Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 83,434 bioRxiv papers from 359,620 authors.
Most downloaded bioRxiv papers, since beginning of last month
81,665 results found. For more information, click each entry to expand.
786 downloads genomics
qpAdm is a statistical tool for studying the ancestry of populations with histories that involve admixture between two or more source populations. Using qpAdm, it is possible to identify plausible models of admixture that fit the population history of a group of interest and to calculate the relative proportion of ancestry that can be ascribed to each source population in the model. Although qpAdm is widely used in studies of population history of human (and non-human) groups, relatively little has been done to assess its performance. We performed a simulation study to assess the behavior of qpAdm under various scenarios in order to identify areas of potential weakness and establish recommended best practices for use. We find that qpAdm is a robust tool that yields accurate results in many cases, including when data coverage is low, there are high rates of missing data or ancient DNA damage, or when diploid calls cannot be made. However, we caution against co-analyzing ancient and present-day data, the inclusion of an extremely large number of reference populations in a single model, and analyzing population histories involving extended periods of gene flow. We provide a user guide suggesting best practices for the use of qpAdm. ### Competing Interest Statement The authors have declared no competing interest.
786 downloads microbiology
Philipp Walch, Joel Selkrig, Leigh A. Knodler, Mandy Rettel, Frank Stein, Keith Fernandez, Cristina Viéitez, Clément M. Potel, Karoline Scholzen, Matthias Geyer, Klemens Rottner, Olivia Steele-Mortimer, Mikhail M. Savitski, David W. Holden, Athanasios Typas
Intracellular bacterial pathogens inject effector proteins into host cells to hijack diverse cellular processes and promote their survival and proliferation. To systematically map effector-host protein-protein interactions (PPIs) during infection, we generated a library of 32 Salmonella enterica serovar Typhimurium (STm) strains expressing chromosomally encoded affinity-tagged effector proteins, and quantified PPIs in macrophages and epithelial cells by Affinity-Purification Quantitative Mass-Spectrometry. Thereby, we identified 25 previously described and 421 novel effector-host PPIs. While effectors converged on the same host cellular processes, most had multiple targets, which often differed between cell types. Using reciprocal co-immunoprecipitations, we validated 13 out of 22 new PPIs. We then used this host-pathogen physical interactome resource to demonstrate that SseJ and SseL collaborate in redirecting cholesterol to the Salmonella Containing Vacuole (SCV) via NPC1, PipB directly recruits the organelle contact site protein PDZD8 to the SCV, and SteC promotes actin bundling by directly phosphorylating formin-like proteins. ### Competing Interest Statement The authors have declared no competing interest.
785 downloads immunology
Hydroxychloroquine (HCQ) has emerged as a potential and controversial antiviral candidate therapy for COVID-19. While many clinical trials are underway to test the efficacy of HCQ as a treatment for COVID-19, underlying mechanisms of HCQ in the setting of COVID-19 remain unclear. Hence, we examined differential gene expression signatures of HCQ exposure, in vitro SARS-CoV-2 infection, and host signatures of COVID-19 in blood, bronchoalveolar lavage, and postmortem lung to evaluate whether HCQ transcriptome signatures associate with restoration of SARS-CoV-2-related host transcriptional responses. Here, we show that 24 hours of in vitro treatment of peripheral blood mononuclear cells (PBMC) with HCQ significantly impacted transcription of 16 genes involved in immune regulation and lipid metabolism. Using transcriptome data from in vitro SARS-CoV-2 infected NHBE and A549 cells and PBMC derived from confirmed COVID-19 infected patients, we determined that only 0.24% of the COVID-19 PBMC differentially expressed gene set and 0.39% of the in vitro SARS-CoV-2 cells differentially expressed gene set overlapped with HCQ-related differentially expressed genes. Moreover, we observed that HCQ treatment significantly impacted transcription of 159 genes in human primary monocyte-derived macrophages involved in cholesterol biosynthetic process and chemokine activity. Notably, when we compared the macrophage HCQ-related gene lists with genes transcriptionally altered during SARS-CoV-2 infection and in bronchoalveolar lavage of COVID-19+ patients, the CXCL6 gene was impacted in all three transcriptional signatures revealing evidence in favor of chemokine modulation. HCQ-related transcriptional changes minimally overlapped with host genes altered in postmortem lung biopsies from COVID-19 participants. These results may provide insight into the immunomodulation mechanisms of HCQ treatment in the setting of COVID-19 and suggest HCQ is not a panacea to SARS-CoV-2 infection. ### Competing Interest Statement The authors have declared no competing interest.
