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Rxivist combines biology preprints from bioRxiv and medRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 125,201 papers from 537,614 authors.

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.

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

41: Glutamic acid promotes hair growth in mice
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Posted 28 Sep 2020

Glutamic acid promotes hair growth in mice
1 tweet bioRxiv pharmacology and toxicology

Carlos Poblete Jara, Beatriz de Andrade Berti, Natalia Ferreira Mendes, Daiane F. Engel, Ariane Maria Zanesco, Gabriela Freitas Souza, Lício Augusto Velloso, Eliana Pereira de Araújo

Glutamic Acid is the main excitatory neurotransmitter in neurons. Abnormal distributions of the glutamic acid receptors have been shown in hyper proliferative models such as psoriasis and skin regeneration. However, the biological function of glutamic acid in the skin remains unclear. Using ex vivo, in vivo and in silico approaches, we showed for the first time that exogenous glutamic acid promotes hair growth and keratinocyte proliferation. Topical application of glutamic acid decreased expression of genes related to apoptosis signaling in the skin. Also, we showed Glutamic acid increased viability and proliferation in cultured human keratinocyte. For the first time, we identified the excitotoxic GA concentration and we provided evidence for the existence of a novel skin signaling pathway mediated by a neurotransmitter controlling keratinocyte and hair follicle proliferation. In perspective, we anticipate our results could be the starting point to elucidate how exogenous glutamic acid from food intake or even endogenous GA from neuropsychiatric disorders modulate skin diseases. ### Competing Interest Statement The authors have declared no competing interest.

42: Time-restricted feeding prolongs lifespan in Drosophila in a peripheral clock-dependent manner
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Posted 15 Sep 2020

Time-restricted feeding prolongs lifespan in Drosophila in a peripheral clock-dependent manner
1 tweet bioRxiv physiology

Daniel Cabrera, Michael W. Young, Sofia Axelrod

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.

43: Ambroxol Hydrochloride Inhibits the Interaction between Severe Acute Respiratory Syndrome Coronavirus 2 Spike Protein’s Receptor Binding Domain and Recombinant Human ACE2
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Posted 14 Sep 2020

Ambroxol Hydrochloride Inhibits the Interaction between Severe Acute Respiratory Syndrome Coronavirus 2 Spike Protein’s Receptor Binding Domain and Recombinant Human ACE2
1 tweet bioRxiv pharmacology and toxicology

Omonike A Olaleye, Manvir Kaur, Collins C. Onyenaka

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), enters the host cells through two main pathways, both involving key interactions between viral envelope-anchored spike glycoprotein of the novel coronavirus and the host receptor, angiotensin-converting enzyme 2 (ACE2). To date, SARS-CoV-2 has infected up to 26 million people worldwide; yet, there is no clinically approved drug or vaccine available. Therefore, a rapid and coordinated effort to re-purpose clinically approved drugs that prevent or disrupt these critical entry pathways of SARS-CoV-2 spike glycoprotein interaction with human ACE2, could potentially accelerate the identification and clinical advancement of prophylactic and/or treatment options against COVID-19, thus providing possible countermeasures against viral entry, pathogenesis and survival. Herein, we discovered that Ambroxol hydrochloride (AMB), and its progenitor, Bromhexine hydrochloride (BHH), both clinically approved drugs are potent effective modulators of the key interaction between the receptor binding domain (RBD) of SARS-CoV-2 spike protein and human ACE2. We also found that both compounds inhibited SARS-CoV-2 infection-induced cytopathic effect at micromolar concentrations. Therefore, in addition to the known TMPRSS2 activity of BHH; we report for the first time that the BHH and AMB pharmacophore has the capacity to target and modulate yet another key protein-protein interaction essential for the two known SARS-CoV-2 entry pathways into host cells. Altogether, the potent efficacy, excellent safety and pharmacologic profile of both drugs along with their affordability and availability, makes them promising candidates for drug repurposing as possible prophylactic and/or treatment options against SARS-CoV-2 infection. ### Competing Interest Statement The authors have declared no competing interest.

