Showing papers by "Ludwig Maximilian University of Munich published in 2021"
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
Université Paris-Saclay1, Autonomous University of Barcelona2, University of Cambridge3, National Institute for Occupational Safety and Health4, German Center for Neurodegenerative Diseases5, University of Bonn6, Harvard University7, University of Lausanne8, University of Padua9, National Research Council10, Heidelberg University11, Salk Institute for Biological Studies12, University of Minnesota13, Pasteur Institute14, Tel Aviv University15, Johns Hopkins University16, University of Portsmouth17, Katholieke Universiteit Leuven18, PSL Research University19, Trinity College, Dublin20, Baylor College of Medicine21, University College London22, University of Edinburgh23, Oregon Health & Science University24, National Institutes of Health25, Columbia University26, University of Rochester27, University of Copenhagen28, Ludwig Maximilian University of Munich29, University of Málaga30, Tufts University31, University of Freiburg32, Utrecht University33, Nihon University34, Max Delbrück Center for Molecular Medicine35, University of California, Los Angeles36, University of Yamanashi37, New York University38, University of British Columbia39, King Abdullah University of Science and Technology40, University of Wisconsin-Madison41, University of California, San Francisco42, McGill University43, University of Kentucky44, Kyushu University45, University of Bordeaux46, University of Minho47, Polytechnic Institute of Cávado and Ave48, University of Alabama at Birmingham49, University of Gothenburg50, University of Poitiers51, Cajal Institute52, King's College London53, University of Strasbourg54, Virginia Tech55, University of Düsseldorf56, Russian Academy of Sciences57, I.M. Sechenov First Moscow State Medical University58, University of Seville59, Georgia Institute of Technology60, University of Texas Health Science Center at Houston61, University of California, San Diego62, Universidade Federal do Rio Grande do Sul63, University of Ljubljana64, Ikerbasque65, University of Manchester66
TL;DR: In this article, the authors point out the shortcomings of binary divisions of reactive astrocytes into good-vs-bad, neurotoxic vs-neuroprotective or A1-vs.A2.
Abstract: Reactive astrocytes are astrocytes undergoing morphological, molecular, and functional remodeling in response to injury, disease, or infection of the CNS. Although this remodeling was first described over a century ago, uncertainties and controversies remain regarding the contribution of reactive astrocytes to CNS diseases, repair, and aging. It is also unclear whether fixed categories of reactive astrocytes exist and, if so, how to identify them. We point out the shortcomings of binary divisions of reactive astrocytes into good-vs-bad, neurotoxic-vs-neuroprotective or A1-vs-A2. We advocate, instead, that research on reactive astrocytes include assessment of multiple molecular and functional parameters-preferably in vivo-plus multivariate statistics and determination of impact on pathological hallmarks in relevant models. These guidelines may spur the discovery of astrocyte-based biomarkers as well as astrocyte-targeting therapies that abrogate detrimental actions of reactive astrocytes, potentiate their neuro- and glioprotective actions, and restore or augment their homeostatic, modulatory, and defensive functions.
797 citations
University of Zurich1, Erasmus University Rotterdam2, Medical University of Vienna3, Ludwig Maximilian University of Munich4, University of Siena5, University Hospital Heidelberg6, Aix-Marseille University7, Leiden University Medical Center8, Sahlgrenska University Hospital9, Heidelberg University10, German Cancer Research Center11, St James's University Hospital12, University of Düsseldorf13
TL;DR: These evidence-based guidelines incorporate major changes in diagnostic algorithms based on the 2016 update of the WHO Classification of Tumors of the Central Nervous System as well as on evidence from recent large clinical trials.
Abstract: In response to major changes in diagnostic algorithms and the publication of mature results from various large clinical trials, the European Association of Neuro-Oncology (EANO) recognized the need to provide updated guidelines for the diagnosis and management of adult patients with diffuse gliomas. Through these evidence-based guidelines, a task force of EANO provides recommendations for the diagnosis, treatment and follow-up of adult patients with diffuse gliomas. The diagnostic component is based on the 2016 update of the WHO Classification of Tumors of the Central Nervous System and the subsequent recommendations of the Consortium to Inform Molecular and Practical Approaches to CNS Tumour Taxonomy - Not Officially WHO (cIMPACT-NOW). With regard to therapy, we formulated recommendations based on the results from the latest practice-changing clinical trials and also provide guidance for neuropathological and neuroradiological assessment. In these guidelines, we define the role of the major treatment modalities of surgery, radiotherapy and systemic pharmacotherapy, covering current advances and cognizant that unnecessary interventions and expenses should be avoided. This document is intended to be a source of reference for professionals involved in the management of adult patients with diffuse gliomas, for patients and caregivers, and for health-care providers.
629 citations
01 Jun 2021
TL;DR: This work shows that performance similar to GPT-3 can be obtained with language models that are much “greener” in that their parameter count is several orders of magnitude smaller, and identifies key factors required for successful natural language understanding with small language models.
