Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 77,926 bioRxiv papers from 337,673 authors.
Most downloaded bioRxiv papers, since beginning of last month
76,070 results found. For more information, click each entry to expand.
3,447 downloads microbiology
Barry Rockx, Thijs Kuiken, Sander Herfst, Theo Bestebroer, Mart M. Lamers, Dennis de Meulder, Geert van Amerongen, Judith van den Brand, Nisreen M.A. Okba, Debby Schipper, Peter van Run, Lonneke Leijten, Ernst Verschoor, Babs Verstrepen, Jan Langermans, Christian Drosten, Martje Fentener van Vlissingen, Ron Fouchier, Rik de Swart, Marion Koopmans, Bart L. Haagmans
A novel coronavirus, SARS-CoV-2, was recently identified in patients with an acute respiratory syndrome, COVID-19. To compare its pathogenesis with that of previously emerging coronaviruses, we inoculated cynomolgus macaques with SARS-CoV-2 or MERS-CoV and compared with historical SARS-CoV infections. In SARS-CoV-2-infected macaques, virus was excreted from nose and throat in absence of clinical signs, and detected in type I and II pneumocytes in foci of diffuse alveolar damage and mucous glands of the nasal cavity. In SARS-CoV-infection, lung lesions were typically more severe, while they were milder in MERS-CoV infection, where virus was detected mainly in type II pneumocytes. These data show that SARS-CoV-2 can cause a COVID-19-like disease, and suggest that the severity of SARS-CoV-2 infection is intermediate between that of SARS-CoV and MERS-CoV.
3,426 downloads neuroscience
Recent reports suggest an association between COVID-19 and altered olfactory function. Here we analyze bulk and single cell RNA-Seq datasets to identify cell types in the olfactory epithelium that express molecules that mediate infection by SARS-CoV-2 (CoV-2), the causal agent in COVID-19. We find in both mouse and human datasets that olfactory sensory neurons do not express two key genes involved in CoV-2 entry, ACE2 and TMPRSS2. In contrast, olfactory epithelial support cells and stem cells express both of these genes, as do cells in the nasal respiratory epithelium. Taken together, these findings suggest possible mechanisms through which CoV-2 infection could lead to anosmia or other forms of olfactory dysfunction.
3,368 downloads microbiology
Tran Thi Nhu Thao, Fabien Labroussaa, Nadine Ebert, Philip V’kovski, Hanspeter Stalder, Jasmine Portmann, Jenna Kelly, Silvio Steiner, Melle Holwerda, Annika Kratzel, Mitra Gultom, Laura Laloli, Linda Hüsser, Manon Wider, Stephanie Pfaender, Dagny Hirt, Valentina Cippà, Silvia Crespo-Pomar, Simon Schröder, Doreen Muth, Daniela Niemeyer, Marcel A Müller, Christian Drosten, Ronald Dijkman, Joerg Jores, Volker Thiel
Reverse genetics has been an indispensable tool revolutionising our insights into viral pathogenesis and vaccine development. Large RNA virus genomes, such as from Coronaviruses, are cumbersome to clone and to manipulate in E. coli hosts due to size and occasional instability. Therefore, an alternative rapid and robust reverse genetics platform for RNA viruses would benefit the research community. Here we show the full functionality of a yeast-based synthetic genomics platform for the genetic reconstruction of diverse RNA viruses, including members of the Coronaviridae, Flaviviridae and Paramyxoviridae families. Viral subgenomic fragments were generated using viral isolates, cloned viral DNA, clinical samples, or synthetic DNA, and reassembled in one step in Saccharomyces cerevisiae using transformation associated recombination (TAR) cloning to maintain the genome as a yeast artificial chromosome (YAC). T7-RNA polymerase has been used to generate infectious RNA, which was then used to rescue viable virus. Based on this platform we have been able to engineer and resurrect chemically-synthetized clones of the recent epidemic SARS-CoV-2 in only a week after receipt of the synthetic DNA fragments. The technical advance we describe here allows to rapidly responding to emerging viruses as it enables the generation and functional characterization of evolving RNA virus variants - in real-time - during an outbreak.
