Showing papers by "University of Münster published in 2016"
TL;DR: In this paper, the authors present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macro-autophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes.
Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes.
For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy.
Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.
5,187 citations
TL;DR: The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015) as discussed by the authors was used to estimate the incidence, prevalence, and years lived with disability for diseases and injuries at the global, regional, and national scale over the period of 1990 to 2015.
5,050 citations
University of California, San Diego1, University of Montana2, Stanford University3, Scripps Institution of Oceanography4, National Autonomous University of Mexico5, Salk Institute for Biological Studies6, San Diego State University7, Strathclyde Institute of Pharmacy and Biomedical Sciences8, Lawrence Berkeley National Laboratory9, Harvard University10, University of Rennes11, University of Minnesota12, University of Lorraine13, Technical University of Denmark14, J. Craig Venter Institute15, University of California, Los Angeles16, University of Washington17, ETH Zurich18, University of Illinois at Chicago19, National Sun Yat-sen University20, Academia Sinica21, University of Münster22, Victoria University of Wellington23, University of North Carolina at Chapel Hill24, Indiana University25, Smithsonian Tropical Research Institute26, Federal University of Mato Grosso do Sul27, University of São Paulo28, University of Notre Dame29, University of California, Santa Cruz30, Oregon State University31, University of California, Berkeley32, Florida International University33, University of Hawaii at Manoa34, University of Geneva35, Institut de Chimie des Substances Naturelles36, Pacific Northwest National Laboratory37, National Institutes of Health38, Chinese Academy of Sciences39
TL;DR: In GNPS, crowdsourced curation of freely available community-wide reference MS libraries will underpin improved annotations and data-driven social-networking should facilitate identification of spectra and foster collaborations.
Abstract: The potential of the diverse chemistries present in natural products (NP) for biotechnology and medicine remains untapped because NP databases are not searchable with raw data and the NP community has no way to share data other than in published papers. Although mass spectrometry (MS) techniques are well-suited to high-throughput characterization of NP, there is a pressing need for an infrastructure to enable sharing and curation of data. We present Global Natural Products Social Molecular Networking (GNPS; http://gnps.ucsd.edu), an open-access knowledge base for community-wide organization and sharing of raw, processed or identified tandem mass (MS/MS) spectrometry data. In GNPS, crowdsourced curation of freely available community-wide reference MS libraries will underpin improved annotations. Data-driven social-networking should facilitate identification of spectra and foster collaborations. We also introduce the concept of 'living data' through continuous reanalysis of deposited data.
2,365 citations
TL;DR: This review presents the current state of the art in this field and detail C-H activation transformations reported since 2011 that proceed either at or below ambient temperature, in the absence of strongly acidic or basic additives or without strong oxidants.
Abstract: Organic reactions that involve the direct functionalization of non-activated C–H bonds represent an attractive class of transformations which maximize atom- and step-economy, and simplify chemical synthesis. Due to the high stability of C–H bonds, these processes, however, have most often required harsh reaction conditions, which has drastically limited their use as tools for the synthesis of complex organic molecules. Following the increased understanding of mechanistic aspects of C–H activation gained over recent years, great strides have been taken to design and develop new protocols that proceed efficiently under mild conditions and duly benefit from improved functional group tolerance and selectivity. In this review, we present the current state of the art in this field and detail C–H activation transformations reported since 2011 that proceed either at or below ambient temperature, in the absence of strongly acidic or basic additives or without strong oxidants. Furthermore, by identifying and discussing the major strategies that have led to these improvements, we hope that this review will serve as a useful conceptual overview and inspire the next generation of mild C–H transformations.
1,373 citations
James Bentham1, Mariachiara Di Cesare2, Mariachiara Di Cesare1, Gretchen A Stevens3 +787 more•Institutions (246)
TL;DR: The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries.
Abstract: Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.5–22.7) and 16.5 cm (13.3–19.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8–144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries.
1,348 citations
TL;DR: In this article, the results of a genome-wide association study (GWAS) for educational attainment were reported, showing that single-nucleotide polymorphisms associated with educational attainment disproportionately occur in genomic regions regulating gene expression in the fetal brain.
Abstract: Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.
1,102 citations
TL;DR: The rate of complete remission was higher with inotuzumab ozogamicin than with standard therapy, and a higher percentage of patients in the inotzumabozogamic in group had results below the threshold for minimal residual disease.
Abstract: BackgroundThe prognosis for adults with relapsed acute lymphoblastic leukemia is poor. We sought to determine whether inotuzumab ozogamicin, an anti-CD22 antibody conjugated to calicheamicin, results in better outcomes in patients with relapsed or refractory acute lymphoblastic leukemia than does standard therapy. MethodsIn this phase 3 trial, we randomly assigned adults with relapsed or refractory acute lymphoblastic leukemia to receive either inotuzumab ozogamicin (inotuzumab ozogamicin group) or standard intensive chemotherapy (standard-therapy group). The primary end points were complete remission (including complete remission with incomplete hematologic recovery) and overall survival. ResultsOf the 326 patients who underwent randomization, the first 218 (109 in each group) were included in the primary intention-to-treat analysis of complete remission. The rate of complete remission was significantly higher in the inotuzumab ozogamicin group than in the standard-therapy group (80.7% [95% confidence in...
