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Showing papers by "University of Tübingen 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
TL;DR: Nivolumab plus cabozantinib had significant benefits over sunitinib with respect to progression-free survival, overall survival, and likelihood of response in patients with previously untreated advanced renal-cell carcinoma.
Abstract: Background The efficacy and safety of nivolumab plus cabozantinib as compared with those of sunitinib in the treatment of previously untreated advanced renal-cell carcinoma are not known. ...

816 citations


Journal ArticleDOI
TL;DR: In this article, a B-cell maturation antigen-directed chimeric antigen receptor (CAR) T-cell therapy, has shown clinical activity with expecable clinical outcomes with the use of idecabtagene vicleucel (ide-cel), also called bb2121.
Abstract: Background Idecabtagene vicleucel (ide-cel, also called bb2121), a B-cell maturation antigen–directed chimeric antigen receptor (CAR) T-cell therapy, has shown clinical activity with expec...

776 citations


Journal ArticleDOI
TL;DR: In this article, Lenvatinib in combination with pembrolizumab or everolimus has been shown to have activity against advanced renal cell carcinoma (RCC).
Abstract: Background Lenvatinib in combination with pembrolizumab or everolimus has activity against advanced renal cell carcinoma. The efficacy of these regimens as compared with that of sunitinib ...

722 citations


Journal ArticleDOI
Dominik Pfister1, Dominik Pfister2, Nicolás Gonzalo Núñez3, Roser Pinyol4, Olivier Govaere5, Matthias Pinter6, Marta Szydlowska2, Revant Gupta7, Mengjie Qiu8, Aleksandra Deczkowska9, Assaf Weiner9, Florian Müller2, Ankit Sinha10, Ankit Sinha11, Ekaterina Friebel3, Thomas Engleitner2, Thomas Engleitner11, Daniela Lenggenhager3, Anja Moncsek3, Danijela Heide2, Kristin Stirm2, Jan Kosla2, Eleni Kotsiliti2, Valentina Leone2, Michael Dudek11, Suhail Yousuf8, Donato Inverso12, Donato Inverso2, Indrabahadur Singh2, Ana Teijeiro, Florian Castet4, Carla Montironi4, Philipp K. Haber13, Dina Tiniakos14, Dina Tiniakos5, Pierre Bedossa5, Simon Cockell5, Ramy Younes15, Ramy Younes5, Michele Vacca16, Fabio Marra17, Jörn M. Schattenberg, Michael Allison16, Elisabetta Bugianesi15, Vlad Ratziu18, Tiziana Pressiani, Antonio D'Alessio, Nicola Personeni19, Lorenza Rimassa19, Ann K. Daly5, Bernhard Scheiner6, Katharina Pomej6, Martha M. Kirstein20, Arndt Vogel20, Markus Peck-Radosavljevic, F. Hucke, Fabian Finkelmeier, Oliver Waidmann, Jörg Trojan, Kornelius Schulze21, Henning Wege21, Sandra Koch22, Arndt Weinmann22, Marco Bueter3, Fabian Rössler3, Alexander Siebenhüner3, Sara De Dosso, Jan-Philipp Mallm2, Viktor Umansky12, Viktor Umansky2, Manfred Jugold2, Tom Luedde23, Andrea Schietinger24, Andrea Schietinger25, Peter Schirmacher8, Brinda Emu2, Hellmut G. Augustin12, Hellmut G. Augustin2, Adrian T. Billeter8, Beat P. Müller-Stich8, Hiroto Kikuchi26, Dan G. Duda26, Fabian Kütting27, Dirk Waldschmidt27, Matthias P. Ebert12, Nuh N. Rahbari12, Henrik E. Mei28, Axel Schulz28, Marc Ringelhan11, Nisar P. Malek, Stephan Spahn, Michael Bitzer, Marina Ruiz de Galarreta13, Amaia Lujambio13, Jean-François Dufour29, Thomas U. Marron13, Thomas U. Marron30, Ahmed Kaseb31, Masatoshi Kudo32, Yi Hsiang Huang33, Yi Hsiang Huang34, Nabil Djouder, Katharina Wolter7, Lars Zender2, Lars Zender7, Parice N. Marche35, Parice N. Marche36, Thomas Decaens35, Thomas Decaens36, David J. Pinato37, Roland Rad2, Roland Rad11, Joachim C. Mertens3, Achim Weber3, Kristian Unger, Felix Meissner10, Susanne Roth8, Zuzana Macek Jilkova35, Zuzana Macek Jilkova36, Zuzana Macek Jilkova37, Manfred Claassen7, Quentin M. Anstee5, Ido Amit9, Percy A. Knolle11, Burkhard Becher3, Josep M. Llovet38, Josep M. Llovet4, Josep M. Llovet13, Mathias Heikenwalder2 
15 Apr 2021-Nature
TL;DR: The progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers provides a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment.
Abstract: Hepatocellular carcinoma (HCC) can have viral or non-viral causes1-5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment.