3,140 downloads bioinformatics
Starting from December 2019, a novel coronavirus, later named 2019-nCoV, was found to cause severe and rapid pandemic in China. Basing on the structural information, we have predicted a list of commercial medicines which may function as inhibitors for 2019-nCoV by targeting its main protease Mpro. These drugs may also be effective for other coronaviruses with similar Mpro binding sites and pocket structures.
3,091 downloads bioinformatics
Coronavirus disease 2019 (COVID-19) is a new emerging human infectious disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2, also previously known as 2019-nCoV), originated in Wuhan seafood and animal market, China. Since December 2019, more than 69,000 cases of COVID-19 have been confirmed in China and quickly spreads to other counties. Currently, researchers put their best efforts to identify effective drugs for COVID-19. The neutralizing antibody, which binds to viral capsid in a manner that inhibits cellular entry of virus and uncoating of the genome, is the specific defense against viral invaders. In this study, we investigate to identify neutralizing antibodies that can bind to SARS-CoV-2 Sipke (S) protein and interfere with the interaction between viral S protein and a host receptor by bioinformatic methods. The sequence analysis of S protein showed two major differences in the RBD region of the SARS-CoV-2 S protein compared to SARS-CoV and SARS-CoV related bat viruses (btSARS-CoV). The insertion regions were close to interacting residues with the human ACE2 receptor. Epitope analysis of neutralizing antibodies revealed that SARS-CoV neutralizing antibodies used conformational epitopes, whereas MERS-CoV neutralizing antibodies used a common linear epitope region, which contributes to form the β-sheet structure in MERS-CoV S protein and deleted in SARS-CoV-2 S protein. To identify effective neutralizing antibodies for SARS-CoV-2, the binding affinities of neutralizing antibodies with SARS-CoV-2 S protein were predicted and compared by antibody-antigen docking simulation. The result showed that CR3022 neutralizing antibody from human may have higher binding affinity with SARS-CoV-2 S protein than SARS-CoV S protein. We also found that F26G19 and D12 mouse antibodies could bind to SARS-CoV S protein with high affinity. Our findings provide crucial clues towards the development of antigen diagnosis, therapeutic antibody, and the vaccine against SARS-CoV-2.
3,059 downloads systems biology
Yiyue Ge, Tingzhong Tian, Suling Huang, Fangping Wan, Jingxin Li, Shuya Li, Hui Yang, Lixiang Hong, Nian Wu, Enming Yuan, Lili Cheng, Yipin Lei, Hantao Shu, Xiaolong Feng, Ziyuan Jiang, Ying Chi, Xiling Guo, Lunbiao Cui, Liang Xiao, Zeng Li, Chunhao Yang, Zehong Miao, Haidong Tang, Ligong Chen, Hainian Zeng, Dan Zhao, Fengcai Zhu, Xiaokun Shen, Jianyang Zeng
The global spread of SARS-CoV-2 requires an urgent need to find effective therapeutics for the treatment of COVID-19. We developed a data-driven drug repositioning framework, which applies both machine learning and statistical analysis approaches to systematically integrate and mine large-scale knowledge graph, literature and transcriptome data to discover the potential drug candidates against SARS-CoV-2. The retrospective study using the past SARS-CoV and MERS-CoV data demonstrated that our machine learning based method can successfully predict effective drug candidates against a specific coronavirus. Our in silico screening followed by wet-lab validation indicated that a poly-ADP-ribose polymerase 1 (PARP1) inhibitor, CVL218, currently in Phase I clinical trial, may be repurposed to treat COVID-19. Our in vitro assays revealed that CVL218 can exhibit effective inhibitory activity against SARS-CoV-2 replication without obvious cytopathic effect. In addition, we showed that CVL218 is able to suppress the CpG-induced IL-6 production in peripheral blood mononuclear cells, suggesting that it may also have anti-inflammatory effect that is highly relevant to the prevention immunopathology induced by SARS-CoV-2 infection. Further pharmacokinetic and toxicokinetic evaluation in rats and monkeys showed a high concentration of CVL218 in lung and observed no apparent signs of toxicity, indicating the appealing potential of this drug for the treatment of the pneumonia caused by SARS-CoV-2 infection. Moreover, molecular docking simulation suggested that CVL218 may bind to the N-terminal domain of nucleocapsid (N) protein of SARS-CoV-2, providing a possible model to explain its antiviral action. We also proposed several possible mechanisms to explain the antiviral activities of PARP1 inhibitors against SARS-CoV-2, based on the data present in this study and previous evidences reported in the literature. In summary, the PARP1 inhibitor CVL218 discovered by our data-driven drug repositioning framework can serve as a potential therapeutic agent for the treatment of COVID-19.
