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Showing papers by "University of Bonn published in 2021"


Journal ArticleDOI
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


Journal ArticleDOI
Carole Escartin1, Elena Galea2, Andras Lakatos3, James P. O'Callaghan4, Gabor C. Petzold5, Gabor C. Petzold6, Alberto Serrano-Pozo7, Christian Steinhäuser5, Andrea Volterra8, Giorgio Carmignoto9, Giorgio Carmignoto10, Amit Agarwal11, Nicola J. Allen12, Alfonso Araque13, Luis Barbeito14, Ari Barzilai15, Dwight E. Bergles16, Gilles Bonvento1, Arthur M. Butt17, Wei Ting Chen18, Martine Cohen-Salmon19, Colm Cunningham20, Benjamin Deneen21, Bart De Strooper18, Bart De Strooper22, Blanca Diaz-Castro23, Cinthia Farina, Marc R. Freeman24, Vittorio Gallo25, James E. Goldman26, Steven A. Goldman27, Steven A. Goldman28, Magdalena Götz29, Antonia Gutierrez30, Philip G. Haydon31, Dieter Henrik Heiland32, Elly M. Hol33, Matthew Holt18, Masamitsu Iino34, Ksenia V. Kastanenka7, Helmut Kettenmann35, Baljit S. Khakh36, Schuichi Koizumi37, C. Justin Lee, Shane A. Liddelow38, Brian A. MacVicar39, Pierre J. Magistretti8, Pierre J. Magistretti40, Albee Messing41, Anusha Mishra24, Anna V. Molofsky42, Keith K. Murai43, Christopher M. Norris44, Seiji Okada45, Stéphane H. R. Oliet46, João Filipe Oliveira47, João Filipe Oliveira48, Aude Panatier46, Vladimir Parpura49, Marcela Pekna50, Milos Pekny50, Luc Pellerin51, Gertrudis Perea52, Beatriz G. Pérez-Nievas53, Frank W. Pfrieger54, Kira E. Poskanzer42, Francisco J. Quintana7, Richard M. Ransohoff, Miriam Riquelme-Perez1, Stefanie Robel55, Christine R. Rose56, Jeffrey D. Rothstein16, Nathalie Rouach19, David H. Rowitch3, Alexey Semyanov57, Alexey Semyanov58, Swetlana Sirko29, Harald Sontheimer55, Raymond A. Swanson42, Javier Vitorica59, Ina B. Wanner36, Levi B. Wood60, Jia Qian Wu61, Binhai Zheng62, Eduardo R. Zimmer63, Robert Zorec64, Michael V. Sofroniew36, Alexei Verkhratsky65, Alexei Verkhratsky66 
Université Paris-Saclay1, Autonomous University of Barcelona2, University of Cambridge3, National Institute for Occupational Safety and Health4, University of Bonn5, German Center for Neurodegenerative Diseases6, 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, Polytechnic Institute of Cávado and Ave47, University of Minho48, 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, I.M. Sechenov First Moscow State Medical University57, Russian Academy of Sciences58, 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


Journal ArticleDOI
TL;DR: The xTB model as discussed by the authors is derived from a density functional (DFT) perturbation expansion of the electron density in fluctuation terms to various orders similar to the original density functional tight binding model.
Abstract: This review covers a family of atomistic, mostly quantum chemistry (QC) based semiempirical methods for the fast and reasonably accurate description of large molecules in gas and condensed phase. The theory is derived from a density functional (DFT) perturbation expansion of the electron density in fluctuation terms to various orders similar to the original density functional tight binding model. The term “eXtended” in their name (xTB) emphasizes the parameter availability for almost the entire periodic table of elements (Z ≤ 86) and improvements of the underlying theory regarding, for example, the atomic orbital basis set, the level of multipole approximation and the treatment of the important electrostatic and dispersion interactions. A common feature of most members is their consistent parameterization on accurate gas phase theoretical reference data for geometries, vibrational frequencies and noncovalent interactions, which are the primary properties of interest in typical applications to systems composed of up to a few thousand atoms. Further specialized versions were developed for the description of electronic spectra and corresponding response properties. Besides a provided common theoretical background with some important implementation details in the efficient and free xtb program, various benchmarks for structural and thermochemical properties including (transition‐)metal systems are discussed. The review is completed by recent extensions of the model to the force‐field (FF) level as well as its application to solids under periodic boundary conditions. The general applicability together with the excellent cost‐accuracy ratio and the high robustness make the xTB family of methods very attractive for various fields of computer‐aided chemical research.

