Showing papers by "University of Hamburg published in 2021"
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Daniel J. Klionsky1, Amal Kamal Abdel-Aziz2, Sara Abdelfatah3, Mahmoud Abdellatif4 +2980 more•Institutions (777)
TL;DR: In this article, the authors present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes.
Abstract: In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
1,129 citations
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Harvard University1, university of lille2, University of California, San Francisco3, Icahn School of Medicine at Mount Sinai4, Sarah Cannon Research Institute5, Emory University6, Rutgers University7, Centre Hospitalier Universitaire de Nantes8, Lille University of Science and Technology9, Katholieke Universiteit Leuven10, University of Würzburg11, Heidelberg University12, German Cancer Research Center13, University of Hamburg14, University of Tübingen15, Autonomous University of Barcelona16, University of Milan17, Bristol-Myers Squibb18, University of Navarra19
TL;DR: In this article, a B-cell maturation antigen-directed chimeric antigen receptor (CAR) T-cell therapy, has shown clinical activity with expecable clinical outcomes with the use of idecabtagene vicleucel (ide-cel), also called bb2121.
Abstract: Background Idecabtagene vicleucel (ide-cel, also called bb2121), a B-cell maturation antigen–directed chimeric antigen receptor (CAR) T-cell therapy, has shown clinical activity with expec...
776 citations
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Novo Nordisk1, German Cancer Research Center2, University of Zurich3, University of Barcelona4, Newcastle University5, Medical University of Vienna6, University of Tübingen7, University Hospital Heidelberg8, Weizmann Institute of Science9, Technische Universität München10, Max Planck Society11, Heidelberg University12, Icahn School of Medicine at Mount Sinai13, National and Kapodistrian University of Athens14, University of Turin15, University of Cambridge16, University of Florence17, Paris Diderot University18, Humanitas University19, Hannover Medical School20, University of Hamburg21, University of Mainz22, University of Düsseldorf23, Cornell University24, Memorial Sloan Kettering Cancer Center25, Harvard University26, University of Cologne27, Leibniz Association28, University of Bern29, Mount Sinai Hospital30, University of Texas MD Anderson Cancer Center31, Kindai University32, National Yang-Ming University33, Taipei Veterans General Hospital34, French Institute of Health and Medical Research35, University of Grenoble36, Imperial College London37, Catalan Institution for Research and Advanced Studies38
TL;DR: The progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers provides a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment.
Abstract: Hepatocellular carcinoma (HCC) can have viral or non-viral causes1-5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment.
526 citations
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TL;DR: In this article, the population of 47 compact binary mergers detected with a false-alarm rate of 0.614 were dynamically assembled, and the authors found that the BBH rate likely increases with redshift, but not faster than the star formation rate.
Abstract: We report on the population of 47 compact binary mergers detected with a false-alarm rate of 0.01 are dynamically assembled. Third, we estimate merger rates, finding RBBH = 23.9-+8.614.3 Gpc-3 yr-1 for BBHs and RBNS = 320-+240490 Gpc-3 yr-1 for binary neutron stars. We find that the BBH rate likely increases with redshift (85% credibility) but not faster than the star formation rate (86% credibility). Additionally, we examine recent exceptional events in the context of our population models, finding that the asymmetric masses of GW190412 and the high component masses of GW190521 are consistent with our models, but the low secondary mass of GW190814 makes it an outlier.
468 citations
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TL;DR: In this article, the authors investigated the impact of the COVID-19 pandemic on health-related quality of life (HRQoL) and mental health of children and adolescents in Germany from the perspective of children themselves.
Abstract: The COVID-19 pandemic has caused unprecedented changes in the lives of 1.6 billion children and adolescents. First non-representative studies from China, India, Brazil, the US, Spain, Italy, and Germany pointed to a negative mental health impact. The current study is the first nationwide representative study to investigate the impact of the COVID-19 pandemic on health-related quality of life (HRQoL) and mental health of children and adolescents in Germany from the perspective of children themselves. A representative online survey was conducted among n = 1586 families with 7- to 17-year-old children and adolescents between May 26 and June 10. The survey included internationally established and validated instruments for measuring HRQoL (KIDSCREEN-10), mental health problems (SDQ), anxiety (SCARED), and depression (CES-DC). Results were compared with data from the nationwide, longitudinal, representative BELLA cohort study (n = 1556) conducted in Germany before the pandemic. Two-thirds of the children and adolescents reported being highly burdened by the COVID-19 pandemic. They experienced significantly lower HRQoL (40.2% vs. 15.3%), more mental health problems (17.8% vs. 9.9%) and higher anxiety levels (24.1% vs. 14.9%) than before the pandemic. Children with low socioeconomic status, migration background and limited living space were affected significantly more. Health promotion and prevention strategies need to be implemented to maintain children's and adolescents' mental health, improve their HRQoL, and mitigate the burden caused by COVID-19, particularly for children who are most at risk.
