Showing papers by "University of Bonn published in 2013"
Jean-Charles Lambert1, Jean-Charles Lambert2, Jean-Charles Lambert3, Carla A. Ibrahim-Verbaas4 +212 more•Institutions (75)
TL;DR: In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10−8) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.
Abstract: Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10−8) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.
3,726 citations
TL;DR: The complex regulatory mechanisms that facilitate a balanced but effective inflammasome-mediated immune response are discussed, and the similarities to another molecular signalling platform — the apoptosome — that monitors cellular health are highlighted.
Abstract: Inflammasomes are key signalling platforms that detect pathogenic microorganisms and sterile stressors, and that activate the highly pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18. In this Review, we discuss the complex regulatory mechanisms that facilitate a balanced but effective inflammasome-mediated immune response, and we highlight the similarities to another molecular signalling platform - the apoptosome - that monitors cellular health. Extracellular regulatory mechanisms are discussed, as well as the intracellular control of inflammasome assembly, for example, via ion fluxes, free radicals and autophagy.
2,361 citations
Paris Diderot University1, University of Barcelona2, University of Padua3, Autonomous University of Barcelona4, Université libre de Bruxelles5, University of Paris6, University of Bologna7, University of Cambridge8, University of Turin9, Katholieke Universiteit Leuven10, Goethe University Frankfurt11, University of Bonn12
TL;DR: Diagnostic criteria for ACLF was established and showed that it is distinct from AD, based not only on the presence of organ failure(s) and high mortality rate but also on age, precipitating events, and systemic inflammation.
2,110 citations
TL;DR: In dit artikel zullen the authors LOFAR beschrijven: van de astronomische mogelijkheden met de nieuwe telescoop tot aan een nadere technische beshrijving of het instrument.
Abstract: LOFAR, the LOw-Frequency ARray, is a new-generation radio interferometer constructed in the north of the Netherlands and across europe. Utilizing a novel phased-array design, LOFAR covers the largely unexplored low-frequency range from 10-240 MHz and provides a number of unique observing capabilities. Spreading out from a core located near the village of Exloo in the northeast of the Netherlands, a total of 40 LOFAR stations are nearing completion. A further five stations have been deployed throughout Germany, and one station has been built in each of France, Sweden, and the UK. Digital beam-forming techniques make the LOFAR system agile and allow for rapid repointing of the telescope as well as the potential for multiple simultaneous observations. With its dense core array and long interferometric baselines, LOFAR achieves unparalleled sensitivity and angular resolution in the low-frequency radio regime. The LOFAR facilities are jointly operated by the International LOFAR Telescope (ILT) foundation, as an observatory open to the global astronomical community. LOFAR is one of the first radio observatories to feature automated processing pipelines to deliver fully calibrated science products to its user community. LOFAR's new capabilities, techniques and modus operandi make it an important pathfinder for the Square Kilometre Array (SKA). We give an overview of the LOFAR instrument, its major hardware and software components, and the core science objectives that have driven its design. In addition, we present a selection of new results from the commissioning phase of this new radio observatory.
2,067 citations
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
TL;DR: The evidence supports the need for considerable investment in adaptation and mitigation actions toward a “climate-smart food system” that is more resilient to climate change influences on food security.
Abstract: Climate change could potentially interrupt progress toward a world without hunger. A robust and coherent global pattern is discernible of the impacts of climate change on crop productivity that could have consequences for food availability. The stability of whole food systems may be at risk under climate change because of short-term variability in supply. However, the potential impact is less clear at regional scales, but it is likely that climate variability and change will exacerbate food insecurity in areas currently vulnerable to hunger and undernutrition. Likewise, it can be anticipated that food access and utilization will be affected indirectly via collateral effects on household and individual incomes, and food utilization could be impaired by loss of access to drinking water and damage to health. The evidence supports the need for considerable investment in adaptation and mitigation actions toward a “climate-smart food system” that is more resilient to climate change influences on food security.
2,050 citations
TL;DR: The role of the NLRP3/caspase-1 axis in the pathogenesis of Alzheimer's disease was investigated in this article, which showed an important role for the inflammasome.
