Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 94,912 bioRxiv papers from 404,161 authors.
Most downloaded bioRxiv papers, since beginning of last month
93,099 results found. For more information, click each entry to expand.
1,890 downloads genomics
The COVID-19 pandemic is caused by the coronavirus SARS-CoV-2, which jumped into the human population in late 2019 from a currently uncharacterised animal reservoir. Due to this extremely recent association with humans, SARS-CoV-2 may not yet be fully adapted to its human host. This has led to speculations that some lineages of SARS-CoV-2 may be evolving towards higher transmissibility. The most plausible candidate mutations under putative natural selection are those which have emerged repeatedly and independently (homoplasies). Here, we formally test whether any of the recurrent mutations that have been observed in SARS-CoV-2 are significantly associated with increased viral transmission. To do so, we develop a phylogenetic index to quantify the relative number of descendants in sister clades with and without a specific allele. We apply this index to a carefully curated set of recurrent mutations identified within a dataset of 46,723 SARS-CoV-2 genomes isolated from patients worldwide. We do not identify a single recurrent mutation in this set convincingly associated with increased viral transmission. Instead, recurrent SARS-CoV-2 mutations currently in circulation appear to be evolutionary neutral. Recurrent mutations also seem primarily induced by the human immune system via host RNA editing, rather than being signatures of adaptation to the novel human host. In conclusion, we find no evidence at this stage for the emergence of significantly more transmissible lineages of SARS-CoV-2 due to recurrent mutations. ### Competing Interest Statement The authors have declared no competing interest.
1,885 downloads pharmacology and toxicology
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly identified pathogen causing coronavirus disease 2019 (COVID-19) pandemic. Hydroxychloroquine (HCQ), an antimalarial and anti-inflammatory drug, has been shown to inhibit SARS-CoV-2 infection in vitro and tested in clinical studies. However, lung concentration (6.7 μg/mL) to predict the in vivo antiviral efficacy might not be achievable with the currently proposed oral dosing regimen. Further, a high cumulative doses of HCQ may raise concerns of systemic toxicity, including cardiotoxicity. Here, we described a non-clinical study to investigate the pharmacokinetics of a novel formulation of liposomal HCQ administrated by intratracheal (IT) instillation in Sprague-Dawley (SD) rats which achieved 129.4 μg/g (Cmax) in the lung. Compared to unformulated HCQ administered intravenous (IV), liposomal HCQ with normalized dose showed higher (~30-fold) lung exposure, longer (~2.5-fold) half-life in lung, but lower blood exposure with ~20% of Cmax and 74% of AUC and lower heart exposure with 24% of Cmax and 58% of AUC. In conclusion, the pharmacokinetics results in an animal model demonstrate the proof of concept that inhalable liposomal HCQ may provide clinical benefit and serve as a potential treatment for COVID-19.
1,877 downloads neuroscience
Kunal Sahasrabuddhe, Aamir A Khan, Aditya P Singh, Tyler M Stern, Yeena Ng, Aleksandar Tadić, Peter Orel, Chris LaReau, Daniel Pouzzner, Kurtis Nishimura, Kevin M Boergens, Sashank Shivakumar, Matthew S Hopper, Bryan Kerr, Mina-Elraheb S. Hanna, Robert J Edgington, Ingrid McNamara, Devin Fell, Peng Gao, Amir Babaie-Fishani, Sampsa Veijalainen, Alexander V Klekachev, Alison M Stuckey, Bert Luyssaert, Takashi DY Kozai, Chong Xie, Vikash Gilja, Bart Dierickx, Yifan Kong, Malgorzata Straka, Harbaljit S Sohal, Matthew R Angle
Here we demonstrate the Argo System, a massively parallel neural recording system based on platinum-iridium microwire electrode arrays bonded to a CMOS voltage amplifier array. The Argo system is the highest channel count in vivo neural recording system built to date, supporting simultaneous recording from 65,536 channels, sampled at over 32 kHz and 12-bit resolution. This system is designed for cortical recordings, compatible with both penetrating and surface microelectrodes. We have validated this system by recording spiking activity from 791 neurons in rats and cortical surface Local Field Potential (LFP) activity from over 30,000 channels in sheep. While currently adapted for head-fixed recording, the microwire-CMOS architecture is well suited for clinical translation. Thus, this demonstration helps pave the way for a future high data rate intracortical implant. ### Competing Interest Statement K.S., A.A.K., A.P.S., T.M.S, Y.N., A.T., P.O., C.L., D.P., K.N., K.M.B., S.S., M.S.H., B.K., M-E.S.H., R.J.E., I.M., D.F., A.M.S., V.G., Y.K., M.S., H.S.S., M.R.A. are current or former compensated employees or consultants of Paradromics, Inc., a brain-computer interface company. P.G., A.B-F, S.V., A.V.K, B.L., B.D. are compensated employees or consultants of Caeleste, CVBA, a circuit design company.
