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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 125,808 papers from 540,130 authors.

Most tweeted biology preprints, last 7 days

*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.

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

1: SARS-CoV-2 RNA reverse-transcribed and integrated into the human genome
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Posted 13 Dec 2020

SARS-CoV-2 RNA reverse-transcribed and integrated into the human genome
144 tweets bioRxiv genomics

Liguo Zhang, Alexsia Richards, Andrew Khalil, Emile Wogram, Haiting Ma, Richard A. Young, Rudolf Jaenisch

Prolonged SARS-CoV-2 RNA shedding and recurrence of PCR-positive tests have been widely reported in patients after recovery, yet these patients most commonly are non-infectious. Here we investigated the possibility that SARS-CoV-2 RNAs can be reverse-transcribed and integrated into the human genome and that transcription of the integrated sequences might account for PCR-positive tests. In support of this hypothesis, we found chimeric transcripts consisting of viral fused to cellular sequences in published data sets of SARS-CoV-2 infected cultured cells and primary cells of patients, consistent with the transcription of viral sequences integrated into the genome. To experimentally corroborate the possibility of viral retro-integration, we describe evidence that SARS-CoV-2 RNAs can be reverse transcribed in human cells by reverse transcriptase (RT) from LINE-1 elements or by HIV-1 RT, and that these DNA sequences can be integrated into the cell genome and subsequently be transcribed. Human endogenous LINE-1 expression was induced upon SARS-CoV-2 infection or by cytokine exposure in cultured cells, suggesting a molecular mechanism for SARS-CoV-2 retro-integration in patients. This novel feature of SARS-CoV-2 infection may explain why patients can continue to produce viral RNA after recovery and suggests a new aspect of RNA virus replication.

2: Host-directed therapies against early-lineage SARS-CoV-2 retain efficacy against B.1.1.7 variant
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Posted 24 Jan 2021

Host-directed therapies against early-lineage SARS-CoV-2 retain efficacy against B.1.1.7 variant
138 tweets bioRxiv microbiology

Ann-Kathrin Reuschl, Lucy Thorne, Lorena Zuliani Alvarez, Mehdi Bouhaddou, Kirsten Obernier, Margaret Soucheray, Jane Turner, Jacqueline Fabius, Gina T. Nguyen, Danielle Swaney, Romel Rosales, Kris M. White, Pablo Aviles, Ilsa T Kirby, James E Melnyk, Ying Shi, Ziyang Zhang, Kevan Shokat, Adolfo Garcia-Sastre, Clare Jolly, Gregory J Towers, Nevan J Krogan

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths worldwide and massive societal and economic burden. Recently, a new variant of SARS-CoV-2, known as B.1.1.7, was first detected in the United Kingdom and is spreading in several other countries, heightening public health concern and raising questions as to the resulting effectiveness of vaccines and therapeutic interventions. We and others previously identified host-directed therapies with antiviral efficacy against SARS-CoV-2 infection. Less prone to the development of therapy resistance, host-directed drugs represent promising therapeutic options to combat emerging viral variants as host genes possess a lower propensity to mutate compared to viral genes. Here, in the first study of the full-length B.1.1.7 variant virus, we find two host-directed drugs, plitidepsin (aplidin; inhibits translation elongation factor eEF1A) and ralimetinib (inhibits p38 MAP kinase cascade), as well as remdesivir, to possess similar antiviral activity against both the early-lineage SARS-CoV-2 and the B.1.1.7 variant, evaluated in both human gastrointestinal and lung epithelial cell lines. We find that plitidepsin is over an order of magnitude more potent than remdesivir against both viruses. These results highlight the importance of continued development of host-directed therapeutics to combat current and future coronavirus variant outbreaks.