3,028 downloads bioengineering
2019-nCoV, which is a novel coronavirus emerged in Wuhan, China, at the end of 2019, has caused at least infected 11,844 as of Feb 1, 2020. However, there is no specific antiviral treatment or vaccine currently. Very recently report had suggested that novel CoV would use the same cell entry receptor, ACE2, as the SARS-CoV. In this report, we generated a novel recombinant protein by connecting the extracellular domain of human ACE2 to the Fc region of the human immunoglobulin IgG1. An ACE2 mutant with low catalytic activity was also used in the study. The fusion proteins were then characterized. Both fusion proteins has high affinity binding to the receptor-binding domain (RBD) of SARS-CoV and 2019-nCoV and exerted desired pharmacological properties. Moreover, fusion proteins potently neutralized SARS-CoV and 2019-nCoV in vitro. As these fusion proteins exhibit cross-reactivity against coronaviruses, they could have potential applications for diagnosis, prophylaxis, and treatment of 2019-nCoV.
2,980 downloads biochemistry
Yan Gao, Liming Yan, Yucen Huang, Fengjiang Liu, Yao Zhao, Lin Cao, Tao Wang, Qianqian Sun, Zhenhua Ming, Lianqi Zhang, Ji Ge, Litao Zheng, Ying Zhang, Haofeng Wang, Yan Zhu, Chen Zhu, Tianyu Hu, Tian Hua, Bing Zhang, Xiuna Yang, Jun Li, Haitao Yang, Zhijie Liu, Wenqing Xu, Luke W. Guddat, Quan Wang, Zhiyong Lou, Zihe Rao
A novel coronavirus (2019-nCoV) outbreak has caused a global pandemic resulting in tens of thousands of infections and thousands of deaths worldwide. The RNA-dependent RNA polymerase (RdRp, also named nsp12), which catalyzes the synthesis of viral RNA, is a key component of coronaviral replication/transcription machinery and appears to be a primary target for the antiviral drug, remdesivir. Here we report the cryo-EM structure of 2019-nCoV full-length nsp12 in complex with cofactors nsp7 and nsp8 at a resolution of 2.9 angstrom. Additional to the conserved architecture of the polymerase core of the viral polymerase family and a nidovirus RdRp-associated nucleotidyltransferase (NiRAN) domain featured in coronaviral RdRp, nsp12 possesses a newly identified β-hairpin domain at its N-terminal. Key residues for viral replication and transcription are observed. A comparative analysis to show how remdesivir binds to this polymerase is also provided. This structure provides insight into the central component of coronaviral replication/transcription machinery and sheds light on the design of new antiviral therapeutics targeting viral RdRp.
2,931 downloads evolutionary biology
Recent finding of a fossil − Oculudentavis khaungraae Xing et al. 2020 − entombed in a Late Cretaceous amber, was claimed to represent a humming bird-sized dinosaur1. Regardless of the intriguing evolutionary hypotheses about the bauplan of Mesozoic dinosaurs (including birds) posited therein, this enigmatic animal demonstrates various morphologies resembling lizards. If Oculudentavis was a bird, it challenges several fundamental morphological differences between Lepidosauria and Archosauria. Here we reanalyze the original computed tomography scan data of Oculudentavis . Morphological evidences demonstrated here highly contradict the avian or even archosaurian phylogenetic placement of Oculudentavis . In contrast, our analysis revealed multiple synapomorphies of the Squamata in this taxon, including pleurodont marginal teeth and an open infratemporal fenestra, which suggests a squamate rather than avian or dinosaurian affinity of Oculudentavis .