942 citations
TL;DR: This work critically address both catalyst-free and catalytic radical reactions through the lens of radical chemistry, using basic principles of kinetics and thermodynamics to address problems of initiation, propagation, and inhibition of radical chains.
Abstract: The area of catalysis of radical reactions has recently flourished. Various reaction conditions have been discovered and explained in terms of catalytic cycles. These cycles rarely stand alone as unique paths from substrates to products. Instead, most radical reactions have innate chains which form products without any catalyst. How do we know if a species added in "catalytic amounts" is a catalyst, an initiator, or something else? Herein we critically address both catalyst-free and catalytic radical reactions through the lens of radical chemistry. Basic principles of kinetics and thermodynamics are used to address problems of initiation, propagation, and inhibition of radical chains. The catalysis of radical reactions differs from other areas of catalysis. Whereas efficient innate chain reactions are difficult to catalyze because individual steps are fast, both inefficient chain processes and non-chain processes afford diverse opportunities for catalysis, as illustrated with selected examples.
843 citations
Stellenbosch University1, University of Western Australia2, University of Kiel3, University of Geneva4, Free University of Berlin5, University of Nova Gorica6, Slovenian Academy of Sciences and Arts7, Macedonian Academy of Sciences and Arts8, Academy of Sciences of the Czech Republic9, University of Vienna10, University of Bayreuth11, Complutense University of Madrid12, Masaryk University13, Sapienza University of Rome14, University of Zielona Góra15, University of Münster16, University of Göttingen17, Russian Academy of Sciences18, Slovak Academy of Sciences19, Wageningen University and Research Centre20, Radboud University Nijmegen21, National Academy of Sciences of Ukraine22, University of Lisbon23, University of Vechta24, University of California, Davis25, University of Patras26
TL;DR: This paper features the first comprehensive and critical account of European syntaxa and synthesizes more than 100 yr of classification effort by European phytosociologists.
Abstract: Aims: Vegetation classification consistent with the
Braun-Blanquet approach is widely used in Europe for applied
vegetation science, conservation planning and land management.
During the long history of syntaxonomy, many concepts and names
of vegetation units have been proposed, but there has been no
single classification system integrating these units. Here we
(1) present a comprehensive, hierarchical, syntaxonomic system
of alliances, orders and classes of Braun-Blanquet syntaxonomy
for vascular plant, bryophyte and lichen, and algal communities
of Europe; (2) briefly characterize in ecological and
geographic terms accepted syntaxonomic concepts; (3) link
available synonyms to these accepted concepts; and (4) provide
a list of diagnostic species for all classes. LocationEuropean
mainland, Greenland, Arctic archipelagos (including Iceland,
Svalbard, Novaya Zemlya), Canary Islands, Madeira, Azores,
Caucasus, Cyprus. Methods: We evaluated approximately 10000
bibliographic sources to create a comprehensive list of
previously proposed syntaxonomic units. These units were
evaluated by experts for their floristic and ecological
distinctness, clarity of geographic distribution and compliance
with the nomenclature code. Accepted units were compiled into
three systems of classes, orders and alliances
(EuroVegChecklist, EVC) for communities dominated by vascular
plants (EVC1), bryophytes and lichens (EVC2) and algae (EVC3).
Results: EVC1 includes 109 classes, 300 orders and 1108
alliances; EVC2 includes 27 classes, 53 orders and 137
alliances, and EVC3 includes 13 classes, 24 orders and 53
alliances. In total 13448 taxa were assigned as indicator
species to classes of EVC1, 2087 to classes of EVC2 and 368 to
classes of EVC3. Accepted syntaxonomic concepts are summarized
in a series of appendices, and detailed information on each is
accessible through the software tool EuroVegBrowser.
Conclusions: This paper features the first comprehensive and
critical account of European syntaxa and synthesizes more than
100 yr of classification effort by European phytosociologists.
It aims to document and stabilize the concepts and nomenclature
of syntaxa for practical uses, such as calibration of habitat
classification used by the European Union, standardization of
terminology for environmental assessment, management and
conservation of nature areas, landscape planning and education.
The presented classification systems provide a baseline for
future development and revision of European syntaxonomy.
817 citations
TL;DR: To determine whether early initiation of RRT in patients who are critically ill with AKI reduces 90-day all-cause mortality, a single-center randomized clinical trial of 231 critically ill patients with KDIGO stage 2 found that more patients in the early group recovered renal function by day 90.
