Most tweeted biology preprints, last 24 hours
*There are gaps in historical Twitter data, most notably in spring 2020. This may result in some preprints appearing with less tweets than they should.
157 results found. For more information, click each entry to expand.
2 tweets bioRxiv neuroscience
Clathrin has established roles in endocytosis, with clathrin-cages enclosing membrane infoldings, followed by rapid disassembly and reuse of monomers. However, in neurons, clathrin synthesized in cell-bodies is conveyed into axons and synapses via slow axonal transport; as shown by classic pulse-chase radiolabeling. What is the cargo-structure, and mechanisms underlying transport and presynaptic-targeting of clathrin? What is the precise organization at synapses? Combining live-imaging, mass-spectrometry (MS), Apex-labeled EM-tomography and super-resolution, we found that unlike dendrites where clathrin transiently assembles/disassembles as expected, axons contain stable ‘transport-packets’ that move intermittently with an anterograde bias; with actin/myosin-VI as putative tethers. Transport-packets are unrelated to endocytosis, and the overall kinetics generate a slow biased flow of axonal clathrin. Synapses have integer-numbers of clathrin-packets circumferentially abutting the synaptic-vesicle cluster, advocating a model where delivery of clathrin-packets by slow axonal transport generates a radial organization of clathrin at synapses. Our experiments reveal novel trafficking mechanisms, and an unexpected nanoscale organization of synaptic clathrin.
2 tweets bioRxiv zoology
The physical mechanism of aerial dispersal of spiders, "ballooning behavior," is still unclear because of the lack of serious scientific observations and experiments. Therefore, as a first step in clarifying the phenomenon, we studied the ballooning behavior of relatively large spiders (heavier than 5 mg) in nature. Additional wind tunnel tests to identify ballooning silks were implemented in the laboratory. From our observation, it seems obvious that spiders actively evaluate the condition of the wind with their front leg (leg I) and wait for the preferable wind condition for their ballooning takeoff. In the wind tunnel tests, as yet unknown physical properties of ballooning fibers (length, thickness and number of fibers) were identified. Large spiders, 16-20 mg Xysticus species, spun 50 to 60 nanoscale fibers, with a diameter of 121 to 323 nm. The length of these threads was 3.22 ± 1.31 m (N = 22). These physical properties of ballooning fibers can explain the ballooning of large spiders with relatively light updrafts, 0.1-0.5 m s-1, which exist in a light breeze of 1.5-3.3 m s-1. Additionally, in line with previous research on turbulence in atmospheric boundary layers and from our wind measurements, it is hypothesized that spiders use the ascending air current for their aerial dispersal, the "ejection" regime, which is induced by hairpin vortices in the atmospheric boundary layer turbulence. This regime is highly correlated with lower wind speeds. This coincides well with the fact that spiders usually balloon when the wind speed is lower than 3 m s-1.
2 tweets bioRxiv biophysics
The SARS-CoV-2 Spike protein needs to be in an open-state conformation to interact with ACE2 as part of the viral entry mechanism. We utilise coarse-grained normal-mode analyses to model the dynamics of Spike and calculate transition probabilities between states for 17081 Spike variants. Our results correctly model an increase in open-state occupancy for the more infectious D614G via an increase in flexibility of the closed-state and decrease of flexibility of the open-state. We predict the same effect for several mutations on Glycine residues (404, 416, 504, 252) as well as residues K417, D467 and N501, including the N501Y mutation, explaining the higher infectivity of the B.1.1.7 and 501.V2 strains. This is, to our knowledge, the first use of normal-mode analysis to model conformational state transitions and the effect of mutations thereon. The specific mutations of Spike identified here may guide future studies to increase our understanding of SARS-CoV-2 infection mechanisms and guide public health in their surveillance efforts.