44: A prefusion SARS-CoV-2 spike RNA vaccine is highly immunogenic and prevents lung infection in non-human primates
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Posted 08 Sep 2020

A prefusion SARS-CoV-2 spike RNA vaccine is highly immunogenic and prevents lung infection in non-human primates
1 tweet 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][1]). ### 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. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04368728&atom=%2Fbiorxiv%2Fearly%2F2020%2F09%2F08%2F2020.09.08.280818.atom

45: The Effect of Population Structure on Murine Genome-Wide Association Studies
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Posted 03 Sep 2020

The Effect of Population Structure on Murine Genome-Wide Association Studies
1 tweet bioRxiv genetics

Meiyue Wang, Zhuoqing Fang, Boyoung Yoo, Gill Bejerano, Gary Peltz

Population structure (PS) has been shown to cause false positive signals in genome-wide association studies (GWAS). Since PS correction is routinely used in human GWAS, it was assumed that it also should be utilized for murine GWAS using inbred strains. Nevertheless, there are fundamental differences between murine and human GWAS, and the impact of PS on murine GWAS results has not been thoroughly investigated. To assess the impact of PS on murine GWAS, we examined 8223 datasets that characterized biomedical responses in panels of inbred mouse strains. Surprisingly, we found that the PS had a minimal impact on datasets characterizing responses in <20 strains; and relatively little impact on the majority of datasets characterizing >20 strains. Moreover, there were examples where association signals within known causative genes could be rejected if PS correction methods were utilized. PS assessment should be carefully used and should be considered in conjunction with other criteria when assessing the candidate genes identified in GWAS using inbred mouse strains.

46: DNA methylation signatures of duplicate gene evolution in angiosperms
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Posted 31 Aug 2020

DNA methylation signatures of duplicate gene evolution in angiosperms
1 tweet bioRxiv plant biology

Sunil K. Kenchanmane Raju, S. Marshall Ledford, Chad Niederhuth

Gene duplications have greatly shaped the gene content of plants. Multiple factors, such as the epigenome, can shape the subsequent evolution of duplicate genes and are the subject of ongoing study. We analyze genic DNA methylation patterns in 43 angiosperm species and 928 Arabidopsis thaliana ecotypes to finding differences in the association of whole-genome and single-gene duplicates with genic DNA methylation patterns. Whole-genome duplicates were enriched for patterns associated with higher gene expression and depleted for patterns of non-CG DNA methylation associated with gene silencing. Single-gene duplicates showed variation in DNA methylation patterns based on modes of duplication (tandem, proximal, transposed, and dispersed) and species. Age of gene duplication was a key factor in the DNA methylation of single-gene duplicates. In single-gene duplicates, non-CG DNA methylation patterns associated with silencing were younger, less conserved, and enriched for presence-absence variation. In comparison, DNA methylation patterns associated with constitutive expression were older and more highly conserved. Surprisingly, across the phylogeny, genes marked by non-CG DNA methylation were enriched for duplicate pairs with evidence of positive selection. We propose that DNA methylation has a role in maintaining gene-dosage balance and silencing by non-CG methylation and may facilitate the evolutionary fate of duplicate genes.

