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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.

21: Increased Expression of Chondroitin Sulfotransferases following AngII may Contribute to Pathophysiology Underlying Covid-19 Respiratory Failure: Impact may be Exacerbated by Decline in Arylsulfatase B Activity
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Posted 25 Jun 2020

Increased Expression of Chondroitin Sulfotransferases following AngII may Contribute to Pathophysiology Underlying Covid-19 Respiratory Failure: Impact may be Exacerbated by Decline in Arylsulfatase B Activity
2 tweets bioRxiv biochemistry

Sumit Bhattacharyya, Kumar Kotlo, Joanne Kramer Tobacman

The precise mechanisms by which Covid-19 infection leads to hypoxia and respiratory failure have not yet been elucidated. Interactions between sulfated glycosaminoglycans (GAGs) and the SARS-CoV-2 spike glycoprotein have been identified as participating in viral adherence and infectivity. The spike glycoprotein binds to respiratory epithelium through the angiotensin converting enzyme 2 (ACE2) receptor, which endogenously interacts with Angiotensin (Ang) II to yield Angiotensin 1-7. In this report, we show that stimulation of human vascular smooth muscle cells by Ang II leads to increased mRNA expression of two chondroitin sulfotransferases (CHST11 and CHST15), which are required for synthesis of chondroitin 4-sulfate (C4S) and chondroitin 4,6-disulfate (CSE), respectively. Also, increased total sulfated GAGs, increased sulfotransferase activity, and increased expression of the proteoglycans biglycan, syndecan, perlecan, and versican followed treatment by Ang II. Candesartan, an Angiotensin II receptor blocker (Arb), largely, but incompletely, inhibited these increases, and the differences from baseline remained significant. These results suggest that another effect of Ang II also contributes to the increased expression of chondroitin sulfotransferases, total sulfated GAGs, and proteoglycans. We hypothesize that activation of ACE2 may contribute to these increases and suggest that the SARS-CoV-2 spike glycoprotein interaction with ACE2 may also increase chondroitin sulfotransferases, sulfated GAGs, and proteoglycans and thereby contribute to viral adherence to bronchioalveolar cells and to respiratory compromise in SARS-CoV-2 infection.

22: Muscle strength, size and composition following 12 months of gender-affirming treatment in transgender individuals: retained advantage for the transwomen
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Posted 26 Sep 2019

Muscle strength, size and composition following 12 months of gender-affirming treatment in transgender individuals: retained advantage for the transwomen
2 tweets bioRxiv physiology

A Wiik, TR Lundberg, E Rullman, DP Andersson, M Holmberg, M Mandić, TB Brismar, O Dahlqvist Leinhard, S Chanpen, J Flanagan, S Arver, T Gustafsson

Objectives: This study explored the effects of gender-affirming treatment, which includes inhibition of endogenous sex hormones and replacement with cross-sex hormones, on muscle function, size and composition in 11 transwomen (TW) and 12 transmen (TM). Methods: Isokinetic knee extensor and flexor muscle strength was assessed at baseline (T00), 4 weeks after gonadal suppression of endogenous hormones but before hormone replacement (T0), and 3 (T3) and 11 (T12) months after hormone replacement. In addition, at T00 and T12, we assessed lower-limb muscle volume using MRI, and cross-sectional area (CSA) and radiological density using CT. Results: Thigh muscle volume increased (15%) in TM, which was paralleled by increased quadriceps CSA (15%) and radiological density (6%). In TW, the corresponding parameters decreased by -5% (muscle volume) and -4% (CSA), while density remained unaltered. The TM increased strength over the assessment period, while the TW generally maintained or slightly increased in strength. Baseline muscle volume correlated highly with strength (R>0.75), yet the relative change in muscle volume and strength correlated only moderately (R=0.65 in TW and R=0.32 in TM). The absolute levels of muscle volume and knee extension strength after the intervention still favored the TW. Conclusion: Cross-sex hormone treatment markedly affects muscle strength, size and composition in transgender individuals. Despite the robust increases in muscle mass and strength in TM, the TW were still stronger and had more muscle mass following 12 months of treatment. These findings add new knowledge that could be relevant when evaluating transwomen's eligibility to compete in the women's category of athletic competitions.