1,867 downloads immunology
Ami Patel, Jewell Walters, Emma L Reuschel, Katherine Schultheis, Elizabeth Parzych, Ebony N. Gary, Igor Maricic, Mansi Purwar, Zeena Eblimit, Susanne N. Walker, Diana Guimet, Pratik Bhojnagarwala, Arthur Doan, Ziyang Xu, Dustin Elwood, Sophia M Reeder, Laurent Pessaint, Kevin Y. Kim, Anthony Cook, Neethu Chokkalingam, Brad Finneyfrock, Edgar Tello-Ruiz, Alan Dodson, Jihae Choi, Alison Generotti, John Harrison, Nicholas J Tursi, Viviane M Andrade, Yaya Dia, Faraz I Zaidi, Hanne Andersen, Mark G Lewis, Kar Muthumani, J Joseph Kim, Daniel W. Kulp, Laurent M Humeau, Stephanie Ramos, Trevor R.F. Smith, David B Weiner, Kate E. Broderick
Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 virus, has had a dramatic global impact on public health, social, and economic infrastructures. Here, we assess immunogenicity and anamnestic protective efficacy in rhesus macaques of the intradermal (ID)-delivered SARS-CoV-2 spike DNA vaccine, INO-4800. INO-4800 is an ID-delivered DNA vaccine currently being evaluated in clinical trials. Vaccination with INO-4800 induced T cell responses and neutralizing antibody responses against both the D614 and G614 SARS-CoV-2 spike proteins. Several months after vaccination, animals were challenged with SARS-CoV-2 resulting in rapid recall of anti-SARS-CoV-2 spike protein T and B cell responses. These responses were associated with lower viral loads in the lung and with faster nasal clearance of virus. These studies support the immune impact of INO-4800 for inducing both humoral and cellular arms of the adaptive immune system which are likely important for providing durable protection against COVID-19 disease. ### Competing Interest Statement A.P., E.R., E.P., E.N.G., M.P., S.N.W., P.B., Z.X., S.R., K.Y.K., N.C., E.T-R., J.C., N.J.T., K.M., D.K.W., declare no competing interests. J.W., K.S., I.M., Z.E., D.G., A.D., D.E., A.G., V.M.A., J.J.K., L.M.H., S.R., T.R.F.S., K.E.B. are employees of Inovio Pharmaceuticals and as such receive salary and benefits, including ownership of stock and stock options, from the company. D.B.W. discloses the following paid associations with commercial partners: GeneOne (Consultant), Geneos (Advisory Board), Astrazeneca (Advisory Board, Speaker), Inovio (BOD, SRA, Stock), Pfizer (Speaker), Merck (Speaker), Sanofi (Advisory Board), BBI (Advisory Board).
1,862 downloads genomics
The application of polygenic risk scores (PRS) has become routine in genetic epidemiological studies. Among a range of applications, PRS are commonly used to assess shared aetiology among different phenotypes and to evaluate the predictive power of genetic data, while they are also now being exploited as part of study design, in which experiments are performed on individuals, or their biological samples (eg. tissues, cells), at the tails of the PRS distribution and contrasted. As GWAS sample sizes increase and PRS become more powerful, they are also set to play a key role in personalised medicine. Despite their growing application and importance, there are limited guidelines for performing PRS analyses, which can lead to inconsistency between studies and misinterpretation of results. Here we provide detailed guidelines for performing polygenic risk score analyses relevant to different methods for their calculation, outlining standard quality control steps and offering recommendations for best-practice. We also discuss different methods for the calculation of PRS, common misconceptions regarding the interpretation of results and future challenges.