Abstract: When scaled to hundreds of billions of parameters, pretrained language models such as GPT-3 (Brown et al., 2020) achieve remarkable few-shot performance. However, enormous amounts of compute are required for training and applying such big models, resulting in a large carbon footprint and making it difficult for researchers and practitioners to use them. We show that performance similar to GPT-3 can be obtained with language models that are much “greener” in that their parameter count is several orders of magnitude smaller. This is achieved by converting textual inputs into cloze questions that contain a task description, combined with gradient-based optimization; exploiting unlabeled data gives further improvements. We identify key factors required for successful natural language understanding with small language models.
548 citations
TL;DR: In this article, a provider-facing registry-based study collected cases of cutaneous manifestations after COVID-19 vaccination and found that delayed large local reactions were most common, followed by local injection site reactions, urticarial eruptions, and morbilliform eruptions.
Abstract: Background Cutaneous reactions after messenger RNA (mRNA)-based COVID-19 vaccines have been reported but are not well characterized. Objective To evaluate the morphology and timing of cutaneous reactions after mRNA COVID-19 vaccines. Methods A provider-facing registry-based study collected cases of cutaneous manifestations after COVID-19 vaccination. Results From December 2020 to February 2021, we recorded 414 cutaneous reactions to mRNA COVID-19 vaccines from Moderna (83%) and Pfizer (17%). Delayed large local reactions were most common, followed by local injection site reactions, urticarial eruptions, and morbilliform eruptions. Forty-three percent of patients with first-dose reactions experienced second-dose recurrence. Additional less common reactions included pernio/chilblains, cosmetic filler reactions, zoster, herpes simplex flares, and pityriasis rosea-like reactions. Limitations Registry analysis does not measure incidence. Morphologic misclassification is possible. Conclusions We report a spectrum of cutaneous reactions after mRNA COVID-19 vaccines. We observed some dermatologic reactions to Moderna and Pfizer vaccines that mimicked SARS-CoV-2 infection itself, such as pernio/chilblains. Most patients with first-dose reactions did not have a second-dose reaction and serious adverse events did not develop in any of the patients in the registry after the first or second dose. Our data support that cutaneous reactions to COVID-19 vaccination are generally minor and self-limited, and should not discourage vaccination.
546 citations
European Bioinformatics Institute1, Newcastle upon Tyne Hospitals NHS Foundation Trust2, Newcastle University3, Oregon Health & Science University4, Istituto Giannina Gaslini5, University of Genoa6, King Edward Memorial Hospital7, University of Western Australia8, American College of Medical Genetics9, Anschutz Medical Campus10, Johns Hopkins University11, Ludwig Maximilian University of Munich12, Children's Hospital of Philadelphia13, Austrian Academy of Sciences14, University of Connecticut15, French Institute of Health and Medical Research16, Lawrence Berkeley National Laboratory17, University of Michigan18, University of Freiburg19, University of Luxembourg20, Oregon State University21, Chestnut Hill College22, Medical University of Graz23, Queen Mary University of London24, Hebrew University of Jerusalem25, University of Pennsylvania26
TL;DR: Recent major extensions of the Human Phenotype Ontology for neurology, nephrology, immunology, pulmonology, newborn screening, and other areas are presented and new efforts to harmonize computational definitions of phenotypic abnormalities across the HPO and multiple phenotype ontologies used for animal models of disease are presented.
Abstract: The Human Phenotype Ontology (HPO, https://hpo.jax.org) was launched in 2008 to provide a comprehensive logical standard to describe and computationally analyze phenotypic abnormalities found in human disease. The HPO is now a worldwide standard for phenotype exchange. The HPO has grown steadily since its inception due to considerable contributions from clinical experts and researchers from a diverse range of disciplines. Here, we present recent major extensions of the HPO for neurology, nephrology, immunology, pulmonology, newborn screening, and other areas. For example, the seizure subontology now reflects the International League Against Epilepsy (ILAE) guidelines and these enhancements have already shown clinical validity. We present new efforts to harmonize computational definitions of phenotypic abnormalities across the HPO and multiple phenotype ontologies used for animal models of disease. These efforts will benefit software such as Exomiser by improving the accuracy and scope of cross-species phenotype matching. The computational modeling strategy used by the HPO to define disease entities and phenotypic features and distinguish between them is explained in detail.We also report on recent efforts to translate the HPO into indigenous languages. Finally, we summarize recent advances in the use of HPO in electronic health record systems.
503 citations
Ludwig Maximilian University of Munich1, University of Cambridge2, University of Hyderabad3, Katholieke Universiteit Leuven4, Massachusetts Institute of Technology5, University of Antwerp6, Indian Institute of Science7, Yantai University8, University of Vigo9, King Abdullah University of Science and Technology10, Nanjing University of Science and Technology11, University of California, Berkeley12, Lawrence Berkeley National Laboratory13, Nanyang Technological University14, Soochow University (Suzhou)15, Technische Universität München16, ETH Zurich17, Lund University18, Hokkaido University19, University of California, Santa Cruz20, Chinese Academy of Sciences21, Beijing Institute of Technology22, City University of Hong Kong23, University of Texas at Austin24, Indian Association for the Cultivation of Science25, San Diego State University26, University of Washington27, Texas A&M University28, Bilkent University29, James I University30, Max Planck Society31, National Renewable Energy Laboratory32, University of Valencia33, Shanghai Jiao Tong University34, Istituto Italiano di Tecnologia35, Swiss Federal Laboratories for Materials Science and Technology36, University of Notre Dame37, Monash University, Clayton campus38, Imperial College London39
TL;DR: A comprehensive review of metal-halide perovskite nanocrystals can be found in this article, where researchers having expertise in different fields (chemistry, physics, and device engineering) have joined together to provide a state-of-the-art overview and future prospects of metalhalide nanocrystal research.