442 citations


Journal ArticleDOI
01 Apr 2021-Cell
TL;DR: In this article, a conceptual framework for the interaction of the human innate immune system with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was provided to link the clinical observations with experimental findings that have been made during the first year of the pandemic.

422 citations


Journal ArticleDOI
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


Journal ArticleDOI
TL;DR: In this paper, the authors summarize the latest discoveries in the three most well understood modalities of cell death, namely, apoptosis, necroptosis, and pyroptosis.
Abstract: Cell death is a fundamental physiological process in all living organisms Its roles extend from embryonic development, organ maintenance, and aging to the coordination of immune responses and autoimmunity In recent years, our understanding of the mechanisms orchestrating cellular death and its consequences on immunity and homeostasis has increased substantially Different modalities of what has become known as ‘programmed cell death’ have been described, and some key players in these processes have been identified We have learned more about the intricacies that fine tune the activity of common players and ultimately shape the different types of cell death These studies have highlighted the complex mechanisms tipping the balance between different cell fates Here, we summarize the latest discoveries in the three most well understood modalities of cell death, namely, apoptosis, necroptosis, and pyroptosis, highlighting common and unique pathways and their effect on the surrounding cells and the organism as a whole

376 citations


Journal ArticleDOI
Peter Predehl1, Robert Andritschke1, V. Arefiev, V. Babyshkin, O. Batanov, Werner Becker1, Hans Böhringer1, A. V. Bogomolov, Th. Boller1, Katharina Borm2, Katharina Borm3, W. Bornemann1, Heinrich Bräuninger1, Marcus Brüggen4, Hermann Brunner1, Marcella Brusa5, Marcella Brusa6, Esra Bulbul1, M. Buntov, Vadim Burwitz1, Wolfgang Burkert1, N. Clerc7, E. Churazov1, D. Coutinho1, Thomas Dauser8, Konrad Dennerl1, Victor Doroshenko9, Josef Eder1, Valentin Emberger1, Tanja Eraerds1, Alexis Finoguenov1, Michael Freyberg1, Peter Friedrich1, S. Friedrich1, Maria Fürmetz1, Antonis Georgakakis, Marat Gilfanov1, S. Granato1, Christoph Grossberger1, A. Gueguen1, P. Gureev, Frank Haberl1, O. Hälker1, Gisela Hartner1, Guenther Hasinger, H. Huber1, Long Ji9, Andreas von Kienlin1, W. Kink1, F. Korotkov, Ingo Kreykenbohm8, Georg Lamer10, I. Lomakin, I. Lapshov, Tie Liu1, Chandreyee Maitra1, Norbert Meidinger1, B. Menz1, Andrea Merloni1, T. Mernik3, Benjamin Mican1, Joseph J. Mohr11, Sebastian Müller1, Kirpal Nandra1, V. Nazarov, Florian Pacaud2, M. N. Pavlinsky, Emanuele Perinati9, Elmar Pfeffermann1, Daniel Pietschner1, Miriam E. Ramos-Ceja1, Arne Rau1, Jonas Reiffers1, Thomas H. Reiprich2, Jan Robrade4, Mara Salvato1, Jeremy S. Sanders1, Andrea Santangelo9, Manami Sasaki8, H. Scheuerle3, Christian Schmid8, Jürgen H. M. M. Schmitt4, Axel Schwope10, A. Shirshakov, Matthias Steinmetz10, Ian M. Stewart1, Lothar Strüder1, Rashid Sunyaev1, C. Tenzer9, Lars Tiedemann1, Joachim Trümper1, V. Voron, P. Weber8, Joern Wilms8, Valeri Yaroshenko1 
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


Journal ArticleDOI
TL;DR: The authors reviewed the intricacies of COVID-19 pathophysiology, its various phenotypes, and the anti-SARS-CoV-2 host response at the humoral and cellular levels.

