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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 124,632 papers from 535,495 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.

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

61: High dimensional immunotyping of the obese tumor microenvironment reveals model specific adaptation
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Posted 16 Oct 2020

High dimensional immunotyping of the obese tumor microenvironment reveals model specific adaptation
2 tweets bioRxiv cancer biology

Cara E Wogsland, Hilde E Lien, Line Pedersen, Pahul Hanjra, Sturla M Grondal, Rolf A Brekken, James B Lorens, Nils Halberg

Obesity is a disease characterized by chronic low-grade systemic inflammation and has been causally linked to the development of 13 cancer types. Several studies have been undertaken to determine if tumors evolving in obese environments adapt differential interactions with immune cells and if this can be connected to disease outcome. Most of these studies have been limited to single cell lines and tumor models and analysis of limited immune cell populations. Given the multicellular complexity of the immune system and its dysregulation in obesity, we applied high-dimensional suspension mass cytometry to investigate how obesity affects tumor immunity. We used a 36-marker immune-focused mass cytometry panel to interrogate the immune landscape of orthotopic syngeneic mouse models of pancreatic and breast cancer. Unanchored batch correction was implemented to enable simultaneous analysis of tumor cohorts to uncover the immunotypes of each cancer model and reveal remarkably model-specific immune regulation. In the E0771 breast cancer model, we demonstrate an important link to obesity with an increase in two T cell suppressive cell types and a decrease in CD8 T-cells.

62: Restriction of SARS-CoV-2 Replication by Targeting Programmed −1 Ribosomal Frameshifting In Vitro
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Posted 21 Oct 2020

Restriction of SARS-CoV-2 Replication by Targeting Programmed −1 Ribosomal Frameshifting In Vitro
2 tweets bioRxiv molecular biology

Yu Sun, Laura Abriola, Yulia V Surovtseva, Brett D. Lindenbach, Junjie U Guo

Translation of open reading frame 1b (ORF1b) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires programmed −1 ribosomal frameshifting (−1 PRF) promoted by an RNA pseudoknot. The extent to which SARS-CoV-2 replication may be sensitive to changes in −1 PRF efficiency is currently unknown. Through an unbiased, reporter-based high-throughput compound screen, we identified merafloxacin, a fluoroquinolone antibacterial, as a −1 PRF inhibitor of SARS-CoV-2. Frameshift inhibition by merafloxacin is robust to mutations within the pseudoknot region and is similarly effective on −1 PRF of other beta coronaviruses. Importantly, frameshift inhibition by merafloxacin substantially impedes SARS-CoV-2 replication in Vero E6 cells, thereby providing the proof of principle of targeting −1 PRF as an effective antiviral strategy for SARS-CoV-2. ### Competing Interest Statement Yale University has filed a provisional patent application related to this work entitled 'Compounds and Compositions for Disrupting Programmed Ribosomal Frameshifting'.

63: Landscape analysis of escape variants identifies SARS-CoV-2 spike mutations that attenuate monoclonal and serum antibody neutralization
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Posted 08 Nov 2020

Landscape analysis of escape variants identifies SARS-CoV-2 spike mutations that attenuate monoclonal and serum antibody neutralization
2 tweets bioRxiv microbiology

Zhuoming Liu, Laura A VanBlargan, Louis-Marie Bloyet, Paul W Rothlauf, Rita E. Chen, Spencer Stumpf, Haiyan Zhao, John M Errico, Elitza S Theel, Mariel J. Liebeskind, Brynn Alford, William J. Buchser, Ali H Ellebedy, Daved H Fremont, Michael S. Diamond, Sean P. J. Whelan

Although neutralizing antibodies against the SARS-CoV-2 spike (S) protein are a goal of COVID-19 vaccines and have received emergency use authorization as therapeutics, viral escape mutants could compromise their efficacy. To define the immune-selected mutational landscape in S protein, we used a VSV-eGFP-SARS-CoV-2-S chimeric virus and 19 neutralizing monoclonal antibodies (mAbs) against the receptor-binding domain (RBD) to generate 50 different escape mutants. The variants were mapped onto the RBD structure and evaluated for cross-resistance to mAbs and convalescent human sera. Each mAb had a unique resistance profile, although many shared residues within an epitope. Some variants (e.g., S477N) were resistant to neutralization by multiple mAbs, whereas others (e.g., E484K) escaped neutralization by convalescent sera, suggesting some humans induce a narrow repertoire of neutralizing antibodies. Comparing the antibody-mediated mutational landscape in S with sequence variation in circulating SARS-CoV-2, we define substitutions that may attenuate neutralizing immune responses in some humans.

64: Non-canonical odor coding ensures unbreakable mosquito attraction to humans
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Posted 08 Nov 2020

Non-canonical odor coding ensures unbreakable mosquito attraction to humans
2 tweets bioRxiv neuroscience

Meg A Younger, Margaret Herre, Alison R Ehrlich, Zhongyan Gong, Zachary N Gilbert, Saher Rahiel, Benjamin J Matthews, Leslie B Vosshall