784 downloads genomics
Daniel Taliun, Daniel N. Harris, Michael D Kessler, Jedidiah Carlson, Zachary A. Szpiech, Raul Torres, Jo Knight, André Corvelo, Stephanie M Gogarten, Hyun Min Kang, Achilleas N Pitsillides, Jonathon LeFaive, Seung-been Lee, Xiaowen Tian, Brian L. Browning, Sayantan Das, Anne-Katrin Emde, Wayne E. Clarke, Douglas P. Loesch, Amol C. Shetty, Thomas W Blackwell, Quenna Wong, François Aguet, Christine Albert, Alvaro Alonso, Kristin G. Ardlie, Stella Aslibekyan, Paul L. Auer, John Barnard, R. Graham Barr, Lewis C. Becker, Rebecca L Beer, Emelia J. Benjamin, Lawrence F Bielak, John Blangero, Michael Boehnke, Donald W Bowden, Jennifer A Brody, Esteban G. Burchard, Brian E. Cade, James F. Casella, Brandon Chalazan, Yii-Der Ida Chen, Michael H Cho, Seung Hoan Choi, Mina K. Chung, Clary B. Clish, Adolfo Correa, Joanne E. Curran, Brian Custer, Dawood Darbar, Michelle Daya, Mariza de Andrade, Dawn L DeMeo, Susan K Dutcher, Patrick T. Ellinor, Leslie S Emery, Diane Fatkin, Lukas Forer, Myriam Fornage, Nora Franceschini, Christian Fuchsberger, Stephanie M Fullerton, Soren Germer, Mark T Gladwin, Daniel J Gottlieb, Xiuqing Guo, Michael E Hall, Jiang He, Nancy L. Heard-Costa, Susan R. Heckbert, Marguerite R Irvin, Jill M Johnsen, Andrew D. Johnson, Sharon LR Kardia, Tanika Kelly, Shannon Kelly, Eimear E Kenny, Douglas P. Kiel, Robert Klemmer, Barbara A Konkle, Charles Kooperberg, Anna Köttgen, Leslie A Lange, Jessica Lasky-Su, Daniel Levy, Xihong Lin, Keng-Han Lin, Chunyu Liu, Ruth J.F. Loos, Lori Garman, Robert Gerszten, Steven A. Lubitz, Kathryn L. Lunetta, Angel C.Y. Mak, Ani Manichaikul, Alisa K Manning, Rasika A. Mathias, David D McManus, Stephen T McGarvey, James B. Meigs, Deborah A Meyers, Julie L Mikulla, Mollie A Minear, Braxton Mitchell, Sanghamitra Mohanty, May E. Montasser, Courtney Montgomery, Alanna C. Morrison, Joanne M Murabito, Andrea Natale, Pradeep Natarajan, Sarah C. Nelson, Kari E. North, Jeffrey R. O’Connell, Nicholette D Palmer, Nathan Pankratz, Gina M Peloso, Patricia A. Peyser, Wendy S. Post, Bruce M. Psaty, DC Rao, Susan Redline, Alexander P. Reiner, Dan Roden, Jerome I. Rotter, Ingo Ruczinski, Chloé Sarnowski, Sebastian Schoenherr, Jeong-Sun Seo, Sudha Seshadri, Vivien A Sheehan, M. Benjamin Shoemaker, Albert V Smith, Nicholas L. Smith, Jennifer A. Smith, Nona Sotoodehnia, Adrienne M. Stilp, Weihong Tang, Kent D Taylor, Marilyn Telen, Timothy A. Thornton, Russell P Tracy, David J. Van Den Berg, Ramachandran S Vasan, Karine A Viaud-Martinez, Scott Vrieze, Daniel E Weeks, Bruce S. Weir, Scott T Weiss, Lu-Chen Weng, Cristen J Willer, Yingze Zhang, Xutong Zhao, Donna K. Arnett, Allison E Ashley-Koch, Kathleen C Barnes, Eric Boerwinkle, Stacey Gabriel, Richard Gibbs, Kenneth M Rice, Stephen S Rich, Edwin Silverman, Pankaj Qasba, Weiniu Gan, Trans-Omics for Precision Medicine (TOPMed) Program, TOPMed Population Genetics Working Group, George J Papanicolaou, Deborah A. Nickerson, Sharon R. Browning, Michael C. Zody, Sebastian Zöllner, James G Wilson, L. Adrienne Cupples, Cathy C Laurie, Cashell E Jaquish, Ryan D Hernandez, Timothy D. O’Connor, Gonçalo R. Abecasis