Abstract: Alzheimer's disease is the world's most common dementing illness. Deposition of amyloid-β peptide drives cerebral neuroinflammation by activating microglia. Indeed, amyloid-β activation of the NLRP3 inflammasome in microglia is fundamental for interleukin-1β maturation and subsequent inflammatory events. However, it remains unknown whether NLRP3 activation contributes to Alzheimer's disease in vivo. Here we demonstrate strongly enhanced active caspase-1 expression in human mild cognitive impairment and brains with Alzheimer's disease, suggesting a role for the inflammasome in this neurodegenerative disease. Nlrp3(-/-) or Casp1(-/-) mice carrying mutations associated with familial Alzheimer's disease were largely protected from loss of spatial memory and other sequelae associated with Alzheimer's disease, and demonstrated reduced brain caspase-1 and interleukin-1β activation as well as enhanced amyloid-β clearance. Furthermore, NLRP3 inflammasome deficiency skewed microglial cells to an M2 phenotype and resulted in the decreased deposition of amyloid-β in the APP/PS1 model of Alzheimer's disease. These results show an important role for the NLRP3/caspase-1 axis in the pathogenesis of Alzheimer's disease, and suggest that NLRP3 inflammasome inhibition represents a new therapeutic intervention for the disease.
1,930 citations
TL;DR: Dipeptidyl peptidase 4 (DPP4; also known as CD26) is identified as a functional receptor for hCoV-EMC and will contribute critically to the understanding of the pathogenesis and epidemiology of this emerging human coronavirus, and may facilitate the development of intervention strategies.
Abstract: Most human coronaviruses cause mild upper respiratory tract disease but may be associated with more severe pulmonary disease in immunocompromised individuals. However, SARS coronavirus caused severe lower respiratory disease with nearly 10% mortality and evidence of systemic spread. Recently, another coronavirus (human coronavirus-Erasmus Medical Center (hCoV-EMC)) was identified in patients with severe and sometimes lethal lower respiratory tract infection. Viral genome analysis revealed close relatedness to coronaviruses found in bats. Here we identify dipeptidyl peptidase 4 (DPP4; also known as CD26) as a functional receptor for hCoV-EMC. DPP4 specifically co-purified with the receptor-binding S1 domain of the hCoV-EMC spike protein from lysates of susceptible Huh-7 cells. Antibodies directed against DPP4 inhibited hCoV-EMC infection of primary human bronchial epithelial cells and Huh-7 cells. Expression of human and bat (Pipistrellus pipistrellus) DPP4 in non-susceptible COS-7 cells enabled infection by hCoV-EMC. The use of the evolutionarily conserved DPP4 protein from different species as a functional receptor provides clues about the host range potential of hCoV-EMC. In addition, it will contribute critically to our understanding of the pathogenesis and epidemiology of this emerging human coronavirus, and may facilitate the development of intervention strategies.
1,743 citations
TL;DR: To help older people (>65 years) maintain and regain lean body mass and function, the PROT-AGE study group recommends average daily intake at least in the range of 1.2 g protein per kilogram of body weight per day.
1,700 citations
Alternatives1, John Innes Centre2, University of Bonn3, University of North Carolina at Chapel Hill4, University of Wisconsin-Madison5, University of Utah6, University of Southern California7, University of Edinburgh8, University of Warwick9, Harvard University10, University College Cork11, University of Queensland12, University of Hertfordshire13, University of Potsdam14, University of California, San Diego15, Goethe University Frankfurt16, University of California, San Francisco17, University of Delaware18, Uppsala University19, Medical University of Vienna20, J. Craig Venter Institute21, University of Hawaii at Manoa22, Leibniz Association23, University of Iowa24, University of Aberdeen25, Georgia Institute of Technology26, University of California, Berkeley27, University of Groningen28, Princeton University29, University of Marburg30, University of Illinois at Urbana–Champaign31, Saarland University32, Norwegian University of Life Sciences33, Massey University34, Toyama Prefectural University35, ETH Zurich36, University of Saskatchewan37, Rutgers University38, Scripps Research Institute39, University of Helsinki40, Texas A&M University41, National Institutes of Health42, Technical University of Berlin43, University of Otago44, University of Cambridge45, University of Alberta46, Michigan State University47, Hofstra University48
TL;DR: This review presents recommended nomenclature for the biosynthesis of ribosomally synthesized and post-translationally modified peptides (RiPPs), a rapidly growing class of natural products.