23: Functional Immune Deficiency Syndrome via Intestinal Infection in COVID-19
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Posted 10 Apr 2020

Functional Immune Deficiency Syndrome via Intestinal Infection in COVID-19
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.

24: Ivermectin reduces coronavirus infection in vivo: a mouse experimental model
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Posted 02 Nov 2020

Ivermectin reduces coronavirus infection in vivo: a mouse experimental model
2 tweets bioRxiv pathology

Ana Paula Arevalo, Romina Pagotto, Jorge Porfido, Hellen Daghero, Mercedes Segovia, Kanji Yamasaki, Belen Varela, Marcelo Hill, Jose Manuel Verdes, Maite Duhalde Vega, Mariela Bollati-Fogolin, Martina Crispo

SARS-CoV2 is a single strand RNA virus member of the type 2 coronavirus family, responsible for causing COVID-19 disease in humans. The objective of this study was to test the ivermectin drug in a murine model of coronavirus infection using a type 2 family RNA coronavirus similar to SARS-CoV2, the mouse hepatitis virus (MHV). BALB/cJ female mice were infected with 6,000 PFU of MHV-A59 (Group Infected; n=20) and immediately treated with one single dose of 500 ug/kg of ivermectin (Group Infected + IVM; n=20), or were not infected and treated with PBS (Control group; n=16). Five days after infection/treatment, mice were euthanized to obtain different tissues to check general health status and infection levels. Overall results demonstrated that viral infection induces the typical MHV disease in infected animals, with livers showing severe hepatocellular necrosis surrounded by a severe lymphoplasmacytic inflammatory infiltration associated with a high hepatic viral load (52,158 AU), while ivermectin administration showed a better health status with lower viral load (23,192 AU; p<0.05) and few livers with histopathological damage (p<0.05), not showing statistical differences with control mice (P=NS). Furthermore, serum transaminase levels (aspartate aminotransferase and alanine aminotransferase) were significantly lower in treated mice compared to infected animals. In conclusion, ivermectin seems to be effective to diminish MHV viral load and disease in mice, being a useful model for further understanding new therapies against coronavirus diseases. ### Competing Interest Statement The authors have declared no competing interest.

25: High Throughput Computational Mouse Genetic Analysis
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Posted 01 Sep 2020

High Throughput Computational Mouse Genetic Analysis
2 tweets bioRxiv bioinformatics

Ahmed Arslan, YUAN GUAN, Xinyu Chen, Wan Zhu, Manhong Wu, Ming Zheng, David L. Dill, Gary Peltz, Robin Donaldson, Madeline Ford, Zhuoqing Fang

Background: Genetic factors affecting multiple biomedical traits in mice have been identified when GWAS data, which measured responses in panels of inbred mouse strains, was analyzed using haplotype-based computational genetic mapping (HBCGM). Although this method was previously used to analyze one dataset at a time; but now, a vast amount of mouse phenotypic data is now publicly available, which could enable many more genetic discoveries. Results: HBCGM and a whole genome SNP map covering 43 inbred strains was used to analyze 8300 publicly available datasets of biomedical responses (1.52M individual datapoints) measured in panels of inbred mouse strains. As proof of concept, causative genetic factors affecting susceptibility for eye, metabolic and infectious diseases were identified when structured automated methods were used to analyze the output. One analysis identified a novel genetic effector mechanism; allelic differences within the mitochondrial targeting sequence affected the subcellular localization of a protein. We also found allelic differences within the mitochondrial targeting sequences of many murine and human proteins, and these could affect a wide range of biomedical phenotypes. Implications: These initial results indicate that genetic factors affecting biomedical responses could be identified through analysis of very large datasets, and they provide an early indication of how this type of 'augmented intelligence' can facilitate genetic discovery. Abbreviations: cSNP, codon-changing SNP; GWAS, genome-wide association study; HBCGM, haplotype-based computational genetic mapping; MTS, Mitochondrial targeting sequence.