Abstract: Metal-halide perovskites have rapidly emerged as one of the most promising materials of the 21st century, with many exciting properties and great potential for a broad range of applications, from photovoltaics to optoelectronics and photocatalysis. The ease with which metal-halide perovskites can be synthesized in the form of brightly luminescent colloidal nanocrystals, as well as their tunable and intriguing optical and electronic properties, has attracted researchers from different disciplines of science and technology. In the last few years, there has been a significant progress in the shape-controlled synthesis of perovskite nanocrystals and understanding of their properties and applications. In this comprehensive review, researchers having expertise in different fields (chemistry, physics, and device engineering) of metal-halide perovskite nanocrystals have joined together to provide a state of the art overview and future prospects of metal-halide perovskite nanocrystal research.
471 citations
TL;DR: In this paper, the authors proposed that SARS-CoV-2 infection induces a process known as immunothrombosis, in which activated neutrophils and monocytes interact with platelets and the coagulation cascade, leading to intravascular clot formation in small and larger vessels.
Abstract: Coronavirus disease 2019 (COVID-19) is a clinical syndrome caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients with severe disease show hyperactivation of the immune system, which can affect multiple organs besides the lungs. Here, we propose that SARS-CoV-2 infection induces a process known as immunothrombosis, in which activated neutrophils and monocytes interact with platelets and the coagulation cascade, leading to intravascular clot formation in small and larger vessels. Microthrombotic complications may contribute to acute respiratory distress syndrome (ARDS) and other organ dysfunctions. Therapeutic strategies aimed at reducing immunothrombosis may therefore be useful. Several antithrombotic and immunomodulating drugs have been proposed as candidates to treat patients with SARS-CoV-2 infection. The growing understanding of SARS-CoV-2 infection pathogenesis and how it contributes to critical illness and its complications may help to improve risk stratification and develop targeted therapies to reduce the acute and long-term consequences of this disease.
448 citations
University of Siena1, University of Göttingen2, UCL Institute of Neurology3, City College of New York4, National Institutes of Health5, Brown University6, University of Toronto7, Università Campus Bio-Medico8, Beth Israel Deaconess Medical Center9, Medical University of South Carolina10, Cincinnati Children's Hospital Medical Center11, Aristotle University of Thessaloniki12, Aalto University13, Paris 12 Val de Marne University14, Vita-Salute San Raffaele University15, University of Trento16, Ludwig Maximilian University of Munich17, Harvard University18, Duke University19, University of Messina20, Copenhagen University Hospital21, Fukushima Medical University22, Ben-Gurion University of the Negev23, University of Tübingen24
TL;DR: New operational guidelines are provided for safety in planning future trials based on traditional and patterned TMS protocols, as well as a summary of the minimal training requirements for operators, and a note on ethics of neuroenhancement.
387 citations
Niamh Mullins1, Andreas J. Forstner2, Andreas J. Forstner3, Andreas J. Forstner4 +396 more•Institutions (119)
TL;DR: The authors performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci, including genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics.
Abstract: Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.
378 citations
TL;DR: In this article, a first-in-class catalytic inhibitor of METTL3 was identified and characterized, and a crystal structure of STM2457 in complex with METTL 3 and METTL14 was presented.
Abstract: N6-methyladenosine (m6A) is an abundant internal RNA modification1,2 that is catalysed predominantly by the METTL3–METTL14 methyltransferase complex3,4. The m6A methyltransferase METTL3 has been linked to the initiation and maintenance of acute myeloid leukaemia (AML), but the potential of therapeutic applications targeting this enzyme remains unknown5–7. Here we present the identification and characterization of STM2457, a highly potent and selective first-in-class catalytic inhibitor of METTL3, and a crystal structure of STM2457 in complex with METTL3–METTL14. Treatment of tumours with STM2457 leads to reduced AML growth and an increase in differentiation and apoptosis. These cellular effects are accompanied by selective reduction of m6A levels on known leukaemogenic mRNAs and a decrease in their expression consistent with a translational defect. We demonstrate that pharmacological inhibition of METTL3 in vivo leads to impaired engraftment and prolonged survival in various mouse models of AML, specifically targeting key stem cell subpopulations of AML. Collectively, these results reveal the inhibition of METTL3 as a potential therapeutic strategy against AML, and provide proof of concept that the targeting of RNA-modifying enzymes represents a promising avenue for anticancer therapy. Treatment with a specific inhibitor of the N6-methyladenosine methyltransferase METTL3 leads to reduced growth of cancer cells, indicating the potential of approaches targeting RNA-modifying enzymes for anticancer therapy.