The Trans-Omics for Precision Medicine (TOPMed) program seeks to elucidate the genetic architecture and disease biology of heart, lung, blood, and sleep disorders, with the ultimate goal of improving diagnosis, treatment, and prevention. The initial phases of the program focus on whole genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here, we describe TOPMed goals and design as well as resources and early insights from the sequence data. The resources include a variant browser, a genotype imputation panel, and sharing of genomic and phenotypic data via dbGaP. In 53,581 TOPMed samples, >400 million single-nucleotide and insertion/deletion variants were detected by alignment with the reference genome. Additional novel variants are detectable through assembly of unmapped reads and customized analysis in highly variable loci. Among the >400 million variants detected, 97% have frequency <1% and 46% are singletons. These rare variants provide insights into mutational processes and recent human evolutionary history. The nearly complete catalog of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and non-coding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and extends the reach of nearly all genome-wide association studies to include variants down to ~0.01% in frequency.
784 downloads ecology
Greg Boyce, Emile Gluck-Thaler, Jason C. Slot, Jason E. Stajich, William J. Davis, Tim Y. James, John R. Cooley, Daniel G. Panaccione, Jørgen Eilenberg, Henrik H. De Fine Licht, Angie M. Macias, Matthew C. Berger, Kristen L. Wickert, Cameron M. Stauder, Ellie J. Spahr, Matthew D. Maust, Amy M. Metheny, Chris Simon, Gene Kritsky, Kathie T. Hodge, Richard A. Humber, Terry Gullion, Dylan P. G. Short, Teiya Kijimoto, Dan Mozgai, Nidia Arguedas, Matt T. Kasson
Entomopathogenic fungi routinely kill their hosts before releasing infectious spores, but select species keep insects alive while sporulating, which enhances dispersal. Transcriptomics and metabolomics studies of entomopathogens with post-mortem dissemination from their parasitized hosts have unraveled infection processes and host responses, yet mechanisms underlying active spore transmission by Entomophthoralean fungi in living insects remain elusive. Here we report the discovery, through metabolomics, of the plant-associated amphetamine, cathinone, in four Massospora cicadina-infected periodical cicada populations, and the mushroom-associated tryptamine, psilocybin, in annual cicadas infected with Massospora platypediae or Massospora levispora, which appear to represent a single fungal species. The absence of some fungal enzymes necessary for cathinone and psilocybin biosynthesis along with the inability to detect intermediate metabolites or gene orthologs are consistent with possibly novel biosynthesis pathways in Massospora. The neurogenic activities of these compounds suggest the extended phenotype of Massospora that modifies cicada behavior to maximize dissemination is chemically-induced.
782 downloads microbiology
Rapid and widespread implementation of infectious disease surveillance is a critical component in the response to novel health threats. Molecular assays are the preferred method to detect a broad range of pathogens with high sensitivity and specificity. The implementation of molecular assay testing in a rapidly evolving public health emergency can be hindered by resource availability or technical constraints. In the context of the COVID-19 pandemic, the applicability of a pooled-sample testing protocol to screen large populations more rapidly and with limited resources is discussed. A Bayesian inference analysis in which hierarchical testing stages can have different sensitivities is implemented and benchmarked against early COVID-19 testing data. Optimal pool size and increases in throughput and case detection are calculated as a function of disease prevalence. Even for moderate losses in test sensitivity upon pooling, substantial increases in testing throughput and detection efficiency are predicted, suggesting that sample pooling is a viable avenue to circumvent current testing bottlenecks for COVID-19.
