligand complexes, and give recent examples where halogen bonding has been successfully harnessed for lead identification and optimization. In light of these data, we discuss the potential and limitations of exploiting halogen bonds for molecular recognition and rational drug design.
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TL;DR: In this paper, the authors investigated teachers' pedagogical content knowledge, professional beliefs, work-related motivation, and self-regulation as aspects of their professional competence and examined how these aspects impact instruction and, in turn, student outcomes.
Abstract: This study investigates teachers’ pedagogical content knowledge, professional beliefs, work-related motivation, and self-regulation as aspects of their professional competence. Specifically, it examines how these aspects impact instruction and, in turn, student outcomes. In a nationally representative sample of 194 German secondary school mathematics classes, multiple measures were used to assess teacher competence, instructional quality, and students’ achievement and motivation. The effect of teachers’ professional competence on student outcomes was estimated in a 1-year repeated-measures design. Two-level structural equation models revealed positive effects of teachers’ pedagogical content knowledge, enthusiasm for teaching, and self-regulatory skills on instructional quality, which in turn affected student outcomes. In contrast, teachers’ general academic ability did not affect their instruction. The multidimensional model of teachers’ professional competence introduced in this article seems suited to stimulate further research on the personal indicators of teacher quality.
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Aix-Marseille University1, Scripps Health2, Gyeongsang National University3, University of Florida4, Columbia University5, National Health Service6, University of Tübingen7, Medical University of Vienna8, Medical University of Graz9, Duke University10, Harvard University11, MedStar Washington Hospital Center12, University of Patras13, University of Florence14, University of Geneva15, University of Freiburg16, Ludwig Maximilian University of Munich17
TL;DR: An updated consensus document reviews the available evidence and proposes cutoff values for high and low on-treatment platelet reactivity to ADP that might be used in future investigations of personalized antiplatelet therapy and proposes a therapeutic window concept for P2Y12 inhibitor therapy.
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French Institute of Health and Medical Research1, University of Cambridge2, Case Western Reserve University3, Columbia University4, University of Bristol5, University of Sydney6, Ghent University7, Harvard University8, University of Copenhagen9, University of Tübingen10, Centre national de la recherche scientifique11, University of Bonn12, University of Göttingen13, Medical University of Vienna14, Umeå University15, University of Liège16, University of Freiburg17, University of California, Davis18, Mayo Clinic19, Anschutz Medical Campus20, Royal Melbourne Hospital21, University of Chicago22, Karolinska Institutet23
TL;DR: Cardiorespiratory data showed a consistent and previously unrecognised pattern whereby rapid breathing developed after secondary generalised tonic-clonic seizure, followed within 3 min by transient or terminal cardiore Spiratory dysfunction, probably aggravated by suboptimum supervision and possibly by antiepileptic drug withdrawal.
Abstract: Summary Background Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in people with chronic refractory epilepsy Very rarely, SUDEP occurs in epilepsy monitoring units, providing highly informative data for its still elusive pathophysiology The MORTEMUS study expanded these data through comprehensive evaluation of cardiorespiratory arrests encountered in epilepsy monitoring units worldwide Methods Between Jan 1, 2008, and Dec 29, 2009, we did a systematic retrospective survey of epilepsy monitoring units located in Europe, Israel, Australia, and New Zealand, to retrieve data for all cardiorespiratory arrests recorded in these units and estimate their incidence Epilepsy monitoring units from other regions were invited to report similar cases to further explore the mechanisms An expert panel reviewed data, including video electroencephalogram (VEEG) and electrocardiogram material at the time of cardiorespiratory arrests whenever available Findings 147 (92%) of 160 units responded to the survey 29 cardiorespiratory arrests, including 16 SUDEP (14 at night), nine near SUDEP, and four deaths from other causes, were reported Cardiorespiratory data, available for ten cases of SUDEP, showed a consistent and previously unrecognised pattern whereby rapid breathing (18–50 breaths per min) developed after secondary generalised tonic-clonic seizure, followed within 3 min by transient or terminal cardiorespiratory dysfunction Where transient, this dysfunction later recurred with terminal apnoea occurring within 11 min of the end of the seizure, followed by cardiac arrest SUDEP incidence in adult epilepsy monitoring units was 5·1 (95% CI 2·6–9·2) per 1000 patient-years, with a risk of 1·2 (0·6–2·1) per 10 000 VEEG monitorings, probably aggravated by suboptimum supervision and possibly by antiepileptic drug withdrawal Interpretation SUDEP in epilepsy monitoring units primarily follows an early postictal, centrally mediated, severe alteration of respiratory and cardiac function induced by generalised tonic-clonic seizure, leading to immediate death or a short period of partly restored cardiorespiratory function followed by terminal apnoea then cardiac arrest Improved supervision is warranted in epilepsy monitoring units, in particular during night time Funding Commission of European Affairs of the International League Against Epilepsy
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TL;DR: The data indicate that metabolic alterations, including sugar metabolites, amino acids, and choline-containing phospholipids, are associated early on with a higher risk of T2D.