3: Bio-instantiated recurrent neural networks
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Posted 23 Jan 2021

Bio-instantiated recurrent neural networks
74 tweets bioRxiv neuroscience

Alexandros Goulas, Fabrizio Damicelli, Claus C. Hilgetag

Biological neuronal networks (BNNs) constitute a niche for inspiration and analogy making for researchers that focus on artificial neuronal networks (ANNs). Moreover, neuroscientists increasingly use ANNs as a model for the brain. However, apart from certain similarities and analogies that can be drawn between ANNs and BNNs, such networks exhibit marked differences, specifically with respect to their network topology. Here, we investigate to what extent network topology found in nature can lead to beneficial aspects in recurrent neural networks (RNNs): i) the prediction performance itself, that is, the capacity of the network to minimize the desired function at hand in test data and ii) speed of training, that is, how fast during training the network reaches its optimal performance. To this end, we examine different ways to construct RNNs that instantiate the network topology of brains of different species. We refer to such RNNs as bio-instantiated. We examine the bio-instantiated RNNs in the context of a key cognitive capacity, that is, working memory, defined as the ability to track task-relevant information as a sequence of events unfolds in time. We highlight what strategies can be used to construct RNNs with the network topology found in nature, without sacrificing prediction capacity and speed of training. Despite that we observe no enhancement of performance when compared to randomly wired RNNs, our approach demonstrates how empirical neural network data can be used for constructing RNNs, thus, facilitating further experimentation with biologically realistic networks topology.

4: Striatal Direct Pathway Targets Npas1+ Pallidal Neurons
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Posted 02 Sep 2020

Striatal Direct Pathway Targets Npas1+ Pallidal Neurons
50 tweets bioRxiv neuroscience

Qiaoling Cui, Xixun Du, Isaac Chang, Arin Pamukcu, Varoth Lilascharoen, Brianna Berceau, Daniela Garcia, Darius Hong, Uree Chon, Ahana Narayanan, Yongsoo Kim, Byungkook Lim, Savio Chan

The classic basal ganglia circuit model asserts a complete segregation of the two striatal output pathways. Empirical data argue that, in addition to indirect-pathway striatal projection neurons (iSPNs), direct-pathway striatal projection neurons (dSPNs) innervate the external globus pallidus (GPe). However, the functions of the latter were not known. In this study, we interrogated the organization principles of striatopallidal projections and their roles in full-body movement in mice (both males and females). In contrast to the canonical motor-promoting response of dSPNs in the dorsomedial striatum (DMSdSPNs), optogenetic stimulation of dSPNs in the dorsolateral striatum (DLSdSPNs) suppressed locomotion. Circuit analyses revealed that dSPNs selectively target Npas1+ neurons in the GPe. In a chronic 6-hydroxydopamine lesion model of Parkinsons disease, the dSPN-Npas1+ projection was dramatically strengthened. As DLSdSPN-Npas1+ projection suppresses movement, the enhancement of this projection represents a circuit mechanism for the hypokinetic symptoms of Parkinsons disease that has not been previously considered. In sum, our results suggest that dSPN input to the GPe is a critical circuit component that is involved in the regulation of movement in both healthy and parkinsonian states.

5: In situ characterization of the 3D microanatomy of the pancreas and pancreatic cancer at single cell resolution
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Posted 09 Dec 2020

In situ characterization of the 3D microanatomy of the pancreas and pancreatic cancer at single cell resolution
49 tweets bioRxiv cancer biology

Ashley L. Kiemen, Alicia M. Braxton, Mia P. Grahn, Kyu S. Han, Jaanvi Mahesh Babu, Rebecca Reichel, Falone Amoa, Seung-Mo Hong, Toby C. Cornish, Elizabeth D Thompson, Laura D. Wood, Ralph H. Hruban, Pei-Hsun Wu, Denis Wirtz