526 citations


Journal ArticleDOI
TL;DR: It is shown how the popular workflow management system Snakemake can be used to guarantee reproducibility, and how it enables an ergonomic, combined, unified representation of all steps involved in data analysis, ranging from raw data processing, to quality control and fine-grained, interactive exploration and plotting of final results.
Abstract: Data analysis often entails a multitude of heterogeneous steps, from the application of various command line tools to the usage of scripting languages like R or Python for the generation of plots and tables. It is widely recognized that data analyses should ideally be conducted in a reproducible way. Reproducibility enables technical validation and regeneration of results on the original or even new data. However, reproducibility alone is by no means sufficient to deliver an analysis that is of lasting impact (i.e., sustainable) for the field, or even just one research group. We postulate that it is equally important to ensure adaptability and transparency. The former describes the ability to modify the analysis to answer extended or slightly different research questions. The latter describes the ability to understand the analysis in order to judge whether it is not only technically, but methodologically valid. Here, we analyze the properties needed for a data analysis to become reproducible, adaptable, and transparent. We show how the popular workflow management system Snakemake can be used to guarantee this, and how it enables an ergonomic, combined, unified representation of all steps involved in data analysis, ranging from raw data processing, to quality control and fine-grained, interactive exploration and plotting of final results.

519 citations


Journal ArticleDOI
TL;DR: Improved standardization of available invasive and noninvasive diagnostic tools and a consensus on their specific use are needed to allow specific diagnosis and stratification of patient cohorts for the implementation of aetiology-based therapies.
Abstract: Inflammatory cardiomyopathy, characterized by inflammatory cell infiltration into the myocardium and a high risk of deteriorating cardiac function, has a heterogeneous aetiology. Inflammatory cardiomyopathy is predominantly mediated by viral infection, but can also be induced by bacterial, protozoal or fungal infections as well as a wide variety of toxic substances and drugs and systemic immune-mediated diseases. Despite extensive research, inflammatory cardiomyopathy complicated by left ventricular dysfunction, heart failure or arrhythmia is associated with a poor prognosis. At present, the reason why some patients recover without residual myocardial injury whereas others develop dilated cardiomyopathy is unclear. The relative roles of the pathogen, host genomics and environmental factors in disease progression and healing are still under discussion, including which viruses are active inducers and which are only bystanders. As a consequence, treatment strategies are not well established. In this Review, we summarize and evaluate the available evidence on the pathogenesis, diagnosis and treatment of myocarditis and inflammatory cardiomyopathy, with a special focus on virus-induced and virus-associated myocarditis. Furthermore, we identify knowledge gaps, appraise the available experimental models and propose future directions for the field. The current knowledge and open questions regarding the cardiovascular effects associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are also discussed. This Review is the result of scientific cooperation of members of the Heart Failure Association of the ESC, the Heart Failure Society of America and the Japanese Heart Failure Society.

502 citations


Journal ArticleDOI
TL;DR: It is hypothesized that age-related decline and dysregulation of immune function, i.e., immunosenescence and inflammaging play a major role in contributing to heightened vulnerability to severe COVID-19 outcomes in older adults and partitioning all immunological outcome data by age to better understand disease heterogeneity and aging.

495 citations


Journal ArticleDOI
TL;DR: This work identifies and characterize multiple dominant and subdominant SARS-CoV-2 HLA class I and HLA-DR peptides as potential T cell epitopes in COVID-19 convalescent and unexposed individuals to enable identification of heterologous and post-infectious T cell immunity and facilitate development of diagnostic, preventive and therapeutic measures for CO VID-19.
Abstract: T cell immunity is central for the control of viral infections. To characterize T cell immunity, but also for the development of vaccines, identification of exact viral T cell epitopes is fundamental. Here we identify and characterize multiple dominant and subdominant SARS-CoV-2 HLA class I and HLA-DR peptides as potential T cell epitopes in COVID-19 convalescent and unexposed individuals. SARS-CoV-2-specific peptides enabled detection of post-infectious T cell immunity, even in seronegative convalescent individuals. Cross-reactive SARS-CoV-2 peptides revealed pre-existing T cell responses in 81% of unexposed individuals and validated similarity with common cold coronaviruses, providing a functional basis for heterologous immunity in SARS-CoV-2 infection. Diversity of SARS-CoV-2 T cell responses was associated with mild symptoms of COVID-19, providing evidence that immunity requires recognition of multiple epitopes. Together, the proposed SARS-CoV-2 T cell epitopes enable identification of heterologous and post-infectious T cell immunity and facilitate development of diagnostic, preventive and therapeutic measures for COVID-19.

