Showing papers by "University of Bonn published in 2016"
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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
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T. Prusti1, J. H. J. de Bruijne1, Anthony G. A. Brown2, Antonella Vallenari3 +621 more•Institutions (93)
TL;DR: Gaia as discussed by the authors is a cornerstone mission in the science programme of the European Space Agency (ESA). The spacecraft construction was approved in 2006, following a study in which the original interferometric concept was changed to a direct-imaging approach.
Abstract: Gaia is a cornerstone mission in the science programme of the EuropeanSpace Agency (ESA). The spacecraft construction was approved in 2006, following a study in which the original interferometric concept was changed to a direct-imaging approach. Both the spacecraft and the payload were built by European industry. The involvement of the scientific community focusses on data processing for which the international Gaia Data Processing and Analysis Consortium (DPAC) was selected in 2007. Gaia was launched on 19 December 2013 and arrived at its operating point, the second Lagrange point of the Sun-Earth-Moon system, a few weeks later. The commissioning of the spacecraft and payload was completed on 19 July 2014. The nominal five-year mission started with four weeks of special, ecliptic-pole scanning and subsequently transferred into full-sky scanning mode. We recall the scientific goals of Gaia and give a description of the as-built spacecraft that is currently (mid-2016) being operated to achieve these goals. We pay special attention to the payload module, the performance of which is closely related to the scientific performance of the mission. We provide a summary of the commissioning activities and findings, followed by a description of the routine operational mode. We summarise scientific performance estimates on the basis of in-orbit operations. Several intermediate Gaia data releases are planned and the data can be retrieved from the Gaia Archive, which is available through the Gaia home page.
5,164 citations
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TL;DR: In this article, the authors used a Bayesian hierarchical model to estimate trends in diabetes prevalence, defined as fasting plasma glucose of 7.0 mmol/L or higher, or history of diagnosis with diabetes, or use of insulin or oral hypoglycaemic drugs in 200 countries and territories in 21 regions, by sex and from 1980 to 2014.
2,782 citations
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Anthony G. A. Brown1, Antonella Vallenari2, T. Prusti2, J. H. J. de Bruijne3 +587 more•Institutions (89)
TL;DR: The first Gaia data release, Gaia DR1 as discussed by the authors, consists of three components: a primary astrometric data set which contains the positions, parallaxes, and mean proper motions for about 2 million of the brightest stars in common with the Hipparcos and Tycho-2 catalogues.
Abstract: Context. At about 1000 days after the launch of Gaia we present the first Gaia data release, Gaia DR1, consisting of astrometry and photometry for over 1 billion sources brighter than magnitude 20.7. Aims: A summary of Gaia DR1 is presented along with illustrations of the scientific quality of the data, followed by a discussion of the limitations due to the preliminary nature of this release. Methods: The raw data collected by Gaia during the first 14 months of the mission have been processed by the Gaia Data Processing and Analysis Consortium (DPAC) and turned into an astrometric and photometric catalogue. Results: Gaia DR1 consists of three components: a primary astrometric data set which contains the positions, parallaxes, and mean proper motions for about 2 million of the brightest stars in common with the Hipparcos and Tycho-2 catalogues - a realisation of the Tycho-Gaia Astrometric Solution (TGAS) - and a secondary astrometric data set containing the positions for an additional 1.1 billion sources. The second component is the photometric data set, consisting of mean G-band magnitudes for all sources. The G-band light curves and the characteristics of 3000 Cepheid and RR Lyrae stars, observed at high cadence around the south ecliptic pole, form the third component. For the primary astrometric data set the typical uncertainty is about 0.3 mas for the positions and parallaxes, and about 1 mas yr-1 for the proper motions. A systematic component of 0.3 mas should be added to the parallax uncertainties. For the subset of 94 000 Hipparcos stars in the primary data set, the proper motions are much more precise at about 0.06 mas yr-1. For the secondary astrometric data set, the typical uncertainty of the positions is 10 mas. The median uncertainties on the mean G-band magnitudes range from the mmag level to0.03 mag over the magnitude range 5 to 20.7. Conclusions: Gaia DR1 is an important milestone ahead of the next Gaia data release, which will feature five-parameter astrometry for all sources. Extensive validation shows that Gaia DR1 represents a major advance in the mapping of the heavens and the availability of basic stellar data that underpin observational astrophysics. Nevertheless, the very preliminary nature of this first Gaia data release does lead to a number of important limitations to the data quality which should be carefully considered before drawing conclusions from the data.
