Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 77,873 bioRxiv papers from 337,457 authors.
Most downloaded bioRxiv papers, since beginning of last month
76,080 results found. For more information, click each entry to expand.
2,430 downloads cancer biology
The U.S. National Toxicology Program (NTP) has carried out extensive rodent toxicology and carcinogenesis studies of radiofrequency radiation (RFR) at frequencies and modulations used in the U.S. telecommunications industry. This report presents partial findings from these studies. The occurrences of two tumor types in male Harlan Sprague Dawley rats exposed to RFR, malignant gliomas in the brain and schwannomas of the heart, were considered of particular interest and are the subject of this report. The findings in this report were reviewed by expert peer reviewers selected by the NTP and National Institutes of Health (NIH). These reviews and responses to comments are included as appendices to this report, and revisions to the current document have incorporated and addressed these comments. When the studies are completed, they will undergo additional peer review before publication in full as part of the NTP's Toxicology and Carcinogenesis Technical Reports Series. No portion of this work has been submitted for publication in a scientific journal. Supplemental information in the form of four additional manuscripts has or will soon be submitted for publication. These manuscripts describe in detail the designs and performance of the RFR exposure system, the dosimetry of RFR exposures in rats and mice, the results to a series of pilot studies establishing the ability of the animals to thermoregulate during RFR exposures, and studies of DNA damage. (1) Capstick M, Kuster N, Kuhn S, Berdinas-Torres V, Wilson P, Ladbury J, Koepke G, McCormick D, Gauger J, and Melnick R. A radio frequency radiation reverberation chamber exposure system for rodents; (2) Yijian G, Capstick M, McCormick D, Gauger J, Horn T, Wilson P, Melnick RL, and Kuster N. Life time dosimetric assessment for mice and rats exposed to cell phone radiation; (3) Wyde ME, Horn TL, Capstick M, Ladbury J, Koepke G, Wilson P, Stout MD, Kuster N, Melnick R, Bucher JR, and McCormick D. Pilot studies of the National Toxicology Program's cell phone radiofrequency radiation reverberation chamber exposure system; (4) Smith-Roe SL, Wyde ME, Stout MD, Winters J, Hobbs CA, Shepard KG, Green A, Kissling GE, Tice RR, Bucher JR, and Witt KL. Evaluation of the genotoxicity of cell phone radiofrequency radiation in male and female rats and mice following subchronic exposure.
2,326 downloads microbiology
A novel coronavirus (nCoV-2019) was the cause of an outbreak of respiratory illness detected in Wuhan, Hubei Province, China in December of 2019. Genomic analyses of nCoV-2019 determined a 96% resemblance with a coronavirus isolated from a bat in 2013 (RaTG13); however, the receptor binding motif (RBM) of these two genomes share low sequence similarity. This divergence suggests a possible alternative source for the RBM coding sequence in nCoV-2019. We identified high sequence similarity in the RBM between nCoV-2019 and a coronavirus genome reconstructed from a viral metagenomic dataset from pangolins possibly indicating a more complex origin for nCoV-2019.
2,296 downloads biochemistry
Many pathogens take advantage of the dependence of the host on the interaction of hundreds of extracellular proteins with the glycosaminoglycans heparan sulfate to regulate homeostasis and use heparan sulfate as a means to adhere and gain access to cells. Moreover, mucosal epithelia such as that of the respiratory tract are protected by a layer of mucin polysaccharides, which are usually sulfated. Consequently, the polydisperse, natural products of heparan sulfate and the allied polysaccharide, heparin have been found to be involved and prevent infection by a range of viruses including S-associated coronavirus strain HSR1. Here we use surface plasmon resonance and circular dichroism to measure the interaction between the SARS-CoV-2 Spike S1 protein receptor binding domain (SARS-CoV-2 S1 RBD) and heparin. The data demonstrate an interaction between the recombinant surface receptor binding domain and the polysaccharide. This has implications for the rapid development of a first-line therapeutic by repurposing heparin and for next-generation, tailor-made, GAG-based antivirals.