436 citations
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TL;DR: In this article, the authors reported the observation of gravitational waves from two compact binary coalescences in LIGO's and Virgo's third observing run with properties consistent with neutron star-black hole (NSBH) binaries.
Abstract: We report the observation of gravitational waves from two compact binary coalescences in LIGO’s and Virgo’s third observing run with properties consistent with neutron star–black hole (NSBH) binaries. The two events are named GW200105_162426 and GW200115_042309, abbreviated as GW200105 and GW200115; the first was observed by LIGO Livingston and Virgo and the second by all three LIGO–Virgo detectors. The source of GW200105 has component masses 8.9−1.5+1.2 and 1.9−0.2+0.3M⊙ , whereas the source of GW200115 has component masses 5.7−2.1+1.8 and 1.5−0.3+0.7M⊙ (all measurements quoted at the 90% credible level). The probability that the secondary’s mass is below the maximal mass of a neutron star is 89%–96% and 87%–98%, respectively, for GW200105 and GW200115, with the ranges arising from different astrophysical assumptions. The source luminosity distances are 280−110+110 and 300−100+150Mpc , respectively. The magnitude of the primary spin of GW200105 is less than 0.23 at the 90% credible level, and its orientation is unconstrained. For GW200115, the primary spin has a negative spin projection onto the orbital angular momentum at 88% probability. We are unable to constrain the spin or tidal deformation of the secondary component for either event. We infer an NSBH merger rate density of 45−33+75Gpc−3yr−1 when assuming that GW200105 and GW200115 are representative of the NSBH population or 130−69+112Gpc−3yr−1 under the assumption of a broader distribution of component masses.
374 citations
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TL;DR: This work uses programmable arrays of individual atoms trapped in optical tweezers, with interactions controlled by laser excitation to Rydberg states, to implement an iconic many-body problem-the antiferromagnetic two-dimensional transverse-field Ising model, and demonstrates that this platform can be readily used to address open questions in many- body physics.
Abstract: Quantum simulation using synthetic systems is a promising route to solve outstanding quantum many-body problems in regimes where other approaches, including numerical ones, fail1. Many platforms are being developed towards this goal, in particular based on trapped ions2–4, superconducting circuits5–7, neutral atoms8–11 or molecules12,13. All of these platforms face two key challenges: scaling up the ensemble size while retaining high-quality control over the parameters, and validating the outputs for these large systems. Here we use programmable arrays of individual atoms trapped in optical tweezers, with interactions controlled by laser excitation to Rydberg states11, to implement an iconic many-body problem—the antiferromagnetic two-dimensional transverse-field Ising model. We push this platform to a regime with up to 196 atoms manipulated with high fidelity and probe the antiferromagnetic order by dynamically tuning the parameters of the Hamiltonian. We illustrate the versatility of our platform by exploring various system sizes on two qualitatively different geometries—square and triangular arrays. We obtain good agreement with numerical calculations up to a computationally feasible size (approximately 100 particles). This work demonstrates that our platform can be readily used to address open questions in many-body physics. Programmable quantum simulation of two-dimensional antiferromagnets is achieved with up to 196 neutral atoms, and the capability of the platform is demonstrated on square and triangular arrays.
348 citations
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Abstract: eROSITA (extended ROentgen Survey with an Imaging Telescope Array) is the primary instrument on the Spectrum-Roentgen-Gamma (SRG) mission, which was successfully launched on July 13, 2019, from the Baikonour cosmodrome. After the commissioning of the instrument and a subsequent calibration and performance verification phase, eROSITA started a survey of the entire sky on December 13, 2019. By the end of 2023, eight complete scans of the celestial sphere will have been performed, each lasting six months. At the end of this program, the eROSITA all-sky survey in the soft X-ray band (0.2–2.3 keV) will be about 25 times more sensitive than the ROSAT All-Sky Survey, while in the hard band (2.3–8 keV) it will provide the first ever true imaging survey of the sky. The eROSITA design driving science is the detection of large samples of galaxy clusters up to redshifts z > 1 in order to study the large-scale structure of the universe and test cosmological models including Dark Energy. In addition, eROSITA is expected to yield a sample of a few million AGNs, including obscured objects, revolutionizing our view of the evolution of supermassive black holes. The survey will also provide new insights into a wide range of astrophysical phenomena, including X-ray binaries, active stars, and diffuse emission within the Galaxy. Results from early observations, some of which are presented here, confirm that the performance of the instrument is able to fulfil its scientific promise. With this paper, we aim to give a concise description of the instrument, its performance as measured on ground, its operation in space, and also the first results from in-orbit measurements.
338 citations
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TL;DR: The data recorded by these instruments during their first and second observing runs are described, including the gravitational-wave strain arrays, released as time series sampled at 16384 Hz.