2,174 citations
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TL;DR: The theory of weak gravitational lensing is discussed in this paper, and applications to galaxies, galaxy clusters and larger-scale structures in the universe are reviewed and summarised in detail.
Abstract: According to the theory of general relativity, masses deflect light in a way similar to convex glass lenses. This gravitational lensing effect is astigmatic, giving rise to image distortions. These distortions allow to quantify cosmic structures statistically on a broad range of scales, and to map the spatial distribution of dark and visible matter. We summarise the theory of weak gravitational lensing and review applications to galaxies, galaxy clusters and larger-scale structures in the Universe.
1,761 citations
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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
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Oregon Health & Science University1, University of Bonn2, Icahn School of Medicine at Mount Sinai3, University of Rochester4, Regeneron5, University of Sheffield6, Northwestern University7, Aarhus University8, Centre Hospitalier Universitaire de Nice9, University of Tartu10, Ludwig Maximilian University of Munich11, Charité12, Laval University13, Sanofi S.A.14
TL;DR: Dupilumab improved the signs and symptoms of atopic dermatitis, including pruritus, symptoms of anxiety and depression, and quality of life, as compared with placebo in two phase 3 trials of identical design.
Abstract: BackgroundDupilumab, a human monoclonal antibody against interleukin-4 receptor alpha, inhibits signaling of interleukin-4 and interleukin-13, type 2 cytokines that may be important drivers of atopic or allergic diseases such as atopic dermatitis. MethodsIn two randomized, placebo-controlled, phase 3 trials of identical design (SOLO 1 and SOLO 2), we enrolled adults with moderate-to-severe atopic dermatitis whose disease was inadequately controlled by topical treatment. Patients were randomly assigned in a 1:1:1 ratio to receive, for 16 weeks, subcutaneous dupilumab (300 mg) or placebo weekly or the same dose of dupilumab every other week alternating with placebo. The primary outcome was the proportion of patients who had both a score of 0 or 1 (clear or almost clear) on the Investigator’s Global Assessment and a reduction of 2 points or more in that score from baseline at week 16. ResultsWe enrolled 671 patients in SOLO 1 and 708 in SOLO 2. In SOLO 1, the primary outcome occurred in 85 patients (38%) who...
1,318 citations
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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
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Lars G. Fritsche1, Wilmar Igl2, Jessica N. Cooke Bailey3, Felix Grassmann2 +182 more•Institutions (58)
TL;DR: The results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.
Abstract: Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.
1,088 citations
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Smithsonian Institution1, Sun Yat-sen University2, University of California, Berkeley3, Naturalis4, Paris-Sorbonne University5, Universidade Federal de Minas Gerais6, University of Vermont7, Federal University of Western Pará8, University of Florida9, James Cook University10, Duke University11, University of Bonn12, University of Neuchâtel13, University of Turku14, University of Alaska Fairbanks15, Missouri Botanical Garden16, National Taiwan University17, Museum of New Zealand Te Papa Tongarewa18, National University of Río Cuarto19, University of Arizona20, Council of Agriculture21, Kaohsiung Medical University22, Chongqing Normal University23, Universidade Federal de Juiz de Fora24, Nanjing Forestry University25, Iowa State University26, Complutense University of Madrid27, University of Kansas28, Denison University29, University of Zurich30
TL;DR: A modern, comprehensive classification for lycophytes and ferns, down to the genus level, utilizing a community‐based approach, that uses monophyly as the primary criterion for the recognition of taxa, but also aims to preserve existing taxa and circumscriptions that are both widely accepted and consistent with the understanding of pteridophyte phylogeny.
Abstract: Phylogeny has long informed pteridophyte classification. As our ability to infer evolutionary trees has improved, classifications aimed at recognizing natural groups have become increasingly predic ...
971 citations
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TL;DR: This Review describes the recent developments (including some historical aspects) of dispersion corrections with an emphasis on methods that can be employed routinely with reasonable accuracy in large-scale applications.