430 citations


Journal ArticleDOI
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


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.

Journal ArticleDOI
TL;DR: In 2019, TB remained the most common cause of death from a single infectious pathogen globally, and an estimated 10.0 million people developed TB disease in 2019, and there were an estimated 1.2 million TB deaths among HIV-negative people and an additional 208, 000 deaths among people living with HIV as discussed by the authors.

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. Mernik2, Benjamin Mican1, Joseph J. Mohr11, Sebastian Müller1, Kirpal Nandra1, V. Nazarov, Florian Pacaud3, M. N. Pavlinsky, Emanuele Perinati9, Elmar Pfeffermann1, Daniel Pietschner1, Miriam E. Ramos-Ceja1, Arne Rau1, Jonas Reiffers1, Thomas H. Reiprich3, Jan Robrade4, Mara Salvato1, Jeremy S. Sanders1, Andrea Santangelo9, Manami Sasaki8, H. Scheuerle2, 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.

Journal ArticleDOI
03 Feb 2021
TL;DR: In this paper, the authors identify the human pancreas as a target of SARS-CoV-2 infection and suggest that β-cell infection could contribute to the metabolic dysregulation observed in patients with COVID-19.
Abstract: Infection-related diabetes can arise as a result of virus-associated β-cell destruction. Clinical data suggest that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing the coronavirus disease 2019 (COVID-19), impairs glucose homoeostasis, but experimental evidence that SARS-CoV-2 can infect pancreatic tissue has been lacking. In the present study, we show that SARS-CoV-2 infects cells of the human exocrine and endocrine pancreas ex vivo and in vivo. We demonstrate that human β-cells express viral entry proteins, and SARS-CoV-2 infects and replicates in cultured human islets. Infection is associated with morphological, transcriptional and functional changes, including reduced numbers of insulin-secretory granules in β-cells and impaired glucose-stimulated insulin secretion. In COVID-19 full-body postmortem examinations, we detected SARS-CoV-2 nucleocapsid protein in pancreatic exocrine cells, and in cells that stain positive for the β-cell marker NKX6.1 and are in close proximity to the islets of Langerhans in all four patients investigated. Our data identify the human pancreas as a target of SARS-CoV-2 infection and suggest that β-cell infection could contribute to the metabolic dysregulation observed in patients with COVID-19.

Journal ArticleDOI
TL;DR: COVID-19-associated GBS seems to share most features of classic post-infectious GBS and possibly the same immune-mediated pathogenetic mechanisms, Nevertheless, more extensive epidemiological studies are needed to clarify these issues.
Abstract: Since coronavirus disease-2019 (COVID-19) outbreak in January 2020, several pieces of evidence suggested an association between the spectrum of Guillain–Barre syndrome (GBS) and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Most findings were reported in the form of case reports or case series, whereas a comprehensive overview is still lacking. We conducted a systematic review and searched for all published cases until July 20th 2020. We included 73 patients reported in 52 publications. A broad age range was affected (mean 55, min 11–max 94 years) with male predominance (68.5%). Most patients showed respiratory and/or systemic symptoms, and developed GBS manifestations after COVID-19. However, asymptomatic cases for COVID-19 were also described. The distributions of clinical variants and electrophysiological subtypes resemble those of classic GBS, with a higher prevalence of the classic sensorimotor form and the acute inflammatory demyelinating polyneuropathy, although rare variants like Miller Fisher syndrome were also reported. Cerebrospinal fluid (CSF) albuminocytological dissociation was present in around 71% cases, and CSF SARS-CoV-2 RNA was absent in all tested cases. More than 70% of patients showed a good prognosis, mostly after treatment with intravenous immunoglobulin. Patients with less favorable outcome were associated with a significantly older age in accordance with previous findings regarding both classic GBS and COVID-19. COVID-19-associated GBS seems to share most features of classic post-infectious GBS and possibly the same immune-mediated pathogenetic mechanisms. Nevertheless, more extensive epidemiological studies are needed to clarify these issues.