325 citations


Journal ArticleDOI
TL;DR: The review discusses the new classes of RiPPs that have been discovered, the advances in the understanding of the installation of both primary and secondary post-translational modifications, and the mechanisms by which the enzymes recognize the leader peptides in their substrates.

318 citations


Journal ArticleDOI
TL;DR: In this paper, a joint cosmological analysis of weak gravitational lensing observations from the Kilo-Degree Survey (KiDS-1000), with Baryon Oscillation Spectroscopic Survey (BOSS) and galaxy-galaxy lensing was presented.
Abstract: We present a joint cosmological analysis of weak gravitational lensing observations from the Kilo-Degree Survey (KiDS-1000), with redshift-space galaxy clustering observations from the Baryon Oscillation Spectroscopic Survey (BOSS) and galaxy-galaxy lensing observations from the overlap between KiDS-1000, BOSS, and the spectroscopic 2-degree Field Lensing Survey (2dFLenS). This combination of large-scale structure probes breaks the degeneracies between cosmological parameters for individual observables, resulting in a constraint on the structure growth parameter S 8 = σ8 √ Ωm/0.3 = 0.766+0.020 −0.014, which has the same overall precision as that reported by the full-sky cosmic microwave background observations from Planck. The recovered S 8 amplitude is low, however, by 8.3 ± 2.6% relative to Planck. This result builds from a series of KiDS-1000 analyses where we validate our methodology with variable depth mock galaxy surveys, our lensing calibration with image simulations and null-tests, and our optical-to-near-infrared redshift calibration with multi-band mock catalogues and a spectroscopic-photometric clustering analysis. The systematic uncertainties identified by these analyses are folded through as nuisance parameters in our cosmological analysis. Inspecting the offset between the marginalised posterior distributions, we find that the S 8-difference with Planck is driven by a tension in the matter fluctuation amplitude parameter, σ8. We quantify the level of agreement between the cosmic microwave background and our large-scale structure constraints using a series of different metrics, finding differences with a significance ranging between ∼ 3σ, when considering the offset in S 8, and ∼2σ, when considering the full multi-dimensional parameter space.

305 citations


Journal ArticleDOI
TL;DR: The SAVE-MORE trial as discussed by the authors evaluated the efficacy and safety of anakinra, an IL-1α/β inhibitor, in 594 patients with COVID-19 at risk of progressing to respiratory failure.
Abstract: Early increase of soluble urokinase plasminogen activator receptor (suPAR) serum levels is indicative of increased risk of progression of coronavirus disease 2019 (COVID-19) to respiratory failure. The SAVE-MORE double-blind, randomized controlled trial evaluated the efficacy and safety of anakinra, an IL-1α/β inhibitor, in 594 patients with COVID-19 at risk of progressing to respiratory failure as identified by plasma suPAR ≥6 ng ml−1, 85.9% (n = 510) of whom were receiving dexamethasone. At day 28, the adjusted proportional odds of having a worse clinical status (assessed by the 11-point World Health Organization Clinical Progression Scale (WHO-CPS)) with anakinra, as compared to placebo, was 0.36 (95% confidence interval 0.26–0.50). The median WHO-CPS decrease on day 28 from baseline in the placebo and anakinra groups was 3 and 4 points, respectively (odds ratio (OR) = 0.40, P < 0.0001); the respective median decrease of Sequential Organ Failure Assessment (SOFA) score on day 7 from baseline was 0 and 1 points (OR = 0.63, P = 0.004). Twenty-eight-day mortality decreased (hazard ratio = 0.45, P = 0.045), and hospital stay was shorter. The SAVE-MORE phase 3 study demonstrates the efficacy of anakinra, an IL-1α/β inhibitor, in patients with COVID-19 and high serum levels of soluble plasminogen activator receptor.

