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Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 83,819 bioRxiv papers from 361,076 authors.

Most downloaded bioRxiv papers, since beginning of last month

82,003 results found. For more information, click each entry to expand.

301: Artificial intelligence predicts the immunogenic landscape of SARS-CoV-2: toward universal blueprints for vaccine designs
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Posted to bioRxiv 21 Apr 2020

Artificial intelligence predicts the immunogenic landscape of SARS-CoV-2: toward universal blueprints for vaccine designs
1,482 downloads bioinformatics

Brandon Malone, Boris Simovski, Clément Moliné, Jun Cheng, Marius Gheorghe, Hugues Fontenelle, Ioannis Vardaxis, Simen Tennøe, Jenny-Ann Malmberg, Richard Stratford, Trevor Clancy

The global population is at present suffering from a pandemic of Coronavirus disease 2019 (COVID-19), caused by the novel coronavirus Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The goals of this study were to use artificial intelligence (AI) to predict blueprints for designing universal vaccines against SARS-CoV-2, that contain a sufficiently broad repertoire of T-cell epitopes capable of providing coverage and protection across the global population. To help achieve these aims, we profiled the entire SARS-CoV-2 proteome across the most frequent 100 HLA-A, HLA-B and HLA-DR alleles in the human population, using host-infected cell surface antigen presentation and immunogenicity predictors from the NEC Immune Profiler suite of tools, and generated comprehensive epitope maps. We then used these epitope maps as input for a Monte Carlo simulation designed to identify statistically significant epitope hotspot regions in the virus that are most likely to be immunogenic across a broad spectrum of HLA types. We then removed epitope hotspots that shared significant homology with proteins in the human proteome to reduce the chance of inducing off-target autoimmune responses. We also analyzed the antigen presentation and immunogenic landscape of all the nonsynonymous mutations across 3400 different sequences of the virus, to identify a trend whereby SARS-COV-2 mutations are predicted to have reduced potential to be presented by host-infected cells, and consequently detected by the host immune system. A sequence conservation analysis then removed epitope hotspots that occurred in less-conserved regions of the viral proteome. Finally, we used a database of the HLA genotypes of approximately 22 000 individuals to develop a digital twin type simulation to model how effective different combinations of hotspots would work in a diverse human population, and used the approach to identify an optimal constellation of epitopes hotspots that could provide maximum coverage in the global population. By combining the antigen presentation to the infected-host cell surface and immunogenicity predictions of the NEC Immune Profiler with a robust Monte Carlo and digital twin simulation, we have managed to profile the entire SARS-CoV-2 proteome and identify a subset of epitope hotspots that could be harnessed in a vaccine formulation to provide a broad coverage across the global population. ### Competing Interest Statement BS, CM, MG, HF, IV, ST, JM, RS and TC are employees of NEC OncoImmunity, a subsidiary of NEC Corporation. BM and JC are employees of NEC Laboratories Europe.

302: rehh 2.0: a reimplementation of the R package rehh to detect positive selection from haplotype structure.
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Posted to bioRxiv 03 Aug 2016

rehh 2.0: a reimplementation of the R package rehh to detect positive selection from haplotype structure.
1,472 downloads evolutionary biology

Mathieu Gautier, Alexander Klassmann, Renaud Vitalis

Identifying genomic regions with unusually high local haplotype homozygosity represents a powerful strategy to characterize candidate genes responding to natural or artificial positive selection. To that end, statistics measuring the extent of haplotype homozygosity within (e.g., EHH, IHS) and between (Rsb or XP-EHH) populations have been proposed in the literature. The rehh package for R was previously developed to facilitate genome-wide scans of selection, based on the analysis of long-range haplotypes. However, its performance wasn't sufficient to cope with the growing size of available data sets. Here we propose a major upgrade of the rehh package, which includes an improved processing of the input files, a faster algorithm to enumerate haplotypes, as well as multi-threading. As illustrated with the analysis of large human haplotype data sets, these improvements decrease the computation time by more than an order of magnitude. This new version of rehh will thus allow performing iHS-, Rsb- or XP-EHH-based scans on large data sets. The package rehh 2.0 is available from the CRAN repository (http://cran.r-project.org/web/packages/rehh/index.html) together with help files and a detailed manual.