2,166 downloads microbiology
Severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronaviruses (CoVs) are zoonotic pathogens with high fatality rates and pandemic potential. Vaccine development has focussed on the principal target of the neutralizing humoral immune response, the spike (S) glycoprotein, which mediates receptor recognition and membrane fusion. Coronavirus S proteins are extensively glycosylated viral fusion proteins, encoding around 69-87 N-linked glycosylation sites per trimeric spike. Using a multifaceted structural approach, we reveal a specific area of high glycan density on MERS S that results in the formation of under-processed oligomannose-type glycan clusters, which was absent on SARS and HKU1 CoVs. We provide a comparison of the global glycan density of coronavirus spikes with other viral proteins including HIV-1 envelope, Lassa virus glycoprotein complex, and influenza hemagglutinin, where glycosylation plays a known role in shielding immunogenic epitopes. Consistent with the ability of the antibody-mediated immune response to effectively target and neutralize coronaviruses, we demonstrate that the glycans of coronavirus spikes are not able to form an efficacious high-density global shield to thwart the humoral immune response. Overall, our data reveal how differential organisation of viral glycosylation across class I viral fusion proteins influence not only individual glycan compositions but also the immunological pressure across the viral protein surface.
2,122 downloads microbiology
The novel coronavirus 2019-nCoV has affected more than 100 countries and continues to spread. There is an immediate need for effective vaccines that contain antigens which trigger responses from human T-cells and B-cells (known as epitopes). Here we identify potential T-cell epitopes through an analysis of human antigen presentation, as well as B-cell epitopes through an analysis of protein structure. We identify a list of top candidates, including an epitope located on 2019-nCoV spike protein that potentially triggers both T-cell and B-cell responses. Analyzing 68 samples, we observe that viral mutations are more likely to happen in regions with strong antigen presentation, a potential form of immune evasion. Our computational pipeline is validated with experimental data from SARS-CoV.
2,120 downloads systems biology
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.
2,105 downloads ecology
Backgrounds: An ongoing outbreak of a novel coronavirus (2019-nCoV) pneumonia hit a major city of China, Wuhan, December 2019 and subsequently reached other provinces/regions of China and countries. We present estimates of the basic reproduction number, R0, of 2019-nCoV in the early phase of the outbreak. Methods: Accounting for the impact of the variations in disease reporting rate, we modelled the epidemic curve of 2019-nCoV cases time series, in mainland China from January 10 to January 24, 2020, through the exponential growth. With the estimated intrinsic growth rate (γ), we estimated R0 by using the serial intervals (SI) of two other well-known coronavirus diseases, MERS and SARS, as approximations for the true unknown SI. Findings: The early outbreak data largely follows the exponential growth. We estimated that the mean R0 ranges from 2.24 (95%CI: 1.96-2.55) to 3.58 (95%CI: 2.89-4.39) associated with 8-fold to 2-fold increase in the reporting rate. We demonstrated that changes in reporting rate substantially affect estimates of R0. Conclusion: The mean estimate of R0 for the 2019-nCoV ranges from 2.24 to 3.58, and significantly larger than 1. Our findings indicate the potential of 2019-nCoV to cause outbreaks.
2,102 downloads microbiology
The outbreak of COVID-19, which is caused by SARS-CoV-2 virus, continues to spread globally, but there is currently very little understanding of the epitopes on the virus. In this study, we have determined the crystal structure of the receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) protein in complex with CR3022, a neutralizing antibody previously isolated from a convalescent SARS patient. CR3022 targets a highly conserved epitope that enables cross-reactive binding between SARS-CoV-2 and SARS-CoV. Structural modeling further demonstrates that the binding site can only be accessed when at least two RBDs on the trimeric S protein are in the ″up″ conformation. Overall, this study provides structural and molecular insight into the antigenicity of SARS-CoV-2.
2,090 downloads biochemistry
Three anti-HIV drugs, ritonavir, lopinavir and darunavir, might have therapeutic effect on coronavirus disease 2019 (COVID-19). In this study, the structure models of two severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteases, coronavirus endopeptidase C30 (CEP\_C30) and papain like viral protease (PLVP), were built by homology modeling. Ritonavir, lopinavir and darunavir were then docked to the models, respectively, followed by energy minimization of the protease-drug complexes. In the simulations, ritonavir can bind to CEP\_C30 most suitably, and induce significant conformation changes of CEP\_C30; lopinavir can also bind to CEP\_C30 suitably, and induce significant conformation changes of CEP\_C30; darunavir can bind to PLVP suitably with slight conformation changes of PLVP. It is suggested that the therapeutic effect of ritonavir and lopinavir on COVID-19 may be mainly due to their inhibitory effect on CEP\_C30, while ritonavir may have stronger efficacy; the inhibitory effect of darunavir on SARS-CoV-2 and its potential therapeutic effect may be mainly due to its inhibitory effect on PLVP.