Abstract: Importance Optimal timing of initiation of renal replacement therapy (RRT) for severe acute kidney injury (AKI) but without life-threatening indications is still unknown. Objective To determine whether early initiation of RRT in patients who are critically ill with AKI reduces 90-day all-cause mortality. Design, Setting, and Participants Single-center randomized clinical trial of 231 critically ill patients with AKI Kidney Disease: Improving Global Outcomes (KDIGO) stage 2 (≥2 times baseline or urinary output Interventions Early (within 8 hours of diagnosis of KDIGO stage 2; n = 112) or delayed (within 12 hours of stage 3 AKI or no initiation; n = 119) initiation of RRT. Main Outcomes and Measures The primary end point was mortality at 90 days after randomization. Secondary end points included 28- and 60-day mortality, clinical evidence of organ dysfunction, recovery of renal function, requirement of RRT after day 90, duration of renal support, and intensive care unit (ICU) and hospital length of stay. Results Among 231 patients (mean age, 67 years; men, 146 [63.2%]), all patients in the early group (n = 112) and 108 of 119 patients (90.8%) in the delayed group received RRT. All patients completed follow-up at 90 days. Median time (Q1, Q3) from meeting full eligibility criteria to RRT initiation was significantly shorter in the early group (6.0 hours [Q1, Q3: 4.0, 7.0]) than in the delayed group (25.5 h [Q1, Q3: 18.8, 40.3]; difference, −21.0 [95% CI, −24.0 to −18.0]; P P = .03). More patients in the early group recovered renal function by day 90 (60 of 112 patients [53.6%] in the early group vs 46 of 119 patients [38.7%] in the delayed group; odds ratio [OR], 0.55 [95% CI, 0.32 to 0. 93]; difference, 14.9% [95% CI, 2.2% to 27.6%]; P = .02). Duration of RRT and length of hospital stay were significantly shorter in the early group than in the delayed group (RRT: 9 days [Q1, Q3: 4, 44] in the early group vs 25 days [Q1, Q3: 7, >90] in the delayed group; P = .04; HR, 0.69 [95% CI, 0.48 to 1.00]; difference, −18 days [95% CI, −41 to 4]; hospital stay: 51 days [Q1, Q3: 31, 74] in the early group vs 82 days [Q1, Q3: 67, >90] in the delayed group; P Conclusions and Relevance Among critically ill patients with AKI, early RRT compared with delayed initiation of RRT reduced mortality over the first 90 days. Further multicenter trials of this intervention are warranted. Trial Registration German Clinical Trial Registry Identifier:DRKS00004367
810 citations
University of Paris1, Medical University of Vienna2, Leiden University3, Paris Descartes University4, University of Leeds5, Ruhr University Bochum6, Charité7, University College Dublin8, Halmstad University9, Katholieke Universiteit Leuven10, University of Münster11, University of Glasgow12, Charles University in Prague13, University of Erlangen-Nuremberg14, Ghent University Hospital15
TL;DR: These recommendations provide stakeholders with an updated consensus on the pharmacological treatment of PsA and strategies to reach optimal outcomes in PsA, based on a combination of evidence and expert opinion.
Abstract: Background Since the publication of the European League Against Rheumatism recommendations for the pharmacological treatment of psoriatic arthritis (PsA) in 2012, new evidence and new therapeutic agents have emerged. The objective was to update these recommendations. Methods A systematic literature review was performed regarding pharmacological treatment in PsA. Subsequently, recommendations were formulated based on the evidence and the expert opinion of the 34 Task Force members. Levels of evidence and strengths of recommendations were allocated. Results The updated recommendations comprise 5 overarching principles and 10 recommendations, covering pharmacological therapies for PsA from non-steroidal anti-inflammatory drugs (NSAIDs), to conventional synthetic (csDMARD) and biological (bDMARD) disease-modifying antirheumatic drugs, whatever their mode of action, taking articular and extra-articular manifestations of PsA into account, but focusing on musculoskeletal involvement. The overarching principles address the need for shared decision-making and treatment objectives. The recommendations address csDMARDs as an initial therapy after failure of NSAIDs and local therapy for active disease, followed, if necessary, by a bDMARD or a targeted synthetic DMARD (tsDMARD). The first bDMARD would usually be a tumour necrosis factor (TNF) inhibitor. bDMARDs targeting interleukin (IL)12/23 (ustekinumab) or IL-17 pathways (secukinumab) may be used in patients for whom TNF inhibitors are inappropriate and a tsDMARD such as a phosphodiesterase 4-inhibitor (apremilast) if bDMARDs are inappropriate. If the first bDMARD strategy fails, any other bDMARD or tsDMARD may be used. Conclusions These recommendations provide stakeholders with an updated consensus on the pharmacological treatment of PsA and strategies to reach optimal outcomes in PsA, based on a combination of evidence and expert opinion.
Aysu Okbay1, Bart M. L. Baselmans2, Jan-Emmanuel De Neve3, Patrick Turley4 +213 more•Institutions (65)
TL;DR: In this paper, the authors conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n= 161,460), and neuroticism(n = 170,911).
Abstract: Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (|ρ^| ≈ 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.
Stanford University1, Illinois Institute of Technology2, University of Melbourne3, Greifswald University Hospital4, University of Münster5, University of Marburg6, VU University Medical Center7, University of Göttingen8, Humboldt University of Berlin9, Harvard University10, University Medical Center Groningen11, University of Cape Town12, Max Planck Society13, University of Southern California14
TL;DR: Three-dimensional brain magnetic resonance imaging data was meta-analyzed to identify subcortical brain volumes that robustly discriminate major depressive disorder patients from healthy controls and showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.