Journal ArticleDOI
12 Jan 2021-Science
TL;DR: In this paper, the authors used x-ray crystallography and cryo-electron microscopy to define two distinct binding epitopes of the SARS-CoV-2 spike protein.
Abstract: The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread, with devastating consequences. For passive immunization efforts, nanobodies have size and cost advantages over conventional antibodies. In this study, we generated four neutralizing nanobodies that target the receptor binding domain of the SARS-CoV-2 spike protein. We used x-ray crystallography and cryo-electron microscopy to define two distinct binding epitopes. On the basis of these structures, we engineered multivalent nanobodies with more than 100 times the neutralizing activity of monovalent nanobodies. Biparatopic nanobody fusions suppressed the emergence of escape mutants. Several nanobody constructs neutralized through receptor binding competition, whereas other monovalent and biparatopic nanobodies triggered aberrant activation of the spike fusion machinery. These premature conformational changes in the spike protein forestalled productive fusion and rendered the virions noninfectious.

Journal ArticleDOI
TL;DR: In this article, the authors conduct a meta-analysis re-analyzing the ten currently available 16S microbiome datasets to investigate whether common alterations in the gut microbiota of Parkinson's disease patients exist across cohorts.
Abstract: The gut microbiota is emerging as an important modulator of neurodegenerative diseases, and accumulating evidence has linked gut microbes to Parkinson’s disease (PD) symptomatology and pathophysiology. PD is often preceded by gastrointestinal symptoms and alterations of the enteric nervous system accompany the disease. Several studies have analyzed the gut microbiome in PD, but a consensus on the features of the PD-specific microbiota is missing. Here, we conduct a meta-analysis re-analyzing the ten currently available 16S microbiome datasets to investigate whether common alterations in the gut microbiota of PD patients exist across cohorts. We found significant alterations in the PD-associated microbiome, which are robust to study-specific technical heterogeneities, although differences in microbiome structure between PD and controls are small. Enrichment of the genera Lactobacillus, Akkermansia, and Bifidobacterium and depletion of bacteria belonging to the Lachnospiraceae family and the Faecalibacterium genus, both important short-chain fatty acids producers, emerged as the most consistent PD gut microbiome alterations. This dysbiosis might result in a pro-inflammatory status which could be linked to the recurrent gastrointestinal symptoms affecting PD patients.

Journal ArticleDOI
26 May 2021-Nature
TL;DR: Wang et al. as mentioned in this paper proposed Swarm Learning, a decentralized machine learning approach that unifies edge computing, blockchain-based peer-to-peer networking and coordination while maintaining confidentiality without the need for a central coordinator.
Abstract: Fast and reliable detection of patients with severe and heterogeneous illnesses is a major goal of precision medicine1,2. Patients with leukaemia can be identified using machine learning on the basis of their blood transcriptomes3. However, there is an increasing divide between what is technically possible and what is allowed, because of privacy legislation4,5. Here, to facilitate the integration of any medical data from any data owner worldwide without violating privacy laws, we introduce Swarm Learning-a decentralized machine-learning approach that unites edge computing, blockchain-based peer-to-peer networking and coordination while maintaining confidentiality without the need for a central coordinator, thereby going beyond federated learning. To illustrate the feasibility of using Swarm Learning to develop disease classifiers using distributed data, we chose four use cases of heterogeneous diseases (COVID-19, tuberculosis, leukaemia and lung pathologies). With more than 16,400 blood transcriptomes derived from 127 clinical studies with non-uniform distributions of cases and controls and substantial study biases, as well as more than 95,000 chest X-ray images, we show that Swarm Learning classifiers outperform those developed at individual sites. In addition, Swarm Learning completely fulfils local confidentiality regulations by design. We believe that this approach will notably accelerate the introduction of precision medicine.

Journal ArticleDOI
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.

Journal ArticleDOI
TL;DR: The primary hyperoxaluria type 1 (PH1) is a rare genetic disease caused by hepatic overproduction of oxalate that leads to kidney stones, nephrocalcinosis, kidney failure, and syste....
Abstract: Background Primary hyperoxaluria type 1 (PH1) is a rare genetic disease caused by hepatic overproduction of oxalate that leads to kidney stones, nephrocalcinosis, kidney failure, and syste...