26: Genotype-phenotype map of an RNA-ligand complex
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Posted 17 Dec 2020

Genotype-phenotype map of an RNA-ligand complex
2 tweets bioRxiv synthetic biology

Olga Puchta, Grzegorz Sobczyk, Vanessa Smer-Barreto, Hollie Ireland, Marc Vendrell, Diego A. Oyarzún, Janusz M. Bujnicki, Graeme Whyte, Grzegorz Kudla

RNA-ligand interactions play important roles in biology and biotechnology, but they often involve complex three-dimensional folding of RNA and are difficult to predict. To systematically explore the phenotypic landscape of an RNA-ligand complex, we used microarrays to investigate all possible single and double mutants of the 49-nt RNA aptamer Broccoli bound to the fluorophore DFHBI-1T. We collected more than seven million fluorescence measurements in varying conditions, and inferred dissociation rate constants, spectral shifts, and intragenic epistasis. Our results reveal an unexpectedly complex phenotypic landscape, in which mutations near the fluorophore binding pocket modulated magnesium-, potassium- and fluorophore-binding and fluorescence spectra, while distal mutations influenced structural stability and fluorescence intensity. We trained a machine learning model that accurately predicted RNA secondary structure from local epistatic interactions, despite the presence of G-quadruplexes and other noncanonical structures. Our experimental platform will facilitate the discovery and analysis of new RNA-ligand interactions.

27: Vimentin intermediate filaments mediate cell shape on visco-elastic substrates
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Posted 08 Sep 2020

Vimentin intermediate filaments mediate cell shape on visco-elastic substrates
2 tweets bioRxiv biophysics

Maxx Swoger, Sarthak Gupta, Elisabeth E. Charrier, Michael Bates, Heidi Hehnly, Alison Patteson

The ability of cells to take and change shape is a fundamental feature underlying development, wound repair, and tissue maintenance. Central to this process is physical and signaling interactions between the three cytoskeletal polymeric networks: F-actin, microtubules, and intermediate filaments (IFs). Vimentin is an IF protein that is essential to the mechanical resilience of cells and regulates cross-talk amongst the cytoskeleton, but its role in how cells sense and respond to the surrounding extracellular matrix is largely unclear. To investigate vimentin’s role in substrate sensing, we designed polyacrylamide hydrogels that mimic the elastic and viscoelastic nature of in vivo tissues. Using wild-type and vimentin-null mouse embryonic fibroblasts, we show that vimentin enhances cell spreading on viscoelastic substrates, even though it has little effect in the limit of purely elastic substrates. Our results provide compelling evidence that the vimentin cytoskeletal network is a physical modulator of how cells sense and respond to mechanical properties of their extracellular environment. ### Competing Interest Statement The authors have declared no competing interest.

28: Resveratrol And Pterostilbene Potently Inhibit SARS-CoV-2 Infection In Vitro
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Posted 24 Sep 2020

Resveratrol And Pterostilbene Potently Inhibit SARS-CoV-2 Infection In Vitro
2 tweets bioRxiv microbiology

B.M. Ellen ter, N. Dinesh Kumar, E.M. Bouma, B. Troost, D.P.I. Pol van de, H.H. Ende van der-Metselaar, L. Apperloo, D. Gosliga van, M. Berge van den, M.C. Nawijn, P.H.J. Voort van der, J. Moser, I.A. Rodenhuis-Zybert, J.M. Smit

The current COVID-19 pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has an enormous impact on human health and economy[1][1]. In search for therapeutic options, researchers have proposed resveratrol, a food supplement with known antiviral, anti-inflammatory and anti-oxidant properties as an advantageous antiviral therapy for SARS-CoV-2 infection[2][2]–[4][3]. Here, we provide evidence that both resveratrol and its metabolically more stable structural analog, pterostilbene, exhibits potent antiviral properties against SARS-CoV-2 in vitro . Resveratrol and pterostilbene showed antiviral activity in African green monkey kidney cells and in human primary bronchial epithelial cells cultured in an air-liquid interface system. Mechanistic analyses demonstrated that both compounds actively interfere with the post-entry steps of virus replication cycle and their antiviral activity is long-lasting. Collectively, our data indicate that resveratrol and pterostilbene are promising antiviral compounds to treat SARS-CoV-2 infection and advocate evaluation of these compounds in clinical trials ### Competing Interest Statement The authors have declared no competing interest. [1]: #ref-1 [2]: #ref-2 [3]: #ref-4