Abstract: The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited statistical power, disease heterogeneity and the complex interactions between clinical characteristics and brain morphology. To address this, we meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 MDD patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls. Relative to controls, patients had significantly lower hippocampal volumes (Cohen's d=-0.14, % difference=-1.24). This effect was driven by patients with recurrent MDD (Cohen's d=-0.17, % difference=-1.44), and we detected no differences between first episode patients and controls. Age of onset ⩽21 was associated with a smaller hippocampus (Cohen's d=-0.20, % difference=-1.85) and a trend toward smaller amygdala (Cohen's d=-0.11, % difference=-1.23) and larger lateral ventricles (Cohen's d=0.12, % difference=5.11). Symptom severity at study inclusion was not associated with any regional brain volumes. Sample characteristics such as mean age, proportion of antidepressant users and proportion of remitted patients, and methodological characteristics did not significantly moderate alterations in brain volumes in MDD. Samples with a higher proportion of antipsychotic medication users showed larger caudate volumes in MDD patients compared with controls. This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.
Heidelberg University1, German Cancer Research Center2, St. Jude Children's Research Hospital3, Ontario Institute for Cancer Research4, University of Toronto5, Institute of Cancer Research6, University of California, San Francisco7, Cincinnati Children's Hospital Medical Center8, Sapienza University of Rome9, University of Warsaw10, Boston Children's Hospital11, University of Bonn12, University of Hamburg13, Medical University of Vienna14, French Institute of Health and Medical Research15, Karolinska Institutet16, University of Freiburg17, Cork University Hospital18, Hadassah Medical Center19, Otto-von-Guericke University Magdeburg20, Copenhagen University Hospital21, Vanderbilt University Medical Center22, Children's Hospital of Philadelphia23, Washington University in St. Louis24, University of Göttingen25, Augsburg College26, University of Münster27, Radboud University Nijmegen28, VU University Medical Center29, University Medical Center Freiburg30, Ludwig Maximilian University of Munich31, University of Tübingen32, University of Basel33, Masaryk University34, University of Cambridge35, University of Amsterdam36, Necker-Enfants Malades Hospital37, Institut Gustave Roussy38, Aix-Marseille University39, University of Düsseldorf40, Virginia Commonwealth University41, University of Würzburg42, New York University43, Henry Ford Hospital44, University of Texas MD Anderson Cancer Center45, University of Queensland46, McGill University47
TL;DR: It is demonstrated that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors.
Columbia University1, University of Amsterdam2, University of Bologna3, University of Mainz4, University of Coimbra5, Weizmann Institute of Science6, New York University Abu Dhabi7, University of Zurich8, Stockholm University9, Rensselaer Polytechnic Institute10, Max Planck Society11, University of Münster12, University of Bern13, Purdue University14, École des mines de Nantes15, University of California, Los Angeles16, Rice University17
TL;DR: In this article, the expected sensitivity of the Xenon1T experiment to the spin-independent WIMP-nucleon interaction cross section was investigated based on Monte Carlo predictions of the electronic and nuclear recoil backgrounds.
Abstract: The XENON1T experiment is currently in the commissioning phase at the Laboratori Nazionali del Gran Sasso, Italy. In this article we study the experiment's expected sensitivity to the spin-independent WIMP-nucleon interaction cross section, based on Monte Carlo predictions of the electronic and nuclear recoil backgrounds. The total electronic recoil background in 1 tonne fiducial volume and (1, 12) keV electronic recoil equivalent energy region, before applying any selection to discriminate between electronic and nuclear recoils, is (1.80 ± 0.15) · 10(−)(4) (kg·day·keV)(−)(1), mainly due to the decay of (222)Rn daughters inside the xenon target. The nuclear recoil background in the corresponding nuclear recoil equivalent energy region (4, 50) keV, is composed of (0.6 ± 0.1) (t·y)(−)(1) from radiogenic neutrons, (1.8 ± 0.3) · 10(−)(2) (t·y)(−)(1) from coherent scattering of neutrinos, and less than 0.01 (t·y)(−)(1) from muon-induced neutrons. The sensitivity of XENON1T is calculated with the Profile Likelihood Ratio method, after converting the deposited energy of electronic and nuclear recoils into the scintillation and ionization signals seen in the detector. We take into account the systematic uncertainties on the photon and electron emission model, and on the estimation of the backgrounds, treated as nuisance parameters. The main contribution comes from the relative scintillation efficiency Script L(eff), which affects both the signal from WIMPs and the nuclear recoil backgrounds. After a 2 y measurement in 1 t fiducial volume, the sensitivity reaches a minimum cross section of 1.6 · 10(−)(47) cm(2) at m(χ) = 50 GeV/c(2).
TL;DR: The LSC17 score provides clinicians with a rapid and powerful tool to identify AML patients who do not benefit from standard therapy and who should be enrolled in trials evaluating novel upfront or post-remission strategies.