303: High-surety isothermal amplification and detection of SARS-CoV-2, including with crude enzymes
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Posted to bioRxiv 14 Apr 2020

High-surety isothermal amplification and detection of SARS-CoV-2, including with crude enzymes
1,471 downloads molecular biology

Sanchita Bhadra, Timothy E Riedel, Simren Lakhotia, Nicholas D Tran, Andrew D. Ellington

Isothermal nucleic acid amplification tests (iNAT), such as loop-mediated isothermal amplification (LAMP), are good alternatives to polymerase chain reaction (PCR)-based amplification assays, especially for point-of-care and low resource use, in part because they can be carried out with relatively simple instrumentation. However, iNATs can generate spurious amplicons, especially in the absence of target sequences, resulting in false positive results. This is especially true if signals are based on non-sequence-specific probes, such as intercalating dyes or pH changes. In addition, pathogens often prove to be moving, evolving targets, and can accumulate mutations that will lead to inefficient primer binding and thus false negative results. Internally redundant assays targeting different regions of the target sequence can help to reduce such false negatives. Here we describe rapid conversion of three previously described SARS-CoV-2 LAMP assays that relied on non-sequence-specific readout into assays that can be visually read using sequence-specific fluorogenic oligonucleotide strand exchange (OSD) probes. We evaluate one-pot operation of both individual and multiplex LAMP-OSD assays and demonstrate detection of SARS-CoV-2 virions in crude human saliva. ### Competing Interest Statement The authors have declared no competing interest.

304: Clinical Knowledge Graph Integrates Proteomics Data into Clinical Decision-Making
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Posted to bioRxiv 10 May 2020

Clinical Knowledge Graph Integrates Proteomics Data into Clinical Decision-Making
1,469 downloads bioinformatics

Alberto Santos, Ana R. Colaço, Annelaura B. Nielsen, Lili Niu, Philipp E Geyer, Fabian Coscia, Nicolai J. Wewer Albrechtsen, Filip Mundt, Lars Juhl Jensen, Matthias Mann

The promise of precision medicine is to deliver personalized treatment based on the unique physiology of each patient. This concept was fueled by the genomic revolution, but it is now evident that integrating other types of omics data, like proteomics, into the clinical decision-making process will be essential to accomplish precision medicine goals. However, quantity and diversity of biomedical data, and the spread of clinically relevant knowledge across myriad biomedical databases and publications makes this exceptionally difficult. To address this, we developed the Clinical Knowledge Graph (CKG), an open source platform currently comprised of more than 16 million nodes and 220 million relationships to represent relevant experimental data, public databases and the literature. The CKG also incorporates the latest statistical and machine learning algorithms, drastically accelerating analysis and interpretation of typical proteomics workflows. We use several biomarker studies to illustrate how the CKG may support, enrich and accelerate clinical decision-making. ### Competing Interest Statement The authors have declared no competing interest.

305: Mechanistic modeling of the SARS-CoV-2 disease map
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Posted to bioRxiv 12 Apr 2020

Mechanistic modeling of the SARS-CoV-2 disease map
1,469 downloads systems biology

Kinza Rian, Marina Esteban-Medina, Marta R. Hidalgo, Cankut Çubuk, Matias M. Falco, Carlos Loucera, Devrim Gunyel, Marek Ostaszewski, María Peña-Chilet, Joaquín Dopazo

Here we present a web interface that implements a comprehensive mechanistic model of the SARS-CoV-2 disease map in which the detailed activity of the human signaling circuits related to the viral infection and the different antiviral responses, including immune and inflammatory activities, can be inferred from gene expression experiments. Moreover, given to the mechanistic properties of the model, the effect of potential interventions, such as knock-downs, over-expression or drug effects (currently the system models the effect of more than 8000 DrugBank drugs) can be studied in specific conditions. This tool, with the holistic, systems biology approach to the understanding of the complexities of the viral infection process, will become an important asset in the search for efficient antiviral treatments. The tool is freely available at: http://hipathia.babelomics.org/covid19/. ### Competing Interest Statement The authors have declared no competing interest.