1,826 downloads neuroscience
David H. Brann, Tatsuya Tsukahara, Caleb Weinreb, Marcela Lipovsek, Koen Van den Berge, Boying Gong, Rebecca Chance, Iain C Macaulay, Hsin-jung Chou, Russell Fletcher, Diya Das, Kelly Street, Hector Roux de Bézieux, Yoon-Gi Choi, Davide Risso, Sandrine Dudoit, Elizabeth Purdom, Jonathan S Mill, Ralph Abi Hachem, Hiroaki Matsunami, Darren W. Logan, Bradley J. Goldstein, Matthew S Grubb, John Ngai, Sandeep Robert Datta
Altered olfactory function is a common symptom of COVID-19, but its etiology is unknown. A key question is whether SARS-CoV-2 (CoV-2) - the causal agent in COVID-19 - affects olfaction directly by infecting olfactory sensory neurons or their targets in the olfactory bulb, or indirectly, through perturbation of supporting cells. Here we identify cell types in the olfactory epithelium and olfactory bulb that express SARS-CoV-2 cell entry molecules. Bulk sequencing revealed that mouse, non-human primate and human olfactory mucosa expresses two key genes involved in CoV-2 entry, ACE2 and TMPRSS2. However, single cell sequencing and immunostaining demonstrated ACE2 expression in support cells, stem cells, and perivascular cells; in contrast, neurons in both the olfactory epithelium and bulb did not express ACE2 message or protein. These findings suggest that CoV-2 infection of non-neuronal cell types leads to anosmia and related disturbances in odor perception in COVID-19 patients. ### Competing Interest Statement DL is an employee of Mars, Inc. None of the other authors have competing interests to declare.
1,806 downloads microbiology
Qiang Gao, Linlin Bao, Haiyan Mao, Lin Wang, Kangwei Xu, Minnan Yang, Yajing Li, Ling Zhu, Nan Wang, Zhe Lv, Hong Gao, Xiaoqin Ge, Biao Kan, Yaling Hu, Jiangning Liu, Fang Cai, Deyu Jiang, Yanhui Yin, Chengfeng Qin, Jing Li, Xuejie Gong, Xiuyu Lou, Wen Shi, Dongdong Wu, Hengming Zhang, Lang Zhu, Wei Deng, Yurong Li, Jinxing Lu, Changgui Li, Xiangxi Wang, Weidong Yin, Yanjun Zhang, Chuan Qin
The COVID-19 caused by SARS-CoV-2 has brought about an unprecedented crisis, taking a heavy toll on human health, lives as well as the global economy. There are no SARS-CoV-2-specific treatments or vaccines available due to the novelty of this virus. Hence, rapid development of effective vaccines against SARS-CoV-2 is urgently needed. Here we developed a pilot-scale production of a purified inactivated SARS-CoV-2 virus vaccine candidate (PiCoVacc), which induced SARS-CoV-2-specific neutralizing antibodies in mice, rats and non-human primates. These antibodies potently neutralized 10 representative SARS-CoV-2 strains, indicative of a possible broader neutralizing ability against SARS-CoV-2 strains circulating worldwide. Immunization with two different doses (3 μg or 6 μg per dose) provided partial or complete protection in macaques against SARS-CoV-2 challenge, respectively, without any antibody-dependent enhancement of infection. Systematic evaluation of PiCoVacc via monitoring clinical signs, hematological and biochemical index, and histophathological analysis in macaques suggests that it is safe. These data support the rapid clinical development of SARS-CoV-2 vaccines for humans. ### Competing Interest Statement The authors have declared no competing interest.
1,800 downloads microbiology
Lorena Sanchez Felipe, Thomas Vercruysse, Sapna Sharma, Ji Ma, Viktor Lemmens, Dominique van Looveren, Mahadesh Prasad Arkalagud Javarappa, Robbert Boudewijns, Bert Malengier-Devlies, Suzanne F. Kaptein, Laurens Liesenborghs, Carolien De Keyzer, Lindsey Bervoets, Madina Rasulova, Laura Seldeslachts, Sander Jansen, Michael Bright Yakass, Osbourne Quaye, Li-Hsin Li, Xin Zhang, Sebastiaan ter Horst, Niraj Mishra, Lotte Coelmont, Christopher Cawthorne, Koen Van Laere, Ghislain Opdenakker, Greetje Van de Velde, Birgit Weynand, Dirk E. Teuwen, Patrick Matthys, Johan Neyts, Hendrik Jan Thibaut, Kai Dallmeier
The explosively expanding COVID-19 pandemic urges the development of safe, efficacious and fast-acting vaccines to quench the unrestrained spread of SARS-CoV-2. Several promising vaccine platforms, developed in recent years, are leveraged for a rapid emergency response to COVID-19. We employed the live-attenuated yellow fever 17D (YF17D) vaccine as a vector to express the prefusion form of the SARS-CoV-2 Spike antigen. In mice, the vaccine candidate, tentatively named YF-S0, induces high levels of SARS-CoV-2 neutralizing antibodies and a favorable Th1 cell-mediated immune response. In a stringent hamster SARS-CoV-2 challenge model, vaccine candidate YF-S0 prevents infection with SARS-CoV-2. Moreover, a single dose confers protection from lung disease in most vaccinated animals even within 10 days. These results warrant further development of YF-S0 as a potent SARS-CoV-2 vaccine candidate. ### Competing Interest Statement The authors have declared no competing interest.