320 citations
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RWTH Aachen University1, Bayer HealthCare Pharmaceuticals2, Martin Luther University of Halle-Wittenberg3, Heidelberg University4, Radboud University Nijmegen5, Boston Children's Hospital6, University of Edinburgh7, University of Hamburg8, Monash University9, Erasmus University Rotterdam10, Molecular Medicine Partnership Unit11
TL;DR: Using single-cell RNA sequencing, the transcriptomes of cells from the proximal and non-proximal tubules of healthy and fibrotic human kidneys are profiled to map the entire human kidney and identify distinct subpopulations of pericytes and fibroblasts as the main cellular sources of scar-forming myofibro Blasts during human kidney fibrosis.
Abstract: Kidney fibrosis is the hallmark of chronic kidney disease progression; however, at present no antifibrotic therapies exist1-3. The origin, functional heterogeneity and regulation of scar-forming cells that occur during human kidney fibrosis remain poorly understood1,2,4. Here, using single-cell RNA sequencing, we profiled the transcriptomes of cells from the proximal and non-proximal tubules of healthy and fibrotic human kidneys to map the entire human kidney. This analysis enabled us to map all matrix-producing cells at high resolution, and to identify distinct subpopulations of pericytes and fibroblasts as the main cellular sources of scar-forming myofibroblasts during human kidney fibrosis. We used genetic fate-tracing, time-course single-cell RNA sequencing and ATAC-seq (assay for transposase-accessible chromatin using sequencing) experiments in mice, and spatial transcriptomics in human kidney fibrosis, to shed light on the cellular origins and differentiation of human kidney myofibroblasts and their precursors at high resolution. Finally, we used this strategy to detect potential therapeutic targets, and identified NKD2 as a myofibroblast-specific target in human kidney fibrosis.
301 citations
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VU University Amsterdam1, Harvard University2, University of Bern3, University of Oxford4, Public Health Research Institute5, University of Wuppertal6, Kyoto University7, University of Amsterdam8, University of New South Wales9, University of Melbourne10, City University London11, University of Gothenburg12, Free University of Berlin13, University of Texas at Austin14, Carlos III Health Institute15, James I University16, Ohio State University17, Northwestern University18, University of Erlangen-Nuremberg19, University of Bristol20, University Hospitals Bristol NHS Foundation Trust21, Trinity College, Dublin22, University of York23, Karolinska Institutet24, Peking Union Medical College25, Linköping University26, University of Regina27, University of Sydney28, McLean Hospital29, University of Lübeck30, University of Zaragoza31, Imperial College London32, University of Nottingham33, University of Hamburg34, Oregon Research Institute35, Australian National University36, The Ohio State University Wexner Medical Center37, Hofstra University38, Stockholm University39, Hull York Medical School40, Tilburg University41, Linnaeus University42
TL;DR: In this article, the authors conducted a systematic review and IPD network meta-analysis and estimated relative treatment effect sizes across different patient characteristics through IPD-network meta-regression, and found that both guided and unguided iCBT were associated with more effectiveness as measured by PHQ-9 scores than control treatments over the short term and the long term.
Abstract: Importance Personalized treatment choices would increase the effectiveness of internet-based cognitive behavioral therapy (iCBT) for depression to the extent that patients differ in interventions that better suit them. Objective To provide personalized estimates of short-term and long-term relative efficacy of guided and unguided iCBT for depression using patient-level information. Data Sources We searched PubMed, Embase, PsycInfo, and Cochrane Library to identify randomized clinical trials (RCTs) published up to January 1, 2019. Study Selection Eligible RCTs were those comparing guided or unguided iCBT against each other or against any control intervention in individuals with depression. Available individual patient data (IPD) was collected from all eligible studies. Depression symptom severity was assessed after treatment, 6 months, and 12 months after randomization. Data Extraction and Synthesis We conducted a systematic review and IPD network meta-analysis and estimated relative treatment effect sizes across different patient characteristics through IPD network meta-regression. Main Outcomes and Measures Patient Health Questionnaire–9 (PHQ-9) scores. Results Of 42 eligible RCTs, 39 studies comprising 9751 participants with depression contributed IPD to the IPD network meta-analysis, of which 8107 IPD were synthesized. Overall, both guided and unguided iCBT were associated with more effectiveness as measured by PHQ-9 scores than control treatments over the short term and the long term. Guided iCBT was associated with more effectiveness than unguided iCBT (mean difference [MD] in posttreatment PHQ-9 scores, −0.8; 95% CI, −1.4 to −0.2), but we found no evidence of a difference at 6 or 12 months following randomization. Baseline depression was found to be the most important modifier of the relative association for efficacy of guided vs unguided iCBT. Differences between unguided and guided iCBT in people with baseline symptoms of subthreshold depression (PHQ-9 scores 5-9) were small, while guided iCBT was associated with overall better outcomes in patients with baseline PHQ-9 greater than 9. Conclusions and Relevance In this network meta-analysis with IPD, guided iCBT was associated with more effectiveness than unguided iCBT for individuals with depression, benefits were more substantial in individuals with moderate to severe depression. Unguided iCBT was associated with similar effectiveness among individuals with symptoms of mild/subthreshold depression. Personalized treatment selection is entirely possible and necessary to ensure the best allocation of treatment resources for depression.