782 downloads molecular biology
The pneumonia-causing COVID-19 pandemia has prompt worldwide efforts to understand its biological and clinical traits of newly identified HCoV-19 virus. In this study, post-translational modification (PTM) of recombinant HCoV-19 S and hACE2 were characterized by LC-MSMS. We revealed that both proteins were highly decorated with specific proportions of N-glycan subtypes. Out of 21 possible glycosites in HCoV-19 S protein, 20 were confirmed completely occupied by N-glycans, with oligomannose glycans being the most abundant type. All 7 possible glycosylation sites in hACE2 were completely occupied mainly by complex type N-glycans. However, we shown that glycosylation does not directly contribute to the binding affinity between SARS-CoV spike protein and hACE2. Additionally, we also identified multiple sites methylated in both proteins, and multiple prolines in hACE2 are converted to hydroxylproline. Refined structural model were built by adding N-glycan and PTMs to recently published cryo-EM structure of the HCoV-19 S and hACE2 generated with glycosylation sites in the vicinity of binding surface. The PTM and glycan maps of both HCoV-19 S and hACE2 provide additional structural details to study mechanisms underlying host attachment, immune response mediated by S protein and hACE2, as well as knowledge to develop remedies and vaccines desperately needed nowadays. ### Competing Interest Statement The authors have declared no competing interest.
780 downloads bioengineering
Continuous directed evolution rapidly implements cycles of mutagenesis, selection, and replication to accelerate protein engineering. However, individual experiments are typically cumbersome, reagent-intensive, and require manual readjustment, limiting the number of evolutionary trajectories that can be explored. We report the design and validation of Phage-and-Robotics-Assisted Near-Continuous Evolution (PRANCE), an automation platform for the continuous directed evolution of biomolecules that enables real-time activity-dependent reporter and absorbance monitoring of up to 96 parallel evolution experiments. We use this platform to characterize the evolutionary stochasticity of T7 RNA polymerase evolution, conserve precious reagents with miniaturized evolution volumes during evolution of aminoacyl-tRNA synthetases, and perform a massively parallel evolution of diverse candidate quadruplet tRNAs. Finally, we implement a feedback control system that autonomously modifies the selection strength in response to real-time fitness measurements. By addressing many of the limitations of previous methods within a single platform, PRANCE simultaneously enables multiplexed, miniaturized, and feedback-controlled continuous directed evolution.
780 downloads neuroscience
Most sensory information destined for the neocortex is relayed through the thalamus, where considerable transformation occurs. One powerful means of transformation involves interactions between excitatory thalamocortical neurons that carry data to cortex and inhibitory neurons of the thalamic reticular nucleus (TRN) that regulate flow of those data. Despite enduring recognition of its importance, understanding of TRN cell types, their organization, and their functional properties has lagged that of the thalamocortical systems they control. Here we address this, investigating somatosensory and visual circuits of the TRN. In the somatosensory TRN we observed two groups of genetically defined neurons that are topographically segregated, physiologically distinct, and connect reciprocally with independent thalamocortical nuclei via dynamically divergent synapses. Calbindin-expressing cells, located in the central core, connect with the ventral posterior nucleus (VP), the primary somatosensory thalamocortical relay. In contrast, somatostatin-expressing cells, residing along the surrounding edges of TRN, synapse with the posterior medial thalamic nucleus (POM), a higher-order structure that carries both top-down and bottom-up information. The two TRN cell groups process their inputs in pathway-specific ways. Synapses from VP to central TRN cells transmit rapid excitatory currents that depress deeply during repetitive activity, driving phasic spike output. Synapses from POM to edge TRN cells evoke slower, less depressing excitatory currents that drive more persistent spiking. Differences in intrinsic physiology of TRN cell types, including state-dependent bursting, contribute to these output dynamics. Thus, processing specializations of two somatosensory TRN subcircuits appear to be tuned to the signals they carry; a primary central subcircuit to discrete sensory events, and a higher-order edge subcircuit to temporally distributed signals integrated from multiple sources. The structure and function of visual TRN subcircuits closely resemble those of the somatosensory TRN. These results provide fundamental insights about how subnetworks of TRN neurons may differentially process distinct classes of thalamic information. ### Competing Interest Statement The authors have declared no competing interest.