2 tweets bioRxiv immunology
Takuya Sekine, André Perez-Potti, Olga Rivera-Ballesteros, Kristoffer Strålin, Jean-Baptiste Gorin, Annika Olsson, Sian Llewellyn-Lacey, Habiba Kamal, Gordana Bogdanovic, Sandra Muschiol, David J. Wullimann, Tobias Kammann, Johanna Emgård, Tiphaine Parrot, Elin Folkesson, Olav Rooyackers, Lars I Eriksson, Anders Sönnerborg, Tobias Allander, Jan Albert, Morten Nielsen, Jonas Klingström, Sara Gredmark-Russ, Niklas K Björkström, Johan K. Sandberg, David A. Price, Hans-Gustaf Ljunggren, Soo Aleman, Marcus Buggert, Karolinska COVID-19 Study Group
SARS-CoV-2-specific memory T cells will likely prove critical for long-term immune protection against COVID-19. We systematically mapped the functional and phenotypic landscape of SARS-CoV-2-specific T cell responses in a large cohort of unexposed individuals as well as exposed family members and individuals with acute or convalescent COVID-19. Acute phase SARS-CoV-2-specific T cells displayed a highly activated cytotoxic phenotype that correlated with various clinical markers of disease severity, whereas convalescent phase SARS-CoV-2-specific T cells were polyfunctional and displayed a stem-like memory phenotype. Importantly, SARS-CoV-2-specific T cells were detectable in antibody-seronegative family members and individuals with a history of asymptomatic or mild COVID-19. Our collective dataset shows that SARS-CoV-2 elicits robust memory T cell responses akin to those observed in the context of successful vaccines, suggesting that natural exposure or infection may prevent recurrent episodes of severe COVID-19 also in seronegative individuals. ### Competing Interest Statement The authors have declared no competing interest.
2 tweets bioRxiv neuroscience
Background: Exposure to childhood adversity has been consistently associated with poor developmental outcomes, but it is unclear whether these associations vary across different forms of adversity. We examined cross-sectional and longitudinal associations between two types of adversity, threat and deprivation, with cognition, emotional processing, and psychopathology in a middle-income country. Methods: The sample consisted of 2,511 children and adolescents (6-17 years old) from the Brazilian High-Risk Cohort for Psychiatric Disorders. Parent reports on childhood adversity were used to construct threat and deprivation latent constructs. Psychopathology was measured by the CBCL which generated a measure of general psychopathology (the p factor). Executive function (EF) and attention orienting toward angry faces were assessed using cognitive tasks. All measures were acquired at two time-points 3-years apart. Cross-lagged panel models were estimated to evaluate longitudinal associations. Results: Psychopathology was associated with threat and deprivation cross-sectionally, and higher levels of threat and deprivation predicted increases in general psychopathology at follow-up. For EF, worse performance was more strongly associated with deprivation than threat at baseline, and only with deprivation at follow-up. Deprivation was associated with attention orienting away from angry faces cross-sectionally, but neither form of adversity was associated with changes over time in attention bias. Conclusion: Both types of adversity are associated with current and future psychopathology and with current, but not future, EF. Threat was more strongly linked to higher psychopathology, whereas deprivation was more strongly linked to lower EF. Lack of longitudinal associations between deprivation and EF mean reverse causality cannot be excluded.
2 tweets bioRxiv cell biology
Talin, vinculin, and paxillin are mechanosensitive proteins that are recruited early to integrin-based nascent adhesions (NAs). Using machine learning, traction microscopy, single-particle-tracking, and fluorescence fluctuation analysis, we find that talin, vinculin, and paxillin are recruited in near-synchrony to NAs maturing to focal adhesions. After initial recruitment of all three proteins under minimal load, vinculin accumulates in these NAs at a ~5 fold higher rate than in non-maturing NAs and with faster growth in traction. We identify a domain in talin, R8, which exposes a vinculin-binding-site (VBS) without requiring load. Stabilizing this domain via mutation lowers load-free vinculin binding to talin, impairs maturation of NAs, and reduces the rate of additional vinculin recruitment. Taken together, our data show that talins concurrent localization with vinculin, before engagement with integrins, is essential for NA maturation, which entails traction-mediated unfolding of talin and exposure of additional VBSs triggering further vinculin binding.