1,795 downloads systems biology
Alexey Stukalov, Virginie Girault, Vincent Grass, Valter Bergant, Ozge Karayel, Christian Urban, Darya A. Haas, Yiqi Huang, Lila Oubraham, Anqi Wang, Sabri M. Hamad, Antonio Piras, Maria Tanzer, Fynn M Hansen, Thomas Enghleitner, Maria Reinecke, Teresa M. Lavacca, Rosina Ehmann, Roman Wölfel, Jörg Jores, Bernhard Kuster, Ulrike Protzer, Roland Rad, John Ziebuhr, Volker Thiel, Pietro Scaturro, Matthias Mann, Andreas Pichlmair
The sudden global emergence of SARS-CoV-2 urgently requires an in-depth understanding of molecular functions of viral proteins and their interactions with the host proteome. Several omics studies have extended our knowledge of COVID-19 pathophysiology, including some focused on proteomic aspects. To understand how SARS-CoV-2 and related coronaviruses manipulate the host we here characterized interactome, proteome and signaling processes in a systems-wide manner. This identified connections between the corresponding cellular events, revealed functional effects of the individual viral proteins and put these findings into the context of host signaling pathways. We investigated the closely related SARS-CoV-2 and SARS-CoV viruses as well as the influence of SARS-CoV-2 on transcriptome, proteome, ubiquitinome and phosphoproteome of a lung-derived human cell line. Projecting these data onto the global network of cellular interactions revealed relationships between the perturbations taking place upon SARS-CoV-2 infection at different layers and identified unique and common molecular mechanisms of SARS coronaviruses. The results highlight the functionality of individual proteins as well as vulnerability hotspots of SARS-CoV-2, which we targeted with clinically approved drugs. We exemplify this by identification of kinase inhibitors as well as MMPase inhibitors with significant antiviral effects against SARS-CoV-2. ### Competing Interest Statement The authors have declared no competing interest.
1,790 downloads bioengineering
Jon Arizti-Sanz, Catherine A. Freije, Alexandra C. Stanton, Chloe K. Boehm, Brittany A. Petros, Sameed Siddiqui, Bennett M. Shaw, Gordon Adams, Tinna-Solveig F Kosoko-Thoroddsen, Molly E. Kemball, Robin Gross, Loni Wronka, Katie Caviness, Lisa E Hensley, Nicholas H. Bergman, Bronwyn L MacInnis, Jacob E. Lemieux, Pardis C Sabeti, Cameron Myhrvold
The COVID-19 pandemic has highlighted that new diagnostic technologies are essential for controlling disease transmission. Here, we develop SHINE (SHERLOCK and HUDSON Integration to Navigate Epidemics), a sensitive and specific integrated diagnostic tool that can detect SARS-CoV-2 RNA from unextracted samples. We combine the steps of SHERLOCK into a single-step reaction and optimize HUDSON to accelerate viral inactivation in nasopharyngeal swabs and saliva. SHINE's results can be visualized with an in-tube fluorescent readout - reducing contamination risk as amplification reaction tubes remain sealed - and interpreted by a companion smartphone application. We validate SHINE on 50 nasopharyngeal patient samples, demonstrating 90% sensitivity and 100% specificity compared to RT-PCR with a sample-to-answer time of 50 minutes. SHINE has the potential to be used outside of hospitals and clinical laboratories, greatly enhancing diagnostic capabilities. ### Competing Interest Statement C.A.F., P.C.S., and C.M. are inventors on patent filings related to this work. J.E.L. consults for Sherlock Biosciences, Inc. P.C.S. is a co-founder of, shareholder in, and advisor to Sherlock Biosciences, Inc, as well as a Board member of and shareholder in Danaher Corporation.
1,771 downloads biochemistry
In December 2019, the first cases of a novel coronavirus infection causing COVID-19 were diagnosed in Wuhan, China. Viral Papain-Like cysteine protease (PLpro, NSP3) is essential for SARS-CoV-2 replication and represents a promising target for the development of antiviral drugs. Here, we used a combinatorial substrate library containing natural and a wide variety of nonproteinogenic amino acids and performed comprehensive activity profiling of SARS-CoV-2-PLpro. On the scaffold of best hits from positional scanning we designed optimal fluorogenic substrates and irreversible inhibitors with a high degree of selectivity for SARS PLpro variants versus other proteases. We determined crystal structures of two of these inhibitors (VIR250 and VIR251) in complex with SARS-CoV-2-PLpro which reveals their inhibitory mechanisms and provides a structural basis for the observed substrate specificity profiles. Lastly, we demonstrate that SARS-CoV-2-PLpro harbors deISGylating activities similar to SARS-CoV-1-PLpro but its ability to hydrolyze K48-linked Ub chains is diminished, which our sequence and structure analysis provides a basis for. Altogether this work has revealed the molecular rules governing PLpro substrate specificity and provides a framework for development of inhibitors with potential therapeutic value or drug repositioning. ### Competing Interest Statement F.E.O. declares competing financial interests as co-founders and shareholder of UbiQ Bio BV. M.B. is an employee and shareholder of Arvinas, Inc. The remaining authors declare no competing interests.