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Stephen P.H. Alexander1, Arthur Christopoulos2, Anthony P. Davenport3, Eamonn Kelly4 +151 more•Institutions (85)
TL;DR: The Concise Guide to PHARMACOLOGY 2021/22 as mentioned in this paper provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands.
Abstract: The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15538. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
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TL;DR: A conceptual framework of circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) assays is proposed in this paper, which point out current challenges of CTC and ctDNA research.
Abstract: Over the past 10 years, circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) have received enormous attention as new biomarkers and subjects of translational research. Although both biomarkers are already used in numerous clinical trials, their clinical utility is still under investigation with promising first results. Clinical applications include early cancer detection, improved cancer staging, early detection of relapse, real-time monitoring of therapeutic efficacy, and detection of therapeutic targets and resistance mechanisms. Here, we propose a conceptual framework of CTC and ctDNA assays and point out current challenges of CTC and ctDNA research, which might structure this dynamic field of translational cancer research. SIGNIFICANCE: The analysis of blood for CTCs or cell-free nucleic acids called "liquid biopsy" has opened new avenues for cancer diagnostics, including early detection of tumors, improved risk assessment and staging, as well as early detection of relapse and monitoring of tumor evolution in the context of cancer therapies.
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TL;DR: In this article, a meta-analysis was conducted to summarize available RCTs on the performance of real-time computer-aided polyp detection (CADe) in colorectal neoplasia detection.
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Centre national de la recherche scientifique1, University of Montpellier2, Agricultural Research Service3, University of Dundee4, James Hutton Institute5, University of Natural Resources and Life Sciences, Vienna6, University of Manchester7, Wageningen University and Research Centre8, University of Reading9, Czech University of Life Sciences Prague10, Morton Arboretum11, University of Göttingen12, University of Hamburg13, Forschungszentrum Jülich14, Macquarie University15, Spanish National Research Council16, University of Georgia17, Polish Academy of Sciences18, Adam Mickiewicz University in Poznań19, ETH Zurich20, University of Minnesota21, Oak Ridge National Laboratory22, University of Auvergne23, Laurentian University24, University of Freiburg25, Leiden University26, Chinese Academy of Sciences27, Florida International University28, Leipzig University29
TL;DR: It is found that below-ground traits with widest importance in plant and ecosystem functioning are not those most commonly measured, and advocate that establishing causal hierarchical links among root traits will provide a hypothesis-based framework to identify the most parsimonious sets of traits with strongest influence on the functions, and to link genotypes to plant andcosystem functioning.
Abstract: The effects of plants on the biosphere, atmosphere and geosphere are key determinants of terrestrial ecosystem functioning. However, despite substantial progress made regarding plant belowground components, we are still only beginning to explore the complex relationships between root traits and functions. Drawing on the literature in plant physiology, ecophysiology, ecology, agronomy and soil science, we reviewed 24 aspects of plant and ecosystem functioning and their relationships with a number of root system traits, including aspects of architecture, physiology, morphology, anatomy, chemistry, biomechanics and biotic interactions. Based on this assessment, we critically evaluated the current strengths and gaps in our knowledge, and identify future research challenges in the field of root ecology. Most importantly, we found that belowground traits with the broadest importance in plant and ecosystem functioning are not those most commonly measured. Also, the estimation of trait relative importance for functioning requires us to consider a more comprehensive range of functionally relevant traits from a diverse range of species, across environments and over time series. We also advocate that establishing causal hierarchical links among root traits will provide a hypothesis-based framework to identify the most parsimonious sets of traits with the strongest links on functions, and to link genotypes to plant and ecosystem functioning.
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TL;DR: This paper conducted a meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants.
Abstract: Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84–5.29) for men of European ancestry to 3.74 (95% CI, 3.36–4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14–2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71–0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.
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TL;DR: Cell-free DNA derived from tumours is present in the plasma of cancer patients and can be used to analyse different features of DNA, such as methylation status, size fragment patterns, transcriptomics and viral load, which open new avenues for the analysis of liquid biopsy samples from cancer patients.
Abstract: Cell-free DNA (cfDNA) derived from tumours is present in the plasma of cancer patients. The majority of currently available studies on the use of this circulating tumour DNA (ctDNA) deal with the detection of mutations. The analysis of cfDNA is often discussed in the context of the noninvasive detection of mutations that lead to resistance mechanisms and therapeutic and disease monitoring in cancer patients. Indeed, substantial advances have been made in this area, with the development of methods that reach high sensitivity and can interrogate a large number of genes. Interestingly, however, cfDNA can also be used to analyse different features of DNA, such as methylation status, size fragment patterns, transcriptomics and viral load, which open new avenues for the analysis of liquid biopsy samples from cancer patients. This review will focus on the new perspectives and challenges of cfDNA analysis from mutation detection in patients with solid malignancies.