47: Individual-based simulations of genome evolution with ancestry: the GENOMEADMIXR R package
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Posted 19 Oct 2020

Individual-based simulations of genome evolution with ancestry: the GENOMEADMIXR R package
1 tweet bioRxiv bioinformatics

Thijs Janzen, Fernando Diaz

Hybridization between populations or species results in a mosaic of the two parental genomes. Genome admixture has received increasing attention for its implications in speciation, human evolution, Evolve and Resequencing (E&R) and genetic mapping. However, a thorough understanding of how local ancestry changes after admixture, and how selection affects patterns of local ancestry remains elusive. The complexity of these questions limits analytical treatment, but these scenarios are specifically suitable for simulation. Currently, there is no simulation framework that models whole-genome evolution of local ancestry following admixture. Here, we present the R package GENOMEADMIXR, which uses an individual-based model to simulate genomic patterns of local ancestry following admixture forward in time. GENOMEADMIXR provides user-friendly functions to set up and analyze simulations under evolutionary scenarios with selection, linkage and migration. We show the flexible functionality of the GENOMEADMIXR workflow by demonstrating 1) how to design an E&R simulation using GENOMEADMIXR and 2) how to use GENOMEADMIXR to verify analytical expectations following from the theory of junctions. GENOMEADMIXR provides a mechanistic approach to explore expected genome responses to realistic admixture scenarios. With this package, we aim to aid researchers in testing specific hypotheses based on empirical findings involving admixing populations. ### Competing Interest Statement The authors have declared no competing interest.

48: Serotonin neurons modulate learning rate through uncertainty
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Posted 24 Oct 2020

Serotonin neurons modulate learning rate through uncertainty
1 tweet bioRxiv neuroscience

Cooper D Grossman, Bilal A. Bari, Jeremiah Y. Cohen

Regulating how fast to learn is critical for flexible behavior. Learning about the consequences of actions should be slow in stable environments, but accelerate when that environment changes. Recognizing stability and detecting change is difficult in environments with noisy relationships between actions and outcomes. Under these conditions, theories propose that uncertainty can be used to modulate learning rates ("meta-learning"). We show that mice behaving in a dynamic foraging task exhibit choice behavior that varied as a function of two forms of uncertainty estimated from a meta-learning model. The activity of dorsal raphe serotonin neurons tracked both types of uncertainty in the foraging task, as well as in a dynamic Pavlovian task. Reversible inhibition of serotonin neurons in the foraging task reproduced changes in learning predicted by a simulated lesion of meta-learning in the model. We thus provide a quantitative link between serotonin neuron activity, learning, and decision making. ### Competing Interest Statement The authors have declared no competing interest.

49: Towards end-to-end disease prediction from raw metagenomic data
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Posted 29 Oct 2020

Towards end-to-end disease prediction from raw metagenomic data
1 tweet bioRxiv genomics

Maxence Queyrel, Edi Prifti, Alexandre Templier, Jean-Daniel Zucker

Analysis of the human microbiome using metagenomic sequencing data has demonstrated high ability in discriminating various human diseases. Raw metagenomic sequencing data require multiple complex and computationally heavy bioinformatics steps prior to data analysis. Such data contain millions of short sequences read from the fragmented DNA sequences and are stored as fastq files. Conventional processing pipelines consist multiple steps including quality control, filtering, alignment of sequences against genomic catalogs (genes, species, taxonomic levels, functional pathways, etc.). These pipelines are complex to use, time consuming and rely on a large number of parameters that often provide variability and impact the estimation of the microbiome elements. Recent studies have demonstrated that training Deep Neural Networks directly from raw sequencing data is a promising approach to bypass some of the challenges associated with mainstream bioinformatics pipelines. Most of these methods use the concept of word and sentence embeddings that create a meaningful and numerical representation of DNA sequences, while extracting features and reducing the dimentionality of the data. In this paper we present an end-to-end approach that classifies patients into disease groups directly from raw metagenomic reads: metagenome2vec. This approach is composed of four steps (i) generating a vocabulary of k-mers and learning their numerical embeddings; (ii) learning DNA sequence (read) embeddings; (iii) identifying the genome from which the sequence is most likely to come and (iv) training a multiple instance learning classifier which predicts the phenotype based on the vector representation of the raw data. An attention mechanism is applied in the network so that the model can be interpreted, assigning a weight to the influence of the prediction for each genome. Using two public real-life data-sets as well a simulated one, we demonstrated that this original approach reached very high performances, comparable with the state-of-the-art methods applied directly on processed data though mainstream bioinformatics workflows. These results are encouraging for this proof of concept work. We believe that with further dedication, the DNN models have the potential to surpass mainstream bioinformatics workflows in disease classification tasks.