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer. Accumulating evidence indicates the tumor microenvironment is highly associated with tumorigenesis through regulation of cellular physiology, signaling systems, and gene expression profiles of cancer cells. Yet the mechanisms by which the microenvironment evolves from normal pancreas architecture to precursor lesions and invasive cancer is poorly understood. Obtaining high-content and high-resolution information from a complex tumor microenvironment in large volumetric landscapes represents a key challenge in the field of cancer biology. To address this challenge, we established a novel method to reconstruct three-dimensional (3D) centimeter-scale tissues containing billions of cells from serially sectioned histological samples, utilizing deep learning approaches to recognize eight distinct tissue subtypes from hematoxylin and eosin stained sections at micrometer and single-cell resolution. Using samples from a range of normal, precancerous, and invasive pancreatic cancer tissue, we map in 3D modes of cancer invasion in the tumor microenvironment, and emphasize the need for further 3D quantification of biological systems.

6: An integrative analysis of genomic and exposomic data for complex traits and phenotypic prediction
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Posted 10 Nov 2020

An integrative analysis of genomic and exposomic data for complex traits and phenotypic prediction
39 tweets bioRxiv genetics

Xuan Zhou, Sang Hong Lee

Complementary to the genome, the concept of exposome has been proposed to capture the totality of human environmental exposures. While there has been some recent progress on the construction of the exposome, few tools exist that can integrate the genome and exposome for complex trait analyses. Here we propose a linear mixed model approach to bridge this gap, which jointly models the random effects of the two omics layers on phenotypes of complex traits. We illustrate our approach using traits from the UK Biobank (e.g., BMI & height for N ~ 40,000) with a small fraction of the exposome that comprises 28 lifestyle factors. The joint model of the genome and exposome explains substantially more phenotypic variance and significantly improves phenotypic prediction accuracy, compared to the model based on the genome alone. The additional phenotypic variance captured by the exposome includes its additive effects as well as non-additive effects such as genome-exposome (gxe) and exposome-exposome (exe) interactions. For example, 19% of variation in BMI is explained by additive effects of the genome, while additional 7.2% by additive effects of the exposome, 1.9% by exe interactions and 4.5% by gxe interactions. Correspondingly, the prediction accuracy for BMI, computed using Pearsons correlation between the observed and predicted phenotypes, improves from 0.15 (based on the genome alone) to 0.35 (based on the genome & exposome). We also show, using established theories, integrating genomic and exposomic data is essential to attaining a clinically meaningful level of prediction accuracy for disease traits. In conclusion, the genomic and exposomic effects can contribute to phenotypic variation via their latent relationships, i.e. genome-exposome correlation, and gxe and exe interactions, and modelling these effects has a great potential to improve phenotypic prediction accuracy and thus holds a great promise for future clinical practice.

7: Hi-C Analyses with GENOVA: a case study with cohesin variants
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Posted 24 Jan 2021

Hi-C Analyses with GENOVA: a case study with cohesin variants
36 tweets bioRxiv genomics

Robin H. van der Weide, Teun van den Brand, Judith H.I. Haarhuis, Hans Teunissen, Benjamin Rowland, Elzo de Wit

Conformation capture-approaches like Hi-C can elucidate chromosome structure at a genome-wide scale. Hi-C datasets are large and require specialised software. Here, we present GENOVA: a user-friendly software package to analyse and visualise conformation capture data. GENOVA is an R-package that includes the most common Hi-C analyses, such as compartment and insulation score analysis. It can create annotated heatmaps to visualise the contact frequency at a specific locus and aggregate Hi-C signal over user-specified genomic regions such as ChIP-seq data. Finally, our package supports output from the major mapping-pipelines. We demonstrate the capabilities of GENOVA by analysing Hi-C data from HAP1 cell lines in which the cohesin-subunits SA1 and SA2 were knocked out. We find that {Delta}SA1 cells gain intra-TAD interactions and increase compartmentalisation. {Delta}SA2 cells have longer loops and a less compartmentalised genome. These results suggest that cohesinSA1 forms longer loops, while cohesinSA2 plays a role in forming and maintaining intra-TAD interactions. Our data supports the model that the genome is provided structure in 3D by the counter-balancing of loop formation on one hand, and compartmentalization on the other hand. By differentially controlling loops, cohesinSA1 and cohesinSA2 therefore also affect nuclear compartmentalization. We show that GENOVA is an easy to use R-package, that allows researchers to explore Hi-C data in great detail.