306: A Single-Objective Light-Sheet Microscope with 200 nm-Scale Resolution
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Posted to bioRxiv 08 Apr 2020

A Single-Objective Light-Sheet Microscope with 200 nm-Scale Resolution
1,468 downloads biophysics

Etai Sapoznik, Bo-Jui Chang, Robert J. Ju, Erik S Welf, David Broadbent, Alexandre F. Carisey, Samantha J. Stehbens, Kyung-min Lee, Arnaldo Marín, Ariella B. Hanker, Jens C. Schmidt, Carlos L. Arteaga, Bin Yang, Rory Kruithoff, Doug P. Shepherd, Alfred Millett-Sikking, Andrew G. York, Kevin M. Dean, Reto Fiolka

We present a single-objective light-sheet microscope, also known as an oblique-plane microscope, that uses a bespoke glass-tipped tertiary objective and improves the resolution, field of view, usability, and stability over previous variants. Owing to its high numerical aperture optics, this microscope achieves the highest lateral resolution in light-sheet fluorescence microscopy, and its axial resolution is similar to that of Lattice Light-Sheet Microscopy. Given this performance, we demonstrate high-resolution imaging of clathrin-mediated endocytosis, vimentin, the endoplasmic reticulum, membrane dynamics, and natural killer cell-mediated cell death. Furthermore, we image biological phenomena that would be otherwise challenging or impossible to perform in a traditional light-sheet microscope geometry, including cell migration through a confined space within a microfluidic device, photoactivation of PI3K, and diffusion of cytoplasmic rheological tracers at a volumetric rate of 14 Hz. ### Competing Interest Statement

307: A virus that has gone viral: Amino acid mutation in S protein of Indian isolate of Coronavirus COVID-19 might impact receptor binding and thus infectivity
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Posted to bioRxiv 11 Apr 2020

A virus that has gone viral: Amino acid mutation in S protein of Indian isolate of Coronavirus COVID-19 might impact receptor binding and thus infectivity
1,466 downloads microbiology

Priyanka Saha, Arup Kumar Banerjee, Prem Prakash Tripathi, Amit Kumar Srivastava, Upasana Ray

Since 2002, beta coronaviruses (CoV) have caused three zoonotic outbreaks, SARS-CoV in 2002, MERS-CoV in 2012, and the recent outbreak of SARS-CoV-2 late in 2019 (also named as COVID-19 or novel coronavirus 2019 or nCoV2019. Spike(S) protein, one of the structural proteins of this virus plays key role in receptor (ACE2) binding and thus virus entry. Thus, this protein has attracted scientists for detailed study and therapeutic targeting. As the 2019 novel coronavirus takes its course throughout the world, more and more sequence analyses are been done and genome sequences getting deposited in various databases. From India two clinical isolates have been sequenced and the full genome deposited in GenBank. We have performed sequence analyses of the spike protein of the Indian isolates and compared with that of the Wuhan, China (where the outbreak was first reported). While all the sequences of Wuhan isolates are identical, we found point mutations in the Indian isolates. Out of the two isolates one was found to harbour a mutation in its Receptor binding domain (RBD) at position 407. At this site arginine (a positively charged amino acid) was replaced by isoleucine (a hydrophobic amino acid that is also a C-beta branched amino acid). This mutation has been seen to change the secondary structure of the protein at that region and this can potentially alter receptor ding of the virus. Although this finding needs further validation and more sequencing, the information might be useful in rational drug designing and vaccine engineering. ### Competing Interest Statement

308: A mathematical model for simulating the transmission of Wuhan novel Coronavirus
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Posted to bioRxiv 19 Jan 2020

A mathematical model for simulating the transmission of Wuhan novel Coronavirus
1,464 downloads systems biology

Tianmu Chen, Jia Rui, Qiupeng Wang, Zeyu Zhao, Jing-An Cui, Ling Yin

As reported by the World Health Organization, a novel coronavirus (2019-nCoV) was identified as the causative virus of Wuhan pneumonia of unknown etiology by Chinese authorities on 7 January, 2020. In this study, we developed a Bats-Hosts-Reservoir-People transmission network model for simulating the potential transmission from the infection source (probable be bats) to the human infection. Since the Bats-Hosts-Reservoir network was hard to explore clearly and public concerns were focusing on the transmission from a seafood market (reservoir) to people, we simplified the model as Reservoir-People transmission network model. The basic reproduction number (R0) was calculated from the RP model to assess the transmissibility of the 2019-nCoV.