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Joint Global Change Research Institute1, German Aerospace Center2, University of Bremen3, ETH Zurich4, École Polytechnique5, University of Exeter6, University of Leeds7, Met Office8, University of Denver9, Centre national de la recherche scientifique10, Netherlands Environmental Assessment Agency11, International Institute for Applied Systems Analysis12, University of Melbourne13, University of Maryland, College Park14, Potsdam Institute for Climate Impact Research15, National Center for Atmospheric Research16, Goddard Institute for Space Studies17, University of Paris18, University of Hamburg19, Max Planck Society20, Korea Meteorological Administration21, Commonwealth Scientific and Industrial Research Organisation22, Central Maine Community College23, Geophysical Fluid Dynamics Laboratory24, Pukyong National University25, Korean Ocean Research and Development Institute26, Nanjing University of Information Science and Technology27, Norwegian Meteorological Institute28, Indian Institute of Tropical Meteorology29, Ontario Ministry of Natural Resources30, University of Toulouse31, Alfred Wegener Institute for Polar and Marine Research32, Oak Ridge National Laboratory33, Deutscher Wetterdienst34, University of Arizona35, Japan Agency for Marine-Earth Science and Technology36, Lawrence Livermore National Laboratory37, Swedish Meteorological and Hydrological Institute38, China Meteorological Administration39, Danish Meteorological Institute40, Chinese Academy of Sciences41
TL;DR: In this paper, the authors present a range of its outcomes by synthesizing results from the participating global coupled Earth system models for concentration driven simulations, focusing mainly on the analysis of strictly geophysical outcomes: mainly global averages and spatial patterns of change for surface air temperature and precipitation.
Abstract: . The Scenario Model Intercomparison Project (ScenarioMIP) defines and coordinates the primary future climate projections within the Coupled Model Intercomparison Project Phase 6 (CMIP6). This paper presents a range of its outcomes by synthesizing results from the participating global coupled Earth system models for concentration driven simulations. We limit our scope to the analysis of strictly geophysical outcomes: mainly global averages and spatial patterns of change for surface air temperature and precipitation. We also compare CMIP6 projections to CMIP5 results, especially for those scenarios that were designed to provide continuity across the CMIP phases, at the same time highlighting important differences in forcing composition, as well as in results. The range of future temperature and precipitation changes by the end of the century encompassing the Tier 1 experiments (SSP1-2.6, SSP2-4.5, SSP3-7.0 and SSP5-8.5) and SSP1-1.9 spans a larger range of outcomes compared to CMIP5, due to higher warming (by 1.15 °C) reached at the upper end of the 5–95 % envelope of the highest scenario, SSP5-8.5. This is due to both the wider range of radiative forcing that the new scenarios cover and to higher climate sensitivities in some of the new models compared to their CMIP5 predecessors. Spatial patterns of change for temperature and precipitation averaged over models and scenarios have familiar features, and an analysis of their variations confirms model structural differences to be the dominant source of uncertainty. Models also differ with respect to the size and evolution of internal variability as measured by individual models' initial condition ensembles' spread, according to a set of initial condition ensemble simulations available under SSP3-7.0. The same experiments suggest a tendency for internal variability to decrease along the course of the century, a new result that will benefit from further analysis over a larger set of models. Benefits of mitigation, all else being equal in terms of societal drivers, appear clearly when comparing scenarios developed under the same SSP, but to which different degrees of mitigation have been applied. It is also found that a mild overshoot in temperature of a few decades in mid-century, as represented in SSP5-3.4OS, does not affect the end outcome in terms of temperature and precipitation changes by 2100, which return to the same level as those reached by the gradually increasing SSP4-3.4. Central estimates of the time at which the ensemble means of the different scenarios reach a given warming level show all scenarios reaching 1.5 °C of warming compared to the 1850–1900 baseline in the second half of the current decade, with the time span between slow and fast warming covering 20–28 years from present. 2 °C of warming is reached as early as the late '30s by the ensemble mean under SSP5-8.5, but as late as the late '50s under SSP1-2.6. The highest warming level considered, 5 °C, is reached only by the ensemble mean under SSP5-8.5, and not until the mid-90s.
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Bernhard Nocht Institute for Tropical Medicine1, University of Hamburg2, European XFEL3, Heinrich Pette Institute4, Max Planck Society5, University of California, Irvine6, Hamburg University of Technology7, California Institute of Technology8, Fraunhofer Society9, European Bioinformatics Institute10, University of Lübeck11, Woodward, Inc.12, Helmholtz-Zentrum Berlin13, Jožef Stefan Institute14, Leibniz University of Hanover15, University of Greifswald16
TL;DR: In this article, a high-throughput x-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease (Mpro), which is essential for viral replication, was performed.
Abstract: The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous human suffering. To date, no effective drug is available to directly treat the disease. In a search for a drug against COVID-19, we have performed a high-throughput x-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease (Mpro), which is essential for viral replication. In contrast to commonly applied x-ray fragment screening experiments with molecules of low complexity, our screen tested already-approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds that bind to Mpro In subsequent cell-based viral reduction assays, one peptidomimetic and six nonpeptidic compounds showed antiviral activity at nontoxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS-CoV-2.