29: Courtship behaviour reveals temporal regularity is a critical social cue in mouse communication
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Posted 28 Jan 2020

Courtship behaviour reveals temporal regularity is a critical social cue in mouse communication
2 tweets bioRxiv neuroscience

Catherine Perrodin, Colombine Verzat, Daniel Bendor

While animals navigating the real world face a barrage of sensory input, their brains evolved to perceptually compress multidimensional information by selectively extracting the features relevant for survival. Notably, communication signals supporting social interactions in several mammalian species consist of acoustically complex sequences of vocalizations. However, little is known about what information listeners extract from such time-varying sensory streams. Here, we utilize female mice’s natural behavioural response to male courtship songs to identify the relevant acoustic dimensions used in their social decisions. We found that females were highly sensitive to disruptions of song temporal regularity, and preferentially approached playbacks of intact over rhythmically irregular versions of male songs. In contrast, female behaviour was invariant to manipulations affecting the songs’ sequential organization, or the spectro-temporal structure of individual syllables. The results reveal temporal regularity as a key acoustic cue extracted by mammalian listeners from complex vocal sequences during goal-directed social behaviour. ### Competing Interest Statement The authors have declared no competing interest.

30: Lineage and Spatial Mapping of Glioblastoma-associated Immunity
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Posted 02 Jun 2020

Lineage and Spatial Mapping of Glioblastoma-associated Immunity
2 tweets bioRxiv cancer biology

Vidhya Madapusi Ravi, Nicolas Neidert, Paulina Will, Kevin Joseph, Jan Kuekelhaus, Lea Vollmer, Jonathan Goeldner, Simon Behringer, Florian Scherer, Melanie Boerries, Marie Follo, Tobias Weiss, Daniel Delev, Julius Kernbach, Pamela Franco, Nils Schallner, Christian Scheiwe, Maria Stella Carro, Ulrich G. Hofmann, Christian Fung, Juergen Beck, Roman Sankowski, Marco Prinz, Oliver Schnell, Dieter Henrik Heiland

The diversity of molecular states and cellular plasticity of immune cells in the glioblastoma environment is still poorly understood. Here, we performed scRNA sequencing of the immune compartment and mapped potential cellular interactions leading to an immunosuppressive microenvironment and dysfunction of T cells. Through inferring the dynamic adaptation during T cell activation, we identified three different terminal states with unique transcriptional programs. Modeling of driver genes for terminal T cell fate identified IL-10 signaling alterations in a subpopulation of HAVCR2(+) T cells. To explore in depth cellular interactions, we established an in-silico model by the integration of spatial transcriptomic and scRNA-sequencing, and identified a subset of HMOX1+ myeloid cells defined by IL10 release leading to T cell exhaustion. We found a spatial overlap between HMOX(+) myeloid and HAVCR2(+) T cells, suggesting that myeloid-lymphoid interaction causes immunosuppression present in tumor regions with enriched mesenchymal gene expression. Using human neocortical GBM model, coupled with patient-derived T cells, we confirmed that the functional interaction between myeloid and lymphoid cells, leads to a dysfunctional state of T cells. This IL-10 driven T cell exhaustion was found to be rescued by JAK/STAT inhibition. A comprehensive understanding of the cellular states and plasticity of lymphoid cells in GBM will aid towards successful immuno-therapeutic approaches.