309: SARS-CoV-2 receptor and entry genes are expressed by sustentacular cells in the human olfactory neuroepithelium
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Posted to bioRxiv 02 Apr 2020

SARS-CoV-2 receptor and entry genes are expressed by sustentacular cells in the human olfactory neuroepithelium
1,462 downloads neuroscience

Leon Fodoulian, Joel Tuberosa, Daniel Rossier, Basile N. Landis, Alan Carleton, Ivan Rodriguez

The recent emergence of the pathogenic SARS-CoV-2 initiated a worldwide health crisis. The entry of the virus into cells is mediated by the binding of the viral Spike protein to the angiotensin-converting enzyme-2 (ACE2), followed by its priming by the TMPRSS2 serine protease, both present on the cellular membrane of the target cells. In the respiratory tract, these targets are ciliated cells. Interestingly, various reports indicate an association between SARS-CoV-2 infection and anosmia, suggesting an alteration not restricted to the respiratory tissue, but that might also include the olfactory sensory epithelium. We explored this possibility by generating RNA-seq libraries from human neuroepithelium, in which we found significant expression of ACE2 and TMPRSS2. To determine whether specific cell types of this chemosensory tissue may coexpress both of the virus entry genes, we analyzed a scRNA-seq dataset. We determined that sustentacular cells, which are in direct contact with the external world and maintain the integrity of olfactory sensory neurons, represents a prime candidate for SARS-CoV-2 infection via the nose, and possibly for SARS-CoV-2-induced anosmia.

310: Designing a multi-epitope peptide-based vaccine against SARS-CoV-2
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Posted to bioRxiv 16 Apr 2020

Designing a multi-epitope peptide-based vaccine against SARS-CoV-2
1,461 downloads bioinformatics

Abhishek Singh, Mukesh Thakur, Lalit Kumar Sharma, Kailash Chandra

COVID-19 pandemic has resulted so far 14,395,16 confirmed cases with 85,711 deaths from the 212 countries, or territories. Due to multifacet issues and challenges in implementation of the safety & preventive measures, inconsistent coordination between societies-governments and most importanly lack of specific vaccine to SARS-CoV-2, the spread of Wuhan originated virus is still uprising after taking a heavy toll on human life. In the present study, we mapped several immunogenic epitopes (B-cell, T-cell, and IFN-gamma) over the entire structural proteins of SARS-CoV-2 and by applying various computational and immunoinformatics approaches, we designed a multi-epitope peptide based vaccine that predicted high immunogenic response in the largest proportion of world's human population. To ensure high expression of the recombinant vaccine in E. coli, codon optimization and in-silico cloning were also carried out. The designed vaccine with high molecular affinity to TLR3 and TLR4, was found capable to initiate effective innate and adaptive immune response. The immune simulation also suggested uprising high levels of both B-cell and T-cell mediated immunity which on subsequent exposure cleared antigen from the system. The proposed vaccine found promising by yielding desired results and hence, should be tested by practical experimentations for its functioning and efficacy to neutralize SARS-CoV-2. ### Competing Interest Statement The authors have declared no competing interest.

311: Novel and potent inhibitors targeting DHODH, a rate-limiting enzyme in de novo pyrimidine biosynthesis, are broad-spectrum antiviral against RNA viruses including newly emerged coronavirus SARS-CoV-2
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Posted to bioRxiv 12 Mar 2020

Novel and potent inhibitors targeting DHODH, a rate-limiting enzyme in de novo pyrimidine biosynthesis, are broad-spectrum antiviral against RNA viruses including newly emerged coronavirus SARS-CoV-2
1,460 downloads microbiology

Rui Xiong, Leike Zhang, Shiliang Li, Yuan Sun, Minyi Ding, Yong Wang, Yongliang Zhao, Yan Wu, Weijuan Shang, Xiaming Jiang, Jiwei Shan, Zihao Shen, Yi Tong, Liuxin Xu, Chen Yu, Yingle Liu, Gang Zou, Dimitri Lavillete, Zhenjiang Zhao, Rui Wang, Lili Zhu, Gengfu Xiao, Ke Lan, Honglin Li, Ke Xu

Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of coronavirus SARS-CoV-2. Existing direct-acting antiviral (DAA) drugs cannot be applied immediately to new viruses because of virus-specificity, and the development of new DAA drugs from the beginning is not timely for outbreaks. Thus, host-targeting antiviral (HTA) drugs have many advantages to fight against a broad spectrum of viruses, by blocking the viral replication and overcoming the potential viral mutagenesis simultaneously. Herein, we identified two potent inhibitors of DHODH, S312 and S416, with favorable drug-like and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus (H1N1, H3N2, H9N2), Zika virus, Ebola virus, and particularly against the recent novel coronavirus SARS-CoV-2. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knocking-out cells. We also proposed the drug combination of DAA and HTA was a promising strategy for anti-virus treatment and proved that S312 showed more advantageous than Oseltamivir to treat advanced influenza diseases in severely infected animals. Notably, S416 is reported to be the most potent inhibitor with an EC50 of 17nM and SI value >5882 in SARS-CoV-2-infected cells so far. This work demonstrates that both our self-designed candidates and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-repression may have clinical potentials not only to influenza but also to COVID-19 circulating worldwide, no matter such viruses mutate or not.

312: Continuous lineage recording reveals rapid, multidirectional metastasis in a lung cancer xenograft model in mouse
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Posted to bioRxiv 17 Apr 2020

Continuous lineage recording reveals rapid, multidirectional metastasis in a lung cancer xenograft model in mouse
1,460 downloads cancer biology

Jeffrey J Quinn, Matthew G Jones, Ross A. Okimoto, Michelle M. Chan, Nir Yosef, Trever G. Bivona, Jonathan S. Weissman

Consequential events in cancer progression are typically rare and occur in the unobserved past. Detailed cell phylogenies can capture the history and chronology of such transient events - including metastasis. Here, we applied our Cas9-based lineage tracer to study metastatic progression in a lung cancer xenograft mouse model, revealing the underlying rates, routes, and patterns of metastasis. We report deeply resolved phylogenies for tens of thousands of metastatically disseminated cancer cells. We observe surprisingly diverse metastatic phenotypes, ranging from metastasis-incompetent to highly aggressive populations, and these differences are associated with characteristic changes in transcriptional state, including differential expression of metastasis-related genes like IFI27 and ID3. We further show that metastases transit via tissue routes that are diverse, complex, and multidirectional, and identify examples of reseeding, seeding cascades, and parallel seeding topologies. More broadly, we demonstrate the power of next-generation lineage tracers to record cancer evolution at high resolution and vast scale. ### Competing Interest Statement J.S.W. is an advisor and/or has equity in KSQ Therapeutics, Maze Therapeutics, Amgen, Tenaya, and 5 AM Ventures. T.G.B. is an advisor to Novartis, Astrazeneca, Revolution Medicines, Array, Springworks, Strategia, Relay, Jazz, Rain and receives research funding from Novartis and Revolution Medicines.

313: A Cryptic Site of Vulnerability on the Receptor Binding Domain of the SARS-CoV-2 Spike Glycoprotein
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Posted to bioRxiv 17 Mar 2020

A Cryptic Site of Vulnerability on the Receptor Binding Domain of the SARS-CoV-2 Spike Glycoprotein
1,457 downloads immunology

M. Gordon Joyce, Rajeshwer S Sankhala, Wei-Hung Chen, Misook Choe, Hongjun Bai, Agnes Hajduczki, Lianying Yan, Spencer L Sterling, Caroline E. Peterson, Ethan C Green, Clayton Smith, Natalia de Val, Mihret Amare, Paul Scott, Eric D Laing, Christopher C Broder, Morgane Rolland, Nelson L. Michael, Kayvon Modjarrad