2,872 downloads molecular biology
Severe Acute Respiratory Syndrome Coronavirus 2 is rapidly spreading around the world. There is no existing vaccine or proven drug to prevent infections and stop virus proliferation. Although this virus is similar to human and animal SARS- and MERS-CoVs the detailed information about SARS-CoV-2 proteins structures and functions is urgently needed to rapidly develop effective vaccines, antibodies and antivirals. We applied high-throughput protein production and structure determination pipeline at the Center for Structural Genomics of Infectious Diseases to produce SARS-CoV-2 proteins and structures. Here we report the high-resolution crystal structure of endoribonuclease Nsp15/NendoU from SARS-CoV-2 - a virus causing current world-wide epidemics. We compare this structure with previously reported models of Nsp15 from SARS and MERS coronaviruses.
2,824 downloads microbiology
The newly identified 2019 novel coronavirus (2019-nCoV) has caused more than 800 laboratory-confirmed human infections, including 25 deaths, posing a serious threat to human health. Currently, however, there is no specific antiviral treatment or vaccine. Considering the relatively high identity of receptor binding domain (RBD) in 2019-nCoV and SARS-CoV, it is urgent to assess the cross-reactivity of anti-SARS-CoV antibodies with 2019-nCoV spike protein, which could have important implications for rapid development of vaccines and therapeutic antibodies against 2019-nCoV. Here, we report for the first time that a SARS-CoV-specific human monoclonal antibody, CR3022, could bind potently with 2019-nCoV RBD (KD of 6.3 nM). The epitope of CR3022 does not overlap with the ACE2 binding site within 2019-nCoV RBD. Therefore, CR3022 has the potential to be developed as candidate therapeutics, alone or in combination with other neutralizing antibodies, for the prevention and treatment of 2019-nCoV infections. Interestingly, some of the most potent SARS-CoV-specific neutralizing antibodies (e.g., m396, CR3014) that target the ACE2 binding site of SARS-CoV failed to bind 2019-nCoV spike protein, indicating that the difference in the RBD of SARS-CoV and 2019-nCoV has a critical impact for the cross-reactivity of neutralizing antibodies, and that it is still necessary to develop novel monoclonal antibodies that could bind specifically to 2019-nCoV RBD.
2,796 downloads microbiology
Since December 2019, a newly identified coronavirus (2019 novel coronavirus, 2019-nCov) is causing outbreak of pneumonia in one of largest cities, Wuhan, in Hubei province of China and has draw significant public health attention. The same as severe acute respiratory syndrome coronavirus (SARS-CoV), 2019-nCov enters into host cells via cell receptor angiotensin converting enzyme II (ACE2). In order to dissect the ACE2-expressing cell composition and proportion and explore a potential route of the 2019-nCov infection in digestive system infection, 4 datasets with single-cell transcriptomes of lung, esophagus, gastric, ileum and colon were analyzed. The data showed that ACE2 was not only highly expressed in the lung AT2 cells, esophagus upper and stratified epithelial cells but also in absorptive enterocytes from ileum and colon. These results indicated along with respiratory systems, digestive system is a potential routes for 2019-nCov infection. In conclusion, this study has provided the bioinformatics evidence of the potential route for infection of 2019-nCov in digestive system along with respiratory tract and may have significant impact for our healthy policy setting regards to prevention of 2019-nCoV infection.
2,792 downloads biophysics
A novel and highly pathogenic coronavirus (2019-nCoV) has caused an outbreak in Wuhan city, Hubei province of China since December 2019, and soon spread nationwide and spilled over to other countries around the world. To better understand the initial step of infection at atomic-level, we determined the crystal structure of the 2019-nCoV spike receptor-binding domain (RBD) bound with the cell receptor ACE2 at 2.45 angstrom resolution. The overall ACE2-binding mode of the 2019-nCoV RBD is nearly identical to that of the SARS-CoV RBD, which also utilizes ACE2 as the cell receptor. Structural analysis identified residues in 2019-nCoV RBD critical for ACE2 binding, and majority of which are either highly conserved or shared similar side chain properties with those in the SARS-CoV RBD. Such similarity in structure and sequence strongly argue for a convergent evolution between 2019-nCoV and SARS-CoV RBD for improved binding to ACE2 despite of being segregated in different genetic lineages in the betacoronavirus genus. The epitopes of two SARS-CoV antibodies targeting the RBD are also analyzed with the 2019-nCoV RBD, providing insights into future identification of cross-reactive antibodies.