Evgeny Epifanovsky, Andrew T.B. Gilbert1, Andrew T.B. Gilbert2, Xintian Feng3 +235 more•Institutions (54)
TL;DR: The Q-Chem quantum chemistry program package as discussed by the authors provides a suite of tools for modeling core-level spectroscopy, methods for describing metastable resonances, and methods for computing vibronic spectra, the nuclear-electronic orbital method, and several different energy decomposition analysis techniques.
Abstract: This article summarizes technical advances contained in the fifth major release of the Q-Chem quantum chemistry program package, covering developments since 2015. A comprehensive library of exchange-correlation functionals, along with a suite of correlated many-body methods, continues to be a hallmark of the Q-Chem software. The many-body methods include novel variants of both coupled-cluster and configuration-interaction approaches along with methods based on the algebraic diagrammatic construction and variational reduced density-matrix methods. Methods highlighted in Q-Chem 5 include a suite of tools for modeling core-level spectroscopy, methods for describing metastable resonances, methods for computing vibronic spectra, the nuclear-electronic orbital method, and several different energy decomposition analysis techniques. High-performance capabilities including multithreaded parallelism and support for calculations on graphics processing units are described. Q-Chem boasts a community of well over 100 active academic developers, and the continuing evolution of the software is supported by an "open teamware" model and an increasingly modular design.
University Medical Center Groningen1, Netherlands Cancer Institute2, European Bioinformatics Institute3, Georgia Institute of Technology4, Leipzig University5, Johns Hopkins University6, University of Cambridge7, NHS Blood and Transplant8, Garvan Institute of Medical Research9, University of Tartu10, Ontario Institute for Cancer Research11, University of Washington12, Public Health Research Institute13, University of Chicago14, Greifswald University Hospital15, Ludwig Maximilian University of Munich16, University of Bristol17, Erasmus University Rotterdam18, Luleå University of Technology19, Royal Devon and Exeter Hospital20, University of Westminster21, University of Lausanne22, Swiss Institute of Bioinformatics23, University of Geneva24, University of Dundee25, Agency for Science, Technology and Research26, University of Queensland27, Leiden University Medical Center28, Radboud University Nijmegen29, University of Liège30, University of Oxford31, Menzies Research Institute32, Icahn School of Medicine at Mount Sinai33, Ikerbasque34, VU University Amsterdam35, Stanford University36, Turku University Hospital37, University of Turku38, Maastricht University39, Karolinska Institutet40, Utrecht University41, University of Helsinki42, National Institutes of Health43, Technische Universität München44, Wellcome Trust Sanger Institute45, German Cancer Research Center46, Westlake University47, University of New South Wales48
TL;DR: In this article, the authors performed cis-and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium.
Abstract: Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-eQTL for 88% of genes, and these were replicable in numerous tissues. Distal trans-eQTL (detected for 37% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans-eQTL. Trans-eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes.
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.
Newcastle University1, University of Cambridge2, European Bioinformatics Institute3, Wellcome Trust Sanger Institute4, University College London5, Ludwig Maximilian University of Munich6, Newcastle upon Tyne Hospitals NHS Foundation Trust7, University College London Hospitals NHS Foundation Trust8, Royal Free Hospital9, UCL Institute of Child Health10, Harvard University11
TL;DR: In this article, the authors performed single-cell transcriptome, surface proteome and T and B lymphocyte antigen receptor analyses of over 780,000 peripheral blood mononuclear cells from a cross-sectional cohort of 130 patients with varying severities of COVID-19.
Abstract: Analysis of human blood immune cells provides insights into the coordinated response to viral infections such as severe acute respiratory syndrome coronavirus 2, which causes coronavirus disease 2019 (COVID-19). We performed single-cell transcriptome, surface proteome and T and B lymphocyte antigen receptor analyses of over 780,000 peripheral blood mononuclear cells from a cross-sectional cohort of 130 patients with varying severities of COVID-19. We identified expansion of nonclassical monocytes expressing complement transcripts (CD16+C1QA/B/C+) that sequester platelets and were predicted to replenish the alveolar macrophage pool in COVID-19. Early, uncommitted CD34+ hematopoietic stem/progenitor cells were primed toward megakaryopoiesis, accompanied by expanded megakaryocyte-committed progenitors and increased platelet activation. Clonally expanded CD8+ T cells and an increased ratio of CD8+ effector T cells to effector memory T cells characterized severe disease, while circulating follicular helper T cells accompanied mild disease. We observed a relative loss of IgA2 in symptomatic disease despite an overall expansion of plasmablasts and plasma cells. Our study highlights the coordinated immune response that contributes to COVID-19 pathogenesis and reveals discrete cellular components that can be targeted for therapy.