50: Robust SARS-CoV-2-specific T-cell immunity is maintained at 6 months following primary infection
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Posted 02 Nov 2020

Robust SARS-CoV-2-specific T-cell immunity is maintained at 6 months following primary infection
1 tweet bioRxiv immunology

Jianmin Zuo, Alex Dowell, Hayden Pearce, Kriti Verma, Heather Long, Jusnara Begum, Felicity Aiano, Zahin Amin-Chowdhury, Bassam Hallis, Lorrain Stapley, Ray Borrow, Ezra Linley, Shazaad Ahmad, Ben Parker, Alex Horsley, Gayatri Amirthalingam, Kevin Brown, Mary E Ramsay, Shamez N Ladhani, Paul Moss

The immune response to SARS-CoV-2 is critical in both controlling primary infection and preventing re-infection. However, there is concern that immune responses following natural infection may not be sustained and that this may predispose to recurrent infection. We analysed the magnitude and phenotype of the SARS-CoV-2 cellular immune response in 100 donors at six months following primary infection and related this to the profile of antibody level against spike, nucleoprotein and RBD over the previous six months. T-cell immune responses to SARS-CoV-2 were present by ELISPOT or ICS analysis in all donors and are characterised by predominant CD4+ T cell responses with strong IL-2 cytokine expression. Median T-cell responses were 50% higher in donors who had experienced an initial symptomatic infection indicating that the severity of primary infection establishes a set-point for cellular immunity that lasts for at least 6 months. The T-cell responses to both spike and nucleoprotein/membrane proteins were strongly correlated with the peak antibody level against each protein. The rate of decline in antibody level varied between individuals and higher levels of nucleoprotein-specific T cells were associated with preservation of NP-specific antibody level although no such correlation was observed in relation to spike-specific responses. In conclusion, our data are reassuring that functional SARS-CoV-2-specific T-cell responses are retained at six months following infection although the magnitude of this response is related to the clinical features of primary infection. ### Competing Interest Statement The authors have declared no competing interest.

51: Experimental evolution of adaptive divergence under varying degrees of gene flow
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Posted 03 Nov 2020

Experimental evolution of adaptive divergence under varying degrees of gene flow
1 tweet bioRxiv evolutionary biology

Sergio Tusso, Bart P.S. Nieuwenhuis, Bernadette Weissensteiner, Simone Immler, Jochen B. W. Wolf

Adaptive divergence is the key evolutionary process generating biodiversity by means of natural selection. Yet, the conditions under which it can arise in the presence of gene flow remain contentious. To address this question, we subjected 132 sexually reproducing fission yeast populations sourced from two independent genetic backgrounds to disruptive ecological selection and manipulated the level of migration between environments. Contrary to theoretical expectations, adaptive divergence was most pronounced when migration was either absent ("allopatry") or maximal ("sympatry"), but was much reduced at intermediate rates ("parapatry", "local mating"). This effect was apparent across central life history components (survival, asexual growth, and mating), but differed in magnitude between ancestral genetic backgrounds. The evolution of some fitness components was constrained by pervasive negative correlations (trade-off between asexual growth and mating), while others changed direction under the influence of migration (e.g. survival and mating). In allopatry, adaptive divergence was mainly conferred by standing genetic variation and resulted in ecological specialization. In sympatry, divergence was mainly mediated by novel mutations enriched in a subset of genes and was characterized by the repeated emergence of two strategies: an ecological generalist and an asexual growth specialist. Multiple loci showed consistent evidence for antagonistic pleiotropy across migration treatments and provide a conceptual link between adaptation and divergence. This evolve-and-resequence experiment demonstrates that rapid ecological differentiation can arise even under high rates of gene flow. It further highlights that adaptive trajectories are governed by complex interactions of gene flow, ancestral variation and genetic correlations. ### Competing Interest Statement The authors have declared no competing interest.