2 tweets bioRxiv neuroscience
Acetylcholine (ACh) is associated with the modulation of brain activity linked to arousal, attention, and emotional valence. We performed dual-color mesoscopic imaging of ACh and calcium across the neocortex of awake mice to investigate the spatiotemporal dynamics of cholinergic signaling and their relationship to cortical output. We find distinct movement-defined behavioral states are represented in spatially heterogeneous cholinergic networks that are differentially coupled to fluctuations in local circuit activity.
2 tweets bioRxiv neuroscience
Introduction: Recently popular sub-perceptual doses of psychedelic substances such as truffles, referred to as microdosing, allegedly have multiple beneficial effects including creativity and problem solving performance, potentially through targeting serotonergic 5-HT2A receptors and promoting cognitive flexibility, crucial to creative thinking. Nevertheless, enhancing effects of microdosing remain anecdotal, and in the absence of quantitative research on microdosing psychedelics it is impossible to draw definitive conclusions on that matter. Here, our main aim was to quantitatively explore the cognitive-enhancing potential of microdosing psychedelics in healthy adults. Methods: During a microdosing event organized by the Dutch Psychedelic Society, we examined the effects of psychedelic truffles (which were later analyzed to quantify active psychedelic alkaloids) on two creativity-related problem-solving tasks: the Picture Concept Task assessing convergent thinking, and the Alternative Uses Task assessing divergent thinking. A short version of the Ravens Progressive Matrices task assessed potential changes in fluid intelligence. We tested once before taking a microdose and once while the effects were manifested. Results: We found that both convergent and divergent thinking performance was improved after a non-blinded microdose, whereas fluid intelligence was unaffected. Conclusion: While this study provides quantitative support for the cognitive enhancing properties of microdosing psychedelics, future research has to confirm these preliminary findings in more rigorous placebo-controlled study designs. Based on these preliminary results we speculate that psychedelics might affect cognitive metacontrol policies by optimizing the balance between cognitive persistence and flexibility. We hope this study will motivate future microdosing studies with more controlled designs to test this hypothesis.
2 tweets bioRxiv bioinformatics
The ever-increasing number of analyzed cells in Single-cell RNA sequencing (scRNA-seq) experiments imposes several challenges on the data analysis. Current analysis methods lack scalability to large datasets hampering interactive visual exploration of the data. We present Cytosplore-Transcriptomics, a framework to analyze scRNA-seq data, including data preprocessing, visualization and downstream analysis. At its core, it uses a hierarchical, manifold preserving representation of the data that allows the inspection and annotation of scRNA-seq data at different levels of detail. Consequently, Cytosplore-Transcriptomics provides interactive analysis of the data using low-dimensional visualizations that scales to millions of cells.
2 tweets bioRxiv microbiology
Zhuoming Liu, Laura A VanBlargan, Louis-Marie Bloyet, Paul W Rothlauf, Rita E. Chen, Spencer Stumpf, Haiyan Zhao, John M Errico, Elitza S Theel, Mariel J. Liebeskind, Brynn Alford, William J. Buchser, Ali H Ellebedy, Daved H Fremont, Michael S. Diamond, Sean P. J. Whelan
Although neutralizing antibodies against the SARS-CoV-2 spike (S) protein are a goal of COVID-19 vaccines and have received emergency use authorization as therapeutics, viral escape mutants could compromise their efficacy. To define the immune-selected mutational landscape in S protein, we used a VSV-eGFP-SARS-CoV-2-S chimeric virus and 19 neutralizing monoclonal antibodies (mAbs) against the receptor-binding domain (RBD) to generate 50 different escape mutants. The variants were mapped onto the RBD structure and evaluated for cross-resistance to mAbs and convalescent human sera. Each mAb had a unique resistance profile, although many shared residues within an epitope. Some variants (e.g., S477N) were resistant to neutralization by multiple mAbs, whereas others (e.g., E484K) escaped neutralization by convalescent sera, suggesting some humans induce a narrow repertoire of neutralizing antibodies. Comparing the antibody-mediated mutational landscape in S with sequence variation in circulating SARS-CoV-2, we define substitutions that may attenuate neutralizing immune responses in some humans.