Institut Gustave Roussy1, Université libre de Bruxelles2, Hospital of the University of Pennsylvania3, Swansea University4, University of Paris5, University of California, Los Angeles6, Seoul National University Hospital7, Ludwig Maximilian University of Munich8, Peter MacCallum Cancer Centre9, University of Auvergne10, Memorial Sloan Kettering Cancer Center11, University of California, San Francisco12, Hebron University13, Queen Mary University of London14, Medical University of Vienna15, Harvard University16, The Royal Marsden NHS Foundation Trust17, University of Milan18, Hebrew University of Jerusalem19
TL;DR: Soehnlein et al. as discussed by the authors consider a gamut of attractive possibilities for modifying inflammation in atherosclerosis, including targeting pivotal inflammatory pathways such as the inflammasomes, inhibiting cytokines, manipulating adaptive immunity and promoting pro-resolution mechanisms.
Abstract: Atherosclerosis, a dominant and growing cause of death and disability worldwide, involves inflammation from its inception to the emergence of complications. Targeting inflammatory pathways could therefore provide a promising new avenue to prevent and treat atherosclerosis. Indeed, clinical studies have now demonstrated unequivocally that modulation of inflammation can forestall the clinical complications of atherosclerosis. This progress pinpoints the need for preclinical investigations to refine strategies for combatting inflammation in the human disease. In this Review, we consider a gamut of attractive possibilities for modifying inflammation in atherosclerosis, including targeting pivotal inflammatory pathways such as the inflammasomes, inhibiting cytokines, manipulating adaptive immunity and promoting pro-resolution mechanisms. Along with lifestyle measures, pharmacological interventions to mute inflammation could complement traditional targets, such as lipids and hypertension, to make new inroads into the management of atherosclerotic risk. The contribution of inflammation to atherosclerosis is substantial, and is just beginning to be understood. In this Review, Soehnlein and Libby discuss how inflammation promotes atherosclerosis and its consequences, and how such processes could be targeted therapeutically. The potential pitfalls of targeting immune processes — namely the increased potential for infections — are also discussed, along with ways to modulate cardiovascular therapies in time and space to make them more effective.
University of Paris1, Northwestern University2, Flanders Institute for Biotechnology3, University College London4, Katholieke Universiteit Leuven5, Ludwig Maximilian University of Munich6, University of Connecticut7, University of Rome Tor Vergata8, Chiesi Farmaceutici S.p.A.9, University of Antwerp10, University of Cambridge11, Janssen Pharmaceutica12, Eisai13, McGill University14, French Institute of Health and Medical Research15
TL;DR: BACE1 concentrations and rates of activity are increased in AD brains and body fluids, thereby supporting the hypothesis that BACE1 plays a critical role in AD pathophysiology, and is a prime drug target for slowing down Aβ production in early AD.
TL;DR: In this article, the fundamental concepts that govern the photocatalytic performance of polymeric polymeric photocatalysis were discussed and the challenges and future of the field of soft photocatalysing was discussed.
Abstract: Solar-to-chemical energy conversion for the generation of high-energy chemicals is one of the most viable solutions to the quest for sustainable energy resources. Although long dominated by inorganic semiconductors, organic polymeric photocatalysts offer the advantage of a broad, molecular-level design space of their optoelectronic and surface catalytic properties, owing to their molecularly precise backbone. In this Review, we discuss the fundamental concepts of polymeric photocatalysis and examine different polymeric photocatalysts, including carbon nitrides, conjugated polymers, covalent triazine frameworks and covalent organic frameworks. We analyse the photophysical and physico-chemical concepts that govern the photocatalytic performance of these materials, and derive design principles and possible future research directions in this emerging field of ‘soft photocatalysis’. In this Review, the authors analyse the fundamental concepts that govern the photocatalytic performance of organic polymer photocatalysts and discuss the challenges and future of the field of ‘soft photocatalysis’.
01 Apr 2021
TL;DR: This article proposed Pattern-Exploiting Training (PET), a semi-supervised training procedure that reformulates input examples as cloze-style phrases to help language models understand a given task.
Abstract: Some NLP tasks can be solved in a fully unsupervised fashion by providing a pretrained language model with "task descriptions" in natural language (e.g., Radford et al., 2019). While this approach underperforms its supervised counterpart, we show in this work that the two ideas can be combined: We introduce Pattern-Exploiting Training (PET), a semi-supervised training procedure that reformulates input examples as cloze-style phrases to help language models understand a given task. These phrases are then used to assign soft labels to a large set of unlabeled examples. Finally, standard supervised training is performed on the resulting training set. For several tasks and languages, PET outperforms supervised training and strong semi-supervised approaches in low-resource settings by a large margin.
Katholieke Universiteit Leuven1, Sapienza University of Rome2, University of Paris3, University of Toulouse4, Boston Children's Hospital5, Harvard University6, University of California, Irvine7, University of Brescia8, Vita-Salute San Raffaele University9, Erasmus University Medical Center10, Hospital Clínico San Carlos11, Complutense University of Madrid12, Epsom and St Helier University Hospitals NHS Trust13, National Institutes of Health14, University of São Paulo15, University of Padua16, University of Naples Federico II17, Ghent University18, Nationwide Children's Hospital19, Marmara University20, Newcastle University21, University Hospital of Wales22, Universidad del Desarrollo23, Saint Louis University Hospital24, Ludwig Maximilian University of Munich25, Icahn School of Medicine at Mount Sinai26, University of Freiburg27, Children's Hospital of Philadelphia28, Garvan Institute of Medical Research29, University of New South Wales30
TL;DR: More than 30% of patients with IEI with SARS-CoV-2 infection had mild coronavirus disease 2019 (COVID-19) and risk factors predisposing to severe disease/mortality in the general population also seemed to affect patients withIEI, including more younger patients.