Abstract: Mean-field electronic structure methods like Hartree–Fock, semilocal density functional approximations, or semiempirical molecular orbital (MO) theories do not account for long-range electron correlation (London dispersion interaction). Inclusion of these effects is mandatory for realistic calculations on large or condensed chemical systems and for various intramolecular phenomena (thermochemistry). This Review describes the recent developments (including some historical aspects) of dispersion corrections with an emphasis on methods that can be employed routinely with reasonable accuracy in large-scale applications. The most prominent correction schemes are classified into three groups: (i) nonlocal, density-based functionals, (ii) semiclassical C6-based, and (iii) one-electron effective potentials. The properties as well as pros and cons of these methods are critically discussed, and typical examples and benchmarks on molecular complexes and crystals are provided. Although there are some areas for furthe...
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Perimeter Institute for Theoretical Physics1, Niigata University2, CERN3, University of Connecticut4, Leiden University5, Korea Astronomy and Space Science Institute6, Federico Santa María Technical University7, University of California, Santa Barbara8, University of Maryland, College Park9, Claude Bernard University Lyon 110, University of Lyon11, Northwestern University12, University of Victoria13, University of Manchester14, University of Bonn15, Technische Universität München16, École Polytechnique Fédérale de Lausanne17, Stony Brook University18, Autonomous University of Madrid19, University of Paris20, Centre national de la recherche scientifique21, Moscow Institute of Physics and Technology22, Autonomous University of Barcelona23, University of Copenhagen24, Université libre de Bruxelles25, University of La Serena26, University of Valencia27, Taras Shevchenko National University of Kyiv28, Heidelberg University29, Yonsei University30, Princeton University31, Harvard University32, University of Geneva33, University of Tübingen34, Tomsk Polytechnic University35, Tomsk State University36, University of Washington37, University of Florida38, University of Hamburg39, TRIUMF40, University of Iowa41, University of Grenoble42, International Centre for Theoretical Physics43, Hokkai Gakuen University44, University of Illinois at Urbana–Champaign45, Durham University46, University of Melbourne47, University of Naples Federico II48, York University49, University of California, Berkeley50, Lawrence Berkeley National Laboratory51
TL;DR: It is demonstrated that the SHiP experiment has a unique potential to discover new physics and can directly probe a number of solutions of beyond the standard model puzzles, such as neutrino masses, baryon asymmetry of the Universe, dark matter, and inflation.
Abstract: This paper describes the physics case for a new fixed target facility at CERN SPS. The SHiP (search for hidden particles) experiment is intended to hunt for new physics in the largely unexplored domain of very weakly interacting particles with masses below the Fermi scale, inaccessible to the LHC experiments, and to study tau neutrino physics. The same proton beam setup can be used later to look for decays of tau-leptons with lepton flavour number non-conservation, $\tau \to 3\mu $ and to search for weakly-interacting sub-GeV dark matter candidates. We discuss the evidence for physics beyond the standard model and describe interactions between new particles and four different portals—scalars, vectors, fermions or axion-like particles. We discuss motivations for different models, manifesting themselves via these interactions, and how they can be probed with the SHiP experiment and present several case studies. The prospects to search for relatively light SUSY and composite particles at SHiP are also discussed. We demonstrate that the SHiP experiment has a unique potential to discover new physics and can directly probe a number of solutions of beyond the standard model puzzles, such as neutrino masses, baryon asymmetry of the Universe, dark matter, and inflation.
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University of Bonn1, Max Planck Society2, University of Alabama3, National Radio Astronomy Observatory4, Commonwealth Scientific and Industrial Research Organisation5, University of Arizona6, University of Hull7, Tartu Observatory8, University of Western Australia9, Australian National University10, University of Sydney11, Kagoshima University12, West Virginia University13
TL;DR: In this paper, the International Max Planck Research School for Astronomy and Astrophysics at the Universities of Bonn and Cologne (IMPRS Bonn/Cologne); Estonian Research Council [IUT26-2]; European Regional Development Fund [TK133]; Australian Research Council Future Fellowship [FT150100024]; NSF CAREER grant [AST-1149491]
Abstract: Deutsche Forschungsgemeinschaft (DFG) [KA1265/5-1, KA1265/5-2, KE757/71, KE757/7-2, KE757/7-3, KE757/11-1.]; International Max Planck Research School for Astronomy and Astrophysics at the Universities of Bonn and Cologne (IMPRS Bonn/Cologne); Estonian Research Council [IUT26-2]; European Regional Development Fund [TK133]; Australian Research Council Future Fellowship [FT150100024]; NSF CAREER grant [AST-1149491]
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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.