8: Mechanistic theory predicts the effects of temperature and humidity on inactivation of SARS-CoV-2 and other enveloped viruses
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Posted 16 Oct 2020

Mechanistic theory predicts the effects of temperature and humidity on inactivation of SARS-CoV-2 and other enveloped viruses
34 tweets bioRxiv microbiology

Dylan H. Morris, Kwe Claude Yinda, Amandine Gamble, Fernando W. Rossine, Qishen Huang, Trenton Bushmaker, Robert J. Fischer, M. Jeremiah Matson, Neeltje van Doremalen, Peter J. Vikesland, Linsey C. Marr, Vincent Munster, James O. Lloyd-Smith

Environmental conditions affect virus inactivation rate and transmission potential. Understanding those effects is critical for anticipating and mitigating epidemic spread. Ambient temperature and humidity strongly affect the inactivation rate of enveloped viruses, but a mechanistic, quantitative theory of those effects has been elusive. We measure the stability of the enveloped respiratory virus SARS-CoV-2 on an inert surface at nine temperature and humidity conditions and develop a mechanistic model to explain and predict how temperature and humidity alter virus inactivation. We find SARS-CoV-2 survives longest at low temperatures and extreme relative humidities; median estimated virus half-life is over 24 hours at 10 {degrees}C and 40 % RH, but approximately 1.5 hours at 27 {degrees}C and 65 % RH. Our mechanistic model uses simple chemistry to explain the increase in virus inactivation rate with increased temperature and the U-shaped dependence of inactivation rate on relative humidity. The model accurately predicts quantitative measurements from existing studies of five different human coronaviruses (including SARS-CoV-2), suggesting that shared mechanisms may determine environmental stability for many enveloped viruses. Our results indicate scenarios of particular transmission risk, point to pandemic mitigation strategies, and open new frontiers in the mechanistic study of virus transmission.

9: 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
32 tweets 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.

10: A human coronavirus evolves antigenically to escape antibody immunity
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Posted 18 Dec 2020

A human coronavirus evolves antigenically to escape antibody immunity
30 tweets bioRxiv microbiology

Rachel Eguia, Katharine H.D. Crawford, Terry Stevens-Ayers, Laurel Kelnhofer-Millevolte, Alexander L. Greninger, Janet A Englund, Michael J. Boeckh, Jesse D. Bloom

There is intense interest in antibody immunity to coronaviruses. However, it is unknown if coronaviruses evolve to escape such immunity, and if so, how rapidly. Here we address this question by characterizing the historical evolution of human coronavirus 229E. We identify human sera from the 1980s and 1990s that have neutralizing titers against contemporaneous 229E that are comparable to the anti-SARS-CoV-2 titers induced by SARS-CoV-2 infection or vaccination. We test these sera against 229E strains isolated after sera collection, and find that neutralizing titers are lower against these "future" viruses. In some cases, sera that neutralize contemporaneous 229E viral strains with titers >1:100 do not detectably neutralize strains isolated 8-17 years later. The decreased neutralization of "future" viruses is due to antigenic evolution of the viral spike, especially in the receptor-binding domain. If these results extrapolate to other coronaviruses, then it may be advisable to periodically update SARS-CoV-2 vaccines.