1,761 downloads microbiology
Kenneth H. Dinnon, Sarah R. Leist, Alexandra Schäfer, Caitlin E. Edwards, David R. Martinez, Stephanie A. Montgomery, Ande West, Boyd L. Yount, Yixuan J. Hou, Lily E Adams, Kendra L Gully, Ariane J Brown, Emily Huang, Matthew D. Bryant, Ingrid C. Choong, Jeffrey S Glenn, Lisa E. Gralinski, Timothy P. Sheahan, Ralph S. Baric
Coronaviruses are prone to emergence into new host species most recently evidenced by SARS- CoV-2, the causative agent of the COVID-19 pandemic. Small animal models that recapitulate SARS-CoV-2 disease are desperately needed to rapidly evaluate medical countermeasures (MCMs). SARS-CoV-2 cannot infect wildtype laboratory mice due to inefficient interactions between the viral spike (S) protein and the murine ortholog of the human receptor, ACE2. We used reverse genetics to remodel the S and mACE2 binding interface resulting in a recombinant virus (SARS-CoV-2 MA) that could utilize mACE2 for entry. SARS-CoV-2 MA replicated in both the upper and lower airways of both young adult and aged BALB/c mice. Importantly, disease was more severe in aged mice, and showed more clinically relevant phenotypes than those seen in hACE2 transgenic mice. We then demonstrated the utility of this model through vaccine challenge studies in immune competent mice with native expression of mACE2. Lastly, we show that clinical candidate interferon (IFN) lambda-1a can potently inhibit SARS-CoV-2 replication in primary human airway epithelial cells in vitro, and both prophylactic and therapeutic administration diminished replication in mice. Our mouse-adapted SARS-CoV-2 model demonstrates age-related disease pathogenesis and supports the clinical use of IFN lambda-1a treatment in human COVID-19 infections. ### Competing Interest Statement M.D.B and I.C.C. are employees, and J.S.G is the founder and a board member, of Eiger BioPharmaceuticals, Inc., which produces peg-IFN-λ1.
1,748 downloads microbiology
Nora Schmidt, Caleb A. Lareau, Hasmik Keshishian, Randy Melanson, Matthias Zimmer, Luisa Kirschner, Jens Ade, Simone Werner, Neva Caliskan, Eric S Lander, Jörg Vogel, Steven A. Carr, Jochen Bodem, Mathias Munschauer
SARS-CoV-2 infections pose a global threat to human health and an unprecedented research challenge. Among the most urgent tasks is obtaining a detailed understanding of the molecular interactions that facilitate viral replication or contribute to host defense mechanisms in infected cells. While SARS-CoV-2 co-opts cellular factors for viral translation and genome replication, a comprehensive map of the host cell proteome in direct contact with viral RNA has not been elucidated. Here, we use RNA antisense purification and mass spectrometry (RAP-MS) to obtain an unbiased and quantitative picture of the human proteome that directly binds the SARS-CoV-2 RNA in infected human cells. We discover known host factors required for coronavirus replication, regulators of RNA metabolism and host defense pathways, along with dozens of potential drug targets among direct SARS-CoV-2 binders. We further integrate the SARS-CoV-2 RNA interactome with proteome dynamics induced by viral infection, linking interactome proteins to the emerging biology of SARS-CoV-2 infections. Validating RAP-MS, we show that CNBP, a regulator of proinflammatory cytokines, directly engages the SARS-CoV-2 RNA. Supporting the functional relevance of identified interactors, we show that the interferon-induced protein RYDEN suppresses SARS-CoV-2 ribosomal frameshifting and demonstrate that inhibition of SARS-CoV-2-bound proteins is sufficient to manipulate viral replication. The SARS-CoV-2 RNA interactome provides an unprecedented molecular perspective on SARS-CoV-2 infections and enables the systematic dissection of host dependency factors and host defense strategies, a crucial prerequisite for designing novel therapeutic strategies. ### Competing Interest Statement The authors have declared no competing interest.