777 downloads microbiology
The current COVID-19 pandemic, caused by a novel coronavirus SARS-CoV-2, poses serious threats to public health and social stability, calling for urgent need for vaccines and therapeutics. SARS-CoV-2 is genetically close to SARS-CoV, thus it is important to define the between antigenic cross-reactivity and neutralization. In this study, we firstly analyzed 20 convalescent serum samples collected from SARS-CoV infected individuals during the 2003 SARS outbreak. All patient sera reacted strongly with the S1 subunit and receptor-binding domain (RBD) of SARS-CoV, cross-reacted with the S ectodomain, S1, RBD, and S2 proteins of SARS-CoV-2, and neutralized both SARS-CoV and SARS-CoV-2 S protein-driven infections. Multiple panels of antisera from mice and rabbits immunized with a full-length S and RBD immunogens of SARS-CoV were also characterized, verifying the cross-reactive neutralization against SARS-CoV-2. Interestingly, we found that a palm civet SARS-CoV-derived RBD elicited more potent cross-neutralizing responses in immunized animals than the RBD from a human SARS-CoV strain, informing a strategy to develop a universe vaccine against emerging CoVs. ### Competing Interest Statement The authors have declared no competing interest.
777 downloads immunology
SARS-CoV-2 is known to infect the neurological, respiratory, enteric, and hepatic systems of human and has already become an unprecedented threat to global healthcare system. COVID-19, the most serious public condition caused by SARS-CoV-2 leads the world to an uncertainty alongside thousands of regular death scenes. Unavailability of specific therapeutics or approved vaccine has made the recovery of COVI-19 more troublesome and challenging. The present in silico study aimed to predict a novel chimeric vaccines by simultaneously targeting four major structural proteins via the establishment of ancestral relationship among different strains of coronaviruses. Conserved regions from the homologous protein sets of spike glycoprotein (S), membrane protein (M), envelope protein and nucleocapsid protein (N) were identified through multiple sequence alignment. The phylogeny analyses of whole genome stated that four proteins (S, E, M and N) reflected the close ancestral relation of SARS-CoV-2 to SARS-COV-1 and bat coronavirus. Numerous immunogenic epitopes (both T cell and B cell) were generated from the common fragments which were further ranked on the basis of antigenicity, transmembrane topology, conservancy level, toxicity and allergenicity pattern and population coverage analysis. Top putative epitopes were combined with appropriate adjuvants and linkers to construct a novel multiepitope subunit vaccine against COVID-19. The designed constructs were characterized based on physicochemical properties, allergenicity, antigenicity and solubility which revealed the superiority of construct V3 in terms safety and efficacy. Essential molecular dynamics and Normal Mode analysis confirmed minimal deformability of the refined model at molecular level. In addition, disulfide engineering was investigated to accelerate the stability of the protein. Molecular docking study ensured high binding affinity between construct V3 and HLA cells, as well as with different host receptors. Microbial expression and translational efficacy of the constructs were checked using pET28a(+) vector of E. coli strain K12. The development of preventive measures to combat COVID-19 infections might be aided the present study. However, the in vivo and in vitro validation might be ensured with wet lab trials using model animals for the implementation of the presented data. ### Competing Interest Statement The authors have declared no competing interest.
773 downloads biochemistry
There is an urgent requirement for improved treatments of COVID-19 disease. A strategy for chemotherapy is to increase levels of endogenous reactive metabolites — such as reactive oxygen species and arginine-directed glycating agent, methylglyoxal — for selective toxicity to SARS-CoV-2. Sequence analysis of functional domains in the SARS-CoV-2 proteome showed 0.8 fold depletion of cysteine residues and 4.9 fold enrichment of arginine residues, suggesting methylglyoxal modification may inactivate the virus. We discovered the peptide motif for MG modification: 3 – 5-fold enrichment of cationic residues preceding the target arginine. There was 5-fold enrichment of methylglyoxal modification sites in the SARS-CoV-2 proteome, compared to the human host - indicating selective toxicity of methylglyoxal to the virus. We found antitumor drugs, doxorubicin and paclitaxel, increase cellular methylglyoxal to virucidal levels. Taken together, these findings reveal a proteomic vulnerability of SARS-CoV-2 to methylglyoxal modification and provide a rationale for repurposing doxorubicin and paclitaxel for COVID-19 treatment. ### Competing Interest Statement
766 downloads synthetic biology
Generative modeling for protein engineering is key to solving fundamental problems in synthetic biology, medicine, and material science. We pose protein engineering as an unsupervised sequence generation problem in order to leverage the exponentially growing set of proteins that lack costly, structural annotations. We train a 1.2B-parameter language model, ProGen, on ∼280M protein sequences conditioned on taxonomic and keyword tags such as molecular function and cellular component. This provides ProGen with an unprecedented range of evolutionary sequence diversity and allows it to generate with fine-grained control as demonstrated by metrics based on primary sequence similarity, secondary structure accuracy, and conformational energy.