Journal ArticleDOI
30 Jun 2021-eLife
TL;DR: In this article, the authors compared the impact of the COVID-19 pandemic between countries or across time by collecting weekly, monthly, or quarterly all-cause mortality data from 103 countries and territories, openly available as the regularly updated World Mortality Dataset.
Abstract: Comparing the impact of the COVID-19 pandemic between countries or across time is difficult because the reported numbers of cases and deaths can be strongly affected by testing capacity and reporting policy. Excess mortality, defined as the increase in all-cause mortality relative to the expected mortality, is widely considered as a more objective indicator of the COVID-19 death toll. However, there has been no global, frequently updated repository of the all-cause mortality data across countries. To fill this gap, we have collected weekly, monthly, or quarterly all-cause mortality data from 103 countries and territories, openly available as the regularly updated World Mortality Dataset. We used this dataset to compute the excess mortality in each country during the COVID-19 pandemic. We found that in several worst-affected countries (Peru, Ecuador, Bolivia, Mexico) the excess mortality was above 50% of the expected annual mortality (Peru, Ecuador, Bolivia, Mexico) or above 400 excess deaths per 100,000 population (Peru, Bulgaria, North Macedonia, Serbia). At the same time, in several other countries (e.g. Australia and New Zealand) mortality during the pandemic was below the usual level, presumably due to social distancing measures decreasing the non-COVID infectious mortality. Furthermore, we found that while many countries have been reporting the COVID-19 deaths very accurately, some countries have been substantially underreporting their COVID-19 deaths (e.g. Nicaragua, Russia, Uzbekistan), by up to two orders of magnitude (Tajikistan). Our results highlight the importance of open and rapid all-cause mortality reporting for pandemic monitoring.

Journal ArticleDOI
TL;DR: In this paper, the authors highlight how obesity and impaired metabolic health increase complications and mortality in COVID-19 and summarize the consequences of SARS-CoV-2 infection for organ function and risk of NCDs.
Abstract: Obesity and impaired metabolic health are established risk factors for the non-communicable diseases (NCDs) type 2 diabetes mellitus, cardiovascular disease, neurodegenerative diseases, cancer and nonalcoholic fatty liver disease, otherwise known as metabolic associated fatty liver disease (MAFLD). With the worldwide spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), obesity and impaired metabolic health also emerged as important determinants of severe coronavirus disease 2019 (COVID-19). Furthermore, novel findings indicate that specifically visceral obesity and characteristics of impaired metabolic health such as hyperglycaemia, hypertension and subclinical inflammation are associated with a high risk of severe COVID-19. In this Review, we highlight how obesity and impaired metabolic health increase complications and mortality in COVID-19. We also summarize the consequences of SARS-CoV-2 infection for organ function and risk of NCDs. In addition, we discuss data indicating that the COVID-19 pandemic could have serious consequences for the obesity epidemic. As obesity and impaired metabolic health are both accelerators and consequences of severe COVID-19, and might adversely influence the efficacy of COVID-19 vaccines, we propose strategies for the prevention and treatment of obesity and impaired metabolic health on a clinical and population level, particularly while the COVID-19 pandemic is present.

Journal ArticleDOI
TL;DR: In this article, the authors present guidelines covering sample preparation, replication and randomization, quantification, recovery and recombination, ion suppression and peak misidentification, as a means to enable high-quality reporting of liquid chromatography and gas chromatography-mass spectrometry-derived data.
Abstract: Mass spectrometry-based metabolomics approaches can enable detection and quantification of many thousands of metabolite features simultaneously. However, compound identification and reliable quantification are greatly complicated owing to the chemical complexity and dynamic range of the metabolome. Simultaneous quantification of many metabolites within complex mixtures can additionally be complicated by ion suppression, fragmentation and the presence of isomers. Here we present guidelines covering sample preparation, replication and randomization, quantification, recovery and recombination, ion suppression and peak misidentification, as a means to enable high-quality reporting of liquid chromatography- and gas chromatography-mass spectrometry-based metabolomics-derived data.

Journal ArticleDOI
19 Aug 2021
TL;DR: In this paper, the authors present a strategic blueprint to substantially improve our ability to discover and develop new antibiotics, and propose both short-term and long-term solutions to overcome the most urgent limitations in the various sectors of research and funding.
Abstract: An ever-increasing demand for novel antimicrobials to treat life-threatening infections caused by the global spread of multidrug-resistant bacterial pathogens stands in stark contrast to the current level of investment in their development, particularly in the fields of natural-product-derived and synthetic small molecules. New agents displaying innovative chemistry and modes of action are desperately needed worldwide to tackle the public health menace posed by antimicrobial resistance. Here, our consortium presents a strategic blueprint to substantially improve our ability to discover and develop new antibiotics. We propose both short-term and long-term solutions to overcome the most urgent limitations in the various sectors of research and funding, aiming to bridge the gap between academic, industrial and political stakeholders, and to unite interdisciplinary expertise in order to efficiently fuel the translational pipeline for the benefit of future generations.