31: UFold: Fast and Accurate RNA Secondary Structure Prediction with Deep Learning
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Posted 18 Aug 2020

UFold: Fast and Accurate RNA Secondary Structure Prediction with Deep Learning
2 tweets bioRxiv bioinformatics

Yingxin Cao, Laiyi Fu, Jie Wu, Qing Nie, Xiaohui Xie

For many RNA molecules, the secondary structure is essential for the correction function of the RNA. Predicting RNA secondary structure from nucleotide sequences is a long-standing problem in genomics, but the prediction performance has reached a plateau over time. Traditional RNA secondary structure prediction algorithms are primarily based on thermodynamic models through free energy minimization. Here we propose a deep learning-based method, called UFold, for RNA secondary structure prediction, trained directly on annotated data without any thermodynamic assumptions. UFold improves substantially upon previous models, with approximately 31% improvement over traditional thermodynamic models and 24.5% improvement over other learning-based methods. It achieves an F1 score of 0.96 on base pair prediction accuracy. An online web server running UFold is publicly available at https://ufold.ics.uci.edu.

32: Open Science Saves Lives: Lessons from the COVID-19 Pandemic
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Posted 14 Aug 2020

Open Science Saves Lives: Lessons from the COVID-19 Pandemic
2 tweets bioRxiv scientific communication and education

Lonni Besançon, Nathan Peiffer-Smadja, Corentin Segalas, Haiting Jiang, Paola Masuzzo, Cooper A Smout, Eric Billy, Maxime Deforet, Clémence Leyrat

In the last decade Open Science principles, such as Open Access, study preregistration, use of preprints, making available data and code, and open peer review, have been successfully advocated for and are being slowly adopted in many different research communities. In response to the COVID-19 pandemic many publishers and researchers have sped up their adoption of some of these Open Science practices, sometimes embracing them fully and sometimes partially or in a sub-optimal manner. In this article, we express concerns about the violation of some of the Open Science principles and its potential impact on the quality of research output. We provide evidence of the misuses of these principles at different stages of the scientific process. We call for a wider adoption of Open Science practices in the hope that this work will encourage a broader endorsement of Open Science principles and serve as a reminder that science should always be a rigorous process, reliable and transparent, especially in the context of a pandemic where research findings are being translated into practice even more rapidly. We provide all data and scripts at https://osf.io/renxy/. ### Competing Interest Statement The authors have declared no competing interest.

33: Morphometric reconstructions atlas shows insult-driven plasticity in cortical VIP/ChAT interneurons
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Posted 25 Aug 2020

Morphometric reconstructions atlas shows insult-driven plasticity in cortical VIP/ChAT interneurons
2 tweets bioRxiv neuroscience

Nadav Yayon, Oren Amsalem, Amir Dudai, Or Yakov, Gil Adam, Marc Tessier-Lavigne, Nicolas Renier, Idan Segev, Mickey London, Hermona Soreq

We developed an automatic morphometric reconstruction pipeline, Pop-Rec, and used it to study the morphologies of cortical cholinergic VIP/ChAT interneurons (VChIs). Cholinergic networks control high cognitive functions, but their local modulation and stress-driven plasticity patterns remained elusive. Reconstructing thousands of local VChIs registered to their exact coordinates in multiple cleared murine cortices highlighted distinct populations of bipolar and multipolar VChIs which differed in their dendritic spatial organization. Following mild unilateral whisker deprivation, Pop-Rec found both ipsi-and contra-lateral VChI dendritic arborization changes. Furthermore, RNA-seq of FACS-sorted VChIs showed differentially expressed dendritic, synapse and axon-modulating transcripts in whisker-deprived mice. Indicating novel steady-state morphological roles, those genes also clustered distinctly in naive single cell VChIs. This VChIs morphe-ome atlas is the first example of unbiased analysis of neuronal populations and holds the possibility to compare neuronal structure-function relationships across experimental conditions. ### Competing Interest Statement The authors have declared no competing interest.

34: Ventricular, atrial and outflow tract heart progenitors arise from spatially and molecularly distinct regions of the primitive streak.
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Posted 12 Jul 2020

Ventricular, atrial and outflow tract heart progenitors arise from spatially and molecularly distinct regions of the primitive streak.
2 tweets bioRxiv developmental biology

Kenzo Ivanovitch, Pablo Soro-Barrio, Probir Chakravarty, Rebecca A Jones, Donald M Bell, S. Neda Mousavy Gharavy, Despina Stamataki, Julien Delile, James C Smith, James Briscoe