Journal ArticleDOI
TL;DR: A common framework is established that describes the experimental standards for defining trained immunity in both in vitro and in vivo settings, as well as in experimental models and human subjects.
Abstract: The similarities and differences between trained immunity and other immune processes are the subject of intense interrogation. Therefore, a consensus on the definition of trained immunity in both in vitro and in vivo settings, as well as in experimental models and human subjects, is necessary for advancing this field of research. Here we aim to establish a common framework that describes the experimental standards for defining trained immunity.

Journal ArticleDOI
TL;DR: In this paper, cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues was assessed.
Abstract: Angiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. ACE2, TMPRSS2 and CTSL are coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology. We performed a meta-analysis of 31 lung single-cell RNA-sequencing studies with 1,320,896 cells from 377 nasal, airway and lung parenchyma samples from 228 individuals. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2, TMPRSS2 and CTSL. Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. Expression programs shared by ACE2+TMPRSS2+ cells in nasal, lung and gut tissues included genes that may mediate viral entry, key immune functions and epithelial-macrophage cross-talk, such as genes involved in the interleukin-6, interleukin-1, tumor necrosis factor and complement pathways. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention.

Journal ArticleDOI
TL;DR: In this paper, the r2SCAN meta-generalized-gradient approximation (mGGA) was used to construct an efficient composite electronic-structure method termed r2-SCAN-3c.
Abstract: The recently proposed r2SCAN meta-generalized-gradient approximation (mGGA) of Furness and co-workers is used to construct an efficient composite electronic-structure method termed r2SCAN-3c. To this end, the unaltered r2SCAN functional is combined with a tailor-made triple-ζ Gaussian atomic orbital basis set as well as with refitted D4 and geometrical counter-poise corrections for London-dispersion and basis set superposition error. The performance of the new method is evaluated for the GMTKN55 database covering large parts of chemical space with about 1500 data points, as well as additional benchmarks for non-covalent interactions, organometallic reactions, and lattice energies of organic molecules and ices, as well as for the adsorption on polar salt and non-polar coinage-metal surfaces. These comprehensive tests reveal a spectacular performance and robustness of r2SCAN-3c: It by far surpasses its predecessor B97-3c at only twice the cost and provides one of the best results of all semi-local density-functional theory (DFT)/QZ methods ever tested for the GMTKN55 database at one-tenth of the cost. Specifically, for reaction and conformational energies as well as non-covalent interactions, it outperforms prominent hybrid-DFT/QZ approaches at two to three orders of magnitude lower cost. Perhaps, the most relevant remaining issue of r2SCAN-3c is self-interaction error (SIE), owing to its mGGA nature. However, SIE is slightly reduced compared to other (m)GGAs, as is demonstrated in two examples. After all, this remarkably efficient and robust method is chosen as our new group default, replacing previous composite DFT and partially even expensive high-level methods in most standard applications for systems with up to several hundreds of atoms.

Journal ArticleDOI
TL;DR: In this paper, the authors report world averages of measurements of b -hadron, c-hadron and -lepton properties obtained by the Heavy Flavour Averaging Group using results available through September 2018.
Abstract: This paper reports world averages of measurements of b -hadron, c -hadron, and -lepton properties obtained by the Heavy Flavour Averaging Group using results available through September 2018. In rare cases, significant results obtained several months later are also used. For the averaging, common input parameters used in the various analyses are adjusted (rescaled) to common values, and known correlations are taken into account. The averages include branching fractions, lifetimes, neutral meson mixing parameters, violation parameters, parameters of semileptonic decays, and Cabibbo–Kobayashi–Maskawa matrix elements.

Journal ArticleDOI
TL;DR: Based on reports of atypically located thromboses following vaccination with the AstraZeneca COVID-19 vaccine, the Society of Thrombosis and Haemostasis Research has issued guidance statements on the recognition, diagnosis, and treatment of this rare complication.
Abstract: The COVID-19 pandemic is an ongoing global healthcare crisis. Based on reports of atypically located thromboses following vaccination with the AstraZeneca COVID-19 vaccine, the Society of Thrombosis and Haemostasis Research (GTH) has issued guidance statements on the recognition, diagnosis, and treatment of this rare complication. It shares pathophysiological features with heparin-induced thrombocytopenia (HIT) and is referred to as vaccine-induced prothrombotic immune thrombocytopenia (VIPIT).