2,691 downloads microbiology
Aiping Wu, Peihua Niu, Lulan Wang, Hangyu Zhou, Xiang Zhao, Wenling Wang, Jingfeng Wang, Chengyang Ji, Xiao Ding, Xianyue Wang, Roujian Lu, Sarah Gold, Saba Aliyari, Shilei Zhang, Ellee Vikram, Angela Zou, Emily Lenh, Janet Chen, Fei Ye, Na Han, Yousong Peng, Haitao Guo, Guizhen Wu, Taijiao Jiang, Wenjie Tan, Genhong Cheng
Background: The 2019 novel coronavirus (2019-nCoV or SARS-CoV-2) has spread more rapidly than any other betacoronavirus including SARS-CoV and MERS-CoV. However, the mechanisms responsible for infection and molecular evolution of this virus remained unclear. Methods: We collected and analyzed 120 genomic sequences of 2019-nCoV including 11 novel genomes from patients in China. Through comprehensive analysis of the available genome sequences of 2019-nCoV strains, we have tracked multiple inheritable SNPs and determined the evolution of 2019-nCoV relative to other coronaviruses. Results: Systematic analysis of 120 genomic sequences of 2019-nCoV revealed co-circulation of two genetic subgroups with distinct SNPs markers, which can be used to trace the 2019-nCoV spreading pathways to different regions and countries. Although 2019-nCoV, human and bat SARS-CoV share high homologous in overall genome structures, they evolved into two distinct groups with different receptor entry specificities through potential recombination in the receptor binding regions. In addition, 2019-nCoV has a unique four amino acid insertion between S1 and S2 domains of the spike protein, which created a potential furin or TMPRSS2 cleavage site. Conclusions: Our studies provided comprehensive insights into the evolution and spread of the 2019-nCoV. Our results provided evidence suggesting that 2019-nCoV may increase its infectivity through the receptor binding domain recombination and a cleavage site insertion.
2,636 downloads microbiology
Vincent J. Munster, Friederike Feldmann, Brandi N. Williamson, Neeltje van Doremalen, Lizzette Pérez-Pérez, Jonathan Schulz, Kimberly Meade-White, Atsushi Okumura, Julie Callison, Beniah Brumbaugh, Victoria A. Avanzato, Rebecca Rosenke, Patrick W. Hanley, Greg Saturday, Dana Scott, Elizabeth R. Fischer, Emmie de Wit
An outbreak of a novel coronavirus, now named SARS-CoV-2, causing respiratory disease and a ~2% case fatality rate started in Wuhan, China in December 2019. Following unprecedented rapid global spread, the World Health Organization declared COVID-19 a pandemic on March 11, 2020. Although data on disease in humans are emerging at a steady pace, certain aspects of the pathogenesis of SARS-CoV-2 can only be studied in detail in animal models, where repeated sampling and tissue collection is possible. Here, we show that SARS-CoV-2 causes respiratory disease in infected rhesus macaques, with disease lasting 8-16 days. Pulmonary infiltrates, a hallmark of human disease, were visible in lung radiographs of all animals. High viral loads were detected in swabs from the nose and throat of all animals as well as in bronchoalveolar lavages; in one animal we observed prolonged rectal shedding. Taken together, the rhesus macaque recapitulates moderate disease observed in the majority of human cases. The establishment of the rhesus macaque as a model of COVID-19 will increase our understanding of the pathogenesis of this disease and will aid development and testing of medical countermeasures.