The heart develops from two sources of mesoderm progenitors, the first and second heart field (FHF and SHF). Using a single cell transcriptomic assay in combination with genetic lineage tracing, we find the FHF and SHF are subdivided into distinct pools of progenitors in gastrulating mouse embryos at earlier stages than previously thought. Each subpopulation has a distinct origin in the primitive streak. The first progenitors to leave the primitive streak contribute to the left ventricle, shortly after right ventricle progenitor emigrate, followed by the outflow tract and atrial progenitors. Moreover, a subset of atrial progenitors are gradually incorporated in posterior locations of the FHF. Although cells allocated to the outflow tract and atrium leave the primitive streak at a similar stage, they arise from different regions. Outflow tract cells originate from distal locations in the primitive streak while atrial progenitors are positioned more proximally. Moreover, single cell RNA sequencing demonstrates that the primitive streak cells contributing to the ventricles have a distinct molecular signature from those forming the outflow tract and atrium. We conclude that cardiac progenitors are pre-patterned within the primitive streak and this prefigures their allocation to distinct anatomical structures of the heart. Together, our data provide a new molecular and spatial map of mammalian cardiac progenitors that will support future studies of heart development, function and disease.

35: Identification of quercetin from fruits to immediately fight Zika
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Posted 11 Sep 2016

Identification of quercetin from fruits to immediately fight Zika
2 tweets bioRxiv biochemistry

Amrita Roy, Liangzhong Lim, Jianxing Song

Zika virus is spread mainly by the bite of an infected mosquito, which can be passed from a pregnant woman to her fetus, thus leading to birth defects including more than microcephaly. It has been recently estimated that one-third of the world population will be infected by Zika in the near future, but unfortunately so far there is no vaccine or medicine for Zika. In particular, the special concern on the vaccine treatment to Zika and Dengue arising from antibody-dependent enhancement strongly emphasizes the key role of its NS2B-NS3 protease (NS2B-NS3pro) as a target for anti-Zika drug discovery/design due to its absolutely-essential role in viral replication. In response to the current global health emergency triggered by the Zika outbreak, we successfully obtained several active forms of Zika NS2B-NS3pro and further attempted to discover its inhibitors from eatable plants and traditional herbal medicines to immediately fight Zika. Here, for the first time, we discovered that quercetin, a flavonoid extensively existing in many fruits and vegetables, effectively inhibits Zika NS2B-NS3pro. We further quantify its inhibitory activity with IC50 of 26 uM; and Ki of 23 uM. As quercetin has been extensively found in fruits, vegetables, leaves and grains, our discovery would benefit the public to immediately fight Zika.

36: Simulations support the interaction of the SARS-CoV-2 spike protein with nicotinic acetylcholine receptors
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Posted 17 Jul 2020

Simulations support the interaction of the SARS-CoV-2 spike protein with nicotinic acetylcholine receptors
2 tweets bioRxiv biochemistry

A. Sofia F. Oliveira, Amaurys Avila Ibarra, Isabel Bermudez, Lorenzo Casalino, Zied Gaieb, Deborah K. Shoemark, Timothy Gallagher, Richard B. Sessions, Rommie E. Amaro, Adrian J Mulholland

Changeux et al . recently suggested that the SARS-CoV-2 spike (S) protein may interact with nicotinic acetylcholine receptors (nAChRs). Such interactions may be involved in pathology and infectivity. Here, we use molecular simulations of validated atomically detailed structures of nAChRs, and of the S protein, to investigate this ‘nicotinic hypothesis’. We examine the binding of the Y674-R685 loop of the S protein to three nAChRs, namely the human α4β2 and α7 subtypes and the muscle-like αβγd receptor from Tetronarce californica . Our results indicate that Y674-R685 has affinity for nAChRs and the region responsible for binding contains the PRRA motif, a four-residue insertion not found in other SARS-like coronaviruses. In particular, R682 has a key role in the stabilisation of the complexes as it forms interactions with loops A, B and C in the receptor’s binding pocket. The conformational behaviour of the bound Y674-R685 region is highly dependent on the receptor subtype, adopting extended conformations in the α4β2 and α7 complexes and more compact ones when bound to the muscle-like receptor. In the α4β2 and αβγd complexes, the interaction of Y674-R685 with the receptors forces the loop C region to adopt an open conformation similar to other known nAChR antagonists. In contrast, in the α7 complex, Y674-R685 penetrates deeply into the binding pocket where it forms interactions with the residues lining the aromatic box, namely with TrpB, TyrC1 and TyrC2. Estimates of binding energy suggest that Y674-R685 forms stable complexes with all three nAChR subtypes. Analyses of the simulations of the full-length S protein show that the Y674-R685 region is accessible for binding, and suggest a potential binding orientation of the S protein with nAChRs. ### Competing Interest Statement The authors have declared no competing interest.