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TL;DR: In this article, super-resolution microscopy visualized vaccine components forming antigenic complexes with platelet factor 4 (PF4) on platelet surfaces to which anti-PF4 antibodies obtained from VITT patients bound.
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TL;DR: In this article, the first and second observing runs of the Advanced LIGO and Virgo detector network were used to obtain the first standard-siren measurement of the Hubble constant (H 0).
Abstract: This paper presents the gravitational-wave measurement of the Hubble constant (H 0) using the detections from the first and second observing runs of the Advanced LIGO and Virgo detector network. The presence of the transient electromagnetic counterpart of the binary neutron star GW170817 led to the first standard-siren measurement of H 0. Here we additionally use binary black hole detections in conjunction with galaxy catalogs and report a joint measurement. Our updated measurement is H 0 = km s−1 Mpc−1 (68.3% of the highest density posterior interval with a flat-in-log prior) which is an improvement by a factor of 1.04 (about 4%) over the GW170817-only value of km s−1 Mpc−1. A significant additional contribution currently comes from GW170814, a loud and well-localized detection from a part of the sky thoroughly covered by the Dark Energy Survey. With numerous detections anticipated over the upcoming years, an exhaustive understanding of other systematic effects are also going to become increasingly important. These results establish the path to cosmology using gravitational-wave observations with and without transient electromagnetic counterparts.
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Rensselaer Polytechnic Institute1, Uppsala University2, University of Minnesota3, Leibniz Association4, Queen's University Belfast5, University of Regina6, University of Missouri7, Miami University8, Dundalk Institute of Technology9, European Space Agency10, University of Helsinki11, University of Nevada, Reno12, University of Gdańsk13, University of Warmia and Mazury in Olsztyn14, Moscow State University15, University of Potsdam16, University of Oklahoma17, Wisconsin Department of Natural Resources18, New York City Department of Environmental Protection19, Institut national de la recherche agronomique20, University of Milan21, National Institute for Environmental Studies22, University of Hamburg23, Ontario Ministry of the Environment24, IRSA25, University of California, Davis26, Laval University27, Swiss Federal Institute of Aquatic Science and Technology28, University of Innsbruck29, Vrije Universiteit Brussel30, ETH Zurich31, National Institute of Water and Atmospheric Research32, Institute of Ecosystem Studies33, State University of New York at Oneonta34
TL;DR: In this paper, the authors analyzed a combined total of 45,148 dissolved oxygen and temperature profiles and calculate trends for 393 temperate lakes that span 1941 to 2017, finding that a decline in dissolved oxygen is widespread in surface and deep water habitats.
Abstract: The concentration of dissolved oxygen in aquatic systems helps to regulate biodiversity1,2, nutrient biogeochemistry3, greenhouse gas emissions4, and the quality of drinking water5. The long-term declines in dissolved oxygen concentrations in coastal and ocean waters have been linked to climate warming and human activity6,7, but little is known about the changes in dissolved oxygen concentrations in lakes. Although the solubility of dissolved oxygen decreases with increasing water temperatures, long-term lake trajectories are difficult to predict. Oxygen losses in warming lakes may be amplified by enhanced decomposition and stronger thermal stratification8,9 or oxygen may increase as a result of enhanced primary production10. Here we analyse a combined total of 45,148 dissolved oxygen and temperature profiles and calculate trends for 393 temperate lakes that span 1941 to 2017. We find that a decline in dissolved oxygen is widespread in surface and deep-water habitats. The decline in surface waters is primarily associated with reduced solubility under warmer water temperatures, although dissolved oxygen in surface waters increased in a subset of highly productive warming lakes, probably owing to increasing production of phytoplankton. By contrast, the decline in deep waters is associated with stronger thermal stratification and loss of water clarity, but not with changes in gas solubility. Our results suggest that climate change and declining water clarity have altered the physical and chemical environment of lakes. Declines in dissolved oxygen in freshwater are 2.75 to 9.3 times greater than observed in the world’s oceans6,7 and could threaten essential lake ecosystem services2,3,5,11. Analysis of temperate lakes finds a widespread decline in dissolved oxygen concentrations in surface and deep waters, which is associated with reduced solubility at warmer surface water temperatures and increased stratification at depth.