52: Leprosy in wild chimpanzees
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Posted 11 Nov 2020

Leprosy in wild chimpanzees
1 tweet bioRxiv evolutionary biology

Kimberley Jane Hockings, Benjamin Mubemba, Charlotte Avanzi, Kamilla Pleh, Ariane Dux, Elena Bersacola, Joana Bessa, Marina Ramon, Sonja Metzger, Livia V Patrono, Jenny E Jaffe, Andrej Benjak, Camille Jane Bonneaud, Philippe Busso, Emmanuel Couacy-Hymann, Moussa Gado, Sebastien Gagneux, Roch C Johnson, Mamoudou Kodio, Joshua G Lynton-Jenkins, Irina Morozova, Kerstin Matz-Rensing, Aissa Regalla, Abilio R Said, Verena J. Schuenemann, Samba O Sow, John S Spencer, Markus Ulrich, Hyacinthe Zoubi, Stewart T Cole, Roman Wittig, Sebastien Calvignac-Spencer, Fabian H Leendertz

Humans are considered the main host for Mycobacterium leprae, the aetiologic agent of leprosy, but spill-over to other mammals such as nine-banded armadillos and red squirrels occurs. Although naturally acquired leprosy has also been described in captive nonhuman primates, the exact origins of infection remain unclear. Here, we report on leprosy-like lesions in two wild populations of western chimpanzees (Pan troglodytes verus) in the Cantanhez National Park, Guinea-Bissau, and the Tai National Park, Cote d'Ivoire, West Africa. Longitudinal monitoring of both populations revealed the progression of disease symptoms compatible with advanced leprosy. Screening of faecal and necropsy samples confirmed the presence of M. leprae as the causative agent at each site and phylogenomic comparisons with other strains from humans and other animals show that the chimpanzee strains belong to different and rare genotypes (4N/O and 2F). The independent evolutionary origin of M. leprae in two geographically distant populations of wild chimpanzees, with no prolonged direct contact with humans, suggests multiple introductions of M. leprae from an unknown animal or environmental source. ### Competing Interest Statement The authors have declared no competing interest.

53: Immunological memory to SARS-CoV-2 assessed for up to eight months after infection
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Posted 16 Nov 2020

Immunological memory to SARS-CoV-2 assessed for up to eight months after infection
1 tweet bioRxiv immunology

Jennifer M Dan, Jose Mateus, Yu Kato, Kathryn M Hastie, Esther Dawen Yu, Caterina E. Faliti, Alba Grifoni, Sydney I Ramirez, Sonya Haupt, April Frazier, Catherine Nakao, Vamseedhar Rayaprolu, Stephen A Rawlings, Bjoern Peters, Florian Krammer, Viviana Simon, Erica Ollmann Saphire, Davey M Smith, Daniela Weiskopf, Alessandro Sette, Shane Crotty

Understanding immune memory to SARS-CoV-2 is critical for improving diagnostics and vaccines, and for assessing the likely future course of the COVID-19 pandemic. We analyzed multiple compartments of circulating immune memory to SARS-CoV-2 in 254 samples from 188 COVID-19 cases, including 43 samples at [&ge;] 6 months post-infection. IgG to the Spike protein was relatively stable over 6+ months. Spike-specific memory B cells were more abundant at 6 months than at 1 month post symptom onset. SARS-CoV-2-specific CD4+ T cells and CD8+ T cells declined with a half-life of 3-5 months. By studying antibody, memory B cell, CD4+ T cell, and CD8+ T cell memory to SARS-CoV-2 in an integrated manner, we observed that each component of SARS-CoV-2 immune memory exhibited distinct kinetics.