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Christian R. Marshall1, Daniel P. Howrigan2, Daniele Merico1, Bhooma Thiruvahindrapuram1 +252 more•Institutions (87)
TL;DR: A collaborative effort in which a centralized analysis pipeline is applied to a SCZ cohort, finding support at a suggestive level for nine additional candidate susceptibility and protective loci, which consist predominantly of CNVs mediated by non-allelic homologous recombination (NAHR).
Abstract: Genomic copy number variants (CNVs) have been strongly implicated in the etiology of schizophrenia (SCZ). However, apart from a small number of risk variants, elucidation of the CNV contribution to risk has been difficult due to the rarity of risk alleles, all occurring in less than 1% of cases. We sought to address this obstacle through a collaborative effort in which we applied a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. We observed a global enrichment of CNV burden in cases (OR=1.11, P=5.7e-15), which persisted after excluding loci implicated in previous studies (OR=1.07, P=1.7e-6). CNV burden is also enriched for genes associated with synaptic function (OR = 1.68, P = 2.8e-11) and neurobehavioral phenotypes in mouse (OR = 1.18, P= 7.3e-5). We identified genome-wide significant support for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. We find support at a suggestive level for nine additional candidate susceptibility and protective loci, which consist predominantly of CNVs mediated by non-allelic homologous recombination (NAHR).
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TL;DR: The most relevant areas of application of sensor-based analyses are precision agriculture and plant phenotyping as discussed by the authors, which is facilitated by highly sophisticated and innovative methods of data analysis that lead to new insights derived from sensor data for complex plant-pathogen systems.
Abstract: Early and accurate detection and diagnosis of plant diseases are key factors in plant production and the reduction of both qualitative and quantitative losses in crop yield. Optical techniques, such as RGB imaging, multi- and hyperspectral sensors, thermography, or chlorophyll fluorescence, have proven their potential in automated, objective, and reproducible detection systems for the identification and quantification of plant diseases at early time points in epidemics. Recently, 3D scanning has also been added as an optical analysis that supplies additional information on crop plant vitality. Different platforms from proximal to remote sensing are available for multiscale monitoring of single crop organs or entire fields. Accurate and reliable detection of diseases is facilitated by highly sophisticated and innovative methods of data analysis that lead to new insights derived from sensor data for complex plant-pathogen systems. Nondestructive, sensor-based methods support and expand upon visual and/or molecular approaches to plant disease assessment. The most relevant areas of application of sensor-based analyses are precision agriculture and plant phenotyping.
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Heidelberg University1, German Cancer Research Center2, St. Jude Children's Research Hospital3, University of Toronto4, Ontario Institute for Cancer Research5, 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.
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TL;DR: It is shown that EMP-derived precursors colonize embryonic tissues and simultaneously acquire a full core macrophage program, which indicates that differentiation of tissue-resident macrophages is an integral part of organogenesis and identifies a spatiotemporal molecular road map for the generation of macrophAGE diversity in vivo.