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German Cancer Research Center1, University Hospital Heidelberg2, Broad Institute3, Harvard University4, Ludwig Maximilian University of Munich5, Heidelberg University6, University of Münster7, Hannover Medical School8, University of Freiburg9, University Hospital of Basel10, Radboud University Nijmegen11, University of Duisburg-Essen12, University of Seville13, University of Navarra14, Boston Children's Hospital15, University of Hamburg16, New York University17, University of Cologne18, University of Amsterdam19, Erasmus University Rotterdam20, University College London Hospitals NHS Foundation Trust21, University College London22, UCL Institute of Neurology23, Dresden University of Technology24, Hospital Sant Joan de Déu Barcelona25, Carlos III Health Institute26, University of Barcelona27, Memorial Sloan Kettering Cancer Center28, Royal National Orthopaedic Hospital29, Charité30
TL;DR: In this paper, a machine learning classifier algorithm based on array-generated DNA methylation data was used for the classification of soft tissue and bone sarcoma. But the performance was validated in a cohort of 428 sarcomatous tumours, of which 322 cases were classified by the classifier.
Abstract: Sarcomas are malignant soft tissue and bone tumours affecting adults, adolescents and children. They represent a morphologically heterogeneous class of tumours and some entities lack defining histopathological features. Therefore, the diagnosis of sarcomas is burdened with a high inter-observer variability and misclassification rate. Here, we demonstrate classification of soft tissue and bone tumours using a machine learning classifier algorithm based on array-generated DNA methylation data. This sarcoma classifier is trained using a dataset of 1077 methylation profiles from comprehensively pre-characterized cases comprising 62 tumour methylation classes constituting a broad range of soft tissue and bone sarcoma subtypes across the entire age spectrum. The performance is validated in a cohort of 428 sarcomatous tumours, of which 322 cases were classified by the sarcoma classifier. Our results demonstrate the potential of the DNA methylation-based sarcoma classification for research and future diagnostic applications.
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TL;DR: The updated taxonomy of Negarnaviricota is presented, as now accepted by the ICTV, after the phylum was amended and emended in March 2020.
Abstract: In March 2020, following the annual International Committee on Taxonomy of Viruses (ICTV) ratification vote on newly proposed taxa, the phylum Negarnaviricota was amended and emended. At the genus rank, 20 new genera were added, two were deleted, one was moved, and three were renamed. At the species rank, 160 species were added, four were deleted, ten were moved and renamed, and 30 species were renamed. This article presents the updated taxonomy of Negarnaviricota as now accepted by the ICTV.
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Stanford University1, Uppsala University2, University of Basel3, University Hospital of Basel4, University of Amsterdam5, Tanta University6, Assiut University7, University of Pennsylvania8, University of Health Sciences Lahore9, University of Pittsburgh10, King Saud bin Abdulaziz University for Health Sciences11, Brigham and Women's Hospital12, Duke University13, Cliniques Universitaires Saint-Luc14, Copenhagen University Hospital15, South Korean Ministry for Health, Welfare and Family Affairs16, University of Oslo17, Akershus University Hospital18, Oswaldo Cruz Foundation19, Utrecht University20, Imperial College Healthcare21, Wellington Management Company22, Auckland City Hospital23, Capital Medical University24, University of Granada25, University of Tübingen26, University of Hamburg27, Bernhard Nocht Institute for Tropical Medicine28, Monash University29, Middlemore Hospital30, University of British Columbia31, UnityPoint Health32, University of Hawaii at Manoa33, The Queen's Medical Center34, Menoufia University35, St John of God Subiaco Hospital36, Ottawa Hospital Research Institute37
TL;DR: In this article, a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients was presented.
Abstract: Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aim to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We present a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/
). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality has been extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses include patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total sample size). The combined OR on all-cause mortality for hydroxychloroquine is 1.11 (95% CI: 1.02, 1.20; I² = 0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I² = 0%; 4 trials; 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine is associated with increased mortality in COVID-19 patients, and there is no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities. Hydroxychloroquine and chloroquine have been investigated as a potential treatment for Covid-19 in several clinical trials. Here the authors report a meta-analysis of published and unpublished trials, and show that treatment with hydroxychloroquine for patients with Covid-19 was associated with increased mortality, and there was no benefit from chloroquine.
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TL;DR: HiggsSignals as discussed by the authors is a program that combines the predictions of models with arbitrary Higgs sectors with the available Higgs signal rate and mass measurements, resulting in a likelihood estimate.
Abstract: The program HiggsSignals confronts the predictions of models with arbitrary Higgs sectors with the available Higgs signal rate and mass measurements, resulting in a likelihood estimate. A new version of the program, HiggsSignals-2, is presented that contains various improvements in its functionality and applicability. In particular, the new features comprise improvements in the theoretical input framework and the handling of possible complexities of beyond-the-SM Higgs sectors, as well as the incorporation of experimental results in the form of simplified template cross section (STXS) measurements. The new functionalities are explained, and a thorough discussion of the possible statistical interpretations of the HiggsSignals results is provided. The performance of HiggsSignals is illustrated for some example analyses. In this context the importance of public information on certain experimental details like efficiencies and uncertainty correlations is pointed out. HiggsSignals is continuously updated to the latest experimental results and can be obtained at https://gitlab.com/higgsbounds/higgssignals.
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TL;DR: In this paper, a preclinical mouse model that displays key features of human NASH (hereafter, NASH mice), was used to detect the hepatic accumulation of CD8 T cells with phenotypes that combined tissue residency (CXCR6) with effector (granzyme) and exhaustion (PD1) characteristics.