SARS-CoV-2 is a zoonotic virus that has caused a pandemic of severe respiratory disease—COVID-19—within several months of its initial identification. Comparable to the first SARS-CoV, this coronaviruses surface Spike (S) glycoprotein mediates cell entry via the human ACE-2 receptor, and, thus, is the principal target for the development of vaccines and immunotherapeutics. Molecular information on the SARS-CoV-2 S glycoprotein remains limited. Here we report the crystal structure of the SARS-CoV-2 S receptor-binding-domain (RBD) at a the highest resolution to date, of 1.95 Å. We identified a set of SARS-reactive monoclonal antibodies with cross-reactivity to SARS-CoV-2 RBD and other betacoronavirus S glycoproteins. One of these antibodies, CR3022, was previously shown to synergize with antibodies that target the ACE-2 binding site on the SARS-CoV RBD and reduce viral escape capacity. We determined the structure of CR3022, in complex with the SARS-CoV-2 RBD, and defined a broadly reactive epitope that is highly conserved across betacoronaviruses. This epitope is inaccessible in the closed prefusion S structure, but is accessible in open conformations. This first-ever resolution of a human antibody in complex with SARS-CoV-2 and the broad reactivity of this set of antibodies to a conserved betacoronavirus epitope will allow antigenic assessment of vaccine candidates, and provide a framework for accelerated vaccine, immunotherapeutic and diagnostic strategies against SARS-CoV-2 and related betacoronaviruses.

314: Muscle strength, size and composition following 12 months of gender-affirming treatment in transgender individuals: retained advantage for the transwomen
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Posted to bioRxiv 26 Sep 2019

Muscle strength, size and composition following 12 months of gender-affirming treatment in transgender individuals: retained advantage for the transwomen
1,454 downloads physiology

A Wiik, TR Lundberg, E Rullman, DP Andersson, M Holmberg, M Mandić, TB Brismar, O Dahlqvist Leinhard, S Chanpen, J Flanagan, S Arver, T Gustafsson

Objectives: This study explored the effects of gender-affirming treatment, which includes inhibition of endogenous sex hormones and replacement with cross-sex hormones, on muscle function, size and composition in 11 transwomen (TW) and 12 transmen (TM). Methods: Isokinetic knee extensor and flexor muscle strength was assessed at baseline (T00), 4 weeks after gonadal suppression of endogenous hormones but before hormone replacement (T0), and 3 (T3) and 11 (T12) months after hormone replacement. In addition, at T00 and T12, we assessed lower-limb muscle volume using MRI, and cross-sectional area (CSA) and radiological density using CT. Results: Thigh muscle volume increased (15%) in TM, which was paralleled by increased quadriceps CSA (15%) and radiological density (6%). In TW, the corresponding parameters decreased by -5% (muscle volume) and -4% (CSA), while density remained unaltered. The TM increased strength over the assessment period, while the TW generally maintained or slightly increased in strength. Baseline muscle volume correlated highly with strength (R>0.75), yet the relative change in muscle volume and strength correlated only moderately (R=0.65 in TW and R=0.32 in TM). The absolute levels of muscle volume and knee extension strength after the intervention still favored the TW. Conclusion: Cross-sex hormone treatment markedly affects muscle strength, size and composition in transgender individuals. Despite the robust increases in muscle mass and strength in TM, the TW were still stronger and had more muscle mass following 12 months of treatment. These findings add new knowledge that could be relevant when evaluating transwomen's eligibility to compete in the women's category of athletic competitions.

315: Population genomics insights into the recent evolution of SARS-CoV-2
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Posted to bioRxiv 23 Apr 2020

Population genomics insights into the recent evolution of SARS-CoV-2
1,447 downloads evolutionary biology

Maria Vasilarou, Nikolaos Alachiotis, Joanna Garefalaki, Apostolos Beloukas, Pavlos Pavlidis

The current coronavirus disease 2019 (COVID-19) pandemic is caused by the SARS-CoV-2 virus and is still spreading rapidly worldwide. Full-genome-sequence computational analysis of the SARS-CoV-2 genome will allow us to understand the recent evolutionary events and adaptability mechanisms more accurately, as there is still neither effective therapeutic nor prophylactic strategy. In this study, we used population genetics analysis to infer the mutation rate and plausible recombination events that may have contributed to the evolution of the SARS-CoV-2 virus. Furthermore, we localized targets of recent and strong positive selection. The genomic regions that appear to be under positive selection are largely co-localized with regions in which recombination from non-human hosts appeared to have taken place in the past. Our results suggest that the pangolin coronavirus genome may have contributed to the SARS-CoV-2 genome by recombination with the bat coronavirus genome. However, we find evidence for additional recombination events that involve coronavirus genomes from other hosts, i.e., Hedgehog and Sparrow. Even though recombination events within human hosts cannot be directly assessed, due to the high similarity of SARS-CoV-2 genomes, we infer that recombinations may have recently occurred within human hosts using a linkage disequilibrium analysis. In addition, we employed an Approximate Bayesian Computation approach to estimate the parameters of a demographic scenario involving an exponential growth of the size of the SARS-CoV-2 populations that have infected European, Asian and Northern American cohorts, and we demonstrated that a rapid exponential growth in population size can support the observed polymorphism patterns in SARS-CoV-2 genomes. ### Competing Interest Statement The authors have declared no competing interest.