11: γδ intraepithelial lymphocytes facilitate pathological epithelial cell shedding via CD103-mediated granzyme release.
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Posted 21 Jan 2021

γδ intraepithelial lymphocytes facilitate pathological epithelial cell shedding via CD103-mediated granzyme release.
25 tweets bioRxiv immunology

Madeleine D. Hu, Natasha B. Golovchenko, Thomas J. Kelly, Jonathan Agos, Matthew R. Zeglinski, Edward M. Bonder, David J. Granville, Alastair JM Watson, Karen L Edelblum

Excessive shedding of enterocytes into the intestinal lumen is observed in inflammatory bowel disease and is correlated with disease relapse. However, the mechanisms underlying this phenomenon remain unclear. Intraepithelial lymphocytes (IEL) expressing the {gamma}{delta} T-cell receptor (TCR) provide surveillance of the intestinal mucosa at steady-state, which is regulated, in part, by CD103. Intravital microscopy of lipopolysaccharide (LPS)-treated mice revealed that {gamma}{delta} IELs make extended contact with shedding enterocytes. These prolonged interactions require CD103 engagement by E-cadherin, as CD103 blockade significantly reduces LPS-induced shedding. Furthermore, we find that granzymes A and B, but not perforin, are required for cell shedding, and that these granzymes are released by {gamma}{delta} IELs both constitutively and following CD103/E-cadherin ligation. These findings indicate that extracellular granzyme facilitates shedding, likely through cleavage of extracellular matrix proteins. Our results uncover a previously unrecognized role for {gamma}{delta} IELs in facilitating pathological cell shedding in a CD103- and granzyme-dependent manner.

12: Cellular crowd control: overriding endogenous cell coordination makes cell migration more susceptible to external programming
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Posted 25 Jan 2021

Cellular crowd control: overriding endogenous cell coordination makes cell migration more susceptible to external programming
25 tweets bioRxiv bioengineering

Gawoon Shim, Danelle Devenport, Daniel J. Cohen

As collective cell migration is essential in biological processes spanning development, healing, and cancer progression, methods to externally program cell migration are of great value. However, problems can arise if the external commands compete with strong, pre-existing collective behaviors in the tissue or system. We investigate this problem by applying a potent external migratory cue--electrical stimulation and electrotaxis--to primary mouse skin monolayers where we can tune cell-cell adhesion strength to modulate endogenous collectivity. Monolayers with high cell-cell adhesion showed strong natural coordination and resisted electrotactic control, with this conflict actively damaging the leading edge of the tissue. However, reducing pre-existing coordination in the tissue by specifically inhibiting E-cadherin-dependent cell-cell adhesion, either by disrupting the formation of cell-cell junctions with E-cadherin specific antibodies or rapidly dismantling E-cadherin junctions with calcium chelators, significantly improved controllability. Finally, we applied this paradigm of weakening existing coordination to improve control to demonstrate accelerated wound closure in vitro. These results are in keeping with those from diverse, non-cellular systems, and confirm that endogenous collectivity should be considered as a key, quantitative design variable when optimizing external control of collective migration.

13: Metagenomics Strain Resolution on Assembly Graphs
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Posted 07 Sep 2020

Metagenomics Strain Resolution on Assembly Graphs
23 tweets bioRxiv bioinformatics

Christopher Quince, Sergey Nurk, Sebastien Raguideau, Robert James, Orkun S Soyer, J. Kimberly Summers, Antoine Limasset, A. Murat Eren, Rayan Chikhi, Aaron E. Darling

We introduce a novel bioinformatics pipeline, STrain Resolution ON assembly Graphs (STRONG), which identifies strains de novo , when multiple metagenome samples from the same community are available. STRONG performs coassembly, followed by binning into metagenome assembled genomes (MAGs), but uniquely it stores the coassembly graph prior to simplification of variants. This enables the subgraphs for individual single-copy core genes (SCGs) in each MAG to be extracted. It can then thread back reads from the samples to compute per sample coverages for the unitigs in these graphs. These graphs and their unitig coverages are then used in a Bayesian algorithm, BayesPaths, that determines the number of strains present, their sequences or haplotypes on the SCGs and their abundances in each of the samples. Our approach both avoids the ambiguities of read mapping and allows more of the information on co-occurrence of variants in reads to be utilised than if variants were treated independently, whilst at the same time exploiting the correlation of variants across samples that occurs when they are linked in the same strain. We compare STRONG to the current state of the art on synthetic communities and demonstrate that we can recover more strains, more accurately, and with a realistic estimate of uncertainty deriving from the variational Bayesian algorithm employed for the strain resolution. On a real anaerobic digestor time series we obtained strain-resolved SCGs for over 300 MAGs that for abundant community members match those observed from long Nanopore reads. ### Competing Interest Statement The authors have declared no competing interest.