Abstract: Metabolomic discovery of biomarkers of type 2 diabetes (T2D) risk may reveal etiological pathways and help to identify individuals at risk for disease. We prospectively investigated the association between serum metabolites measured by targeted metabolomics and risk of T2D in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam (27,548 adults) among all incident cases of T2D (n = 800, mean follow-up 7 years) and a randomly drawn subcohort (n = 2,282). Flow injection analysis tandem mass spectrometry was used to quantify 163 metabolites, including acylcarnitines, amino acids, hexose, and phospholipids, in baseline serum samples. Serum hexose; phenylalanine; and diacyl-phosphatidylcholines C32:1, C36:1, C38:3, and C40:5 were independently associated with increased risk of T2D and serum glycine; sphingomyelin C16:1; acyl-alkyl-phosphatidylcholines C34:3, C40:6, C42:5, C44:4, and C44:5; and lysophosphatidylcholine C18:2 with decreased risk. Variance of the metabolites was largely explained by two metabolite factors with opposing risk associations (factor 1 relative risk in extreme quintiles 0.31 [95% CI 0.21–0.44], factor 2 3.82 [2.64–5.52]). The metabolites significantly improved T2D prediction compared with established risk factors. They were further linked to insulin sensitivity and secretion in the Tubingen Family study and were partly replicated in the independent KORA (Cooperative Health Research in the Region of Augsburg) cohort. The data indicate that metabolic alterations, including sugar metabolites, amino acids, and choline-containing phospholipids, are associated early on with a higher risk of T2D.
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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: Evaluated efficacy of daily brain–machine interface (BMI) training to increase the hypothesized beneficial effects of physiotherapy alone in patients with severe paresis in a double‐blind sham‐controlled design proof of concept study.
Abstract: OBJECTIVE: Chronic stroke patients with severe hand weakness respond poorly to rehabilitation efforts. Here, we evaluated efficacy of daily brain-machine interface (BMI) training to increase the hypothesized beneficial effects of physiotherapy alone in patients with severe paresis in a double-blind sham-controlled design proof of concept study. METHODS: Thirty-two chronic stroke patients with severe hand weakness were randomly assigned to 2 matched groups and participated in 17.8 ± 1.4 days of training rewarding desynchronization of ipsilesional oscillatory sensorimotor rhythms with contingent online movements of hand and arm orthoses (experimental group, n = 16). In the control group (sham group, n = 16), movements of the orthoses occurred randomly. Both groups received identical behavioral physiotherapy immediately following BMI training or the control intervention. Upper limb motor function scores, electromyography from arm and hand muscles, placebo-expectancy effects, and functional magnetic resonance imaging (fMRI) blood oxygenation level-dependent activity were assessed before and after intervention. RESULTS: A significant group × time interaction in upper limb (combined hand and modified arm) Fugl-Meyer assessment (cFMA) motor scores was found. cFMA scores improved more in the experimental than in the control group, presenting a significant improvement of cFMA scores (3.41 ± 0.563-point difference, p = 0.018) reflecting a clinically meaningful change from no activity to some in paretic muscles. cFMA improvements in the experimental group correlated with changes in fMRI laterality index and with paretic hand electromyography activity. Placebo-expectancy scores were comparable for both groups. INTERPRETATION: The addition of BMI training to behaviorally oriented physiotherapy can be used to induce functional improvements in motor function in chronic stroke patients without residual finger movements and may open a new door in stroke neurorehabilitation.
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TL;DR: The Cherenkov Telescope Array (CTA) as discussed by the authors is a very high-energy (VHE) gamma ray observatory with an international collaboration with more than 1000 members from 27 countries in Europe, Asia, Africa and North and South America.