Journal ArticleDOI
TL;DR: Visual outcomes from W48 to W96 confirm the efficacy achieved at W48, and brolucizumab continued to demonstrate greater fluid resolution compared to aflibercept, and exhibited an overall well-tolerated safety profile.


Journal ArticleDOI
TL;DR: To ensure proper mitochondrial function, cells use multiple mechanisms of quality control that survey mitochondrial protein biogenesis, import and folding, and allow mitochondria to adapt to the changing needs as well as to respond to stresses that compromise proteostasis.
Abstract: Mitochondria contain about 1,000-1,500 proteins that fulfil multiple functions. Mitochondrial proteins originate from two genomes: mitochondrial and nuclear. Hence, proper mitochondrial function requires synchronization of gene expression in the nucleus and in mitochondria and necessitates efficient import of mitochondrial proteins into the organelle from the cytosol. Furthermore, the mitochondrial proteome displays high plasticity to allow the adaptation of mitochondrial function to cellular requirements. Maintenance of this complex and adaptable mitochondrial proteome is challenging, but is of crucial importance to cell function. Defects in mitochondrial proteostasis lead to proteotoxic insults and eventually cell death. Different quality control systems monitor the mitochondrial proteome. The cytosolic ubiquitin-proteasome system controls protein transport across the mitochondrial outer membrane and removes damaged or mislocalized proteins. Concomitantly, a number of mitochondrial chaperones and proteases govern protein folding and degrade damaged proteins inside mitochondria. The quality control factors also regulate processing and turnover of native proteins to control protein import, mitochondrial metabolism, signalling cascades, mitochondrial dynamics and lipid biogenesis, further ensuring proper function of mitochondria. Thus, mitochondrial protein quality control mechanisms are of pivotal importance to integrate mitochondria into the cellular environment.

Journal ArticleDOI
TL;DR: In this article, the oral Janus kinase 1 (JAK1) inhibitor abrocitinib, which reduces interleukin-4 and interleucin-13 signaling, was investigated for the treatment of atopic dermatitis.
Abstract: Background The oral Janus kinase 1 (JAK1) inhibitor abrocitinib, which reduces interleukin-4 and interleukin-13 signaling, is being investigated for the treatment of atopic dermatitis. Dat...

Journal ArticleDOI
TL;DR: In this article, the authors highlight the observed immune deviation of neutrophils in COVID-19 and summarize several promising therapeutic attempts to precisely target neutrophILS and their reactivity in patients with COVID19.
Abstract: Strong evidence has been accumulated since the beginning of the COVID-19 pandemic that neutrophils play an important role in the pathophysiology, particularly in those with severe disease courses. While originally considered to be a rather homogeneous cell type, recent attention to neutrophils has uncovered their fascinating transcriptional and functional diversity as well as their developmental trajectories. These new findings are important to better understand the many facets of neutrophil involvement not only in COVID-19 but also many other acute or chronic inflammatory diseases, both communicable and non-communicable. Here, we highlight the observed immune deviation of neutrophils in COVID-19 and summarize several promising therapeutic attempts to precisely target neutrophils and their reactivity in patients with COVID-19.

Journal ArticleDOI
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.