Abstract: INTRODUCTION Embryonic development and tissue homeostasis depend on cooperation between specialized cell types. Resident macrophages are professional phagocytes that survey their surroundings; eliminate unfit cells, microorganisms, and metabolic waste; and produce a large range of bioactive molecules and growth factors. Resident macrophages also serve tissue-specific purposes: For example, microglia in the central nervous system support neuronal circuit development, Kupffer cells scavenge blood particles and dying red blood cells in the liver, and alveolar macrophages uptake surfactant and remove airborne pollutants and microbes from the airways. Resident macrophage diversity in adult mice is reflected in tissue-specific gene expression profiles, which may be due to responses to specific cues from their microenvironment, different developmental processes, and the contribution of distinct progenitors cell types. Altogether, the mechanisms responsible for the generation of tissue-resident macrophage diversity remain unclear. RATIONALE Tissue-resident macrophages originate, at least in part, from mesodermal erythro-myeloid progenitors (EMPs) from the yolk sac, which invade the embryo proper at the onset of organogenesis. These tissue-resident macrophages are also self-maintained in postnatal tissues, independently of definitive hematopoietic stem cells (HSCs) in a steady state. We therefore hypothesized that resident macrophages represent a founding cell type within most organ anlagen. In this model, the generation of macrophage diversity, as observed in the tissues of postnatal mice, may be integral to organogenesis. RESULTS To test this hypothesis and explore the molecular basis of macrophage diversity in mammals, we performed a spatiotemporal analysis of macrophage development in mice, from embryonic day 9 (E9) to 3 weeks after birth. Unbiased single-cell RNA sequencing (RNA-seq) analysis of CD45 + cells, combined with RNA-seq analyses of sorted cell populations, genetic fate mapping, and in situ analyses, revealed that EMPs give rise to a population of premacrophages (pMacs) that colonize the whole embryo from E9.5, as they acquire a core macrophage differentiation program that includes pattern recognition, scavengers, and cytokine receptors. The chemokine receptor Cx3cr1 is up-regulated in pMacs and is important for embryo colonization, which is delayed in Cx3cr1 -deficient embryos. Fate mapping of pMacs using a Tnfrsf11a –Cre reporter labels homogeneously fetal and adult tissue-resident macrophages but not HSCs and their progeny. Transcriptional regulators that identify postnatal tissue-resident macrophages in the brain, liver, kidney, skin, and lung were specifically up-regulated immediately after colonization. These dynamic changes mark the onset of diversification into adult macrophages. We identified Id3 as a Kupffer cell–specific transcriptional regulator. Deletion of Id3 in pMacs resulted in Kupffer cell deficiency but did not affect development of microglia and kidney macrophages. CONCLUSION Our study shows that EMP-derived precursors colonize embryonic tissues and simultaneously acquire a full core macrophage program. This is followed by their diversification into tissue-specific macrophages during organogenesis, likely via the expression of distinct sets of transcriptional regulators. These results indicate that differentiation of tissue-resident macrophages is an integral part of organogenesis and identify a spatiotemporal molecular road map for the generation of macrophage diversity in vivo. Our findings provide a conceptual framework to analyze and understand the consequence(s) of genetic variation for macrophage contribution to development, homeostasis, and disease pathogenesis in different tissues and will support efforts to differentiate specialized macrophages in vitro.
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TL;DR: This perspective focuses on the status of various efficacious anti-SARS-CoV 3CLpro chemotherapies discovered during the last 12 years from all sources, including laboratory synthetic methods, natural products, and virtual screening.
Abstract: Severe acute respiratory syndrome (SARS) is caused by a newly emerged coronavirus that infected more than 8000 individuals and resulted in more than 800 (10–15%) fatalities in 2003. The causative a...
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TL;DR: The main classes of new platinum drug candidates, such as sterically hindered complexes, monofunctional platinum drugs, complexes with biologically active ligands, trans-configured and polynuclear platinum complexes, platinum(IV) prodrugs and platinum-based drug delivery systems are reviewed.
Abstract: Platinum-based drugs cisplatin, carboplatin and oxaliplatin are widely used in the therapy of human neoplasms. Their clinical success is, however, limited due to severe side effects and intrinsic or acquired resistance to the treatment. Much effort has been put into the development of new platinum anticancer complexes, but none of them has reached worldwide clinical application so far. Nedaplatin, lobaplatin and heptaplatin received only regional approval. Some new platinum complexes and platinum drug formulations are undergoing clinical trials. Here, we review the main classes of new platinum drug candidates, such as sterically hindered complexes, monofunctional platinum drugs, complexes with biologically active ligands, trans-configured and polynuclear platinum complexes, platinum(IV) prodrugs and platinum-based drug delivery systems. For each class of compounds, a detailed overview of the mechanism of action is given, the cytotoxicity is compared to that of the clinically used platinum drugs, and the clinical perspectives are discussed. A critical analysis of lessons to be learned is presented. Finally, a general outlook regarding future directions in the field of new platinum drugs is given.