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University of California, Los Angeles1, University of Sydney2, Pfizer3, Radboud University Nijmegen4, Netherlands Cancer Institute5, University of Barcelona6, University of Tübingen7, National and Kapodistrian University of Athens8, Washington University in St. Louis9, Ohio State University10, Charité11, University of Alberta12, Peter MacCallum Cancer Centre13, Mount Vernon Hospital14, University of Pittsburgh15, University of Kiel16
TL;DR: In this article, the authors evaluated overall survival (OS) and other safety and efficacy end points in patients with advanced melanoma treated with tremelimumab or standard-of-care chemotherapy.
Abstract: Purpose In phase I/II trials, the cytotoxic T lymphocyte–associated antigen-4–blocking monoclonal antibody tremelimumab induced durable responses in a subset of patients with advanced melanoma. This phase III study evaluated overall survival (OS) and other safety and efficacy end points in patients with advanced melanoma treated with tremelimumab or standard-of-care chemotherapy. Patients and Methods Patients with treatment-naive, unresectable stage IIIc or IV melanoma were randomly assigned at a ratio of one to one to tremelimumab (15 mg/kg once every 90 days) or physician's choice of standard-of-care chemotherapy (temozolomide or dacarbazine). Results In all, 655 patients were enrolled and randomly assigned. The test statistic crossed the prespecified futility boundary at second interim analysis after 340 deaths, but survival follow-up continued. At final analysis with 534 events, median OS by intent to treat was 12.6 months (95% CI, 10.8 to 14.3) for tremelimumab and 10.7 months (95% CI, 9.36 to 11.96)...
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TL;DR: It is shown in sleeping humans that auditory stimulation in phase with the ongoing rhythmic occurrence of slow oscillation up states profoundly enhances theSlow oscillation rhythm, phase-coupled spindle activity, and, consequently, the consolidation of declarative memory.
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TL;DR: In these times of regional and global species declines, the task of causally linking knowledge about the molecular actions of pesticides to their possible interference with biological processes is challenged in order to develop reliable predictions about the consequences of pesticide use, and misuse, in a rapidly changing world.
Abstract: During the past 50 years, the human population has more than doubled and global agricultural production has similarly risen. However, the productive arable area has increased by just 10%; thus the increased use of pesticides has been a consequence of the demands of human population growth, and its impact has reached global significance. Although we often know a pesticide′s mode of action in the target species, we still largely do not understand the full impact of unintended side effects on wildlife, particularly at higher levels of biological organization: populations, communities, and ecosystems. In these times of regional and global species declines, we are challenged with the task of causally linking knowledge about the molecular actions of pesticides to their possible interference with biological processes, in order to develop reliable predictions about the consequences of pesticide use, and misuse, in a rapidly changing world.
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German Cancer Research Center1, Heidelberg University2, Max Planck Society3, University of Cambridge4, Russian Academy5, McGill University6, University of Amsterdam7, University of Würzburg8, University Hospital Heidelberg9, University of Tübingen10, Stanford University11, Broad Institute12, Harvard University13, University of Toronto14, New York University15, Johns Hopkins University16, Boston Children's Hospital17, University of Münster18, University of Düsseldorf19, McGill University Health Centre20
TL;DR: Recurrent activating mutations in FGFR1 and PTPN11 and new NTRK2 fusion genes in non-cerebellar tumors and new BRAF-activating changes were observed, indicating that pilocytic astrocytoma is predominantly a single-pathway disease.
Abstract: Pilocytic astrocytoma, the most common childhood brain tumor, is typically associated with mitogen-activated protein kinase (MAPK) pathway alterations. Surgically inaccessible midline tumors are therapeutically challenging, showing sustained tendency for progression and often becoming a chronic disease with substantial morbidities. Here we describe whole-genome sequencing of 96 pilocytic astrocytomas, with matched RNA sequencing (n = 73), conducted by the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. We identified recurrent activating mutations in FGFR1 and PTPN11 and new NTRK2 fusion genes in non-cerebellar tumors. New BRAF-activating changes were also observed. MAPK pathway alterations affected all tumors analyzed, with no other significant mutations identified, indicating that pilocytic astrocytoma is predominantly a single-pathway disease. Notably, we identified the same FGFR1 mutations in a subset of H3F3A-mutated pediatric glioblastoma with additional alterations in the NF1 gene. Our findings thus identify new potential therapeutic targets in distinct subsets of pilocytic astrocytoma and childhood glioblastoma.
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TL;DR: This paper provides a survey of existing approaches to human-aware navigation and offers a general classification scheme for the presented methods.