2,608 downloads genomics
The emergence and outbreak of SARS-CoV-2, the causative agent of COVID-19, has rapidly become a global concern and has highlighted the need for fast, sensitive, and specific tools to surveil circulating viruses. Here we provide assay designs and experimental resources, for use with CRISPR-based nucleic acid detection, that could be valuable for ongoing surveillance. We provide assay designs for detection of 67 viral species and subspecies, including: SARS-CoV-2, phylogenetically-related viruses, and viruses with similar clinical presentation. The designs are outputs of algorithms that we are developing for rapidly designing nucleic acid detection assays that are comprehensive across genomic diversity and predicted to be highly sensitive and specific. Of our design set, we experimentally screened 4 SARS-CoV-2 designs with a CRISPR-Cas13 detection system and then extensively tested the highest-performing SARS-CoV-2 assay. We demonstrate the sensitivity and speed of this assay using synthetic targets with fluorescent and lateral flow detection. Moreover, our provided protocol can be extended for testing the other 66 provided designs. Assay designs are available at https://adapt.sabetilab.org/.
2,580 downloads biochemistry
Angiotensin-converting enzyme 2 (ACE2) has been suggested to be the cellular receptor for the new coronavirus (2019-nCoV) that is causing the coronavirus disease 2019 (COVID-19). Like other coronaviruses such as the SARS-CoV, the 2019-nCoV uses the receptor binding domain (RBD) of the surface spike glycoprotein (S protein) to engage ACE2. We most recently determined the structure of the full-length human ACE2 in complex with a neutral amino acid transporter BAT1. Here we report the cryo-EM structure of the full-length human ACE2 bound to the RBD of the 2019-nCoV at an overall resolution of 2.9 Å in the presence of BAT1. The local resolution at the ACE2-RBD interface is 3.5 Å, allowing analysis of the detailed interactions between the RBD and the receptor. Similar to that for the SARS-CoV, the RBD of the 2019-nCoV is recognized by the extracellular peptidase domain (PD) of ACE2 mainly through polar residues. Pairwise comparison reveals a number of variations that may determine the different affinities between ACE2 and the RBDs from these two related viruses.
2,525 downloads microbiology
Since December 2019, the outbreak of a new coronavirus, named 2019-nCoV, has greatly threatened the public health in China and raised great concerns worldwide. No specific treatment for this infection is currently available. We previously reported that teicoplanin, a glycopeptide antibiotic which has routinely been used in the clinic to treat bacterial infection with low toxicity, significantly inhibits the invasion of cells by Ebola virus, SARS-CoV and MERS-CoV, via specifically inhibiting the activity of cathepsin L. Here, we tested the efficacy of teicoplanin against 2019-nCoV virus infection and found that teicoplanin potently prevents the entrance of 2019-nCoV-Spike-pseudoviruses into the cytoplasm, with an IC50 of 1.66 μM. Although the inhibitory effect upon the replication of wildtype viruses ex vivo and in vivo remains to be determined, our preliminary result indicates that the potential antiviral activity of teicoplanin could be applied for the treatment of 2019-nCoV virus infection.
2,519 downloads microbiology
On December 31, 2019, the World Health Organization was notified about a cluster of pneumonia of unknown aetiology in the city of Wuhan, China. Chinese authorities later identified a new coronavirus (2019-nCoV) as the causative agent of the outbreak. As of January 23, 2020, 655 cases have been confirmed in China and several other countries. Understanding the transmission characteristics and the potential for sustained human-to-human transmission of 2019-nCoV is critically important for coordinating current screening and containment strategies, and determining whether the outbreak constitutes a public health emergency of international concern (PHEIC). We performed stochastic simulations of early outbreak trajectories that are consistent with the epidemiological findings to date. We found the basic reproduction number, R_0, to be around 2.2 (90% high density interval 1.4--3.8), indicating the potential for sustained human-to-human transmission. Transmission characteristics appear to be of a similar magnitude to severe acute respiratory syndrome-related coronavirus (SARS-CoV) and the 1918 pandemic influenza. These findings underline the importance of heightened screening, surveillance and control efforts, particularly at airports and other travel hubs, in order to prevent further international spread of 2019-nCoV.
2,508 downloads molecular biology
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has received global attention due to the recent outbreak in China. In this work, we report a CRISPR-Cas12 based diagnostic tool to detect synthetic SARS-CoV-2 RNA sequences in a proof-of-principle evaluation. The test proved to be sensitive, rapid, and potentially portable. These key traits of the CRISPR method are critical for virus detection in regions that lack resources to use the currently available methods.
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