54: COVID-19-associated olfactory dysfunction reveals SARS-CoV-2 neuroinvasion and persistence in the olfactory system
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Posted 18 Nov 2020

COVID-19-associated olfactory dysfunction reveals SARS-CoV-2 neuroinvasion and persistence in the olfactory system
1 tweet bioRxiv neuroscience

Guilherme Dias De Melo, Francoise Lazarini, Sylvain Levallois, Charlotte Hautefort, Vincent Michel, Florence Larrous, Benjamin Verillaud, Caroline Aparicio, Sebastien Wagner, Gilles Gheusi, Lauriane Kergoat, Etienne Kornobis, Thomas Cokelaer, Remi Hervochon, Yoann Madec, Emmanuel Roze, Dominique Salmon, Herve Bourhy, Marc Lecuit, Pierre-Marie Lledo

While recent investigations have revealed viral, inflammatory and vascular factors involved in SARS-CoV-2 lung pathogenesis, the pathophysiology of neurological disorders in COVID-19 remains poorly understood. Yet, olfactory and taste dysfunction are rather common in COVID-19, especially in pauci-symptomatic patients which constitutes the most frequent clinical manifestation of the infection. We conducted a virologic, molecular, and cellular study of the olfactory system from COVID-19 patients presenting acute loss of smell, and report evidence that the olfactory epithelium represents a highly significant infection site where multiple cell types, including olfactory sensory neurons, support cells and immune cells, are infected. Viral replication in the olfactory epithelium is associated with local inflammation. Furthermore, we show that SARS-CoV-2 induces acute anosmia and ageusia in golden Syrian hamsters, both lasting as long as the virus remains in the olfactory epithelium and the olfactory bulb. Finally, olfactory mucosa sampling in COVID-19 patients presenting with persistent loss of smell reveals the presence of virus transcripts and of SARS-CoV-2-infected cells, together with protracted inflammation. Viral persistence in the olfactory epithelium therefore provides a potential mechanism for prolonged or relapsing symptoms of COVID-19, such as loss of smell, which should be considered for optimal medical management and future therapeutic strategies. ### Competing Interest Statement The authors have declared no competing interest.

55: Complement Component 3 expressed by the endometrial ectopic tissue is involved in the endometriotic lesion formation through mast cell activation
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Posted 20 Nov 2020

Complement Component 3 expressed by the endometrial ectopic tissue is involved in the endometriotic lesion formation through mast cell activation
1 tweet bioRxiv immunology

Chiara Agostinis, Sonia Zorzet, Andrea Balduit, Gabriella Zito, Alessandro Mangogna, Paolo Macor, Federico Romano, Miriam Toffoli, Beatrice Belmonte, Anna Martorana, Violetta Borelli, Giuseppe Ricci, Uday Kishore, Roberta Bulla

The pathophysiology of endometriosis (EM) is an excellent example of immune dysfunction, reminiscent of tumor microenvironment as well. Here, we report that an interplay between C3 and mast cells (MCs) is involved in the pathogenesis of ectopic EM. C3 is at the epicenter of the regulatory feed forward loop, amplifying the inflammatory microenvironment, in which the MCs are protagonists. Thus, C3 can be considered a marker of EM and its local synthesis can promote the engraftment of the endometriotic cysts. We generated a murine model of EM via injection of minced uterine tissue from a donor mouse, into the peritoneum of the recipient mice. The wild type mice showed greater amount of cyst formation in the peritoneum compared to C3 knock-out mice. This study offers an opportunity for novel therapeutic intervention in EM, a difficult to treat gynecological condition.