1,560 citations
University of Adelaide1, University of Wisconsin-Madison2, Ghent University3, University of Canterbury4, University of Geneva5, Humboldt University of Berlin6, University of California, Irvine7, University of Mainz8, University of California, Berkeley9, Ohio State University10, Université libre de Bruxelles11, Ruhr University Bochum12, University of Wuppertal13, University of Maryland, College Park14, University of Kansas15, Lawrence Berkeley National Laboratory16, RWTH Aachen University17, Uppsala University18, University of Alberta19, Stockholm University20, Vrije Universiteit Brussel21, University of Bonn22, École Polytechnique Fédérale de Lausanne23, Georgia Institute of Technology24, Pennsylvania State University25, Technical University of Dortmund26, Southern University and A&M College27
TL;DR: The presence of a high-energy neutrino flux containing the most energetic neutrinos ever observed is revealed, including 28 events at energies between 30 and 1200 TeV, although the origin of this flux is unknown and the findings are consistent with expectations for a neutRino population with origins outside the solar system.
Abstract: We report on results of an all-sky search for high-energy neutrino events interacting within the IceCube neutrino detector conducted between May 2010 and May 2012. The search follows up on the previous detection of two PeV neutrino events, with improved sensitivity and extended energy coverage down to about 30 TeV. Twenty-six additional events were observed, substantially more than expected from atmospheric backgrounds. Combined, both searches reject a purely atmospheric origin for the 28 events at the 4 sigma level. These 28 events, which include the highest energy neutrinos ever observed, have flavors, directions, and energies inconsistent with those expected from the atmospheric muon and neutrino backgrounds. These properties are, however, consistent with generic predictions for an additional component of extraterrestrial origin.
TL;DR: The causal network structure is a useful predictor of response to gene perturbations and presents a framework to test models of disease mechanisms underlying LOAD.
TL;DR: It is shown in vivo and in vitro that the cGAS-catalysed reaction product is distinct from previously characterized cyclic dinucleotides, and it is found that the presence of this 2′-5′ linkage was required to exert potent activation of human STING.
Abstract: Detection of cytoplasmic DNA represents one of the most fundamental mechanisms of the innate immune system to sense the presence of microbial pathogens. Moreover, erroneous detection of endogenous DNA by the same sensing mechanisms has an important pathophysiological role in certain sterile inflammatory conditions. The endoplasmic-reticulum-resident protein STING is critically required for the initiation of type I interferon signalling upon detection of cytosolic DNA of both exogenous and endogenous origin. Next to its pivotal role in DNA sensing, STING also serves as a direct receptor for the detection of cyclic dinucleotides, which function as second messenger molecules in bacteria. DNA recognition, however, is triggered in an indirect fashion that depends on a recently characterized cytoplasmic nucleotidyl transferase, termed cGAMP synthase (cGAS), which upon interaction with DNA synthesizes a dinucleotide molecule that in turn binds to and activates STING. We here show in vivo and in vitro that the cGAS-catalysed reaction product is distinct from previously characterized cyclic dinucleotides. Using a combinatorial approach based on mass spectrometry, enzymatic digestion, NMR analysis and chemical synthesis we demonstrate that cGAS produces a cyclic GMP-AMP dinucleotide, which comprises a 2'-5' and a 3'-5' phosphodiester linkage >Gp(2'-5')Ap(3'-5')>. We found that the presence of this 2'-5' linkage was required to exert potent activation of human STING. Moreover, we show that cGAS first catalyses the synthesis of a linear 2'-5'-linked dinucleotide, which is then subject to cGAS-dependent cyclization in a second step through a 3'-5' phosphodiester linkage. This 13-membered ring structure defines a novel class of second messenger molecules, extending the family of 2'-5'-linked antiviral biomolecules.
Utrecht University1, Loyola University Medical Center2, University of North Carolina at Chapel Hill3, University of Bonn4, Autonomous University of Madrid5, Erasmus University Rotterdam6, Health Protection Agency7, Leiden University Medical Center8, University of Iowa9, University of Hong Kong10, Ain Shams University11, University of Giessen12
TL;DR: During the summer of 2012, in Jeddah, Saudi Arabia, a hitherto unknown coronavirus was isolated from the sputum of a patient with acute pneumonia and renal failure and was provisionally called human coronav virus Erasmus Medical Center (EMC).
Abstract: During the summer of 2012, in Jeddah, Saudi Arabia, a hitherto unknown coronavirus (CoV) was isolated from the sputum of a patient with acute pneumonia and renal failure ([1][1], [2][2]). The isolate was provisionally called human coronavirus Erasmus Medical Center (EMC) ([3][3]). Shortly thereafter
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, University of Leeds10, CGIAR11, 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.