Abstract: Nonalcoholic steatohepatitis (NASH) is a manifestation of systemic metabolic disease related to obesity, and causes liver disease and cancer1,2. The accumulation of metabolites leads to cell stress and inflammation in the liver3, but mechanistic understandings of liver damage in NASH are incomplete. Here, using a preclinical mouse model that displays key features of human NASH (hereafter, NASH mice), we found an indispensable role for T cells in liver immunopathology. We detected the hepatic accumulation of CD8 T cells with phenotypes that combined tissue residency (CXCR6) with effector (granzyme) and exhaustion (PD1) characteristics. Liver CXCR6+ CD8 T cells were characterized by low activity of the FOXO1 transcription factor, and were abundant in NASH mice and in patients with NASH. Mechanistically, IL-15 induced FOXO1 downregulation and CXCR6 upregulation, which together rendered liver-resident CXCR6+ CD8 T cells susceptible to metabolic stimuli (including acetate and extracellular ATP) and collectively triggered auto-aggression. CXCR6+ CD8 T cells from the livers of NASH mice or of patients with NASH had similar transcriptional signatures, and showed auto-aggressive killing of cells in an MHC-class-I-independent fashion after signalling through P2X7 purinergic receptors. This killing by auto-aggressive CD8 T cells fundamentally differed from that by antigen-specific cells, which mechanistically distinguishes auto-aggressive and protective T cell immunity.
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TL;DR: In this paper, the authors assess whether endothelial cell activation may be sustained in convalescent COVID-19 patients and contribute to long COVID pathogenesis, and demonstrate that sustained endotheliopathy was more frequent in older, comorbid patients and those requiring hospitalization.
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Centre national de la recherche scientifique1, Oak Ridge National Laboratory2, Agricultural Research Service3, University of Natural Resources and Life Sciences, Vienna4, Polish Academy of Sciences5, Macquarie University6, Forschungszentrum Jülich7, Pennsylvania State University8, Adam Mickiewicz University in Poznań9, University of Dundee10, James Hutton Institute11, VU University Amsterdam12, ETH Zurich13, University of Minnesota14, University of Hamburg15, Wageningen University and Research Centre16, University of Auvergne17, Laurentian University18, University of Freiburg19, Leiden University20, University of Montpellier21, Chinese Academy of Sciences22, Florida International University23, Leipzig University24, University of Georgia25, University of Leeds26, Institute of Ecosystem Studies27, Universidade Federal de Goiás28, University of Western Australia29, Clemson University30, Morton Arboretum31
TL;DR: A major aim of this guide is to help break down barriers between the many subdisciplines of root ecology and ecophysiology, broaden researchers’ views on the multiple aspects of root study and create favourable conditions for the inception of comprehensive experiments on the role of roots in plant and ecosystem functioning.
Abstract: In the context of a recent massive increase in research on plant root functions and their impact on the environment, root ecologists currently face many important challenges to keep on generating cutting-edge, meaningful and integrated knowledge. Consideration of the below-ground components in plant and ecosystem studies has been consistently called for in recent decades, but methodology is disparate and sometimes inappropriate. This handbook, based on the collective effort of a large team of experts, will improve trait comparisons across studies and integration of information across databases by providing standardised methods and controlled vocabularies. It is meant to be used not only as starting point by students and scientists who desire working on below-ground ecosystems, but also by experts for consolidating and broadening their views on multiple aspects of root ecology. Beyond the classical compilation of measurement protocols, we have synthesised recommendations from the literature to provide key background knowledge useful for: (1) defining below-ground plant entities and giving keys for their meaningful dissection, classification and naming beyond the classical fine-root vs coarse-root approach; (2) considering the specificity of root research to produce sound laboratory and field data; (3) describing typical, but overlooked steps for studying roots (e.g. root handling, cleaning and storage); and (4) gathering metadata necessary for the interpretation of results and their reuse. Most importantly, all root traits have been introduced with some degree of ecological context that will be a foundation for understanding their ecological meaning, their typical use and uncertainties, and some methodological and conceptual perspectives for future research. Considering all of this, we urge readers not to solely extract protocol recommendations for trait measurements from this work, but to take a moment to read and reflect on the extensive information contained in this broader guide to root ecology, including sections I-VII and the many introductions to each section and root trait description. Finally, it is critical to understand that a major aim of this guide is to help break down barriers between the many subdisciplines of root ecology and ecophysiology, broaden researchers' views on the multiple aspects of root study and create favourable conditions for the inception of comprehensive experiments on the role of roots in plant and ecosystem functioning.
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TL;DR: In this paper, the brain stems and olfactory bulbs in postmortem patients who had COVID-19 using imaging mass cytometry to understand the local immune response at a spatially resolved, high-dimensional, single-cell level and compared their immune map to non-COVID respiratory failure, multiple sclerosis, and control patients.