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University Medical Center Utrecht1, Radboud University Nijmegen Medical Centre2, Maastricht University Medical Centre3, University of Barcelona4, Goethe University Frankfurt5, University of Tübingen6, La Roche College7, Hospital Universitario de Canarias8, Creighton University Medical Center9, Erasmus University Rotterdam10, Harborview Medical Center11, State University of New York System12, Medical University of Vienna13, Hacettepe University14
TL;DR: The overall attributable mortality of ventilator-associated pneumonia is 13%, with higher rates for surgical patients and patients with a mid-range severity score at admission, which is mainly caused by prolonged exposure to the risk of dying due to increased length of ICU stay.
Abstract: Summary Background Estimating attributable mortality of ventilator-associated pneumonia has been hampered by confounding factors, small sample sizes, and the difficulty of doing relevant subgroup analyses. We estimated the attributable mortality using the individual original patient data of published randomised trials of ventilator-associated pneumonia prevention. Methods We identified relevant studies through systematic review. We analysed individual patient data in a one-stage meta-analytical approach (in which we defined attributable mortality as the ratio between the relative risk reductions [RRR] of mortality and ventilator-associated pneumonia) and in competing risk analyses. Predefined subgroups included surgical, trauma, and medical patients, and patients with different categories of severity of illness scores. Findings Individual patient data were available for 6284 patients from 24 trials. The overall attributable mortality was 13%, with higher mortality rates in surgical patients and patients with mid-range severity scores at admission (ie, acute physiology and chronic health evaluation score [APACHE] 20–29 and simplified acute physiology score [SAPS 2] 35–58). Attributable mortality was close to zero in trauma, medical patients, and patients with low or high severity of illness scores. Competing risk analyses could be done for 5162 patients from 19 studies, and the overall daily hazard for intensive care unit (ICU) mortality after ventilator-associated pneumonia was 1·13 (95% CI 0·98–1·31). The overall daily risk of discharge after ventilator-associated pneumonia was 0·74 (0·68–0·80), leading to an overall cumulative risk for dying in the ICU of 2·20 (1·91–2·54). Highest cumulative risks for dying from ventilator-associated pneumonia were noted for surgical patients (2·97, 95% CI 2·24–3·94) and patients with mid-range severity scores at admission (ie, cumulative risks of 2·49 [1·81–3·44] for patients with APACHE scores of 20–29 and 2·72 [1·95–3·78] for those with SAPS 2 scores of 35–58). Interpretation The overall attributable mortality of ventilator-associated pneumonia is 13%, with higher rates for surgical patients and patients with a mid-range severity score at admission. Attributable mortality is mainly caused by prolonged exposure to the risk of dying due to increased length of ICU stay. Funding None.
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Heidelberg University1, German Cancer Research Center2, Stanford University3, University of Copenhagen4, Centre national de la recherche scientifique5, University of Tübingen6, University of Würzburg7, Institute of Cancer Research8, University of Cambridge9, McGill University10, Necker-Enfants Malades Hospital11
TL;DR: It is shown that reduced H3K27me3 levels and DNA hypomethylation act in concert to activate gene expression in K27M mutant pHGGs, and it is demonstrated that this is caused by aberrant recruitment of the PRC2 complex to K 27M mutant H3.3.
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TL;DR: The B19V capsid protein VP1 is a powerful inhibitor of host cell Na+/K+ ATPase, an effect at least partially due to phospholipase A2 (PLA2) dependent formation of lysophosphatidylcholine.
Abstract: Background/Aims: Human parvovirus B19 (B19V) may cause inflammatory cardiomyopathy (iCMP) which is accompanied by endothelial dysfunction. The B19V capsid protein
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Stig E. Bojesen1, Stig E. Bojesen2, Karen A. Pooley3, Sharon E. Johnatty4 +452 more•Institutions (129)
TL;DR: Using the Illumina custom genotyping array iCOGs, SNPs at the TERT locus in breast, ovarian and BRCA1 mutation carrier cancer cases and controls and leukocyte telomere measurements are analyzed to find associations cluster into three independent peaks.
Abstract: TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOG, we analyzed similar to 480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 x 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 x 10(-8)) and BRCA1 mutation carrier (P = 1.1 x 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 x 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 x 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 x 10(-12)) and BRCA1 mutation carrier (P = 1.6 x 10-14) breast and invasive ovarian (P = 1.3 x 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.