56: A Synthetic Defective Interfering SARS-CoV-2
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Posted 23 Nov 2020

A Synthetic Defective Interfering SARS-CoV-2
1 tweet bioRxiv synthetic biology

Shun Yao, Anoop Narayanan, Sydney Majowicz, Joyce Jose, Marco Archetti

Viruses thrive by exploiting the cells they infect but must also produce viral proteins to replicate and infect other cells. As a consequence, they are also susceptible to exploitation by defective versions of themselves that do not produce such proteins. A defective viral genome with deletions in protein-coding genes could still replicate in cells coinfected with full-length viruses, and even replicate faster due to its shorter size, interfering with the replication of the virus. We have created a synthetic defective interfering version of SARS-CoV-2, the virus causing the recent Covid-19 pandemic, assembling parts of the viral genome that do not code for any functional protein but enable it to be replicated and packaged. This synthetic defective genome replicates three times faster than SARS-CoV-2 in coinfected cells, and interferes with it, reducing the viral load of a cell by half in 24 hours. The synthetic genome is transmitted as efficiently as the full-length genome, confirming the location of the putative packaging signal of SARS-CoV-2. A version of such a synthetic construct could be used as a self-promoting antiviral therapy: by enabling replication of the synthetic genome, the virus promotes its own demise.

57: A Nasal Spray Solution of Grapefruit Seed Extract plus Xylitol Displays Virucidal Activity Against SARS-Cov-2 In Vitro
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Posted 25 Nov 2020

A Nasal Spray Solution of Grapefruit Seed Extract plus Xylitol Displays Virucidal Activity Against SARS-Cov-2 In Vitro
1 tweet bioRxiv cell biology

Gustavo A Ferrer, Arian Betancour, Camille C Go, Hector Vazquez, Jonna B. Westover, Valeria Cagno, Caroline Tapparel, Marcos A Sanchez-Gonzalez

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the ongoing pandemic coronavirus disease 2019 (COVID-19) has triggered worldwide concerted efforts in an attempt to identify effective therapies. In the present study, we have identified two candidate agents with potential activity against SARS-CoV-2 which can be administered intranasally, namely, xylitol and grape seed fruit extract (GSE). A commercially available nasal spray (Xlear) combining xylitol and GSE has been available for years, but the antiviral effects of this solution have not been documented. This in vitro study examined the virucidal effect of Xlear against SARS-CoV-2. To this end, two independent sets of experiments were carried out to test the hypothesis that Xlear is an effective (Experiment I) and replicable (Experiment II) means to deactivate SARS-CoV-2. When tested against SARS-CoV-2, the test compound GSE 0.2% was the only compound effective at reducing >3 log10 CCID50 infectious virus from, 3.67 log10 CCID50/0.1 mL to an undetectable amount of infectious virus. The present results validated by two independent sets of experiments, performed by different labs, on different viral strains, provide early evidence to encourage further pilot and clinical studies aimed at investigating the use of Xlear as a potential treatment for COVID-19

58: Gut microbiome couples gut and brain during calorie restriction in treating obesity
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Posted 05 Dec 2020

Gut microbiome couples gut and brain during calorie restriction in treating obesity
1 tweet bioRxiv microbiology

Qiang Zeng, Qi Wang, Tianyuan Xiang, Lei Ou, Xiaoling Wu, Kaiye Cai, Chunyu Geng, Mo Han, Zhongxia Li, Zhonglin Li, Wen Wang, Tingting Yang, Fengyun Li, Huimin Ma, Xiaojuan Zhao, Hui Gao, Na Mi, Chi Zhang, Li Tong, Linyuan Wang, Bin Yan, Ziya Yu, Canhui Lan, Ziyu Wang, Xiaoning Wang, Yongli Li, Jun Wang