Massachusetts Institute of Technology1, QIMR Berghofer Medical Research Institute2, University of London3, University of California, San Francisco4, Columbia University5, University of Edinburgh6, VU University Amsterdam7, University of Bonn8, University of Washington9, Heidelberg University10, University of Iowa11, University of North Carolina at Chapel Hill12, National Institutes of Health13, Karolinska Institutet14, North Carolina State University15, Harvard University16, University of Lausanne17, University of Southern California18, Howard University19, Rush University Medical Center20, University of Geneva21, University of Sydney22, University of Bristol23, Cardiff University24, Mayo Clinic25, Virginia Commonwealth University26, Leiden University27, Stanford University28
TL;DR: This article conducted a genome-wide association studies (GWAS) mega-analysis for major depressive disorder (MDD) using more than 1.2 million autosomal and X chromosome single-nucleotide polymorphisms (SNPs) in 18,759 independent and unrelated subjects of recent European ancestry.
Abstract: Prior genome-wide association studies (GWAS) of major depressive disorder (MDD) have met with limited success. We sought to increase statistical power to detect disease loci by conducting a GWAS mega-analysis for MDD. In the MDD discovery phase, we analyzed more than 1.2 million autosomal and X chromosome single-nucleotide polymorphisms (SNPs) in 18 759 independent and unrelated subjects of recent European ancestry (9240 MDD cases and 9519 controls). In the MDD replication phase, we evaluated 554 SNPs in independent samples (6783 MDD cases and 50 695 controls). We also conducted a cross-disorder meta-analysis using 819 autosomal SNPs with P<0.0001 for either MDD or the Psychiatric GWAS Consortium bipolar disorder (BIP) mega-analysis (9238 MDD cases/8039 controls and 6998 BIP cases/7775 controls). No SNPs achieved genome-wide significance in the MDD discovery phase, the MDD replication phase or in pre-planned secondary analyses (by sex, recurrent MDD, recurrent early-onset MDD, age of onset, pre-pubertal onset MDD or typical-like MDD from a latent class analyses of the MDD criteria). In the MDD-bipolar cross-disorder analysis, 15 SNPs exceeded genome-wide significance (P<5 × 10(-8)), and all were in a 248 kb interval of high LD on 3p21.1 (chr3:52 425 083-53 822 102, minimum P=5.9 × 10(-9) at rs2535629). Although this is the largest genome-wide analysis of MDD yet conducted, its high prevalence means that the sample is still underpowered to detect genetic effects typical for complex traits. Therefore, we were unable to identify robust and replicable findings. We discuss what this means for genetic research for MDD. The 3p21.1 MDD-BIP finding should be interpreted with caution as the most significant SNP did not replicate in MDD samples, and genotyping in independent samples will be needed to resolve its status.
01 Dec 2013
TL;DR: It is found that high-level pose features greatly outperform low/mid level features, in particular, pose over time is critical, but current pose estimation algorithms are not yet reliable enough to provide this information.
Abstract: Although action recognition in videos is widely studied, current methods often fail on real-world datasets. Many recent approaches improve accuracy and robustness to cope with challenging video sequences, but it is often unclear what affects the results most. This paper attempts to provide insights based on a systematic performance evaluation using thoroughly-annotated data of human actions. We annotate human Joints for the HMDB dataset (J-HMDB). This annotation can be used to derive ground truth optical flow and segmentation. We evaluate current methods using this dataset and systematically replace the output of various algorithms with ground truth. This enables us to discover what is important - for example, should we work on improving flow algorithms, estimating human bounding boxes, or enabling pose estimation? In summary, we find that high-level pose features greatly outperform low/mid level features, in particular, pose over time is critical, but current pose estimation algorithms are not yet reliable enough to provide this information. We also find that the accuracy of a top-performing action recognition framework can be greatly increased by refining the underlying low/mid level features, this suggests it is important to improve optical flow and human detection algorithms. Our analysis and J-HMDB dataset should facilitate a deeper understanding of action recognition algorithms.
University of Alberta1, Chinese Academy of Sciences2, Peking University3, Macquarie University4, Los Alamos National Laboratory5, Northwestern University6, McMaster University7, Radboud University Nijmegen8, Nanjing University9, Xinjiang University10, University of Warwick11, University of Oxford12, University of Cambridge13, Technion – Israel Institute of Technology14, Academia Sinica15, University of Bonn16, Max Planck Society17, University of Amsterdam18, University of Illinois at Urbana–Champaign19
TL;DR: In this paper, the authors present the current best physical understanding of common envelope evolution (CEE) and highlight areas of consensus and disagreement, and stress ideas which should point the way forward for progress in this important but long-standing and largely unconquered problem.