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 IMvigor010 trial as discussed by the authors evaluated atezolizumab as adjuvant therapy in patients with high-risk muscle-invasive urothelial carcinoma.
Abstract: Summary Background Despite standard curative-intent treatment with neoadjuvant cisplatin-based chemotherapy, followed by radical surgery in eligible patients, muscle-invasive urothelial carcinoma has a high recurrence rate and no level 1 evidence for adjuvant therapy. We aimed to evaluate atezolizumab as adjuvant therapy in patients with high-risk muscle-invasive urothelial carcinoma. Method In the IMvigor010 study, a multicentre, open-label, randomised, phase 3 trial done in 192 hospitals, academic centres, and community oncology practices across 24 countries or regions, patients aged 18 years and older with histologically confirmed muscle-invasive urothelial carcinoma and an Eastern Cooperative Oncology Group performance status of 0, 1, or 2 were enrolled within 14 weeks after radical cystectomy or nephroureterectomy with lymph node dissection. Patients had ypT2–4a or ypN+ tumours following neoadjuvant chemotherapy or pT3–4a or pN+ tumours if no neoadjuvant chemotherapy was received. Patients not treated with neoadjuvant chemotherapy must have been ineligible for or declined cisplatin-based adjuvant chemotherapy. No post-surgical radiotherapy or previous adjuvant chemotherapy was allowed. Patients were randomly assigned (1:1) using a permuted block (block size of four) method and interactive voice-web response system to receive 1200 mg atezolizumab given intravenously every 3 weeks for 16 cycles or up to 1 year, whichever occurred first, or to observation. Randomisation was stratified by previous neoadjuvant chemotherapy use, number of lymph nodes resected, pathological nodal status, tumour stage, and PD-L1 expression on tumour-infiltrating immune cells. The primary endpoint was disease-free survival in the intention-to-treat population. Safety was assessed in patients who either received at least one dose of atezolizumab or had at least one post-baseline safety assessment. This trial is registered with ClinicalTrials.gov, NCT02450331, and is ongoing but not recruiting patients. Findings Between Oct 5, 2015, and July 30, 2018, we enrolled 809 patients, of whom 406 were assigned to the atezolizumab group and 403 were assigned to the observation group. Median follow-up was 21·9 months (IQR 13·2–29·8). Median disease-free survival was 19·4 months (95% CI 15·9–24·8) with atezolizumab and 16·6 months (11·2–24·8) with observation (stratified hazard ratio 0·89 [95% CI 0·74–1·08]; p=0·24). The most common grade 3 or 4 adverse events were urinary tract infection (31 [8%] of 390 patients in the atezolizumab group vs 20 [5%] of 397 patients in the observation group), pyelonephritis (12 [3%]) vs 14 [4%]), and anaemia (eight [2%] vs seven [2%]). Serious adverse events occurred in 122 (31%) patients who received atezolizumab and 71 (18%) who underwent observation. 63 (16%) patients who received atezolizumab had a treatment-related grade 3 or 4 adverse event. One treatment-related death, due to acute respiratory distress syndrome, occurred in the atezolizumab group. Interpretation To our knowledge, IMvigor010 is the largest, first-completed phase 3 adjuvant study to evaluate the role of a checkpoint inhibitor in muscle-invasive urothelial carcinoma. The trial did not meet its primary endpoint of improved disease-free survival in the atezolizumab group over observation. Atezolizumab was generally tolerable, with no new safety signals; however, higher frequencies of adverse events leading to discontinuation were reported than in metastatic urothelial carcinoma studies. These data do not support the use of adjuvant checkpoint inhibitor therapy in the setting evaluated in IMvigor010 at this time. Funding F Hoffmann-La Roche/Genentech.

Proceedings ArticleDOI
01 Jun 2021
TL;DR: In this paper, a method that extends neural radiance fields to a dynamic domain, allowing to reconstruct and render novel images of objects under rigid and non-rigid motions from a single camera moving around the scene.
Abstract: Neural rendering techniques combining machine learning with geometric reasoning have arisen as one of the most promising approaches for synthesizing novel views of a scene from a sparse set of images. Among these, stands out the Neural radiance fields (NeRF) [31], which trains a deep network to map 5D input coordinates (representing spatial location and viewing direction) into a volume density and view-dependent emitted radiance. However, despite achieving an unprecedented level of photorealism on the generated images, NeRF is only applicable to static scenes, where the same spatial location can be queried from different images. In this paper we introduce D-NeRF, a method that extends neural radiance fields to a dynamic domain, allowing to reconstruct and render novel images of objects under rigid and non-rigid motions from a single camera moving around the scene. For this purpose we consider time as an additional input to the system, and split the learning process in two main stages: one that encodes the scene into a canonical space and another that maps this canonical representation into the deformed scene at a particular time. Both mappings are simultaneously learned using fully-connected networks. Once the networks are trained, D-NeRF can render novel images, controlling both the camera view and the time variable, and thus, the object movement. We demonstrate the effectiveness of our approach on scenes with objects under rigid, articulated and non-rigid motions. Code, model weights and the dynamic scenes dataset will be available at [1].