2 tweets bioRxiv bioinformatics
Nonlinear data-visualization methods, such as t-SNE and UMAP, have become staple tools for summarizing the complex transcriptomic landscape of single cells in 2D or 3D. However, existing approaches neglect the local density of data points in the original space, often resulting in misleading visualizations where densely populated subpopulations of cells are given more visual space even if they account for only a small fraction of transcriptional diversity within the dataset. We present den-SNE and densMAP, our density-preserving visualization tools based on t-SNE and UMAP, respectively, and demonstrate their ability to facilitate more accurate visual interpretation of single-cell RNA-seq data. On recently published datasets, our methods newly reveal significant changes in transcriptomic variability within a range of biological processes, including cancer, immune cell specialization in human, and the developmental trajectory of C. elegans. Our methods are readily applicable to visualizing high-dimensional data in other scientific domains. ### Competing Interest Statement The authors have declared no competing interest.
2 tweets bioRxiv cell biology
Parkinson's disease (PD) is a major and progressive neurodegenerative disorder, yet the biological mechanisms involved in its aetiology are poorly understood. Evidence links this disorder with mitochondrial dysfunction and/or impaired lysosomal degradation - key features of the autophagy of mitochondria, known as mitophagy. Here we investigated the role of LRRK2, a protein kinase frequently mutated in PD, on this process in vivo. Using mitophagy and autophagy reporter mice, bearing either knockout of LRRK2 or expressing the pathogenic kinase-activating G2019S LRRK2 mutation, we found that basal mitophagy was specifically altered in clinically relevant cells and tissues. Our data show that basal mitophagy inversely correlates with LRRK2 kinase activity in vivo. In support of this, use of distinct LRRK2 kinase inhibitors in cells increased basal mitophagy, and a CNS penetrant LRRK2 kinase inhibitor, GSK3357679A, rescued the mitophagy defects observed in LRRK2 G2019S mice. This study provides the first in vivo evidence that pathogenic LRRK2 directly impairs basal mitophagy, a process with strong links to idiopathic PD, and demonstrates that pharmacological inhibition of LRRK2 is a rational mitophagy-rescue approach and potential PD therapy.
2 tweets bioRxiv neuroscience
Female Aedes aegypti mosquitoes show strong innate attraction to humans. This chemosensory behavior is critical to species survival because females require a blood-meal to reproduce. Humans, the preferred host of Ae. aegypti , produce a complex blend of odor cues along with carbon dioxide (CO2) that attracts females ready to bite. Mosquitoes detect these cues with heteromeric ligand-gated ion channels encoded by three different chemosensory receptor gene families. A common theme in other species is that olfactory neurons express a single receptor that defines their chemical specificity and that they extend axons that converge upon dedicated glomeruli in the first sensory processing center in the brain. Such an organization permits the brain to segregate olfactory information and monitor activity of individual glomeruli to interpret what smell has been encountered. We have discovered that Ae. aegypti uses an entirely different organizational principle for its olfactory system. Using genetic strains that label subpopulations of olfactory neurons, we found that many neurons co-express multiple members of at least two of the chemosensory receptor families. This unexpected co-expression is functional, as assessed by in vivo calcium imaging showing that a given glomerulus is activated by multiple ligands detected by different receptor families. This has direct functional consequences for mosquito behavior. Mutant mosquitoes that cannot sense CO2 can be behaviorally activated by a volatile amine that stimulates the CO2 glomerulus. This non-canonical olfactory system organization featuring overlapping receptor expression may explain the female mosquito's robust and unbreakable attraction to humans. ### Competing Interest Statement The authors have declared no competing interest.