1,720 downloads microbiology
Yfat Yahalom-Ronen, Hadas Tamir, Sharon Melamed, Boaz Politi, Ohad Shifman, Hagit Achdout, Einat. B. Vitner, Ofir Israeli, Elad Milrot, Dana Stein, Inbar Cohen-Gihon, Shlomi Lazar, Hila Gutman, Itai Glinert, Lilach Cherry, Yaron Vagima, Shirley Lazar, Shay Weiss, Amir Ben-Shmuel, Roy Avraham, Reut Puni, Edith Lupu, Elad Bar David, Assa Sittner, Noam Erez, Ran Zichel, Emanuelle Mamroud, Ohad Mazor, Haim Levy, Orly Laskar, Shmuel Yitzhaki, Shmuel C. Shapira, Anat Zvi, Adi Beth-Din, Nir Paran, Tomer Israely
The COVID-19 pandemic caused by SARS-CoV-2 that emerged in December 2019 in China resulted in over 7.8 million infections and over 430,000 deaths worldwide, imposing an urgent need for rapid development of an efficient and cost-effective vaccine, suitable for mass immunization. Here, we generated a replication competent recombinant VSV-ΔG-spike vaccine, in which the glycoprotein of VSV was replaced by the spike protein of the SARS-CoV-2. In vitro characterization of the recombinant VSV-∆G-spike indicated expression and presentation of the spike protein on the viral membrane with antigenic similarity to SARS-CoV-2. A golden Syrian hamster in vivo model for COVID-19 was implemented. We show that vaccination of hamsters with recombinant VSV-ΔG-spike results in rapid and potent induction of neutralizing antibodies against SARS-CoV-2. Importantly, single-dose vaccination was able to protect hamsters against SARS-CoV-2 challenge, as demonstrated by the abrogation of body weight loss of the immunized hamsters compared to unvaccinated hamsters. Furthermore, whereas lungs of infected hamsters displayed extensive tissue damage and high viral titers, immunized hamsters lungs showed only minor lung pathology, and no viral load. Taken together, we suggest recombinant VSV-ΔG-spike as a safe, efficacious and protective vaccine against SARS-CoV-2 infection. ### Competing Interest Statement The authors have declared no competing interest.
1,707 downloads immunology
Yanchun Peng, Alexander J. Mentzer, Guihai Liu, Xuan Yao, Zixi Yin, Danning Dong, Wanwisa Dejnirattisai, Timothy Rostron, Piyada Supasa, Chang Liu, Cesar Lopez-Camacho, Jose Slon-campos, Yuguang Zhao, David I. Stuart, Guido Paeson, Jonathan Grimes, Fred Antson, Oliver W. Bayfield, Dorothy EDP Hawkins, De-Sheng Ker, Lance Turtle, Krishanthi Subramaniam, Paul Thomson, Ping Zhang, Christina Dold, Jeremy Ratcliff, Peter Simmonds, TI de Silva, Paul Sopp, Dannielle Wellington, Ushani Rajapaksa, Yi-Ling Chen, Mariolina Salio, Giorgio Napolitani, Wayne Paes, Persephone Borrow, Benedikt Kessler, Jeremy W Fry, Nikolai F Schwabe, Malcolm G Semple, J. Kenneth Baillie, Shona Moore, Peter JM Openshaw, Azim Ansari, Susanna Dunachie, Ellie Barnes, John Frater, Georgina Kerr, Philip Goulder, Teresa Lockett, Robert Levin, Oxford Immunology Network Covid-19 Response T cell Consortium, Richard J Cornall, Chris Conlon, Paul Klenerman, Andrew McMichael, Gavin Screaton, Juthathip Mongkolsapaya, Julian C. Knight, Graham Ogg, Tao Dong
COVID-19 is an ongoing global crisis in which the development of effective vaccines and therapeutics will depend critically on understanding the natural immunity to the virus, including the role of SARS-CoV-2-specific T cells. We have conducted a study of 42 patients following recovery from COVID-19, including 28 mild and 14 severe cases, comparing their T cell responses to those of 16 control donors. We assessed the immune memory of T cell responses using IFN gamma based assays with overlapping peptides spanning SARS-CoV-2 apart from ORF1. We found the breadth, magnitude and frequency of memory T cell responses from COVID-19 were significantly higher in severe compared to mild COVID-19 cases, and this effect was most marked in response to spike, membrane, and ORF3a proteins. Total and spike-specific T cell responses correlated with the anti-Spike, anti-Receptor Binding Domain (RBD) as well as anti-Nucleoprotein (NP) endpoint antibody titre (p<0.001, <0.001 and =0.002). We identified 39 separate peptides containing CD4+ and/or CD8+ epitopes, which strikingly included six immunodominant epitope clusters targeted by T cells in many donors, including 3 clusters in spike (recognised by 29%, 24%, 18% donors), two in the membrane protein (M, 32%, 47%) and one in the nucleoprotein (Np, 35%). CD8+ responses were further defined for their HLA restriction, including B*4001-restricted T cells showing central memory and effector memory phenotype. In mild cases, higher frequencies of multi-cytokine producing M- and NP-specific CD8+ T cells than spike-specific CD8+ T cells were observed. They furthermore showed a higher ratio of SARS-CoV-2-specific CD8+ to CD4+ T cell responses. Immunodominant epitope clusters and peptides containing T cell epitopes identified in this study will provide critical tools to study the role of virus-specific T cells in control and resolution of SARS-CoV-2 infections. The identification of T cell specificity and functionality associated with milder disease, highlights the potential importance of including non-spike proteins within future COVID-19 vaccine design. ### Competing Interest Statement The authors have declared no competing interest.