766 downloads microbiology
Influenza A virus and coronavirus strains cause a mild to severe respiratory disease that can result in death. Although vaccines exist against circulating influenza A viruses, such vaccines are ineffective against emerging pandemic influenza A viruses. Currently, no vaccine exists against coronavirus infections, including pandemic SARS-CoV-2, the causative agent of the Coronavirus Disease 2019 (COVID-19). To combat these RNA virus infections, alternative antiviral strategies are needed. A key drug target is the viral RNA polymerase, which is responsible for viral RNA synthesis. In January 2020, the World Health Organisation identified enisamium as a candidate therapeutic against SARS-CoV-2. Enisamium is an isonicotinic acid derivative that is an inhibitor of multiple influenza B and A virus strains in cell culture and clinically approved in 11 countries. Here we show using in vitro assays that enisamium and its putative metabolite, VR17-04, inhibit the activity of the influenza virus and the SARS-CoV-2 RNA polymerase. VR17-04 displays similar efficacy against the SARS-CoV-2 RNA polymerase as the nucleotide analogue remdesivir triphosphate. These results suggest that enisamium is a broad-spectrum small molecule inhibitor of RNA virus RNA synthesis, and implicate it as a possible therapeutic option for treating SARS-CoV-2 infection. Unlike remdesivir, enisamium does not require intravenous administration which may be advantageous for the development of COVID-19 treatments outside a hospital setting. ### Competing Interest Statement V.M. is an employee of Farmak Public Joint Stock Company, Kiev, Ukraine. Part of this research was funded by Farmak Public Joint Stock Company, Kiev, Ukraine.
766 downloads evolutionary biology
Coronavirus disease 2019 (COVID-19) is a global health concern as it continues to spread within China and beyond. The causative agent of this disease, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), belongs to the genus Betacoronavirus which also includes severe acute respiratory syndrome related coronavirus (SARSr-CoV) and Middle East respiratory syndrome related coronavirus (MERSr-CoV). Codon usage of viral genes are believed to be subjected to different selection pressures in different host environments. Previous studies on codon usage of influenza A viruses can help identify viral host origins and evolution trends, however, similar studies on coronaviruses are lacking. In this study, global correspondence analysis (CA), within-group correspondence analysis (WCA) and between-group correspondence analysis (BCA) were performed among different genes in coronavirus viral sequences. The amino acid usage pattern of SARS-CoV-2 was generally found similar to bat and human SARSr-CoVs. However, we found greater synonymous codon usage differences between SARS-CoV-2 and its phylogenetic relatives on spike and membrane genes, suggesting these two genes of SARS-CoV-2 are subjected to different evolutionary pressures.
762 downloads genomics
The recent pandemic of coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 was first reported in China (December 2019) and now prevalent in ~170 countries across the globe. Entry of SARS-CoV-2 into mammalian cells require the binding of viral Spike (S) proteins to the ACE2 (angiotensin converting enzyme 2) receptor. Once entered the S protein is primed by a specialised serine protease, TMPRSS2 (Transmembrane Serine Protease 2) in the host cell. Importantly, beside respiratory symptoms, consistent with other common respiratory virus infection when patients become viraemic, a significant number of COVID-19 patients also develop liver comorbidities. We explored if specific target cell-type in the mammalian liver, could be implicated in disease pathophysiology other than the general deleterious response to cytokine storms. Here we employed single-cell RNA-seq (scRNA-seq) to survey the human liver and identified potentially implicated liver cell-type for viral ingress. We report the co-expression of ACE2 and TMPRSS2 in a TROP2+ liver progenitor population. Importantly, we fail to detect the expression of ACE2 in hepatocyte or any other liver (immune and stromal) cell types. These results indicated that in COVID-19 associated liver dysfunction and cell death, viral infection of TROP2+ progenitors in liver may significantly impaired liver regeneration and could lead to pathology.