Journal ArticleDOI
TL;DR: Kappler et al. as discussed by the authors highlighted recent advances in understanding of the biogeochemical iron cycle, exploring the great complexity of the processes involved and novel mechanistic insights that have been gained.
Abstract: Biogeochemical cycling of iron is crucial to many environmental processes, such as ocean productivity, carbon storage, greenhouse gas emissions and the fate of nutrients, toxic metals and metalloids. Knowledge of the underlying processes involved in iron cycling has accelerated in recent years along with appreciation of the complex network of biotic and abiotic reactions dictating the speciation, mobility and reactivity of iron in the environment. Recent studies have provided insights into novel processes in the biogeochemical iron cycle such as microbial ammonium oxidation and methane oxidation coupled to Fe(iii) reduction. They have also revealed that processes in the biogeochemical iron cycle spatially overlap and may compete with each other, and that oxidation and reduction of iron occur cyclically or simultaneously in many environments. This Review discusses these advances with particular focus on their environmental consequences, including the formation of greenhouse gases and the fate of nutrients and contaminants. In this Review, Kappler and colleagues highlight recent advances in our understanding of the biogeochemical iron cycle, exploring the great complexity of the processes involved and novel mechanistic insights that have been gained.

Journal ArticleDOI
07 Oct 2021-Nature
TL;DR: The results suggest that neuronal types in the neocortex do not always form discrete entities, but can form continuous and correlated transcriptomic and morpho-electrical landscapes within families.
Abstract: Cortical neurons exhibit extreme diversity in gene expression as well as in morphological and electrophysiological properties1,2. Most existing neural taxonomies are based on either transcriptomic3,4 or morpho-electric5,6 criteria, as it has been technically challenging to study both aspects of neuronal diversity in the same set of cells7. Here we used Patch-seq8 to combine patch-clamp recording, biocytin staining, and single-cell RNA sequencing of more than 1,300 neurons in adult mouse primary motor cortex, providing a morpho-electric annotation of almost all transcriptomically defined neural cell types. We found that, although broad families of transcriptomic types (those expressing Vip, Pvalb, Sst and so on) had distinct and essentially non-overlapping morpho-electric phenotypes, individual transcriptomic types within the same family were not well separated in the morpho-electric space. Instead, there was a continuum of variability in morphology and electrophysiology, with neighbouring transcriptomic cell types showing similar morpho-electric features, often without clear boundaries between them. Our results suggest that neuronal types in the neocortex do not always form discrete entities. Instead, neurons form a hierarchy that consists of distinct non-overlapping branches at the level of families, but can form continuous and correlated transcriptomic and morpho-electrical landscapes within families. Single-cell transcriptomic, morphological and electrophysiological characteristics are combined to classify more than 1,300 neurons from mouse motor cortex.

Journal ArticleDOI
TL;DR: Higher order tracking accuracy (HOTA) as mentioned in this paper is proposed to explicitly balance the effect of performing accurate detection, association and localization into a single unified metric for comparing trackers, which is able to capture important aspects of MOT performance not previously taken into account by established metrics.
Abstract: Multi-object tracking (MOT) has been notoriously difficult to evaluate. Previous metrics overemphasize the importance of either detection or association. To address this, we present a novel MOT evaluation metric, higher order tracking accuracy (HOTA), which explicitly balances the effect of performing accurate detection, association and localization into a single unified metric for comparing trackers. HOTA decomposes into a family of sub-metrics which are able to evaluate each of five basic error types separately, which enables clear analysis of tracking performance. We evaluate the effectiveness of HOTA on the MOTChallenge benchmark, and show that it is able to capture important aspects of MOT performance not previously taken into account by established metrics. Furthermore, we show HOTA scores better align with human visual evaluation of tracking performance.