Abstract: This work aims to present our current best physical understanding of common-envelope evolution (CEE). We highlight areas of consensus and disagreement, and stress ideas which should point the way forward for progress in this important but long-standing and largely unconquered problem. Unusually for CEE-related work, we mostly try to avoid relying on results from population synthesis or observations, in order to avoid potentially being misled by previous misunderstandings. As far as possible we debate all the relevant issues starting from physics alone, all the way from the evolution of the binary system immediately before CEE begins to the processes which might occur just after the ejection of the envelope. In particular, we include extensive discussion about the energy sources and sinks operating in CEE, and hence examine the foundations of the standard energy formalism. Special attention is also given to comparing the results of hydrodynamic simulations from different groups and to discussing the potential effect of initial conditions on the differences in the outcomes. We compare current numerical techniques for the problem of CEE and also whether more appropriate tools could and should be produced (including new formulations of computational hydrodynamics, and attempts to include 3D processes within 1D codes). Finally we explore new ways to link CEE with observations. We compare previous simulations of CEE to the recent outburst from V1309 Sco, and discuss to what extent post-common-envelope binaries and nebulae can provide information, e.g. from binary eccentricities, which is not currently being fully exploited.
TL;DR: Results on crystal structures, cohesive energies, and solid‐state reaction enthalpies with the modified basis sets, denoted as pob‐TZVP, are compared with selected standard basis sets available from the CRYSTAL basis set database.
Abstract: Consistent basis sets of triple-zeta valence with polarization quality for main group elements and transition metals from row one to three have been derived for periodic quantum-chemical solid-state calculations with the crystalline-orbital program CRYSTAL. They are based on the def2-TZVP basis sets developed for molecules by the Ahlrichs group. Orbital exponents and contraction coefficients have been modified and reoptimized, to provide robust and stable self-consistant field (SCF) convergence for a wide range of different compounds. We compare results on crystal structures, cohesive energies, and solid-state reaction enthalpies with the modified basis sets, denoted as pob-TZVP, with selected standard basis sets available from the CRYSTAL basis set database. The average deviation of calculated lattice parameters obtained with a selected density functional, the hybrid method PW1PW, from experimental reference is smaller with pob-TZVP than with standard basis sets, in particular for metallic systems. The effects of basis set expansion by diffuse and polarization functions were investigated for selected systems.
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
Goddard Institute for Space Studies1, Columbia University2, University of Florida3, United States Department of Agriculture4, Commonwealth Scientific and Industrial Research Organisation5, Oregon State University6, International Food Policy Research Institute7, Wageningen University and Research Centre8, Michigan State University9, University of Bonn10, Institut national de la recherche agronomique11, University of Nebraska–Lincoln12
TL;DR: The Agricultural Model Intercomparison and Improvement Project (AgMIP) as mentioned in this paper is a major international effort linking the climate, crop, and economic modeling communities with cutting-edge information technology to produce improved crop and economic models and the next generation of climate impact projections for the agricultural sector.
TL;DR: These two neutrino-induced events could be a first indication of an astrophysical neutrinos flux; the moderate significance, however, does not permit a definitive conclusion at this time.
Abstract: We report on the observation of two neutrino-induced events which have an estimated deposited energy in the IceCube detector of 1.04 +/- 0.16 and 1.14 +/- 0.17 PeV, respectively, the highest neutrino energies observed so far. These events are consistent with fully contained particle showers induced by neutral-current nu(e,mu,tau) ((nu) over bar (e,mu,tau)) or charged-current nu(e) ((nu) over bar (e)) interactions within the IceCube detector. The events were discovered in a search for ultrahigh energy neutrinos using data corresponding to 615.9 days effective live time. The expected number of atmospheric background is 0.082 +/- 0.004(stat)(-0.057)(+0.041)(syst). The probability of observing two or more candidate events under the atmospheric background-only hypothesis is 2.9 x 10(-3) (2.8 sigma) taking into account the uncertainty on the expected number of background events. These two events could be a first indication of an astrophysical neutrino flux; the moderate significance, however, does not permit a definitive conclusion at this time.