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University of Kiel1, Wellcome Trust2, University of Oxford3, University of Ulsan4, Harvard University5, Broad Institute6, University of Toronto7, University of Oslo8, University of California, San Diego9, University of Tartu10, University of Groningen11, Karolinska Institutet12, Ikerbasque13, Örebro University14, University of Copenhagen15, University of Bonn16, Mayo Clinic17, King's College London18, Veterans Health Administration19, University of Michigan20, Cedars-Sinai Medical Center21, University of Cambridge22, Queensland University of Technology23, University of Queensland24
TL;DR: The COMorbidities among the five immune diseases were best explained by biological pleiotropy rather than heterogeneity (a subgroup of cases genetically identical to those with another disease, possibly owing to diagnostic misclassification, molecular subtypes or excessive comorbidity), and the strong comor bid between primary sclerosing cholangitis and inflammatory bowel disease is likely the result of a unique disease.
Abstract: We simultaneously investigated the genetic landscape of ankylosing spondylitis, Crohn's disease, psoriasis, primary sclerosing cholangitis and ulcerative colitis to investigate pleiotropy and the relationship between these clinically related diseases. Using high-density genotype data from more than 86,000 individuals of European ancestry, we identified 244 independent multidisease signals, including 27 new genome-wide significant susceptibility loci and 3 unreported shared risk loci. Complex pleiotropy was supported when contrasting multidisease signals with expression data sets from human, rat and mouse together with epigenetic and expressed enhancer profiles. The comorbidities among the five immune diseases were best explained by biological pleiotropy rather than heterogeneity (a subgroup of cases genetically identical to those with another disease, possibly owing to diagnostic misclassification, molecular subtypes or excessive comorbidity). In particular, the strong comorbidity between primary sclerosing cholangitis and inflammatory bowel disease is likely the result of a unique disease, which is genetically distinct from classical inflammatory bowel disease phenotypes.
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University of Gothenburg1, Florey Institute of Neuroscience and Mental Health2, University of Newcastle3, University of Wisconsin-Madison4, University of Bonn5, Washington University in St. Louis6, University of Alabama at Birmingham7, Royal Netherlands Academy of Arts and Sciences8, University of Amsterdam9, Utrecht University10, University of California11
TL;DR: It is argued that targeting astrocytes may represent an effective therapeutic strategy for Alexander disease, neurotrauma, stroke, epilepsy and Alzheimer’s disease as well as other neurodegenerative diseases.
Abstract: The neurone-centred view of the past disregarded or downplayed the role of astroglia as a primary component in the pathogenesis of neurological diseases. As this concept is changing, so is also the perceived role of astrocytes in the healthy and diseased brain and spinal cord. We have started to unravel the different signalling mechanisms that trigger specific molecular, morphological and functional changes in reactive astrocytes that are critical for repairing tissue and maintaining function in CNS pathologies, such as neurotrauma, stroke, or neurodegenerative diseases. An increasing body of evidence shows that the effects of astrogliosis on the neural tissue and its functions are not uniform or stereotypic, but vary in a context-specific manner from astrogliosis being an adaptive beneficial response under some circumstances to a maladaptive and deleterious process in another context. There is a growing support for the concept of astrocytopathies in which the disruption of normal astrocyte functions, astrodegeneration or dysfunctional/maladaptive astrogliosis are the primary cause or the main factor in neurological dysfunction and disease. This review describes the multiple roles of astrocytes in the healthy CNS, discusses the diversity of astroglial responses in neurological disorders and argues that targeting astrocytes may represent an effective therapeutic strategy for Alexander disease, neurotrauma, stroke, epilepsy and Alzheimer's disease as well as other neurodegenerative diseases.