14: Resistance to pirimiphos-methyl in West African Anopheles is spreading via duplication and introgression of the Ace1 locus
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Posted 19 May 2020

Resistance to pirimiphos-methyl in West African Anopheles is spreading via duplication and introgression of the Ace1 locus
20 tweets bioRxiv genomics

Xavier Grau-Bové, Eric R. Lucas, Dimitra Pipini, Emily Rippon, Arjèn van’t Hof, Edi Constant, Samuel Dadzie, Alexander Egyir-Yawson, John Essandoh, Joseph Chabi, Luc Djogbenou, Nicholas J. Harding, Alistair Miles, Dominic Kwiatowski, Martin J. Donnelly, David Weetman, The Anopheles gambiae 1000 Genomes Consortium

Vector population control using insecticides is a key element of current strategies to prevent malaria transmission in Africa. The introduction of effective insecticides, such as the organophosphate pirimiphos-methyl, is essential to overcome the recurrent emergence of resistance driven by the highly diverse Anopheles genomes. Here, we use a population genomic approach to investigate the basis of pirimiphos-methyl resistance in the major malaria vectors Anopheles gambiae and A. coluzzii . A combination of copy number variation and a single non-synonymous substitution in the acetylcholinesterase gene, Ace1 , provides the key resistance diagnostic in an A. coluzzii population from Cote d'Ivoire that we used for sequence-based association mapping, with replication in other West African populations. The Ace1 and substitution and duplications occur on a unique resistance haplotype that evolved in A. gambiae and introgressed into A. coluzzii , and is now common in West Africa probably due to cross-resistance with previously used insecticides. Our findings highlight the phenotypic value of this complex resistance haplotype and clarify its evolutionary history, providing tools to understand the current and future effectiveness of pirimiphos-methyl based interventions. ### Competing Interest Statement The authors have declared no competing interest.

15: Neuroinvasion of SARS-CoV-2 in human and mouse brain
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Posted 26 Jun 2020

Neuroinvasion of SARS-CoV-2 in human and mouse brain
19 tweets bioRxiv microbiology

Eric Song, Ce Zhang, Benjamin Israelow, Alice Lu-Culligan, Alba Vieites Prado, Sophie Skriabine, Peiwen Lu, Orr-El Weizman, Feimei Liu, Yile Dai, Klara Szigeti-Buck, Yuki Yasumoto, Guilin Wang, Christopher Castaldi, Jaime Heltke, Evelyn Ng, John Wheeler, Mia Madel Alfajaro, Etienne Levavasseur, Benjamin Fontes, Neal G. Ravindra, David Van Dijk, Shrikant Mane, Murat Gunel, Aaron Ring, Syed A. Jaffar Kazmi, Kai Zhang, Craig B. Wilen, Tamas L Horvath, Isabelle Plu, Stephane Haik, Jean-Leon Thomas, Angeliki Louvi, Shelli F. Farhadian, Anita Huttner, Danielle Seilhean, Nicolas Renier, Kaya Bilguvar, Akiko Iwasaki