TL;DR: It is demonstrated that neoadjuvant local low-dose gamma irradiation (LDI) causes normalization of aberrant vasculature and efficient recruitment of tumor-specific T cells in human pancreatic carcinomas and T-cell-mediated tumor rejection and prolonged survival in otherwise immune refractory spontaneous and xenotransplant mouse tumor models.
National Institutes of Health1, McGill University2, Johns Hopkins University3, University of Washington4, Lund University5, Broad Institute6, University of Iceland7, Harvard University8, University of Duisburg-Essen9, University of California, Los Angeles10, University of Copenhagen11, University of California, San Diego12, Wake Forest University13, University of Bonn14, Boston University15, University of Glasgow16, University of Cambridge17, Cedars-Sinai Medical Center18
TL;DR: Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aortic-valve calcification across multiple ethnic groups and with incident clinical aorti stenosis.
Abstract: Background Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease. Methods We determined genomewide associations with the presence of aortic-valve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis. Results One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aortic-valve calcification (odds ratio per allele, 2.05; P=9.0×10−10), a finding that was replicated in additional white European, African-American, and Hispa...
TL;DR: A collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry, identifies 19 loci associated at P < 5 × 10−8, which show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis.
Abstract: Age-related macular degeneration (AMD) is a common cause of blindness in older individuals To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry We identified 19 loci associated at P < 5 × 10(-8) These loci show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis Our results include seven loci with associations reaching P < 5 × 10(-8) for the first time, near the genes COL8A1-FILIP1L, IER3-DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9 and B3GALTL A genetic risk score combining SNP genotypes from all loci showed similar ability to distinguish cases and controls in all samples examined Our findings provide new directions for biological, genetic and therapeutic studies of AMD
TL;DR: Using two-photon intravital microscopy in mouse models of sterile injury and infection, a critical role is shown for intercellular signal relay among neutrophils mediated by the lipid leukotriene B4, which acutely amplifies local cell death signals to enhance the radius of highly directed interstitial neutrophil recruitment.
Abstract: Neutrophil recruitment from blood to extravascular sites of sterile or infectious tissue damage is a hallmark of early innate immune responses, and the molecular events leading to cell exit from the bloodstream have been well defined. Once outside the vessel, individual neutrophils often show extremely coordinated chemotaxis and cluster formation reminiscent of the swarming behaviour of insects. The molecular players that direct this response at the single-cell and population levels within the complexity of an inflamed tissue are unknown. Using two-photon intravital microscopy in mouse models of sterile injury and infection, we show a critical role for intercellular signal relay among neutrophils mediated by the lipid leukotriene B4, which acutely amplifies local cell death signals to enhance the radius of highly directed interstitial neutrophil recruitment. Integrin receptors are dispensable for long-distance migration, but have a previously unappreciated role in maintaining dense cellular clusters when congregating neutrophils rearrange the collagenous fibre network of the dermis to form a collagen-free zone at the wound centre. In this newly formed environment, integrins, in concert with neutrophil-derived leukotriene B4 and other chemoattractants, promote local neutrophil interaction while forming a tight wound seal. This wound seal has borders that cease to grow in kinetic concert with late recruitment of monocytes and macrophages at the edge of the displaced collagen fibres. Together, these data provide an initial molecular map of the factors that contribute to neutrophil swarming in the extravascular space of a damaged tissue. They reveal how local events are propagated over large-range distances, and how auto-signalling produces coordinated, self-organized neutrophil-swarming behaviour that isolates the wound or infectious site from surrounding viable tissue.
University of Edinburgh1, University of British Columbia2, University of Bonn3, Leiden University4, University of Victoria5, Institut d'Astrophysique de Paris6, University of Oxford7, Academia Sinica8, Shanghai Normal University9, University of Toronto10, Perimeter Institute for Theoretical Physics11, University of Waterloo12, California Institute of Technology13, University College London14, Stanford University15
TL;DR: In this paper, the authors present a finely-binned tomographic weak lensing analysis of the Canada-FranceHawaii Telescope Lensing Survey, CFHTLenS, mitigating contamination to the signal from the presence of intrinsic galaxy alignments via the simultaneous fit of a cosmological model and an intrinsic alignment model.