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Forschungszentrum Jülich1, University of California, Davis2, Université catholique de Louvain3, ETH Zurich4, University of Southampton5, University of Texas at Austin6, University of Bonn7, James Hutton Institute8, University of California, Irvine9, Université Paris-Saclay10, Desert Research Institute11, Ghent University12, Washington State University13, Katholieke Universiteit Leuven14, University of Aberdeen15, Institut national de la recherche agronomique16, Polish Academy of Sciences17, University of Vienna18, University of Sydney19, University of Stuttgart20, Agricultural Research Service21, University of Naples Federico II22, University of California, Riverside23, Netherlands Environmental Assessment Agency24, Monash University25, University of Tübingen26, University of New England (Australia)27
TL;DR: Key challenges in modeling soil processes are identified, including the systematic incorporation of heterogeneity and uncertainty, the integration of data and models, and strategies for effective integration of knowledge on physical, chemical, and biological soil processes.
Abstract: The remarkable complexity of soil and its importance to a wide range of ecosystem services presents major challenges to the modeling of soil processes. Although major progress in soil models has occurred in the last decades, models of soil processes remain disjointed between disciplines or ecosystem services, with considerable uncertainty remaining in the quality of predictions and several challenges that remain yet to be addressed. First, there is a need to improve exchange of knowledge and experience among the different disciplines in soil science and to reach out to other Earth science communities. Second, the community needs to develop a new generation of soil models based on a systemic approach comprising relevant physical, chemical, and biological processes to address critical knowledge gaps in our understanding of soil processes and their interactions. Overcoming these challenges will facilitate exchanges between soil modeling and climate, plant, and social science modeling communities. It will allow us to contribute to preserve and improve our assessment of ecosystem services and advance our understanding of climate-change feedback mechanisms, among others, thereby facilitating and strengthening communication among scientific disciplines and society. We review the role of modeling soil processes in quantifying key soil processes that shape ecosystem services, with a focus on provisioning and regulating services. We then identify key challenges in modeling soil processes, including the systematic incorporation of heterogeneity and uncertainty, the integration of data and models, and strategies for effective integration of knowledge on physical, chemical, and biological soil processes. We discuss how the soil modeling community could best interface with modern modeling activities in other disciplines, such as climate, ecology, and plant research, and how to weave novel observation and measurement techniques into soil models. We propose the establishment of an international soil modeling consortium to coherently advance soil modeling activities and foster communication with other Earth science disciplines. Such a consortium should promote soil modeling platforms and data repository for model development, calibration and intercomparison essential for addressing contemporary challenges.
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TL;DR: It is discussed here how recent discoveries in these areas have led to a multidimensional concept of macrophage ontogeny, activation and function, and how technical advances facilitate a new roadmap for the isolation and analysis ofmacrophages at high resolution.
Abstract: Macrophages have protective roles in immunity to pathogens, tissue development, homeostasis and repair following damage. Maladaptive immunity and inflammation provoke changes in macrophage function that are causative of disease. Despite a historical wealth of knowledge about macrophages, recent advances have revealed unknown aspects of their development and function. Following development, macrophages are activated by diverse signals. Such tissue microenvironmental signals together with epigenetic changes influence macrophage development, activation and functional diversity, with consequences in disease and homeostasis. We discuss here how recent discoveries in these areas have led to a multidimensional concept of macrophage ontogeny, activation and function. In connection with this, we also discuss how technical advances facilitate a new roadmap for the isolation and analysis of macrophages at high resolution.
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TL;DR: This study provides a first assessment of continuous sub-national trajectories of blue water consumption, renewable freshwater availability, and water scarcity for the entire 20th century to suggest measures for alleviating water scarcity and increasing sustainability.
Abstract: Water scarcity is a rapidly growing concern around the globe, but little is known about how it has developed over time. This study provides a first assessment of continuous sub-national trajectories of blue water consumption, renewable freshwater availability, and water scarcity for the entire 20th century. Water scarcity is analysed using the fundamental concepts of shortage (impacts due to low availability per capita) and stress (impacts due to high consumption relative to availability) which indicate difficulties in satisfying the needs of a population and overuse of resources respectively. While water consumption increased fourfold within the study period, the population under water scarcity increased from 0.24 billion (14% of global population) in the 1900s to 3.8 billion (58%) in the 2000s. Nearly all sub-national trajectories show an increasing trend in water scarcity. The concept of scarcity trajectory archetypes and shapes is introduced to characterize the historical development of water scarcity and suggest measures for alleviating water scarcity and increasing sustainability. Linking the scarcity trajectories to other datasets may help further deepen understanding of how trajectories relate to historical and future drivers, and hence help tackle these evolving challenges.