Journal ArticleDOI
TL;DR: This article performed RNA-seq of whole blood cell transcriptomes and granulocyte preparations from mild and severe COVID-19 patients and analyzed the data using a combination of conventional and data-driven co-expression analysis.
Abstract: The SARS-CoV-2 pandemic is currently leading to increasing numbers of COVID-19 patients all over the world. Clinical presentations range from asymptomatic, mild respiratory tract infection, to severe cases with acute respiratory distress syndrome, respiratory failure, and death. Reports on a dysregulated immune system in the severe cases call for a better characterization and understanding of the changes in the immune system. In order to dissect COVID-19-driven immune host responses, we performed RNA-seq of whole blood cell transcriptomes and granulocyte preparations from mild and severe COVID-19 patients and analyzed the data using a combination of conventional and data-driven co-expression analysis. Additionally, publicly available data was used to show the distinction from COVID-19 to other diseases. Reverse drug target prediction was used to identify known or novel drug candidates based on finding from data-driven findings. Here, we profiled whole blood transcriptomes of 39 COVID-19 patients and 10 control donors enabling a data-driven stratification based on molecular phenotype. Neutrophil activation-associated signatures were prominently enriched in severe patient groups, which was corroborated in whole blood transcriptomes from an independent second cohort of 30 as well as in granulocyte samples from a third cohort of 16 COVID-19 patients (44 samples). Comparison of COVID-19 blood transcriptomes with those of a collection of over 3100 samples derived from 12 different viral infections, inflammatory diseases, and independent control samples revealed highly specific transcriptome signatures for COVID-19. Further, stratified transcriptomes predicted patient subgroup-specific drug candidates targeting the dysregulated systemic immune response of the host. Our study provides novel insights in the distinct molecular subgroups or phenotypes that are not simply explained by clinical parameters. We show that whole blood transcriptomes are extremely informative for COVID-19 since they capture granulocytes which are major drivers of disease severity.

Journal ArticleDOI
S. Wehle, Iki Adachi1, Iki Adachi2, K. Adamczyk  +206 moreInstitutions (73)
TL;DR: In this article, the authors acknowledge support from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan, the Japan Society for the Promotion of Science (JSPS), and the Tau-Lepton Physics Research Center of Nagoya University.
Abstract: We acknowledge support from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan, the Japan Society for the Promotion of Science (JSPS), and the Tau-Lepton Physics Research Center of Nagoya University; the Australian Research Council including Grants No. DP180102629, No. DP170102389, No. DP170102204, No. DP150103061, No. FT130100303; Austrian Science Fund (FWF); the National Natural Science Foundation of China under Contracts No. 11435013, No. 11475187, No. 11521505, No. 11575017, No. 11675166, No. 11705209; Key Research Program of Frontier Sciences, Chinese Academy of Sciences (CAS), Grant No. QYZDJ-SSWSLH011; the CAS Center for Excellence in Particle Physics (CCEPP); the Shanghai Pujiang Program under Grant No. 18PJ1401000; the Ministry of Education, Youth and Sports of the Czech Republic under Contract No. LTT17020; the Carl Zeiss Foundation, the Deutsche Forschungsgemeinschaft, the Excellence Cluster Universe, and the VolkswagenStiftung; the Department of Science and Technology of India; the Istituto Nazionale di Fisica Nucleare of Italy; National Research Foundation (NRF) of Korea Grants No. 2016R1D1A1B01010135, No. 2016R1D1A1B02012900, No. 2018R1A2B3003643, No. 2018R1A6A1A06024970, No. 2018R1D1A1B07047294, No. 2019K1A3A7A09033840, No. 2019R1I1A3A01058933; Radiation Science Research Institute, Foreign Large-size Research Facility Application Supporting project, the Global Science Experimental Data Hub Center of the Korea Institute of Science and Technology Information, and KREONET/GLORIAD the Polish Ministry of Science and Higher Education and the National Science Center; the Ministry of Science and Higher Education of the Russian Federation, Agreement No. 14.W03.31.0026; University of Tabuk research Grants No. S-1440-0321, No. S-0256-1438, and No. S-0280-1439 (Saudi Arabia); the Slovenian Research Agency; Ikerbasque, Basque Foundation for Science, Spain; the Swiss National Science Foundation; the Ministry of Education and the Ministry of Science and Technology of Taiwan; and the U.S. Department of Energy and the National Science Foundation.

Journal ArticleDOI
10 Aug 2021-Immunity
TL;DR: The authors integrated 178,651 mononuclear phagocytes (MNPs) from 13 tissues across 41 datasets to generate a MNP single-cell RNA compendium (MNP-VERSE), a publicly available tool to map MNPs and define conserved gene signatures of MNP populations.