Abstract: Background There is uncertainty about the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in individuals with rare inborn errors of immunity (IEI), a population at risk of developing severe coronavirus disease 2019. This is relevant not only for these patients but also for the general population, because studies of IEIs can unveil key requirements for host defense. Objective We sought to describe the presentation, manifestations, and outcome of SARS-CoV-2 infection in IEI to inform physicians and enhance understanding of host defense against SARS-CoV-2. Methods An invitation to participate in a retrospective study was distributed globally to scientific, medical, and patient societies involved in the care and advocacy for patients with IEI. Results We gathered information on 94 patients with IEI with SARS-CoV-2 infection. Their median age was 25 to 34 years. Fifty-three patients (56%) suffered from primary antibody deficiency, 9 (9.6%) had immune dysregulation syndrome, 6 (6.4%) a phagocyte defect, 7 (7.4%) an autoinflammatory disorder, 14 (15%) a combined immunodeficiency, 3 (3%) an innate immune defect, and 2 (2%) bone marrow failure. Ten were asymptomatic, 25 were treated as outpatients, 28 required admission without intensive care or ventilation, 13 required noninvasive ventilation or oxygen administration, 18 were admitted to intensive care units, 12 required invasive ventilation, and 3 required extracorporeal membrane oxygenation. Nine patients (7 adults and 2 children) died. Conclusions This study demonstrates that (1) more than 30% of patients with IEI had mild coronavirus disease 2019 (COVID-19) and (2) risk factors predisposing to severe disease/mortality in the general population also seemed to affect patients with IEI, including more younger patients. Further studies will identify pathways that are associated with increased risk of severe disease and are nonredundant or redundant for protection against SARS-CoV-2.
Augsburg College1, Ikerbasque2, Katholieke Universiteit Leuven3, Maharashtra Institute of Technology4, Massachusetts Institute of Technology5, King Abdullah University of Science and Technology6, Adam Mickiewicz University in Poznań7, Ludwig Maximilian University of Munich8, Scripps Research Institute9
TL;DR: The amalgamation of different disciplines is at the heart of reticular chemistry and has broadened the boundaries of chemistry by opening up an infinite space of chemical composition, structure, and material properties.
Abstract: The amalgamation of different disciplines is at the heart of reticular chemistry and has broadened the boundaries of chemistry by opening up an infinite space of chemical composition, structure, and material properties. Reticular design has enabled the precise prediction of crystalline framework structures, tunability of chemical composition, incorporation of various functionalities onto the framework backbone, and as a consequence, fine-tuning of metal-organic framework (MOF) and covalent organic framework (COF) properties beyond that of any other material class. Leveraging the unique properties of reticular materials has resulted in significant advances from both a fundamental and an applied perspective. Here, we wish to review the milestones in MOF and COF research and give a critical view on progress in their real-world applications. Finally, we briefly discuss the major challenges in the field that need to be addressed to pave the way for industrial applications.
03 Jun 2021
TL;DR: This Primer explains the central concepts of single-molecule localization microscopy before discussing experimental considerations regarding fluorophores, optics and data acquisition, processing and analysis, and describes recent high-impact discoveries made by SMLM techniques.
Abstract: Single-molecule localization microscopy (SMLM) describes a family of powerful imaging techniques that dramatically improve spatial resolution over standard, diffraction-limited microscopy techniques and can image biological structures at the molecular scale. In SMLM, individual fluorescent molecules are computationally localized from diffraction-limited image sequences and the localizations are used to generate a super-resolution image or a time course of super-resolution images, or to define molecular trajectories. In this Primer, we introduce the basic principles of SMLM techniques before describing the main experimental considerations when performing SMLM, including fluorescent labelling, sample preparation, hardware requirements and image acquisition in fixed and live cells. We then explain how low-resolution image sequences are computationally processed to reconstruct super-resolution images and/or extract quantitative information, and highlight a selection of biological discoveries enabled by SMLM and closely related methods. We discuss some of the main limitations and potential artefacts of SMLM, as well as ways to alleviate them. Finally, we present an outlook on advanced techniques and promising new developments in the fast-evolving field of SMLM. We hope that this Primer will be a useful reference for both newcomers and practitioners of SMLM. This Primer explains the central concepts of single-molecule localization microscopy (SMLM) before discussing experimental considerations regarding fluorophores, optics and data acquisition, processing and analysis. The Primer further describes recent high-impact discoveries made by SMLM techniques and concludes by discussing emerging methodologies.