Journal ArticleDOI
Cathrine Axfors1, Cathrine Axfors2, Andreas M. Schmitt3, Andreas M. Schmitt4, Perrine Janiaud4, Janneke van’t Hooft1, Janneke van’t Hooft5, Sherief Abd-Elsalam6, Ehab F. Abdo7, Benjamin S. Abella8, Javed Akram9, Ravi K. Amaravadi8, Derek C. Angus10, Yaseen M. Arabi11, Shehnoor Azhar9, Lindsey R. Baden12, Arthur W. Baker13, Leila Belkhir14, Thomas Benfield15, Marvin A.H. Berrevoets, Cheng-Pin Chen16, Tsung-Chia Chen16, Shu-Hsing Cheng16, Chien-Yu Cheng16, Wei-Sheng Chung16, Yehuda Z. Cohen, Lisa N. Cowan, Olav Dalgard17, Olav Dalgard18, Fernando Val, Marcus V. G. Lacerda19, Gisely Cardoso de Melo, Lennie P. G. Derde20, Vincent Dubée, Anissa Elfakir, Anthony C. Gordon21, Carmen M. Hernández-Cárdenas, Thomas Hills22, Thomas Hills23, Andy I. M. Hoepelman20, Yi-Wen Huang16, Bruno Igau, Ronghua Jin24, Felipe Jurado-Camacho, Khalid S. Khan25, Peter G. Kremsner26, Benno Kreuels27, Benno Kreuels28, Cheng-Yu Kuo16, Thuy Le13, Yi-Chun Lin16, Wu-Pu Lin16, Tse-Hung Lin16, Magnus Nakrem Lyngbakken17, Magnus Nakrem Lyngbakken18, Colin McArthur29, Colin McArthur22, Colin McArthur23, Bryan J. McVerry10, Patricia Meza-Meneses, Wuelton Marcelo Monteiro, Susan C. Morpeth30, Ahmad Mourad13, Mark J. Mulligan, Srinivas Murthy31, Susanna Naggie13, Shanti Narayanasamy13, Alistair Nichol, Lewis A. Novack12, Sean M. O'Brien13, Nwora Lance Okeke13, Léna Perez, Rogelio Perez-Padilla, Laurent Perrin, Arantxa Remigio-Luna, Norma E. Rivera-Martinez, Frank W. Rockhold13, Sebastian Rodriguez-Llamazares, Robert Rolfe13, Rossana Rosa32, Helge Røsjø17, Helge Røsjø18, Vanderson de Souza Sampaio, Todd B. Seto33, Todd B. Seto34, Muhammad Shahzad9, Shaimaa Soliman35, Jason E. Stout13, Ireri Thirion-Romero, Andrea B. Troxel, Ting-Yu Tseng16, Nicholas A Turner13, Robert J. Ulrich, Stephen R. Walsh12, Steve Webb36, Steve Webb29, Jesper M. Weehuizen20, Maria Velinova, Hon-Lai Wong16, Rebekah Wrenn13, Fernando G. Zampieri, Wu Zhong, David Moher37, Steven N. Goodman1, John P. A. Ioannidis, Lars G. Hemkens4, Lars G. Hemkens1 
TL;DR: In this article, a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients was presented.
Abstract: Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aim to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We present a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/ ). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality has been extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses include patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total sample size). The combined OR on all-cause mortality for hydroxychloroquine is 1.11 (95% CI: 1.02, 1.20; I² = 0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I² = 0%; 4 trials; 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine is associated with increased mortality in COVID-19 patients, and there is no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities. Hydroxychloroquine and chloroquine have been investigated as a potential treatment for Covid-19 in several clinical trials. Here the authors report a meta-analysis of published and unpublished trials, and show that treatment with hydroxychloroquine for patients with Covid-19 was associated with increased mortality, and there was no benefit from chloroquine.

Journal ArticleDOI
TL;DR: In this article, the authors used partitioning on variables derived from oral glucose tolerance tests, MRI-measured body fat distribution, liver fat content and genetic risk in a cohort of extensively phenotyped individuals who are at increased risk for type 2 diabetes.
Abstract: The state of intermediate hyperglycemia is indicative of elevated risk of developing type 2 diabetes1. However, the current definition of prediabetes neither reflects subphenotypes of pathophysiology of type 2 diabetes nor is predictive of future metabolic trajectories. We used partitioning on variables derived from oral glucose tolerance tests, MRI-measured body fat distribution, liver fat content and genetic risk in a cohort of extensively phenotyped individuals who are at increased risk for type 2 diabetes2,3 to identify six distinct clusters of subphenotypes. Three of the identified subphenotypes have increased glycemia (clusters 3, 5 and 6), but only individuals in clusters 5 and 3 have imminent diabetes risks. By contrast, those in cluster 6 have moderate risk of type 2 diabetes, but an increased risk of kidney disease and all-cause mortality. Findings were replicated in an independent cohort using simple anthropomorphic and glycemic constructs4. This proof-of-concept study demonstrates that pathophysiological heterogeneity exists before diagnosis of type 2 diabetes and highlights a group of individuals who have an increased risk of complications without rapid progression to overt type 2 diabetes. Clustering of patients with prediabetes using simple clinical features reveals six distinct groups with differing risk of developing type 2 diabetes and its associated complications.