Abstract: Refractoriness to induction chemotherapy and relapse after achievement of remission are the main obstacles to cure in acute myeloid leukaemia (AML). After standard induction chemotherapy, patients are assigned to different post-remission strategies on the basis of cytogenetic and molecular abnormalities that broadly define adverse, intermediate and favourable risk categories. However, some patients do not respond to induction therapy and another subset will eventually relapse despite the lack of adverse risk factors. There is an urgent need for better biomarkers to identify these high-risk patients before starting induction chemotherapy, to enable testing of alternative induction strategies in clinical trials. The high rate of relapse in AML has been attributed to the persistence of leukaemia stem cells (LSCs), which possess a number of stem cell properties, including quiescence, that are linked to therapy resistance. Here, to develop predictive and/or prognostic biomarkers related to stemness, we generated a list of genes that are differentially expressed between 138 LSC+ and 89 LSC- cell fractions from 78 AML patients validated by xenotransplantation. To extract the core transcriptional components of stemness relevant to clinical outcomes, we performed sparse regression analysis of LSC gene expression against survival in a large training cohort, generating a 17-gene LSC score (LSC17). The LSC17 score was highly prognostic in five independent cohorts comprising patients of diverse AML subtypes (n = 908) and contributed greatly to accurate prediction of initial therapy resistance. Patients with high LSC17 scores had poor outcomes with current treatments including allogeneic stem cell transplantation. The LSC17 score provides clinicians with a rapid and powerful tool to identify AML patients who do not benefit from standard therapy and who should be enrolled in trials evaluating novel upfront or post-remission strategies.
University of Amsterdam1, University of Bologna2, University of Mainz3, University of Coimbra4, University of Bern5, Columbia University6, Weizmann Institute of Science7, New York University Abu Dhabi8, University of Zurich9, Rensselaer Polytechnic Institute10, Max Planck Society11, Stockholm University12, University of Nantes13, Karlsruhe Institute of Technology14, University of Münster15, University of Chicago16, Arizona State University17, Purdue University18, Rice University19, University of California, San Diego20, University of Freiburg21, Dresden University of Technology22, Imperial College London23, University of California, Los Angeles24
TL;DR: DARk matter WImp search with liquid xenoN (DARWIN) as mentioned in this paper is an experiment for the direct detection of dark matter using a multi-ton liquid xenon time projection chamber at its core.
Abstract: DARk matter WImp search with liquid xenoN (DARWIN(2)) will be an experiment for the direct detection of dark matter using a multi-ton liquid xenon time projection chamber at its core. Its primary g ...
TL;DR: A review of established in vitro blood-brain barrier models with a focus on their validation regarding a set of well-established bloodbrain barrier characteristics is given in this paper, with an overview of the advantages and drawbacks of the different models described.
Abstract: The endothelial cells lining the brain capillaries separate the blood from the brain parenchyma. The endothelial monolayer of the brain capillaries serves both as a crucial interface for exchange of nutrients, gases, and metabolites between blood and brain, and as a barrier for neurotoxic components of plasma and xenobiotics. This "blood-brain barrier" function is a major hindrance for drug uptake into the brain parenchyma. Cell culture models, based on either primary cells or immortalized brain endothelial cell lines, have been developed, in order to facilitate in vitro studies of drug transport to the brain and studies of endothelial cell biology and pathophysiology. In this review, we aim to give an overview of established in vitro blood-brain barrier models with a focus on their validation regarding a set of well-established blood-brain barrier characteristics. As an ideal cell culture model of the blood-brain barrier is yet to be developed, we also aim to give an overview of the advantages and drawbacks of the different models described.
TL;DR: It is found that mammalian bone marrow stem cell maintenance and leukocyte trafficking are regulated by distinct blood vessel types with different permeability properties, and exposure to blood plasma increases bone marrow HSPC ROS levels, augmenting their migration and differentiation, while compromising their long-term repopulation and survival.
Abstract: Bone marrow endothelial cells (BMECs) form a network of blood vessels that regulate both leukocyte trafficking and haematopoietic stem and progenitor cell (HSPC) maintenance. However, it is not clear how BMECs balance these dual roles, and whether these events occur at the same vascular site. We found that mammalian bone marrow stem cell maintenance and leukocyte trafficking are regulated by distinct blood vessel types with different permeability properties. Less permeable arterial blood vessels maintain haematopoietic stem cells in a low reactive oxygen species (ROS) state, whereas the more permeable sinusoids promote HSPC activation and are the exclusive site for immature and mature leukocyte trafficking to and from the bone marrow. A functional consequence of high permeability of blood vessels is that exposure to blood plasma increases bone marrow HSPC ROS levels, augmenting their migration and differentiation, while compromising their long-term repopulation and survival. These findings may have relevance for clinical haematopoietic stem cell transplantation and mobilization protocols.
University of Erlangen-Nuremberg1, University of Tübingen2, University of Zurich3, University of Duisburg-Essen4, Hannover Medical School5, Heidelberg University6, Otto-von-Guericke University Magdeburg7, University Hospital Heidelberg8, Ludwig Maximilian University of Munich9, University of Münster10, RWTH Aachen University11, University of Würzburg12, Technische Universität München13
TL;DR: Anti-PD1 antibodies can induce a plethora of irAEs, and the knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity.