Although COVID-19 is considered to be primarily a respiratory disease, SARS-CoV-2 affects multiple organ systems including the central nervous system (CNS). Yet, there is no consensus whether the virus can infect the brain, or what the consequences of CNS infection are. Here, we used three independent approaches to probe the capacity of SARS-CoV-2 to infect the brain. First, using human brain organoids, we observed clear evidence of infection with accompanying metabolic changes in the infected and neighboring neurons. However, no evidence for the type I interferon responses was detected. We demonstrate that neuronal infection can be prevented either by blocking ACE2 with antibodies or by administering cerebrospinal fluid from a COVID-19 patient. Second, using mice overexpressing human ACE2, we demonstrate in vivo that SARS-CoV-2 neuroinvasion, but not respiratory infection, is associated with mortality. Finally, in brain autopsy from patients who died of COVID-19, we detect SARS-CoV-2 in the cortical neurons, and note pathologic features associated with infection with minimal immune cell infiltrates. These results provide evidence for the neuroinvasive capacity of SARS-CoV2, and an unexpected consequence of direct infection of neurons by SARS-CoV-2. ### Competing Interest Statement The authors have declared no competing interest.

16: Detecting turnover among complex communities using null models: A case study with sky-island haemosporidian parasites
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Posted 18 Apr 2020

Detecting turnover among complex communities using null models: A case study with sky-island haemosporidian parasites
18 tweets bioRxiv ecology

Lisa N. Barrow, Selina M Bauernfeind, Paxton A Cruz, Jessie L. Williamson, Daniele L Wiley, John E Ford, Matthew J. Baumann, Serina S Brady, Andrea N Chavez, Chauncey R. Gadek, Spencer C. Galen, Andrew B Johnson, Xena M Mapel, Rosario A Marroquin-Flores, Taylor E Martinez, Jenna M McCullough, Jade E McLaughlin, Christopher C. Witt

Turnover in species composition between sites, or beta diversity, is a critical component of species diversity that is typically influenced by geography, environment, and biotic interactions. Quantifying turnover is particularly challenging, however, in multi-host, multi-parasite assemblages where undersampling is unavoidable, resulting in inflated estimates of turnover and uncertainty about its spatial scale. We developed and implemented a framework using null models to test for community turnover in avian haemosporidian communities of three sky islands in the southwestern United States. We screened 776 birds for haemosporidian parasites from three genera ( Parahaemoproteus , Plasmodium , and Leucocytozoon ) by amplifying and sequencing a mitochondrial DNA barcode. We detected infections in 280 birds (36.1%), sequenced 357 infections, and found a total of 99 parasite haplotypes. When compared to communities simulated from a regional pool, we observed more unique, single-mountain haplotypes and fewer haplotypes shared among three mountain ranges than expected, indicating that haemosporidian communities differ to some degree among adjacent mountain ranges. These results were robust even after pruning datasets to include only identical sets of host species, and they were consistent for two of the three haemosporidian genera. The two more distant mountain ranges were more similar to each other than the one located centrally, suggesting that the differences we detected were due to stochastic colonization-extirpation dynamics. These results demonstrate that avian haemosporidian communities of temperate-zone forests differ on relatively fine spatial scales associated with adjacent sky-islands. Null models are essential tools for detecting turnover in complex, undersampled, and poorly known systems. ### Competing Interest Statement The authors have declared no competing interest.

17: Minimal genome-wide human CRISPR-Cas9 library
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Posted 21 Nov 2019

Minimal genome-wide human CRISPR-Cas9 library
17 tweets bioRxiv genomics

Emanuel Gonçalves, Mark Thomas, Fiona M Behan, Gabriele Picco, Clare Pacini, Felicity Allen, Mamta Sharma, David A Jackson, Stacey Price, Charlotte M Beaver, Oliver Dovey, David Parry-Smith, Francesco Iorio, Leopold Parts, Kosuke Yusa, Mathew J Garnett

CRISPR guide-RNA libraries have been iteratively optimised to provide increasingly efficient reagents, although their large size is a barrier for many applications. We designed an optimised minimal genome-wide human CRISPR-Cas9 library (MinLibCas9), by mining existing large-scale gene loss-of-function datasets, resulting in a greater than 42% reduction in size compared to other libraries while preserving assay sensitivity and specificity. MinLibCas9 increases the dynamic range of CRISPR-Cas9 loss-of-function screens and extends their application to complex models and assays. ### Competing Interest Statement The authors have declared no competing interest.