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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.
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University of Barcelona1, Medical University of Graz2, Leiden University Medical Center3, Paris Diderot University4, University College London5, University of Padua6, University of Bologna7, Ludwig Maximilian University of Munich8, King's College London9, Katholieke Universiteit Leuven10, University of Bonn11, University of Paris-Sud12, Goethe University Frankfurt13, Université libre de Bruxelles14, University of Hamburg15
TL;DR: Patients with AD without ACLF showed very high baseline levels of inflammatory cytokines, HNA2, PRC, and PCC, and the strength of association of ACLF with SI was higher than with SCD, supporting SI as the primary driver of ACLf in cirrhosis.
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TL;DR: Genome-wide significant associations for overall microbial variation and individual taxa at multiple genetic loci identify other important points of host–microbe intersection, notably several disease susceptibility genes and sterol metabolism pathway components.
Abstract: Human gut microbiota is an important determinant for health and disease, and recent studies emphasize the numerous factors shaping its diversity. Here we performed a genome-wide association study (GWAS) of the gut microbiota using two cohorts from northern Germany totaling 1,812 individuals. Comprehensively controlling for diet and non-genetic parameters, we identify genome-wide significant associations for overall microbial variation and individual taxa at multiple genetic loci, including the VDR gene (encoding vitamin D receptor). We observe significant shifts in the microbiota of Vdr-/- mice relative to control mice and correlations between the microbiota and serum measurements of selected bile and fatty acids in humans, including known ligands and downstream metabolites of VDR. Genome-wide significant (P < 5 × 10-8) associations at multiple additional loci identify other important points of host-microbe intersection, notably several disease susceptibility genes and sterol metabolism pathway components. Non-genetic and genetic factors each account for approximately 10% of the variation in gut microbiota, whereby individual effects are relatively small.
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TL;DR: In this paper, the authors explore the scenario of massive overcontact binary (MOB) evolution, which involves two very massive stars in a very tight binary that remain fully mixed as a result of their tidally induced high spin.
Abstract: With recent advances in gravitational-wave astronomy, the direct detection of gravitational waves from the merger of two stellar-mass compact objects has become a realistic prospect. Evolutionary scenarios towards mergers of various double compact objects generally invoke so-called common-envelope evolution, which is poorly understood and leads to large uncertainties in the predicted merger rates. Here we explore, as an alternative, the scenario of massive overcontact binary (MOB) evolution, which involves two very massive stars in a very tight binary that remain fully mixed as a result of their tidally induced high spin. While many of these systems merge early on, we find many MOBs that swap mass several times, but survive as a close binary until the stars collapse. The simplicity of the MOB scenario allows us to use the efficient public stellar-evolution code MESA to explore it systematically by means of detailed numerical calculations. We find that, at low metallicity, MOBs produce double-black-hole (BH+BH) systems that will merge within a Hubble time with mass-ratios close to one, in two mass ranges, about 25... 60 M ⊙ and ≳130M ⊙ , with pair-instability supernovae (PISNe) being produced at intermediate masses. Our models are also able to reproduce counterparts of various stages in the MOB scenario in the local Universe, providing direct support for the scenario. We map the initial binary parameter space that produces BH+BH mergers, determine the expected chirp mass distribution, merger times, and expected Kerr parameters, and predict event rates. We find typically one BH+BH merger event for ~1000 core-collapse supernovae for Z ≲ Z ⊙ / 10 . The advanced LIGO (aLIGO) detection rate is more uncertain and depends on the cosmic metallicity evolution. From deriving upper and lower limits from a local and a global approximation for the metallicity distribution of massive stars, we estimate aLIGO detection rates (at the aLIGO design limit) of ~19−550 yr-1 for BH-BH mergers below the PISN gap and of ~2.1−370 yr-1 above the PISN gap. Even with conservative assumptions, we find that aLIGO will probably soon detect BH+BH mergers from the MOB scenario. These could be the dominant source for aLIGO detections.
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TL;DR: Dupilumab improved clinical responses in adults with moderate-to-severe atopic dermatitis in a dose-dependent manner, without significant safety concerns, and shows that IL-4 and IL-13 are key drivers of atopic skinitis.