University of Tübingen1, University of Cologne2, University of Erlangen-Nuremberg3, Ruhr University Bochum4, Ludwig Maximilian University of Munich5, University of Münster6, University of Jena7, University of Düsseldorf8, Saarland University9, Otto-von-Guericke University Magdeburg10, Leipzig University11
TL;DR: Results showed no difference in survival in patients treated with complete lymph node dissection compared with observation only, and complete lymph nodes dissection should not be recommended in patients with melanoma with lymph node micrometastases of at least a diameter of 1 mm or smaller.
Abstract: Summary Background Complete lymph node dissection is recommended in patients with positive sentinel lymph node biopsy results. To date, the effect of complete lymph node dissection on prognosis is controversial. In the DeCOG-SLT trial, we assessed whether complete lymph node dissection resulted in increased survival compared with observation. Methods In this multicentre, randomised, phase 3 trial, we enrolled patients with cutaneous melanoma of the torso, arms, or legs from 41 German skin cancer centres. Patients with positive sentinel lymph node biopsy results were eligible. Patients were randomly assigned (1:1) to undergo complete lymph node dissection or observation with permuted blocks of variable size and stratified by primary tumour thickness, ulceration of primary tumour, and intended adjuvant interferon therapy. Treatment assignment was not masked. The primary endpoint was distant metastasis-free survival and analysed by intention to treat. All patients in the intention-to-treat population of the complete lymph node dissection group were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT02434107. Follow-up is ongoing, but the trial no longer recruiting patients. Findings Between Jan 1, 2006, and Dec 1, 2014, 5547 patients were screened with sentinel lymph node biopsy and 1269 (23%) patients were positive for micrometastasis. Of these, 483 (39%) agreed to randomisation into the clinical trial; due to difficulties enrolling and a low event rate the trial closed early on Dec 1, 2014. 241 patients were randomly assigned to the observation group and 242 to the complete lymph node dissection group. Ten patients did not meet the inclusion criteria, so 233 patients were analysed in the observation group and 240 patients were analysed in the complete lymph node dissection group, as the intention-to-treat population. 311 (66%) patients (158 in the observation group and 153 in the dissection group) had sentinel lymph node metastases of 1 mm or less. Median follow-up was 35 months (IQR 20–54). Distant metastasis-free survival at 3 years was 77·0% (90% CI 71·9–82·1; 55 events) in the observation group and 74·9% (69·5–80·3; 54 events) in the complete lymph node dissection group. In the complete lymph node dissection group, grade 3 and 4 events occurred in 15 patients (6%) and 19 patients (8%) patients, respectively. Adverse events included lymph oedema (grade 3 in seven patients, grade 4 in 13 patients), lymph fistula (grade 3 in one patient, grade 4 in two patients), seroma (grade 3 in three patients, no grade 4), infection (grade 3 in three patients, no grade 4), and delayed wound healing (grade 3 in one patient, grade 4 in four patients); no serious adverse events were reported. Interpretation Although we did not achieve the required number of events, leading to the trial being underpowered, our results showed no difference in survival in patients treated with complete lymph node dissection compared with observation only. Consequently, complete lymph node dissection should not be recommended in patients with melanoma with lymph node micrometastases of at least a diameter of 1 mm or smaller. Funding German Cancer Aid.
TL;DR: In this paper, an isotropic, unbroken power-law flux with a normalization at 100 TeV neutrino energy of (0.90 -0.27 +0.30) × 10-18 Gev-1 cm-2 s-1 sr-1 and a hard spectral index of γ = 2.13 ± 0.13.
Abstract: The IceCube Collaboration has previously discovered a high-energy astrophysical neutrino flux using neutrino events with interaction vertices contained within the instrumented volume of the IceCube detector. We present a complementary measurement using charged current muon neutrino events where the interaction vertex can be outside this volume. As a consequence of the large muon range the effective area is significantly larger but the field of view is restricted to the Northern Hemisphere. IceCube data from 2009 through 2015 have been analyzed using a likelihood approach based on the reconstructed muon energy and zenith angle. At the highest neutrino energies between 194 TeV and 7.8 PeV a significant astrophysical contribution is observed, excluding a purely atmospheric origin of these events at 5.6s significance. The data are well described by an isotropic, unbroken power-law flux with a normalization at 100 TeV neutrino energy of (0.90 -0.27 +0.30) × 10-18 Gev-1 cm-2 s-1 sr-1and a hard spectral index of γ = 2.13 ± 0.13. The observed spectrum is harder in comparison to previous IceCube analyses with lower energy thresholds which may indicate a break in the astrophysical neutrino spectrum of unknown origin. The highest-energy event observed has a reconstructed muon energy of (4.5 ± 1.2) PeV which implies a probability of less than 0.005% for this event to be of atmospheric origin. Analyzing the arrival directions of all events with reconstructed muon energies above 200 TeV no correlation with known γ-ray sources was found. Using the high statistics of atmospheric neutrinos we report the current best constraints on a prompt atmospheric muon neutrino flux originating from charmed meson decays which is below 1.06 in units of the flux normalization of the model in Enberg et al.