18: SpecSeg: cross spectral power-based segmentation of neurons and neurites in chronic calcium imaging datasets
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Posted 21 Oct 2020

SpecSeg: cross spectral power-based segmentation of neurons and neurites in chronic calcium imaging datasets
15 tweets bioRxiv neuroscience

Leander de Kraker, Koen Seignette, Premnath Thamizharasu, Bastijn JG van den Boom, Ildefonso Ferreira Pica, Ingo Willuhn, Christiaan N Levelt, Chris van der Togt

Imaging calcium signals in neurons of awake, behaving animals using single- or multi-photon microscopy facilitates the study of coding in large neural populations. Such experiments produce massive datasets requiring powerful methods to extract responses from hundreds of neurons. We present SpecSeg, a new open-source toolbox for 1) segmentation of regions of interest (ROIs) representing neuronal structures, 2) inspection and manual editing of ROIs, 3) neuropil correction and signal extraction and 4) matching of ROIs in sequential recordings. SpecSeg uses a novel method for ROI registration, based on temporal cross-correlations of low-frequency components derived by Fourier analysis, of each pixel with its neighbors. The approach is insightful and enables ROI detection around neurons or neurites. It works for single- (miniscope) and multi-photon microscopy data, eliminating the need for separate toolboxes. SpecSeg thus provides an efficient and user-friendly approach for analyzing calcium responses in neuronal structures imaged over prolonged periods of time.

19: Ineffectual AEC1 differentiation from KRT8hi transitional state without fibrosis is associated with fatal COVID-19 ARDS
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Posted 13 Jan 2021

Ineffectual AEC1 differentiation from KRT8hi transitional state without fibrosis is associated with fatal COVID-19 ARDS
15 tweets bioRxiv pathology

Christopher Ting, Mohit Aspal, Neil Vaishampayan, Steven K. Huang, Fa Wang, Carol Farver, Rachel Lynne Zemans

COVID-19 ARDS is associated with prolonged ventilator dependence and high mortality, but the underlying mechanisms are unknown. Critical to the pathogenesis of ARDS is injury to the alveolar epithelial cell (AEC) barrier; clinical recovery requires epithelial regeneration. We previously identified a KRT8hi transitional state that regenerating AEC2s adopt during differentiation into AEC1s, the persistence of which may be pathogenic in pulmonary fibrosis. Here, we hypothesize that ineffectual differentiation of transitional cells into AEC1s without fibrosis may underlie ongoing barrier permeability and poor clinical outcomes in COVID-19 ARDS. To test this hypothesis, we examined postmortem lung tissue of COVID-19 ARDS patients. We observed severe epithelial injury, AEC2 proliferation, and abundant transitional cells but ineffectual AEC1 differentiation. Transitional cells were cuboidal, partially spread, or flat and adherent to alveolar septa that were denuded of AEC1s but structurally normal without fibrosis. We conclude that ineffectual AEC1 differentiation from transitional AECs may underlie ongoing barrier permeability and poor clinical outcomes in COVID-19 ARDS. However, in contrast to fibrosis, transitional cells may retain the capacity for AEC1 differentiation with restoration of normal alveolar architecture and function. Novel therapies that promote differentiation of transitional cells into AEC1s may accelerate barrier restoration and clinical recovery in ARDS.

20: Modelling conformational state dynamics and its role on infection for SARS-CoV-2 Spike protein variants
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Posted 17 Dec 2020

Modelling conformational state dynamics and its role on infection for SARS-CoV-2 Spike protein variants
14 tweets bioRxiv biophysics

Natália Teruel, Olivier Mailhot, Rafael Najmanovich

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.

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