2 tweets bioRxiv cell biology
Eukaryotes compartmentalize metabolic pathways into sub-cellular domains, but the role of inter-organelle contacts in organizing metabolic reactions remains poorly understood. Here, we show that in response to acute glucose restriction (AGR) yeast undergo metabolic remodeling of their mevalonate pathway that is spatially coordinated at nucleus-vacuole junctions (NVJs). The NVJ serves as a metabolic platform by selectively retaining HMG-CoA Reductases (HMGCRs), driving mevalonate pathway flux in an Upc2-dependent manner. AGR-induced HMGCR compartmentalization enhances mevalonate metabolism and sterol-ester biosynthesis that generates lipid droplets (LDs) with liquid-crystalline sub-architecture. Loss of NVJ-dependent HMGCR partitioning affects yeast growth, but can be bypassed by artificially multimerizing HMGCRs, indicating NVJ compartmentalization enhances mevalonate pathway flux by promoting HMGCR inter-enzyme associations. We propose a non-canonical mechanism regulating mevalonate metabolism via the spatial compartmentalization of rate-limiting HMGCR enzymes, and reveal that AGR creates LDs with remarkable phase transition properties. One Sentence Summary Spatial compartmentalization of HMG-CoA Reductases at ER-lysosome contacts modulates mevalonate pathway flux ### Competing Interest Statement The authors have declared no competing interest.
2 tweets bioRxiv systems biology
Cristina Viéitez, Bede P. Busby, David Ochoa, André Mateus, Marco Galardini, Areeb Jawed, Danish Memon, Clement M Potel, Sibylle C Vonesch, Chelsea Szu Tu, Mohammed Shahraz, Frank Stein, Lars M. Steinmetz, Mikhail M. Savitski, Athanasios Typas, Pedro Beltrao
Phosphorylation is a critical post-translational modification involved in the regulation of almost all cellular processes. However, less than 5% of thousands of recently discovered phosphorylation sites have a known function. Here, we devised a chemical genetic approach to study the functional relevance of phosphorylation in S. cerevisiae. We generated 474 phospho-deficient mutants that, along with the gene deletion library, were screened for fitness in 102 conditions. Of these, 42% exhibited growth phenotypes, suggesting these phosphosites are likely functional. We inferred their function based on the similarity of their growth profiles with that of gene deletions, and validated a subset by thermal proteome profiling and lipidomics. While some phospho-mutants showed loss-of-function phenotypes, a higher fraction exhibited phenotypes not seen in the corresponding gene deletion suggestive of a gain-of-function effect. For phosphosites conserved in humans, the severity of the yeast phenotypes is indicative of their human functional relevance. This study provides a roadmap for functionally characterizing phosphorylation in a systematic manner.
2 tweets bioRxiv cancer biology
Obesity is a disease characterized by chronic low-grade systemic inflammation and has been causally linked to the development of 13 cancer types. Several studies have been undertaken to determine if tumors evolving in obese environments adapt differential interactions with immune cells and if this can be connected to disease outcome. Most of these studies have been limited to single cell lines and tumor models and analysis of limited immune cell populations. Given the multicellular complexity of the immune system and its dysregulation in obesity, we applied high-dimensional suspension mass cytometry to investigate how obesity affects tumor immunity. We used a 36-marker immune-focused mass cytometry panel to interrogate the immune landscape of orthotopic syngeneic mouse models of pancreatic and breast cancer. Unanchored batch correction was implemented to enable simultaneous analysis of tumor cohorts to uncover the immunotypes of each cancer model and reveal remarkably model-specific immune regulation. In the E0771 breast cancer model, we demonstrate an important link to obesity with an increase in two T cell suppressive cell types and a decrease in CD8 T-cells.