TL;DR: The design of a gas–solid interface reaction to achieve delicate control of oxygen activity through uniformly creating oxygen vacancies without affecting structural integrity of Li-rich layered oxides is reported.
Abstract: Lattice oxygen can play an intriguing role in electrochemical processes, not only maintaining structural stability, but also influencing electron and ion transport properties in high-capacity oxide cathode materials for Li-ion batteries. Here, we report the design of a gas-solid interface reaction to achieve delicate control of oxygen activity through uniformly creating oxygen vacancies without affecting structural integrity of Li-rich layered oxides. Theoretical calculations and experimental characterizations demonstrate that oxygen vacancies provide a favourable ionic diffusion environment in the bulk and significantly suppress gas release from the surface. The target material is achievable in delivering a discharge capacity as high as 301 mAh g(-1) with initial Coulombic efficiency of 93.2%. After 100 cycles, a reversible capacity of 300 mAh g(-1) still remains without any obvious decay in voltage. This study sheds light on the comprehensive design and control of oxygen activity in transition-metal-oxide systems for next-generation Li-ion batteries.
University of Bern1, Technische Universität München2, University of Jena3, Smithsonian Conservation Biology Institute4, University of Natural Resources and Life Sciences, Vienna5, University of Tübingen6, University of Cologne7, Leibniz Association8, University of Freiburg9, Lund University10, Technische Universität Darmstadt11, University of Göttingen12, Helmholtz Centre for Environmental Research - UFZ13, University of Kiel14, University of Potsdam15, University of Münster16, University of Ulm17, University of Würzburg18, Max Planck Society19, Free University of Berlin20, Xavier University21, University of Salzburg22, Smithsonian Tropical Research Institute23, Karlsruhe Institute of Technology24, University of Giessen25
TL;DR: It is demonstrated that primary producers, herbivorous insects and microbial decomposers seem to be particularly important drivers of ecosystem functioning, as shown by the strong and frequent positive associations of their richness or abundance with multiple ecosystem services.
Abstract: Many experiments have shown that loss of biodiversity reduces the capacity of ecosystems to provide the multiple services on which humans depend. However, experiments necessarily simplify the complexity of natural ecosystems and will normally control for other important drivers of ecosystem functioning, such as the environment or land use. In addition, existing studies typically focus on the diversity of single trophic groups, neglecting the fact that biodiversity loss occurs across many taxa and that the functional effects of any trophic group may depend on the abundance and diversity of others. Here we report analysis of the relationships between the species richness and abundance of nine trophic groups, including 4,600 above- and below-ground taxa, and 14 ecosystem services and functions and with their simultaneous provision (or multifunctionality) in 150 grasslands. We show that high species richness in multiple trophic groups (multitrophic richness) had stronger positive effects on ecosystem services than richness in any individual trophic group; this includes plant species richness, the most widely used measure of biodiversity. On average, three trophic groups influenced each ecosystem service, with each trophic group influencing at least one service. Multitrophic richness was particularly beneficial for 'regulating' and 'cultural' services, and for multifunctionality, whereas a change in the total abundance of species or biomass in multiple trophic groups (the multitrophic abundance) positively affected supporting services. Multitrophic richness and abundance drove ecosystem functioning as strongly as abiotic conditions and land-use intensity, extending previous experimental results to real-world ecosystems. Primary producers, herbivorous insects and microbial decomposers seem to be particularly important drivers of ecosystem functioning, as shown by the strong and frequent positive associations of their richness or abundance with multiple ecosystem services. Our results show that multitrophic richness and abundance support ecosystem functioning, and demonstrate that a focus on single groups has led to researchers to greatly underestimate the functional importance of biodiversity.
TL;DR: An overview of dual gold/photoredox catalysis is provided and the potential of this concept to greatly expand the scope of homogeneous gold catalysis and enable the efficient construction of complex organic molecules is highlighted.
Abstract: ConspectusSince the beginning of this century, π-Lewis acidic gold complexes have become the catalysts of choice for a wide range of organic reactions, especially those involving nucleophilic addition to carbon–carbon multiple bonds. For the most part, however, the gold catalyst does not change oxidation state during the course of these processes and two-electron redox cycles of the kind implicated in cross-coupling chemistry are not easily accessible. In order to address this limitation and expand the scope of gold catalysis beyond conventional hydrofunctionalization, extensive efforts have been made to develop new oxidative reactions using strong external oxidants capable of overcoming the high potential of the AuI/AuIII redox couple. However, these processes typically require superstoichiometric amounts of the oxidant and proceed under relatively harsh conditions. Moreover, to date, gold-catalyzed oxidative coupling reactions have remained somewhat limited in scope because, for many systems, the desire...
University of Duisburg-Essen1, University of Zurich2, University of Erlangen-Nuremberg3, University of Tübingen4, Hannover Medical School5, Heidelberg University6, Otto-von-Guericke University Magdeburg7, University Hospital Heidelberg8, University of Münster9, RWTH Aachen University10, University of Würzburg11, Technische Universität München12
TL;DR: Anti-PD-1 antibodies can induce a plethora of irAEs and the knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity.