Journal ArticleDOI
TL;DR: This GeneFocus provides a comprehensive overview and summary of CYP2D6 genetic variation and describes how the information provided by PharmVar is utilized by the Pharmacogenomics Knowledgebase (PharmGKB) and the Clinical Pharmacogenetics Implementation Consortium (CPIC).
Abstract: The Pharmacogene Variation Consortium (PharmVar) catalogues star (*) allele nomenclature for the polymorphic human CYP2C19 gene. CYP2C19 genetic variation impacts the metabolism of many drugs and has been associated with both efficacy and safety issues for several commonly prescribed medications. This GeneFocus provides a comprehensive overview and summary of CYP2C19 and describes how haplotype information catalogued by PharmVar is utilized by the Pharmacogenomics Knowledgebase and the Clinical Pharmacogenetics Implementation Consortium (CPIC).

Journal ArticleDOI
23 Jul 2021-Science
TL;DR: In this article, the authors demonstrated that helper leucine-rich repeat receptors (NLRs) form Ca2+permeable cation channels to directly regulate cytoplasmic Ca 2+ levels and consequent cell death.
Abstract: Plant nucleotide-binding leucine-rich repeat receptors (NLRs) regulate immunity and cell death. In Arabidopsis, a subfamily of "helper" NLRs is required by many "sensor" NLRs. Active NRG1.1 oligomerized, was enriched in plasma membrane puncta, and conferred cytoplasmic calcium ion (Ca2+) influx in plant and human cells. NRG1.1-dependent Ca2+ influx and cell death were sensitive to Ca2+ channel blockers and were suppressed by mutations affecting oligomerization or plasma membrane enrichment. Ca2+ influx and cell death mediated by NRG1.1 and ACTIVATED DISEASE RESISTANCE 1 (ADR1), another helper NLR, required conserved negatively charged N-terminal residues. Whole-cell voltage-clamp recordings demonstrated that Arabidopsis helper NLRs form Ca2+-permeable cation channels to directly regulate cytoplasmic Ca2+ levels and consequent cell death. Thus, helper NLRs transduce cell death signals directly.

Journal ArticleDOI
24 Mar 2021-Nature
TL;DR: In this paper, an IDH1(R132H)-specific peptide vaccine (IDH1-vac) was used to induce specific therapeutic T helper cell responses that are effective against the most common IDH 1 mutation in diffuse gliomas, which harbours a shared clonal neoepitope.
Abstract: Mutated isocitrate dehydrogenase 1 (IDH1) defines a molecularly distinct subtype of diffuse glioma1-3. The most common IDH1 mutation in gliomas affects codon 132 and encodes IDH1(R132H), which harbours a shared clonal neoepitope that is presented on major histocompatibility complex (MHC) class II4,5. An IDH1(R132H)-specific peptide vaccine (IDH1-vac) induces specific therapeutic T helper cell responses that are effective against IDH1(R132H)+ tumours in syngeneic MHC-humanized mice4,6-8. Here we describe a multicentre, single-arm, open-label, first-in-humans phase I trial that we carried out in 33 patients with newly diagnosed World Health Organization grade 3 and 4 IDH1(R132H)+ astrocytomas (Neurooncology Working Group of the German Cancer Society trial 16 (NOA16), ClinicalTrials.gov identifier NCT02454634). The trial met its primary safety endpoint, with vaccine-related adverse events restricted to grade 1. Vaccine-induced immune responses were observed in 93.3% of patients across multiple MHC alleles. Three-year progression-free and death-free rates were 0.63 and 0.84, respectively. Patients with immune responses showed a two-year progression-free rate of 0.82. Two patients without an immune response showed tumour progression within two years of first diagnosis. A mutation-specificity score that incorporates the duration and level of vaccine-induced IDH1(R132H)-specific T cell responses was associated with intratumoral presentation of the IDH1(R132H) neoantigen in pre-treatment tumour tissue. There was a high frequency of pseudoprogression, which indicates intratumoral inflammatory reactions. Pseudoprogression was associated with increased vaccine-induced peripheral T cell responses. Combined single-cell RNA and T cell receptor sequencing showed that tumour-infiltrating CD40LG+ and CXCL13+ T helper cell clusters in a patient with pseudoprogression were dominated by a single IDH1(R132H)-reactive T cell receptor.