2 tweets bioRxiv physiology
Time-restricted feeding/eating (TRF/TRE) - limiting not the amount of food but the daily time window of food intake - is a dietary intervention that has been shown to improve health markers in model organisms and humans, but whether these benefits translate into positive effects on aging and longevity is not clear. We demonstrate here that TRF robustly prolongs lifespan in the short-lived genetically tractable model organism Drosophila melanogaster. Median TRF lifespan extensions range between [~]10% and [~]50% dependent on sex, reproductive status, TRF duration, and genotype. TRFs positive effect on longevity is independent of food intake and at least in part relies on a functioning circadian clock: TRF benefits on longevity are abolished in arrhythmic per0 and tim01 mutants as well as in constant light, suggesting that timed feeding acts as a zeitgeber partitioning eating and associated metabolic processes into certain phases of day and night. TRF-mediated longevity extension is unaffected in flies whose neural circadian clocks have been abolished genetically, pointing towards peripheral clocks as the target of TRF mediating lifespan extension.
2 tweets bioRxiv immunology
Annette B. Vogel, Isis Kanevsky, Ye Che, Kena A. Swanson, Alexander Muik, Mathias Vormehr, Lena M Kranz, Kerstin C. Walzer, Stephanie Hein, Alptekin Güler, Jakob Loschko, Mohan S. Maddur, Kristin Tompkins, Journey Cole, Bonny G. Lui, Thomas Ziegenhals, Arianne Plaschke, David Eisel, Sarah C. Dany, Stephanie Fesser, Stephanie Erbar, Ferdia Bates, Diana Schneider, Bernadette Jesionek, Bianca Sänger, Ann-Kathrin Wallisch, Yvonne Feuchter, Hanna Junginger, Stefanie A. Krumm, André P. Heinen, Petra Adams-Quack, Julia Schlereth, Christoph Kröner, Shannan Hall-Ursone, Kathleen Brasky, Matthew C. Griffor, Seungil Han, Joshua A. Lees, Ellene H. Mashalidis, Parag V. Sahasrabudhe, Charles Y. Tan, Danka Pavliakova, Guy Singh, Camila Fontes-Garfias, Michael Pride, Ingrid L. Scully, Tara Ciolino, Jennifer Obregon, Michal Gazi, Ricardo Carrion, Kendra J. Alfson, Warren V. Kalina, Deepak Kaushal, Pei-Yong Shi, Thorsten Klamp, Corinna Rosenbaum, Andreas N. Kuhn, Özlem Türeci, Philip R. Dormitzer, Kathrin U. Jansen, Ugur Sahin
To contain the coronavirus disease 2019 (COVID-19) pandemic, a safe and effective vaccine against the new severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is urgently needed in quantities sufficient to immunise large populations. In this study, we report the design, preclinical development, immunogenicity and anti-viral protective effect in rhesus macaques of the BNT162b2 vaccine candidate. BNT162b2 contains an LNP-formulated nucleoside-modified mRNA that encodes the spike glycoprotein captured in its prefusion conformation. After expression of the BNT162b2 coding sequence in cells, approximately 20% of the spike molecules are in the one-RBD ‘up’, two-RBD ‘down’ state. Immunisation of mice with a single dose of BNT162b2 induced dose level-dependent increases in pseudovirus neutralisation titers. Prime-boost vaccination of rhesus macaques elicited authentic SARS-CoV-2 neutralising geometric mean titers 10.2 to 18.0 times that of a SARS-CoV-2 convalescent human serum panel. BNT162b2 generated strong TH1 type CD4+ and IFNγ+ CD8+ T-cell responses in mice and rhesus macaques. The BNT162b2 vaccine candidate fully protected the lungs of immunised rhesus macaques from infectious SARS-CoV-2 challenge. BNT162b2 is currently being evaluated in a global, pivotal Phase 2/3 trial ([NCT04368728]). ### Competing Interest Statement U.S. and O.T. are management board members and employees at BioNTech SE (Mainz, Germany); K.C.W., B.G.L., D.S., B.J., T.K. and