2,068 downloads systems biology
The recent outbreak of pneumonia in Wuhan, China caused by the 2019 Novel Coronavirus (2019-nCoV) emphasizes the importance of detecting novel viruses and predicting their risks of infecting people. In this report, we introduced the VHP (Virus Host Prediction) to predict the potential hosts of viruses using deep learning algorithm. Our prediction suggests that 2019-nCoV has close infectivity with other human coronaviruses, especially the severe acute respiratory syndrome coronavirus (SARS-CoV), Bat SARS-like Coronaviruses and the Middle East respiratory syndrome coronavirus (MERS-CoV). Based on our prediction, compared to the Coronaviruses infecting other vertebrates, bat coronaviruses are assigned with more similar infectivity patterns with 2019-nCoVs. Furthermore, by comparing the infectivity patterns of all viruses hosted on vertebrates, we found mink viruses show a closer infectivity pattern to 2019-nCov. These consequences of infectivity pattern analysis illustrate that bat and mink may be two candidate reservoirs of 2019-nCov.These results warn us to beware of 2019-nCoV and guide us to further explore the properties and reservoir of it. One Sentence Summary It is of great value to identify whether a newly discovered virus has the risk of infecting human. Guo et al. proposed a virus host prediction method based on deep learning to detect what kind of host a virus can infect with DNA sequence as input. Applied to the Wuhan 2019 Novel Coronavirus, our prediction demonstrated that several vertebrate-infectious coronaviruses have strong potential to infect human. This method will be helpful in future viral analysis and early prevention and control of viral pathogens.
2,045 downloads microbiology
Over the past 20 years, several coronaviruses have crossed the species barrier into humans, causing outbreaks of severe, and often fatal, respiratory illness. Since SARS-CoV was first identified in animal markets, global viromics projects have discovered thousands of coronavirus sequences in diverse animals and geographic regions. Unfortunately, there are few tools available to functionally test these novel viruses for their ability to infect humans, which has severely hampered efforts to predict the next zoonotic viral outbreak. Here we developed an approach to rapidly screen lineage B betacoronaviruses, such as SARS-CoV and the recent 2019-nCoV, for receptor usage and their ability to infect cell types from different species. We show that host protease processing during viral entry is a significant barrier for several lineage B viruses and that bypassing this barrier allows several lineage B viruses to enter human cells through an unknown receptor. We also demonstrate how different lineage B viruses can recombine to gain entry into human cells and confirm that human ACE2 is the receptor for the recently emerging 2019-nCoV.
2,044 downloads biochemistry
Angiotensin-converting enzyme 2 (ACE2) is the surface receptor for SARS coronavirus (SARS-CoV) through interaction with its spike glycoprotein (S protein). ACE2 is also suggested to be the receptor for the new coronavirus (2019-nCoV), which is causing a serious epidemic in China manifested with severe respiratory syndrome. BAT1 (SLC6A19) is a neutral amino acid transporter whose surface expression in intestinal cells requires ACE2. Here we present the 2.9 Å resolution cryo-EM structure of full-length human ACE2 in complex with BAT1. The complex, assembled as a dimer of ACE2-BAT1 heterodimers, exhibits open and closed conformations due to the shifts of the peptidase domains of ACE2. A newly resolved Collectrin-like domain (CLD) on ACE2 mediates homo-dimerization. The extended TM7 in each BAT1 clamps CLD of ACE2. Structural analysis suggests that the ACE2-BAT1 complex can bind two S proteins simultaneously, providing important clues to the molecular basis for coronavirus recognition and infection.
2,038 downloads microbiology
The recent outbreak of coronavirus disease (COVID-19) caused by SARS-CoV-2 infection in Wuhan, China has posed a serious threat to global public health. To develop specific anti-coronavirus therapeutics and prophylactics, the molecular mechanism that underlies viral infection must first be confirmed. Therefore, we herein used a SARS-CoV-2 spike (S) protein-mediated cell-cell fusion assay and found that SARS-CoV-2 showed plasma membrane fusion capacity superior to that of SARS-CoV. We solved the X-ray crystal structure of six-helical bundle (6-HB) core of the HR1 and HR2 domains in SARS-CoV-2 S protein S2 subunit, revealing that several mutated amino acid residues in the HR1 domain may be associated with enhanced interactions with HR2 domain. We previously developed a pan-coronavirus fusion inhibitor, EK1, which targeted HR1 domain and could inhibit infection by divergent human coronaviruses tested, including SARS-CoV and MERS-CoV. We then generated a series of lipopeptides and found that the EK1C4 was the most potent fusion inhibitor against SARS-CoV-2 S protein-mediated membrane fusion and pseudovirus infection with IC50s of 1.3 and 15.8 nM, about 241- and 149-fold more potent than that of EK1 peptide, respectively. EK1C4 was also highly effective against membrane fusion and infection of other human coronavirus pseudoviruses tested, including SARS-CoV and MERS-CoV, as well as SARSr-CoVs, potently inhibiting replication of 4 live human coronaviruses, including SARS-CoV-2. Intranasal application of EK1C4 before or after challenge with HCoV-OC43 protected mice from infection, suggesting that EK1C4 could be used for prevention and treatment of infection by currently circulating SARS-CoV-2 and emerging SARSr-CoVs.