Oak Ridge National Laboratory1, University of New South Wales2, Ludwig Maximilian University of Munich3, University of Arizona4, Stanford University5, Scripps Institution of Oceanography6, Smithsonian Environmental Research Center7, University of Sydney8, Max Planck Society9, Smithsonian Tropical Research Institute10, Smithsonian Conservation Biology Institute11, Seconda Università degli Studi di Napoli12, University of Leeds13, Swiss Federal Institute for Forest, Snow and Landscape Research14, Aix-Marseille University15, University of California, Santa Barbara16, Commonwealth Scientific and Industrial Research Organisation17, Université Paris-Saclay18, Australian National University19, ETH Zurich20, National University of Singapore21, California Institute of Technology22, Imperial College London23, Northern Arizona University24, Oeschger Centre for Climate Change Research25, University of California, Berkeley26, Lawrence Berkeley National Laboratory27, University of Basel28, Auckland University of Technology29, Indiana University30, University of Oxford31, Spanish National Research Council32, Umeå University33, University of Exeter34, Lawrence Livermore National Laboratory35, University of California, Irvine36, United States Geological Survey37, State University of New York College of Environmental Science and Forestry38, Rutgers University39, Wageningen University and Research Centre40
TL;DR: A range of evidence supports a positive terrestrial carbon sink in response to iCO2, albeit with uncertain magnitude and strong suggestion of a role for additional agents of global change.
Abstract: Atmospheric carbon dioxide concentration ([CO2 ]) is increasing, which increases leaf-scale photosynthesis and intrinsic water-use efficiency. These direct responses have the potential to increase plant growth, vegetation biomass, and soil organic matter; transferring carbon from the atmosphere into terrestrial ecosystems (a carbon sink). A substantial global terrestrial carbon sink would slow the rate of [CO2 ] increase and thus climate change. However, ecosystem CO2 responses are complex or confounded by concurrent changes in multiple agents of global change and evidence for a [CO2 ]-driven terrestrial carbon sink can appear contradictory. Here we synthesize theory and broad, multidisciplinary evidence for the effects of increasing [CO2 ] (iCO2 ) on the global terrestrial carbon sink. Evidence suggests a substantial increase in global photosynthesis since pre-industrial times. Established theory, supported by experiments, indicates that iCO2 is likely responsible for about half of the increase. Global carbon budgeting, atmospheric data, and forest inventories indicate a historical carbon sink, and these apparent iCO2 responses are high in comparison to experiments and predictions from theory. Plant mortality and soil carbon iCO2 responses are highly uncertain. In conclusion, a range of evidence supports a positive terrestrial carbon sink in response to iCO2 , albeit with uncertain magnitude and strong suggestion of a role for additional agents of global change.
Washington University in St. Louis1, Vanderbilt University2, University of California, San Francisco3, University of Washington4, University of Chicago5, University of California, San Diego6, University of Rochester7, Emory University8, Mayo Clinic9, University of Maryland, College Park10, University of California, Los Angeles11, Memorial Sloan Kettering Cancer Center12, Ludwig Maximilian University of Munich13, University of California, Davis14, Utrecht University15, University of Texas MD Anderson Cancer Center16, Harvard University17, Loyola University Chicago18, University of California, Irvine19, University of Rennes20
TL;DR: The pivotal phase 2 results of ZUMA-3, an international, multicentre, single-arm, open-label study evaluating the efficacy and safety of the autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy KTE-X19 in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia remain poor, underlining the need for more effective therapies.
TL;DR: BPNet as discussed by the authors uses DNA sequence to predict base-resolution chromatin immunoprecipitation (ChIP)-nexus binding profiles of pluripotency transcription factor (TF) binding motifs.
Abstract: The arrangement (syntax) of transcription factor (TF) binding motifs is an important part of the cis-regulatory code, yet remains elusive. We introduce a deep learning model, BPNet, that uses DNA sequence to predict base-resolution chromatin immunoprecipitation (ChIP)-nexus binding profiles of pluripotency TFs. We develop interpretation tools to learn predictive motif representations and identify soft syntax rules for cooperative TF binding interactions. Strikingly, Nanog preferentially binds with helical periodicity, and TFs often cooperate in a directional manner, which we validate using clustered regularly interspaced short palindromic repeat (CRISPR)-induced point mutations. Our model represents a powerful general approach to uncover the motifs and syntax of cis-regulatory sequences in genomics data.
Claude Bernard University Lyon 11, French Institute of Health and Medical Research2, UCL Institute of Neurology3, Autonomous University of Barcelona4, University Hospital of Basel5, University of Düsseldorf6, National and Kapodistrian University of Athens7, University of Florence8, University of Southern Denmark9, Children's Hospital of Philadelphia10, University of Pennsylvania11, Anschutz Medical Campus12, Children's Hospital at Westmead13, Harvard University14, University of Paris-Sud15, University of Strasbourg16, Fukushima Medical University17, Walton Centre18, Cleveland Clinic19, Ruhr University Bochum20, Medical University of Vienna21, John Radcliffe Hospital22, University of Glasgow23, Ludwig Maximilian University of Munich24, Humboldt University of Berlin25, National Institute for Health Research26, Moorfields Eye Hospital27, University College London28, Mayo Clinic29, Innsbruck Medical University30, Pontifícia Universidade Católica do Rio Grande do Sul31, University of Warmia and Mazury in Olsztyn32, Istanbul University33, University of Paris34, University of British Columbia35, University of California, San Francisco36, Technische Universität München37
TL;DR: In this paper, the authors identify myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD) as a recently identified autoimmune disorder that presents in both adults and children as CNS demyelination.