1,706 downloads animal behavior and cognition
Scientific datasets are growing rapidly in scale and complexity. Consequently, the task of understanding these data to answer scientific questions increasingly requires the use of compression algorithms that reduce dimensionality by combining correlated features and cluster similar observations to summarize large datasets. Here we introduce a method for both dimension reduction and clustering called VAE-SNE (variational autoencoder stochastic neighbor embedding). Our model combines elements from deep learning, probabilistic inference, and manifold learning to produce interpretable compressed representations while also readily scaling to tens-of-millions of observations. Unlike existing methods, VAE-SNE simultaneously compresses high-dimensional data and automatically learns a distribution of clusters within the data \---| without the need to manually select the number of clusters. This naturally creates a multi-scale representation, which makes it straightforward to generate coarse-grained descriptions for large subsets of related observations and select specific regions of interest for further analysis. VAE-SNE can also quickly and easily embed new samples, detect outliers, and can be optimized with small batches of data, which makes it possible to compress datasets that are otherwise too large to fit into memory. We evaluate VAE-SNE as a general purpose method for dimensionality reduction by applying it to multiple real-world datasets and by comparing its performance with existing methods for dimensionality reduction. We find that VAE-SNE produces high-quality compressed representations with results that are on par with existing nonlinear dimensionality reduction algorithms. As a practical example, we demonstrate how the cluster distribution learned by VAE-SNE can be used for unsupervised action recognition to detect and classify repeated motifs of stereotyped behavior in high-dimensional timeseries data. Finally, we also introduce variants of VAE-SNE for embedding data in polar (spherical) coordinates and for embedding image data from raw pixels. VAE-SNE is a robust, feature-rich, and scalable method with broad applicability to a range of datasets in the life sciences and beyond. ### Competing Interest Statement The authors have declared no competing interest.
1,698 downloads microbiology
COVID-19 is undoubtedly the most impactful viral disease of the current century, afflicting millions worldwide. As yet, there is not an approved vaccine, as well as limited options from existing drugs for treating this disease. We hypothesized that combining drugs with independent mechanisms of action could result in synergy against SARS-CoV-2. Using in silico approaches, we prioritized 73 combinations of 32 drugs with potential activity against SARS-CoV-2 and then tested them in vitro. Overall, we identified 16 synergistic and 8 antagonistic combinations, 4 of which were both synergistic and antagonistic in a dose-dependent manner. Among the 16 synergistic cases, combinations of nitazoxanide with three other compounds (remdesivir, amodiaquine and umifenovir) were the most notable, all exhibiting significant synergy against SARS-CoV-2. The combination of nitazoxanide, an FDA-approved drug, and remdesivir, FDA emergency use authorization for the treatment of COVID-19, demonstrate a strong synergistic interaction. Notably, the combination of remdesivir and hydroxychloroquine demonstrated strong antagonism. Overall, our results emphasize the importance of both drug repurposing and preclinical testing of drug combinations for potential therapeutic use against SARS-CoV-2 infections. ### Competing Interest Statement The authors have declared no competing interest.