1,991 downloads genomics
Single cell transcriptomics (scRNA-seq) has transformed our ability to discover and annotate cell types and states, but deep biological understanding requires more than a taxonomic listing of clusters. As new methods arise to measure distinct cellular modalities, including high-dimensional immunophenotypes, chromatin accessibility, and spatial positioning, a key analytical challenge is to integrate these datasets into a harmonized atlas that can be used to better understand cellular identity and function. Here, we develop a computational strategy to "anchor" diverse datasets together, enabling us to integrate and compare single cell measurements not only across scRNA-seq technologies, but different modalities as well. After demonstrating substantial improvement over existing methods for data integration, we anchor scRNA-seq experiments with scATAC-seq datasets to explore chromatin differences in closely related interneuron subsets, and project single cell protein measurements onto a human bone marrow atlas to annotate and characterize lymphocyte populations. Lastly, we demonstrate how anchoring can harmonize in-situ gene expression and scRNA-seq datasets, allowing for the transcriptome-wide imputation of spatial gene expression patterns, and the identification of spatial relationships between mapped cell types in the visual cortex. Our work presents a strategy for comprehensive integration of single cell data, including the assembly of harmonized references, and the transfer of information across datasets. Availability: Installation instructions, documentation, and tutorials are available at: https://www.satijalab.org/seurat
1,973 downloads genomics
The spread of the novel coronavirus (SARS-CoV-2) has triggered a global emergency, that demands urgent solutions for detection and therapy to prevent escalating health, social and economic impacts. The spike protein (S) of this virus enables binding to the human receptor ACE2, and hence presents a prime target for vaccines preventing viral entry into host cells. The S proteins from SARS-CoV-1 and SARS-CoV-2 are similar, but structural differences in the receptor binding domain (RBD) preclude the use of SARS-CoV-1-specific neutralizing antibodies to inhibit SARS-CoV-2. Here we used comparative pangenomic analysis of all sequenced Betacoronaviruses to reveal that, among all core gene clusters present in these viruses, the envelope protein E shows a variant shared by SARS and SARS-Cov2 with two completely-conserved key functional features, an ion-channel and a PDZ-binding Motif (PBM). These features trigger a cytokine storm that activates the inflammasome, leading to increased edema in lungs causing the acute respiratory distress syndrome (ARDS), the leading cause of death in SARS-CoV-1 and SARS-CoV-2 infection. However, three drugs approved for human use may inhibit SARS-CoV-1 and SARS-CoV-2 Protein E, either acting upon the ion channel (Amantadine and Hexamethylene amiloride) or the PBM (SB203580), thereby potentially increasing the survival of the host, as already demonstrated for SARS-CoV-1in animal models. Hence, blocking the SARS protein E inhibits development of ARDS in vivo. Given that our results demonstrate that the protein E subcluster for the SARS clade is quasi-identical for the key functional regions of SARS-CoV-1 and SARS-CoV-2, we conclude that use of approved drugs shown to act as SARS E protein inhibitors can help prevent further casualties from COVID-2019 while vaccines and other preventive measures are being developed.
1,967 downloads pharmacology and toxicology
The focused drug repurposing of known approved drugs (such as lopinavir/ritonavir) has been reported failed for curing SARS-CoV-2 infected patients. It is urgent to generate new chemical entities against this virus. As a key enzyme in the life-cycle of coronavirus, the 3C-like main protease (3CLpro or Mpro) is the most attractive for antiviral drug design. Based on a recently solved structure (PDB ID: 6LU7), we developed a novel advanced deep Q-learning network with the fragment-based drug design (ADQN-FBDD) for generating potential lead compounds targeting SARS-CoV-2 3CLpro. We obtained a series of derivatives from those lead compounds by our structure-based optimization policy (SBOP). All the 47 lead compounds directly from our AI-model and related derivatives based on SBOP are accessible in our molecular library at https://github.com/tbwxmu/2019-nCov. These compounds can be used as potential candidates for researchers in their development of drugs against SARS-CoV-2.