762 downloads microbiology
Since December, 2019, an outbreak of pneumonia caused by the new coronavirus (2019-nCoV) has hit the city of Wuhan in the Hubei Province. With the continuous development of the epidemic, it has become a national public health crisis and calls for urgent antiviral treatments or vaccines. The spike protein on the coronavirus envelope is critical for host cell infection and virus vitality. Previous studies showed that 2019-nCoV is highly homologous to human SARS-CoV and attaches host cells though the binding of the spike receptor binding domain (RBD) domain to the angiotensin-converting enzyme II (ACE2). However, the molecular mechanisms of 2019- nCoV binding to human ACE2 and evolution of 2019-nCoV remain unclear. In this study, we have extensively studied the RBD-ACE2 complex, spike protein, and free RBD systems of 2019-nCoV and SARS-CoV using protein-protein docking and molecular dynamics (MD) simulations. It was shown that the RBD-ACE2 binding free energy for 2019-nCoV is significantly lower than that for SARS-CoV, which is consistent the fact that 2019-nCoV is much more infectious than SARS-CoV. In addition, the spike protein of 2019-nCoV shows a significantly lower free energy than that of SARS-CoV, suggesting that 2019-nCoV is more stable and able to survive a higher temperature than SARS-CoV. This may also provide insights into the evolution of 2019-nCoV because SARS-like coronaviruses are thought to have originated in bats that are known to have a higher body-temperature than humans. It was also revealed that the RBD of 2019-nCoV is much more flexible especially near the binding site and thus will have a higher entropy penalty upon binding ACE2, compared to the RBD of SARS-CoV. That means that 2019-nCoV will be much more temperature-sensitive in terms of human infection than SARS-CoV. With the rising temperature, 2019-nCoV is expected to decrease its infection ability much faster than SARS-CoV, and get controlled more easily. The present findings are expected to be helpful for the disease prevention and control as well as drug and vaccine development of 2019-nCoV.
759 downloads pharmacology and toxicology
Coronaviruses such as the newly discovered virus from Wuhan, China, 2019-nCoV, and the viruses that cause SARS and MERS, have resulted in regional and global public health emergencies. Based on our molecular insight that the hepatitis C virus and the coronavirus use a similar viral genome replication mechanism, we reasoned that the FDA-approved drug EPCLUSA (Sofosbuvir/Velpatasvir) for the treatment of hepatitis C will also inhibit the above coronaviruses, including 2019-nCoV. To develop broad spectrum anti-viral agents, we further describe a novel strategy to design and synthesize viral polymerase inhibitors, by combining the ProTide Prodrug approach used in the development of Sofosbuvir with the use of 3′-blocking groups that we have previously built into nucleotide analogues that function as polymerase terminators.
759 downloads bioinformatics
Metabolomics experiments can employ non-targeted tandem mass spectrometry to detect hundreds to thousands of molecules in a biological sample. Structural annotation of molecules is typically carried out by searching their fragmentation spectra in spectral libraries or, recently, in structure databases. Annotations are limited to structures present in the library or database employed, prohibiting a thorough utilization of the experimental data. We present a computational tool for systematic compound class annotation: CANOPUS uses a deep neural network to predict 1,270 compound classes from fragmentation spectra, and explicitly targets compounds where neither spectral nor structural reference data are available. CANOPUS even predicts classes for which no MS/MS training data are available. We demonstrate the broad utility of CANOPUS by investigating the effect of the microbial colonization in the digestive system in mice, and through analysis of the chemodiversity of different Euphorbia plants; both uniquely revealing biological insights at the compound class level. ### Competing Interest Statement SB, KD, ML, MF, and MAH are co-founders of Bright Giant GmbH. PCD is scientific advisor for Sirenas LLC.
758 downloads genomics
The COVID-19 pandemic has spread across more than 200 countries and resulted in over 170,000 deaths. For unclear reasons, higher mortality rates from COVID-19 have been reported in men compared to women. While the SARS-CoV-2 receptor ACE2 and serine protease TMPRSS2 have been detected in lung and other tissues, it is not clear what sex differences may exist. We analyzed a publicly-available normal human prostate single-cell RNA sequencing dataset and found TMPRSS2 and ACE2 co-expressing cells in epithelial cells, with a higher proportion in club and hillock cells. Then we investigated datasets of lung epithelial cells and also found club cells co-expressing TMPRSS2 and ACE2. A comparison of ACE2 expression in lung tissue between males and females showed higher expression in males and a larger proportion of ACE2+ cells in male type II pneumocytes, with preliminary evidence that type II pneumocytes of all lung epithelial cell types showed the highest expression of ACE2. These results raise the possibility that sex differences in ACE2 expression and the presence of double-positive cells in the prostate may contribute to the observed disparities of COVID-19. ### Competing Interest Statement The authors have declared no competing interest.
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