316: Rapid community-driven development of a SARS-CoV-2 tissue simulator
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Posted to bioRxiv 05 Apr 2020

Rapid community-driven development of a SARS-CoV-2 tissue simulator
1,446 downloads systems biology

Yafei Wang, Gary An, Andrew Becker, Chase Cockrell, Nicholson Collier, Morgan Craig, Courtney L. Davis, James Faeder, Ashlee N. Ford Versypt, Juliano F. Gianlupi, James A. Glazier, Randy Heiland, Thomas Hillen, Mohammad Aminul Islam, Adrianne Jenner, Bing Liu, Penelope A Morel, Aarthi Narayanan, Jonathan Ozik, P. Rangamani, Jason Edward Shoemaker, Amber M. Smith, Paul Macklin

The 2019 novel coronavirus, SARS-CoV-2, is an emerging pathogen of critical significance to international public health. Knowledge of the interplay between molecular-scale virus-receptor interactions, single-cell viral replication, intracellular-scale viral transport, and emergent tissue-scale viral propagation is limited. Moreover, little is known about immune system-virus-tissue interactions and how these can result in low-level (asymptomatic) infections in some cases and acute respiratory distress syndrome (ARDS) in others, particularly with respect to presentation in different age groups or pre-existing inflammatory risk factors like diabetes. Given the nonlinear interactions within and among each of these processes, multiscale simulation models can shed light on the emergent dynamics that lead to divergent outcomes, identify actionable "choke points" for pharmacologic inter-actions, screen potential therapies, and identify potential biomarkers that differentiate patient outcomes. Given the complexity of the problem and the acute need for an actionable model to guide therapy discovery and optimization, we introduce and iteratively refine a prototype of a multiscale model of SARS-CoV-2 dynamics in lung tissue. The first prototype model was built and shared internationally as open source code and an online interactive model in under 12 hours, and community domain expertise is driving rapid refinements with a two-to-four week release cycle. In a sustained community effort, this consortium effort is integrating data and expertise across virology, immunology, mathematical biology, quantitative systems physiology, cloud and high performance computing, and other domains to accelerate our response to this critical threat to international health. ### Competing Interest Statement The authors have declared no competing interest.

317: Structural basis of RNA recognition by the SARS-CoV-2 nucleocapsid phosphoprotein
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Posted to bioRxiv 05 Apr 2020

Structural basis of RNA recognition by the SARS-CoV-2 nucleocapsid phosphoprotein
1,434 downloads biochemistry

Dhurvas Chandrasekaran Dinesh, Dominika Chalupska, Jan Silhan, Václav Veverka, Evzen Boura

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the Coronavirus disease 2019 (COVID-19) which is currently negatively affecting the population and disrupting the global economy. SARS-CoV-2 belongs to the +RNA virus family that utilize single-stranded positive-sense RNA molecules as genomes. SARS-CoV-2, like other coronaviruses, has an unusually large genome for a +RNA virus that encodes four structural proteins - the matrix (M), small envelope (E), spike (S) and nucleocapsid phosphoprotein (N) - and sixteen nonstructural proteins (nsp1-16) that together ensure replication of the virus in the host cell. The nucleocapsid phosphoprotein N is essential for linking the viral genome to the viral membrane. Its N-terminal RNA binding domain (N-NTD) captures the RNA genome while the C-terminal domain anchors the ribonucleoprotein complex to the viral membrane via its interaction with the M protein. Here, we characterized the structure of the N-NTD and its interaction with RNA using NMR spectroscopy. We observed a positively charged canyon on the surface of the N-NTD lined with arginine residues suggesting a putative RNA binding site. Next, we performed an NMR titration experiment using an RNA duplex. The observed changes in positions of signals in the N-NTD NMR spectra allowed us to construct a model of the N-NTD in complex with RNA.