Abstract: We present a finely-binned tomographic weak lensing analysis of the Canada-FranceHawaii Telescope Lensing Survey, CFHTLenS, mitigating contamination to the signal from the presence of intrinsic galaxy alignments via the simultaneous fit of a cosmological model and an intrinsic alignment model. CFHTLenS spans 154 square degrees in five optical bands, with accurate shear and photometric redshifts for a galaxy sample with a median redshift of zm = 0:70. We estimate the 21 sets of cosmic shear correlation functions associated with six redshift bins, each spanning the angular range of 1:5 < < 35 arcmin. We combine this CFHTLenS data with auxiliary cosmological probes: the cosmic microwave background with data from WMAP7, baryon acoustic oscillations with data from BOSS, and a prior on the Hubble constant from the HST distance ladder. This leads to constraints on the normalisation of the matter power spectrum 8 = 0:799 0:015 and the matter density parameter m = 0:271 0:010 for a flat CDM cosmology. For a flat wCDM cosmology we constrain the dark energy equation of state parameter w = 1:02 0:09. We also provide constraints for curved CDM and wCDM cosmologies. We find the intrinsic alignment contamination to be galaxy-type dependent with a significant intrinsic alignment signal found for early-type galaxies, in contrast to the late-type galaxy sample for which the intrinsic alignment signal is found to be consistent with zero.
TL;DR: Both titres and seroprevalences in sera from different locations in Oman suggest widespread infection of camel populations, and possible animal reservoirs of MERS-CoV are investigated by assessing specific serum antibodies in livestock.
Abstract: Summary Background A new betacoronavirus—Middle East respiratory syndrome coronavirus (MERS-CoV)—has been identified in patients with severe acute respiratory infection. Although related viruses infect bats, molecular clock analyses have been unable to identify direct ancestors of MERS-CoV. Anecdotal exposure histories suggest that patients had been in contact with dromedary camels or goats. We investigated possible animal reservoirs of MERS-CoV by assessing specific serum antibodies in livestock. Methods We took sera from animals in the Middle East (Oman) and from elsewhere (Spain, Netherlands, Chile). Cattle (n=80), sheep (n=40), goats (n=40), dromedary camels (n=155), and various other camelid species (n=34) were tested for specific serum IgG by protein microarray using the receptor-binding S1 subunits of spike proteins of MERS-CoV, severe acute respiratory syndrome coronavirus, and human coronavirus OC43. Results were confirmed by virus neutralisation tests for MERS-CoV and bovine coronavirus. Findings 50 of 50 (100%) sera from Omani camels and 15 of 105 (14%) from Spanish camels had protein-specific antibodies against MERS-CoV spike. Sera from European sheep, goats, cattle, and other camelids had no such antibodies. MERS-CoV neutralising antibody titres varied between 1/320 and 1/2560 for the Omani camel sera and between 1/20 and 1/320 for the Spanish camel sera. There was no evidence for cross-neutralisation by bovine coronavirus antibodies. Interpretation MERS-CoV or a related virus has infected camel populations. Both titres and seroprevalences in sera from different locations in Oman suggest widespread infection. Funding European Union, European Centre For Disease Prevention and Control, Deutsche Forschungsgemeinschaft.
TL;DR: In this paper, the results of the four LEP experiments were combined to determine fundamental properties of the W boson and the electroweak theory, including the branching fraction of W and the trilinear gauge-boson self-couplings.
TL;DR: This work identifies an endocytic pathway mediated by the pattern-recognition receptor CD36 that coordinated the intracellular conversion of soluble ligands into crystals or fibrils, which resulted in lysosomal disruption and activation of the NLRP3 inflammasome in sterile inflammation.
Abstract: Particulate ligands, including cholesterol crystals and amyloid fibrils, induce production of interleukin 1β (IL-1β) dependent on the cytoplasmic sensor NLRP3 in atherosclerosis, Alzheimer's disease and diabetes. Soluble endogenous ligands, including oxidized low-density lipoprotein (LDL), amyloid-β and amylin peptides, accumulate in such diseases. Here we identify an endocytic pathway mediated by the pattern-recognition receptor CD36 that coordinated the intracellular conversion of those soluble ligands into crystals or fibrils, which resulted in lysosomal disruption and activation of the NLRP3 inflammasome. Consequently, macrophages that lacked CD36 failed to elicit IL-1β production in response to those ligands, and targeting CD36 in atherosclerotic mice resulted in lower serum concentrations of IL-1β and accumulation of cholesterol crystals in plaques. Collectively, our findings highlight the importance of CD36 in the accrual and nucleation of NLRP3 ligands from within the macrophage and position CD36 as a central regulator of inflammasome activation in sterile inflammation.