37: Impact of germline and somatic cell cycle checkpoint kinase mutations on breast cancer presentation and prognosis.
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Posted 30 Oct 2020

Impact of germline and somatic cell cycle checkpoint kinase mutations on breast cancer presentation and prognosis.
2 tweets bioRxiv bioinformatics

Sinem Punturi, Nindo Punturi, Matthew Bainbridge, Svasti Haricharan

Cell cycle checkpoint kinases activated by DNA repair pathways, ATM/Chk2 and ATR/Chk1 are important tumor suppressors. Germline mutations in these genes associate with increased cancer incidence. Specifically, ATM and CHEK2 germline variants associate with increased incidence of estrogen receptor (ER)+ breast cancer with poor patient outcome. More recent investigations identified somatic inactivation of ATM/Chk2 as causal to endocrine therapy resistance in ER+ breast cancer patients. However, the relative contributions of germline and somatic inactivation of these cell cycle checkpoint kinases to ER+/HER2- and ER-/PR-/HER2- or triple negative breast cancer (TNBC) incidence and tumor characteristics has not yet been systematically assessed. Here, we comprehensively compare associations of ATM/CHEK2 and ATR/CHEK1 germline and somatic mutations with age, tumor stage and PR status at diagnosis, and metastatic potential using a meta-dataset compiled from six independent primary and metastatic patient datasets. We observe significantly higher frequency of ATM (29.6%) and CHEK2 (9.5%) mutations in metastatic ER+/HER2- breast cancers relative to TNBC (~11% and 5% respectively) (p=0.03). CHEK2 mutations associate with higher PR positivity, higher tumor stage and younger age at diagnosis for metastatic ER+/HER2- breast cancer patients. These associations are primarily driven by germline, rather than somatic CHEK2 mutations. However, both germline and somatic mutations in CHEK2 that are deleterious (nonsense, frameshift or splice site) associate with more rapid disease progression on early rounds of endocrine therapy when compared to tumors with wildtype CHEK2 or with missense mutations in CHEK2. These results provide the first systematic analysis of the contribution of germline and somatic cell cycle checkpoint kinase mutations to tumor characteristics affecting patient prognosis and treatment response. Results of this study suggest potential for streamlined testing for status of these checkpoint kinases as prognostic and/or predictive biomarkers for ER+/HER2- breast cancer patients.

38: Natural selection in the evolution of SARS-CoV-2 in bats, not humans, created a highly capable human pathogen
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Posted 29 May 2020

Natural selection in the evolution of SARS-CoV-2 in bats, not humans, created a highly capable human pathogen
1 tweet bioRxiv evolutionary biology

Oscar A MacLean, Spyros Lytras, Steven Weaver, Joshua B Singer, Maciej F Boni, Philippe Lemey, Sergei L. Kosakovsky Pond, David L. Robertson

RNA viruses are proficient at switching host species, and evolving adaptations to exploit the new host’s cells efficiently. Surprisingly, SARS-CoV-2 has apparently required no significant adaptation to humans since the start of the COVID-19 pandemic, with no observed selective sweeps since genome sampling began. Here we assess the types of natural selection taking place in Sarbecoviruses in horseshoe bats versus SARS-CoV-2 evolution in humans. While there is moderate evidence of diversifying positive selection in SARS-CoV-2 in humans, it is limited to the early phase of the pandemic, and purifying selection is much weaker in SARS-CoV-2 than in related bat Sarbecoviruses . In contrast, our analysis detects significant positive episodic diversifying selection acting on the bat virus lineage SARS-CoV-2 emerged from, accompanied by an adaptive depletion in CpG composition presumed to be linked to the action of antiviral mechanisms in ancestral hosts. The closest bat virus to SARS-CoV-2, RmYN02 (sharing an ancestor ∼1976), is a recombinant with a structure that includes differential CpG content in Spike; clear evidence of coinfection and evolution in bats without involvement of other species. Collectively our results demonstrate the progenitor of SARS-CoV-2 was capable of near immediate human-human transmission as a consequence of its adaptive evolutionary history in bats, not humans. ### Competing Interest Statement The authors have declared no competing interest.