318: A scientometric overview of CORD-19
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Posted to bioRxiv 20 Apr 2020

A scientometric overview of CORD-19
1,434 downloads scientific communication and education

Giovanni Colavizza, Rodrigo Costas, Vincent A. Traag, Nees Jan van Eck, Thed van Leeuwen, Ludo Waltman

As the COVID-19 pandemic unfolds, researchers from all disciplines are coming together and contributing their expertise. CORD-19, a dataset of COVID-19 and coronavirus publications, has recently been published alongside calls to help mine the information it contains, and to create tools to search it more effectively. Here, we focus on the delineation of the publications included in CORD-19, and analyse this delineation from a scientometric perspective. We find that CORD-19 contains research not only on COVID-19 and coronaviruses, but on viruses in general. Publications from CORD-19 mostly focus on a few, well-defined areas, including: coronaviruses (primarily SARS, MERS, COVID-19); public health and viral epidemics; the molecular biology of viruses; influenza and other families of viruses; immunology and antivirals; methodology (testing, diagnosing, clinical trials). CORD-19 publications published in 2020, especially focused on topics of pressing relevance (spread, infection, efficacy of counter-measures), are disproportionately popular on social media. While we fully endorse the initiative that led to CORD-19, we also advise to consider its relatively broad content critically. ### Competing Interest Statement The authors have declared no competing interest.

319: Development of Reverse Transcription Loop-mediated Isothermal Amplification (RT-LAMP) Assays Targeting SARS-CoV-2
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Posted to bioRxiv 12 Mar 2020

Development of Reverse Transcription Loop-mediated Isothermal Amplification (RT-LAMP) Assays Targeting SARS-CoV-2
1,426 downloads microbiology

Gun-Soo Park, Keunbon Ku, Seung-Hwa Baek, Seong Jun Kim, Seung Il Kim, Bum-Tae Kim, Jin-Soo Maeng

Epidemics of Coronavirus Disease 2019 (COVID-19) now have more than 100,000 confirmed cases worldwide. Diagnosis of COVID-19 is currently performed by RT-qPCR methods, but the capacity of RT-qPCR methods is limited by its requirement of high-level facilities and instruments. Here, we developed and evaluated RT-LAMP assays to detect genomic RNA of SARS-CoV-2, the causative virus of COVID-19. RT-LAMP assays in this study can detect as low as 100 copies of SARS-CoV-2 RNA. Cross-reactivity of RT-LAMP assays to other human Coronaviruses was not observed. We also adapted a colorimetric detection method for our RT-LAMP assay so that the tests potentially performed in higher throughput.

320: Epitope-based chimeric peptide vaccine design against S, M and E proteins of SARS-CoV-2 etiologic agent of global pandemic COVID-19: an in silico approach
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Posted to bioRxiv 31 Mar 2020

Epitope-based chimeric peptide vaccine design against S, M and E proteins of SARS-CoV-2 etiologic agent of global pandemic COVID-19: an in silico approach
1,425 downloads microbiology

M. Shaminur Rahman, M. Nazmul Hoque, M. Rafiul Islam, Salma Akter, A. S. M. Rubayet-Ul-Alam, Mohammad Anwar Siddique, Otun Saha, Md. Mizanur Rahaman, Munawar Sultana, M. Anwar Hossain

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the ongoing pandemic of coronavirus disease 2019 (COVID-19), a public health emergency of international concern declared by the World Health Organization (WHO). An immuno-informatics approach along with comparative genomic was applied to design a multi-epitope-based peptide vaccine against SARS-CoV-2 combining the antigenic epitopes of the S, M and E proteins. The tertiary structure was predicted, refined and validated using advanced bioinformatics tools. The candidate vaccine showed an average of ≥ 90.0% world population coverage for different ethnic groups. Molecular docking of the chimeric vaccine peptide with the immune receptors (TLR3 and TLR4) predicted efficient binding. Immune simulation predicted significant primary immune response with increased IgM and secondary immune response with high levels of both IgG1 and IgG2. It also increased the proliferation of T-helper cells and cytotoxic T-cells along with the increased INF-γ and IL-2 cytokines. The codon optimization and mRNA secondary structure prediction revealed the chimera is suitable for high-level expression and cloning. Overall, the constructed recombinant chimeric vaccine candidate demonstrated significant potential and can be considered for clinical validation to fight against this global threat, COVID-19.

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