Abstract: Myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a recently identified autoimmune disorder that presents in both adults and children as CNS demyelination. Although there are clinical phenotypic overlaps between MOGAD, multiple sclerosis, and aquaporin-4 antibody-associated neuromyelitis optica spectrum disorder (NMOSD) cumulative biological, clinical, and pathological evidence discriminates between these conditions. Patients should not be diagnosed with multiple sclerosis or NMOSD if they have anti-MOG antibodies in their serum. However, many questions related to the clinical characterisation of MOGAD and pathogenetic role of MOG antibodies are still unanswered. Furthermore, therapy is mainly based on standard protocols for aquaporin-4 antibody-associated NMOSD and multiple sclerosis, and more evidence is needed regarding how and when to treat patients with MOGAD.
TL;DR: In this paper, the authors evaluated the efficacy and safety of pirfenidone in patients with four non-IPF progressive fibrotic interstitial lung diseases (ILDs), including collagen or vascular diseases (i.e., connective tissue disease-associated ILDs), non-specific interstitial pneumonia, chronic hypersensitivity pneumonitis, or asbestos-induced lung fibrosis.
University of Exeter1, Complutense University of Madrid2, Ludwig Maximilian University of Munich3, German Aerospace Center4, Met Office5, National Oceanic and Atmospheric Administration6, University of Reading7, ETH Zurich8, Hebrew University of Jerusalem9, Courant Institute of Mathematical Sciences10, Free University of Berlin11, National Center for Atmospheric Research12
TL;DR: Sudden stratospheric warmings (SSWs) are impressive fluid dynamical events in which large and rapid temperature increases in the winter polar stratosphere (10−50km) are associated with a complete reversal of the climatological wintertime westerly winds.
Abstract: Sudden stratospheric warmings (SSWs) are impressive fluid dynamical events in which large and rapid temperature increases in the winter polar stratosphere (⁓10‐50km) are associated with a complete reversal of the climatological wintertime westerly winds. SSWs are caused by the breaking of planetary‐scale waves that propagate upwards from the troposphere. During an SSW, the polar vortex breaks down, accompanied by rapid descent and warming of air in polar latitudes, mirrored by ascent and cooling above the warming. The rapid warming and descent of the polar air column affects tropospheric weather, shifting jet streams, storm tracks, and the Northern Annular Mode, making cold air outbreaks over North America and Eurasia more likely. SSWs affect the atmosphere above the stratosphere, producing widespread effects on atmospheric chemistry, temperatures, winds, neutral (non‐ionized) particles and electron densities, and electric fields. These effects span both hemispheres. Given their crucial role in the whole atmosphere, SSWs are also seen as a key process to analyze in climate change studies and subseasonal to seasonal prediction. This work reviews the current knowledge on the most important aspects of SSWs, from the historical background to dynamical processes, modelling, chemistry, and impact on other atmospheric layers.
Ludwig Maximilian University of Munich1, Mount Sinai Hospital2, Charité3, University of Toronto4, Kyoto Prefectural University of Medicine5, Laval University6, Icahn School of Medicine at Mount Sinai7, Indiana University8, Catholic University of Korea9, Hospital Universitario La Paz10, University of Sheffield11, The Catholic University of America12, Leo Pharma13, Oregon Health & Science University14
TL;DR: Tralokinumab, a fully human monoclonal antibody, specifically neutralizes interleukin‐13, a key cytokine driving peripheral inflammation in atopic dermatitis (AD).
Abstract: Background Tralokinumab, a fully human monoclonal antibody, specifically neutralizes interleukin-13, a key cytokine driving peripheral inflammation in atopic dermatitis (AD). In phase II studies, tralokinumab combined with topical corticosteroids provided early and sustained improvements in AD signs and symptoms. Objectives To evaluate the efficacy and safety of tralokinumab monotherapy in adults with moderate-to-severe AD who had an inadequate response to topical treatments. Methods In two, 52-week, randomized, double-blind, placebo-controlled, phase III trials, ECZTRA 1 and ECZTRA 2, adults with moderate-to-severe AD were randomized (3 : 1) to subcutaneous tralokinumab 300 mg every 2 weeks (Q2W), or placebo. Primary endpoints were IGA score of 0 or 1 at week 16 and EASI 75 at week 16. Patient achieving an IGA score of 0/1 and/or EASI 75 with tralokinumab at week 16 were rerandomized to tralokinumab Q2W or every 4 weeks or placebo, for 36 weeks. Results At week 16, more patients who received tralokinumab vs. placebo achieved an IGA score of 0/1: 15·8% vs. 7·1% in ECZTRA 1 [difference (95% CI) 8·6% (4·1-13·1); P = 0·002] and 22·2% vs. 10·9% in ECZTRA 2 [11·1% (5·8-16·4); P Conclusions Tralokinumab monotherapy was superior to placebo at 16 weeks of treatment and was well tolerated up to 52 weeks of treatment.