39: The island rule explains consistent patterns of body size evolution across terrestrial vertebrates
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Posted 28 May 2020

The island rule explains consistent patterns of body size evolution across terrestrial vertebrates
1 tweet bioRxiv ecology

Ana Benítez López, Luca Santini, Juan Gallego-Zamorano, Borja Mila, Patrick Walkden, Mark A.J. Huijbregts, Joseph A. Tobias

Island faunas can be characterized by gigantism in small animals and dwarfism in large animals, but the extent to which this so-called ‘island rule’ provides a general explanation for evolutionary trajectories on islands remains contentious. Here we use a phylogenetic meta-analysis to assess patterns and drivers of body size evolution across a global sample of paired island-mainland populations of terrestrial vertebrates. We show that ‘island rule’ effects are widespread in mammals, birds and reptiles, but less evident in amphibians, which mostly tend towards gigantism. We also found that the magnitude of insular dwarfism and gigantism is mediated by climate as well as island size and isolation, with more pronounced effects in smaller, more remote islands for mammals and reptiles. We conclude that the island rule is pervasive across vertebrates, but that the implications for body size evolution are nuanced and depend on an array of context-dependent ecological pressures and environmental conditions. ### Competing Interest Statement The authors have declared no competing interest.

40: Integration of immunome with disease-gene network reveals common cellular mechanisms between IMIDs and drug repurposing strategies
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Posted 13 Dec 2019

Integration of immunome with disease-gene network reveals common cellular mechanisms between IMIDs and drug repurposing strategies
1 tweet bioRxiv bioinformatics

Abhinandan Devaprasad, Timothy RDJ Radstake, Aridaman Pandit

Objective: Development and progression of immune-mediated inflammatory diseases (IMIDs) involve intricate dysregulation of the disease associated genes (DAGs) and their expressing immune cells. Due to the complex molecular mechanism, identifying the top disease associated cells (DACs) in IMIDs has been challenging. Here, we aim to identify the top DACs and DAGs to help understand the cellular mechanism involved in IMIDs and further explore therapeutic strategies. Method: Using transcriptome profiles of 40 different immune cells, unsupervised machine learning, and disease-gene networks, we constructed the Disease-gene IMmune cell Expression (DIME) network, and identified top DACs and DAGs of 12 phenotypically different IMIDs. We compared the DIME networks of IMIDs to identify common pathways between them. We used the common pathways and publicly available drug-gene network to identify promising drug repurposing targets. Result: We found CD4+Treg, CD4+Th1, and NK cells as top DACs in the inflammatory arthritis such as ankylosing spondylitis (AS), psoriatic arthritis, and rheumatoid arthritis (RA); neutrophils, granulocytes and BDCA1+CD14+ cells in systemic lupus erythematosus and systemic scleroderma; ILC2, CD4+Th1, CD4+Treg, and NK cells in the inflammatory bowel diseases (IBDs). We identified lymphoid cells (CD4+Th1, CD4+Treg, and NK) and their associated pathways to be important in HLA-B27 type diseases (psoriasis, AS, and IBDs) and in primary-joint-inflammation-based inflammatory arthritis (AS and RA). Based on the common cellular mechanisms, we identified lifitegrast as potential drug repurposing candidate for Crohn's disease, and other IMIDs. Conclusion: Our method identified top DACs, DAGs, common pathways, and proposed potential drug repurposing targets between IMIDs. To extend our method to other diseases, we built the DIME tool. Thus paving way for future (pre-)clinical research.

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