1,683 downloads immunology
Michael F Cuccarese, Berton A. Earnshaw, Katie Heiser, Ben Fogelson, Chadwick T Davis, Peter F McLean, Hannah B. Gordon, Kathleen-Rose Skelly, Fiona L Weathersby, Vlad Rodic, Ian K Quigley, Elissa D. Pastuzyn, Brandon M Mendivil, Nathan H. Lazar, Carl A Brooks, Joseph Carpenter, Brandon L Probst, Pamela Jacobson, Seth W Glazier, Jes Ford, James D Jensen, Nicholas D Campbell, Michael A Statnick, Adeline S. Low, Kirk R Thomas, Anne E. Carpenter, Sharath S Hegde, Ronald W. Alfa, Mason L. Victors, Imran S Haque, Yolanda T. Chong, Christopher C Gibson
Development of accurate disease models and discovery of immune-modulating drugs is challenged by the immune system’s highly interconnected and context-dependent nature. Here we apply deep-learning-driven analysis of cellular morphology to develop a scalable “phenomics” platform and demonstrate its ability to identify dose-dependent, high-dimensional relationships among and between immunomodulators, toxins, pathogens, genetic perturbations, and small and large molecules at scale. High-throughput screening on this platform demonstrates rapid identification and triage of hits for TGF-β- and TNF-α-driven phenotypes. We deploy the platform to develop phenotypic models of active SARS-CoV-2 infection and of COVID-19-associated cytokine storm, surfacing compounds with demonstrated clinical benefit and identifying several new candidates for drug repurposing. The presented library of images, deep learning features, and compound screening data from immune profiling and COVID-19 screens serves as a deep resource for immune biology and cellular-model drug discovery with immediate impact on the COVID-19 pandemic. ### Competing Interest Statement We declare competing interests. All authors were employees of or advisors to Recursion during the course of this work. All authors have real or potential ownership interest in Recursion.
1,680 downloads microbiology
Background: The ongoing outbreak of COVID-19 has spread rapidly and sparked global concern. While the transmission of SARS-CoV-2 through human respiratory droplets and contact with infected persons is clear, the aerosol transmission of SARS-CoV-2 has been little studied. Methods: Thirty-five aerosol samples of three different types (total suspended particle, size segregated and deposition aerosol) were collected in Patient Areas (PAA) and Medical Staff Areas (MSA) of Renmin Hospital of Wuhan University (Renmin) and Wuchang Fangcang Field Hospital (Fangcang), and Public Areas (PUA) in Wuhan, China during COVID-19 outbreak. A robust droplet digital polymerase chain reaction (ddPCR) method was employed to quantitate the viral SARS-CoV-2 RNA genome and determine aerosol RNA concentration. Results: The ICU, CCU and general patient rooms inside Renmin, patient hall inside Fangcang had undetectable or low airborne SARS-CoV-2 concentration but deposition samples inside ICU and air sample in Fangcang patient toilet tested positive. The airborne SARS-CoV-2 in Fangcang MSA had bimodal distribution with higher concentration than those in Renmin during the outbreak but turned negative after patients number reduced and rigorous sanitization implemented. PUA had undetectable airborne SARS-CoV-2 concentration but obviously increased with accumulating crowd flow. Conclusions: Room ventilation, open space, proper use and disinfection of toilet can effectively limit aerosol transmission of SARS-CoV-2. Gathering of crowds with asymptomatic carriers is a potential source of airborne SARS-CoV-2. The virus aerosol deposition on protective apparel or floor surface and their subsequent resuspension is a potential transmission pathway and effective sanitization is critical in minimizing aerosol transmission of SARS-CoV-2.
1,663 downloads genomics
Cell differentiation and function are regulated across multiple layers of gene regulation, including the modulation of gene expression by changes in chromatin accessibility. However, differentiation is an asynchronous process precluding a temporal understanding of the regulatory events leading to cell fate commitment. Here, we developed SHARE-seq, a highly scalable approach for measurement of chromatin accessibility and gene expression within the same single cell. Using 34,774 joint profiles from mouse skin, we develop a computational strategy to identify cis-regulatory interactions and define Domains of Regulatory Chromatin (DORCs), which significantly overlap with super-enhancers. We show that during lineage commitment, chromatin accessibility at DORCs precedes gene expression, suggesting changes in chromatin accessibility may prime cells for lineage commitment. We therefore develop a computational strategy (chromatin potential) to quantify chromatin lineage-priming and predict cell fate outcomes. Together, SHARE-seq provides an extensible platform to study regulatory circuitry across diverse cells within tissues. ### Competing Interest Statement A.R. is a founder of and equity holder in Celsius therapeutics, an equity holder in Immunitas, and an SAB member of ThermoFisher Scientific, Syros Pharmaceutical, Asimov, and Neogene Therapeutics. J.D.B. holds patents related to ATAC-seq and is an SAB member of Camp4. J.D.B., A.R., S.M. submitted a provisional patent application based on this work.
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