C.R. are employees at BioNTech SE; A.B.V., A.M., M.V., L.M.K., S.He., A.G., T.Z., A.P., D.E., S.C.D., S.F., S.E., F.B., B.S., A.W., Y.F., H.J., S.A.K., A.P.H., P.A., J.S., C.K., and A.N.K. are employees at BioNTech RNA Pharmaceuticals GmbH (Mainz, Germany); A.B.V., A.M., K.C.W., A.G., S.F., A.N.K and U.S. are inventors on patents and patent applications related to RNA technology and COVID-19 vaccine; A.B.V., A.M., M.V., L.M.K., K.C.W., S.He., B.G.L., A.P., D.E., S.C.D., S.F., S.E., D.S., B.J., B.S., A.P.H., P.A., J.S., C.K., T.K., C.R., A.N.K., O.T. and U.S. have securities from BioNTech SE; I.K., Y.C., K.A.S., J.L., M.M., K.T., M.C.G., S.H., J.A.L.,E.H.M., P.V.S., C.Y.T., D.P., G.S., M.P., I.L.S., T.C., J.O., W.V.K., P.R.D. and K.U.J. are employees of Pfizer and may hold stock options; C.F.-G. and P.-Y.S. received compensation from Pfizer to perform neutralisation assays; J.C., S.H.-U, K.B., R.C., jr., K.J.A. and D.K., are employees of Southwest National Primate Research Center, which received compensation from Pfizer to conduct the animal challenge work; no other relationships or activities that could appear to have influenced the submitted work. : /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04368728&atom=%2Fbiorxiv%2Fearly%2F2020%2F09%2F08%2F2020.09.08.280818.atom
2 tweets bioRxiv molecular biology
Translation of open reading frame 1b (ORF1b) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires programmed −1 ribosomal frameshifting (−1 PRF) promoted by an RNA pseudoknot. The extent to which SARS-CoV-2 replication may be sensitive to changes in −1 PRF efficiency is currently unknown. Through an unbiased, reporter-based high-throughput compound screen, we identified merafloxacin, a fluoroquinolone antibacterial, as a −1 PRF inhibitor of SARS-CoV-2. Frameshift inhibition by merafloxacin is robust to mutations within the pseudoknot region and is similarly effective on −1 PRF of other beta coronaviruses. Importantly, frameshift inhibition by merafloxacin substantially impedes SARS-CoV-2 replication in Vero E6 cells, thereby providing the proof of principle of targeting −1 PRF as an effective antiviral strategy for SARS-CoV-2. ### Competing Interest Statement Yale University has filed a provisional patent application related to this work entitled 'Compounds and Compositions for Disrupting Programmed Ribosomal Frameshifting'.
2 tweets bioRxiv systems biology
Erica T. Prates, Michael R Garvin, Mirko Pavicic, Piet Jones, Manesh Shah, Christiane Alvarez, David Kainer, Omar Demerdash, B Kirtley Amos, Armin Geiger, John Pestian, Kang Jin, Alexis Mitelpunkt, Eric Bardes, Bruce Aronow, Daniel A Jacobson
Using a Systems Biology approach, we integrated genomic, transcriptomic, proteomic, and molecular structure information to provide a holistic understanding of the COVID-19 pandemic. The expression data analysis of the Renin Angiotensin System indicates mild nasal, oral or throat infections are likely and that the gastrointestinal tissues are a common primary target of SARS-CoV-2. Extreme symptoms in the lower respiratory system likely result from a secondary-infection possibly by a comorbidity-driven upregulation of ACE2 in the lung. The remarkable differences in expression of other RAS elements, the elimination of macrophages and the activation of cytokines in COVID-19 bronchoalveolar samples suggest that a functional immune deficiency is a critical outcome of COVID-19. We posit that using a non-respiratory system as a major pathway of infection is likely determining the unprecedented global spread of this coronavirus. ### Competing Interest Statement The authors have declared no competing interest.
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