University of Colorado Boulder1, Pacific Northwest National Laboratory2, United States Department of Energy3, University of Saskatchewan4, Helmholtz Centre for Environmental Research - UFZ5, University of Illinois at Urbana–Champaign6, University of California, Merced7, Flinders University8, Institut national de la recherche agronomique9, University of Aberdeen10, Spanish National Research Council11, Bangor University12, University of Vienna13, HAMK University of Applied Sciences14, University of Wisconsin–Milwaukee15, Swiss Federal Institute of Aquatic Science and Technology16, University of Sydney17, University of Münster18, University of Eastern Finland19, Dresden University of Technology20, University of Girona21, Commonwealth Scientific and Industrial Research Organisation22, University of Texas at Tyler23, University of Montana24, College of William & Mary25, North Dakota State University26, University of Porto27, Southern California Coastal Water Research Project28, Swedish University of Agricultural Sciences29, Virginia Tech30, Yonsei University31, University of Tokyo32, University of Cádiz33, Uppsala University34, Laurentian University35, Duke University36
TL;DR: In this article, a statistical analysis investigating the value of environmental data and microbial community structure independently and in combination for explaining rates of carbon and nitrogen cycling processes within 82 global datasets is presented.
Abstract: Microorganisms are vital in mediating the earth's biogeochemical cycles; yet, despite our rapidly increasing ability to explore complex environmental microbial communities, the relationship between microbial community structure and ecosystem processes remains poorly understood. Here, we address a fundamental and unanswered question in microbial ecology: 'When do we need to understand microbial community structure to accurately predict function?' We present a statistical analysis investigating the value of environmental data and microbial community structure independently and in combination for explaining rates of carbon and nitrogen cycling processes within 82 global datasets. Environmental variables were the strongest predictors of process rates but left 44% of variation unexplained on average, suggesting the potential for microbial data to increase model accuracy. Although only 29% of our datasets were significantly improved by adding information on microbial community structure, we observed improvement in models of processes mediated by narrow phylogenetic guilds via functional gene data, and conversely, improvement in models of facultative microbial processes via community diversity metrics. Our results also suggest that microbial diversity can strengthen predictions of respiration rates beyond microbial biomass parameters, as 53% of models were improved by incorporating both sets of predictors compared to 35% by microbial biomass alone. Our analysis represents the first comprehensive analysis of research examining links between microbial community structure and ecosystem function. Taken together, our results indicate that a greater understanding of microbial communities informed by ecological principles may enhance our ability to predict ecosystem process rates relative to assessments based on environmental variables and microbial physiology.
TL;DR: The nCTEQ15 set of nuclear parton distribution functions with uncertainties is presented in this article, where the uncertainties are determined using the Hessian method with an optimal rescaling of the eigenvectors to accurately represent the uncertainties for the chosen tolerance criteria.
Abstract: We present the new nCTEQ15 set of nuclear parton distribution functions with uncertainties. This fit extends the CTEQ proton PDFs to include the nuclear dependence using data on nuclei all the way up to 208^Pb. The uncertainties are determined using the Hessian method with an optimal rescaling of the eigenvectors to accurately represent the uncertainties for the chosen tolerance criteria. In addition to the Deep Inelastic Scattering (DIS) and Drell-Yan (DY) processes, we also include inclusive pion production data from RHIC to help constrain the nuclear gluon PDF. Furthermore, we investigate the correlation of the data sets with specific nPDF flavor components, and asses the impact of individual experiments. We also provide comparisons of the nCTEQ15 set with recent fits from other groups.
TL;DR: TPH and TPH-Se acceptor-based solar cells show high power conversion efficiency of 8.28% and 9.28%, respectively, which mainly results from the combined properties of broad and strong absorption ability, appropriate LUMO level, desirable aggregation, high electron mobility, and good film morphology with the polymer donor.
Abstract: Two kinds of conjugated C3-symmetric perylene dyes, namely, triperylene hexaimides (TPH) and selenium-annulated triperylene hexaimides (TPH-Se), are efficiently synthesized. Both TPH and TPH-Se have broad and strong absorption in the region 300–600 nm together with suitable LUMO levels of about −3.8 eV. Single-crystal X-ray diffraction studies show that TPH displays an extremely twisted three-bladed propeller configuration and a unique 3D network assembly in which three PBI subunits in one TPH molecule have strong π–π intermolecular interactions with PBI subunits in neighboring molecules. The integration of selenophene to TPH endows TPH-Se with a more distorted propeller configuration and a more compact 3D network assembly due to the Se···O interactions. A single-crystal transistor confirms that both TPH and TPH-Se possess good electron-transport ability. TPH and TPH-Se acceptor-based solar cells show high power conversion efficiency of 8.28% and 9.28%, respectively, which mainly results from the combined...
TL;DR: A meta-analysis of genome-wide association studies for estimated glomerular filtration rate suggests that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
Abstract: Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.