1,946 downloads microbiology
The unprecedented epidemic of pneumonia caused by a novel coronavirus, HCoV-19, in China and beyond has caused public health concern at a global scale. Although bats are regarded as the most likely natural hosts for HCoV-19, the origins of the virus remain unclear. Here, we report a novel bat-derived coronavirus, denoted RmYN02, identified from a metagenomics analysis of samples from 227 bats collected from Yunnan Province in China between May and October, 2019. RmYN02 shared 93.3% nucleotide identity with HCoV-19 at the scale of the complete virus genome and 97.2% identity in the 1ab gene in which it was the closest relative of HCoV-19. In contrast, RmYN02 showed low sequence identity (61.3%) to HCoV-19 in the receptor binding domain (RBD) and might not bind to angiotensin-converting enzyme 2 (ACE2). Critically, however, and in a similar manner to HCoV-19, RmYN02 was characterized by the insertion of multiple amino acids at the junction site of the S1 and S2 subunits of the Spike (S) protein. This provides strong evidence that such insertion events can occur in nature. Together, these data suggest that HCoV-19 originated from multiple naturally occurring recombination events among those viruses present in bats and other wildlife species.
1,940 downloads immunology
Effective countermeasures against the recent emergence and rapid expansion of the 2019-Novel Coronavirus (2019-nCoV) require the development of data and tools to understand and monitor viral spread and immune responses. However, little information about the targets of immune responses to 2019-nCoV is available. We used the Immune Epitope Database and Analysis Resource (IEDB) resource to catalog available data related to other coronaviruses, including SARS-CoV, which has high sequence similarity to 2019-nCoV, and is the best-characterized coronavirus in terms of epitope responses. We identified multiple specific regions in 2019-nCoV that have high homology to SARS virus. Parallel bionformatic predictions identified a priori potential B and T cell epitopes for 2019-nCoV. The independent identification of the same regions using two approaches reflects the high probability that these regions are targets for immune recognition of 2019-nCoV.
1,915 downloads microbiology
Wei Deng, Linlin Bao, Hong Gao, Zhiguang Xiang, Yajin Qu, Zhiqi Song, Shuran Gong, Jiayi Liu, Jiangning Liu, Pin Yu, Feifei Qi, Yanfeng Xu, Fengli Li, Chong Xiao, Qi Lv, Jing Xue, Qiang Wei, Mingya Liu, Guanpeng Wang, Shunyi Wang, Haisheng Yu, Xing Liu, Wenjie Zhao, Yunlin Han, Chuan Qin
The outbreak of Corona Virus Disease 2019 caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2) is highly transmitted. The potential extra-respiratory transmission routes remain uncertain. Five rhesus macaques were inoculated with 106 TCID50 of SARS-CoV-2 via conjunctival (CJ), intratracheal (IT), and intragastric (IG) routes, respectively. Remarkably, the CJ inoculated-macaques developed mild interstitial pneumonia and viral load was detectable in the conjunctival swabs at 1 days post-inoculation (dpi). Only via IT inoculation, viral load was detected in the anal swab at 1-7 dpi and macaque showed weight loss. However, viral load was undetectable after IG inoculation. Comparatively, viral load was higher in the nasolacrimal system but lesions of lung were relatively mild and local via CJ inoculation compared with that via IT inoculation, demonstrating distinct characteristics of virus dispersion. Both the two routes affected the alimentary tract. Therefore the clinicians need to protect eye while working with patients.
1,902 downloads biochemistry
The novel coronavirus disease first identified in 2019 in Wuhan, China (COVID-19) has become a serious global public health concern. One current issue is the ability to adequately screen for the virus causing COVID-2 (SARS-CoV-2). Here we demonstrate the feasibility of shotgun proteomics as a SARS-CoV-2 screening method, through the detection of viral peptides in proteolytically digested body fluids. Using in silico methods, we generated trypsin-based shotgun proteomics methods optimized for LCMS systems from 5 commercial instrument vendors (Thermo, SCIEX, Waters, Shimadzu, and Agilent). First, we generated protein FASTA files and their protein digest maps. Second, the FASTA files were used to generate spectral libraries based on experimental data. Third, transition lists were derived from the spectral libraries using the vendor neutral and open Skyline software environment. Finally, we identified 17 post-translational modifications using linear motif modeling.
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