Calorie restriction (CR) has been widely recognized for its effect in reducing body weight and alleviating diabetes in humans, as well as prolonging life span in animal studies. Gut microbiome shifts contribute to part of the effects of CR, but little is known regarding their influences except on metabolism and immunity. Here we monitored gut microbiome using metagenomics and metatranscriptomics in obese individuals undergoing CR, and revealed microbial determinants that could contribute to successful weight loss. Microbiome changes are linked to changes in blood metabolome and hormones, which eventually correlate to brain functional changes as studied using functional magnetic resonance imaging (fMRI). Brain functional shifts indicate response of central neural system (CNS) to CR, and microbiome constitutes the keystone of gut-brain axis. Animal experiment further reaffirms the gut microbiome changes, metabolic and hormonal shifts of CR, while proteomic analysis of brain tissues suggest that epigenetic modifications of key proteins could explain responses of CNS to CR. Our study establishes linkage between CR, gut microbiome, metabolome/ hormones and CNS function, and demonstrates that CR has multi-facet, coordinated effects on the host, of which many could contribute to weight loss and other beneficial effects.

59: SARS-CoV-2 Requires Cholesterol for Viral Entry and Pathological Syncytia Formation
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Posted 14 Dec 2020

SARS-CoV-2 Requires Cholesterol for Viral Entry and Pathological Syncytia Formation
1 tweet bioRxiv cell biology

David W. Sanders, Chanelle C. Jumper, Paul J. Ackerman, Dan Bracha, Anita Donlic, Hahn Kim, Devin Kenney, Ivan Castello-Serrano, Saori Suzuki, Tomokazu Tamura, Alexander H. Tavares, Mohsan Saeed, Alex S. Holehouse, Alexander Ploss, Ilya Levental, Florian Douam, Robert F. Padera, Bruce D. Levy, Clifford P. Brangwynne

Many enveloped viruses induce multinucleated cells (syncytia), reflective of membrane fusion events caused by the same machinery that underlies viral entry. These syncytia are thought to facilitate replication and evasion of the host immune response. Here, we report that co-culture of human cells expressing the receptor ACE2 with cells expressing SARS-CoV-2 spike, results in synapse-like intercellular contacts that initiate cell-cell fusion, producing syncytia resembling those we identify in lungs of COVID-19 patients. To assess the mechanism of spike/ACE2-driven membrane fusion, we developed a microscopy-based, cell-cell fusion assay to screen ~6000 drugs and >30 spike variants. Together with cell biological and biophysical approaches, the screen reveals an essential role for membrane cholesterol in spike-mediated fusion, which extends to replication-competent SARS-CoV-2 isolates. Our findings provide a molecular basis for positive outcomes reported in COVID-19 patients taking statins, and suggest new strategies for therapeutics targeting the membrane of SARS-CoV-2 and other fusogenic viruses.

60: Learning to use episodic memory for event prediction
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Posted 16 Dec 2020

Learning to use episodic memory for event prediction
1 tweet bioRxiv neuroscience

Qihong Lu, Uri Hasson, Kenneth A. Norman

When should episodic memories be stored and retrieved to support event understanding? Traditional list-learning memory experiments make it obvious when to store and retrieve memories, but it is less obvious when to do this in naturalistic settings. To address this question, we trained a memory-augmented neural network to predict upcoming events, in an environment where situations (sets of parameters governing transitions between events) sometimes reoccurred. The model was allowed to learn a policy for when to consult episodic memory, and we explored how this learned policy varied as a function of the task environment. We found that the learned retrieval policy is shaped by internal uncertainty about upcoming events, the level of penalty associated with incorrect predictions, the confusability of stored memories, the presence of a "familiarity signal" indicating the availability of relevant memories, and the presence of statistical regularities (prototypical events). With regard to encoding policy, we found that selectively storing episodic memories at the end of an event (but not mid-event) leads to better subsequent event prediction performance and less incorrect recall. Additionally, we found that the model can integrate information over long timescales even without the hippocampus; it can link information over many event segments via episodic memory; and it shows classic schema-consistent memory effects when the upcoming time point has a prototypical event. Overall, these modeling results provide a normative explanation of several existing behavioral and neuroimaging findings regarding the use of episodic memory in naturalistic settings, and lead to a wide range of testable predictions.

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