Female Aedes aegypti mosquitoes show strong innate attraction to humans. This chemosensory behavior is critical to species survival because females require a blood-meal to reproduce. Humans, the preferred host of Ae. aegypti , produce a complex blend of odor cues along with carbon dioxide (CO2) that attracts females ready to bite. Mosquitoes detect these cues with heteromeric ligand-gated ion channels encoded by three different chemosensory receptor gene families. A common theme in other species is that olfactory neurons express a single receptor that defines their chemical specificity and that they extend axons that converge upon dedicated glomeruli in the first sensory processing center in the brain. Such an organization permits the brain to segregate olfactory information and monitor activity of individual glomeruli to interpret what smell has been encountered. We have discovered that Ae. aegypti uses an entirely different organizational principle for its olfactory system. Using genetic strains that label subpopulations of olfactory neurons, we found that many neurons co-express multiple members of at least two of the chemosensory receptor families. This unexpected co-expression is functional, as assessed by in vivo calcium imaging showing that a given glomerulus is activated by multiple ligands detected by different receptor families. This has direct functional consequences for mosquito behavior. Mutant mosquitoes that cannot sense CO2 can be behaviorally activated by a volatile amine that stimulates the CO2 glomerulus. This non-canonical olfactory system organization featuring overlapping receptor expression may explain the female mosquito's robust and unbreakable attraction to humans. ### Competing Interest Statement The authors have declared no competing interest.

65: Pharmacological rescue of impaired mitophagy in Parkinson's disease-related LRRK2 G2019S knock-in mice
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Posted 07 Dec 2020

Pharmacological rescue of impaired mitophagy in Parkinson's disease-related LRRK2 G2019S knock-in mice
2 tweets bioRxiv cell biology

Francois Singh, Alan R. Prescott, Graeme Ball, Alastair Reith, Ian Ganley

Parkinson's disease (PD) is a major and progressive neurodegenerative disorder, yet the biological mechanisms involved in its aetiology are poorly understood. Evidence links this disorder with mitochondrial dysfunction and/or impaired lysosomal degradation - key features of the autophagy of mitochondria, known as mitophagy. Here we investigated the role of LRRK2, a protein kinase frequently mutated in PD, on this process in vivo. Using mitophagy and autophagy reporter mice, bearing either knockout of LRRK2 or expressing the pathogenic kinase-activating G2019S LRRK2 mutation, we found that basal mitophagy was specifically altered in clinically relevant cells and tissues. Our data show that basal mitophagy inversely correlates with LRRK2 kinase activity in vivo. In support of this, use of distinct LRRK2 kinase inhibitors in cells increased basal mitophagy, and a CNS penetrant LRRK2 kinase inhibitor, GSK3357679A, rescued the mitophagy defects observed in LRRK2 G2019S mice. This study provides the first in vivo evidence that pathogenic LRRK2 directly impairs basal mitophagy, a process with strong links to idiopathic PD, and demonstrates that pharmacological inhibition of LRRK2 is a rational mitophagy-rescue approach and potential PD therapy.

66: Dual color mesoscopic imaging reveals spatiotemporally heterogeneous coordination of cholinergic and neocortical activity.
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Posted 11 Dec 2020

Dual color mesoscopic imaging reveals spatiotemporally heterogeneous coordination of cholinergic and neocortical activity.
2 tweets bioRxiv neuroscience

Sweyta Lohani, Andrew H Moberly, Hadas Benisty, Boris Landa, Miao Jing, Yulong Li, Michael Higley, Jessica A Cardin

Acetylcholine (ACh) is associated with the modulation of brain activity linked to arousal, attention, and emotional valence. We performed dual-color mesoscopic imaging of ACh and calcium across the neocortex of awake mice to investigate the spatiotemporal dynamics of cholinergic signaling and their relationship to cortical output. We find distinct movement-defined behavioral states are represented in spatially heterogeneous cholinergic networks that are differentially coupled to fluctuations in local circuit activity.

67: Cytosplore-Transcriptomics: a scalable inter-active framework for single-cell RNA sequenc-ing data analysis
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Posted 12 Dec 2020

Cytosplore-Transcriptomics: a scalable inter-active framework for single-cell RNA sequenc-ing data analysis
2 tweets bioRxiv bioinformatics

Tamim Abdelaal, Jeroen Eggermont, Thomas Hollt, Ahmed Mahfouz, Marcel Reinders, Boudewijn Lelieveldt

The ever-increasing number of analyzed cells in Single-cell RNA sequencing (scRNA-seq) experiments imposes several challenges on the data analysis. Current analysis methods lack scalability to large datasets hampering interactive visual exploration of the data. We present Cytosplore-Transcriptomics, a framework to analyze scRNA-seq data, including data preprocessing, visualization and downstream analysis. At its core, it uses a hierarchical, manifold preserving representation of the data that allows the inspection and annotation of scRNA-seq data at different levels of detail. Consequently, Cytosplore-Transcriptomics provides interactive analysis of the data using low-dimensional visualizations that scales to millions of cells.

68: 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
2 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.

69: Spontaneous thought and microstate activity modulation by social imitation
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Posted 18 Jan 2021

Spontaneous thought and microstate activity modulation by social imitation
2 tweets bioRxiv neuroscience

Miralena I. Tomescu, Claudiu C Papasteri, Alexandra Sofonea, Romina Boldasu, Valeria Kebets, Catalina Poalelungi, Ioana R Podina, Catalin I Nedelcea, Alexandru I Berceanu, Ioana Carcea

Social imitation increases well-being and closeness by mechanisms that remain poorly understood. We propose that imitation impacts behavioural states in part by modulating post-imitation mind-wandering. The human mind wanders spontaneously and frequently, revisiting the past and imagining the future of self and of others. External and internal factors can influence wandering spontaneous thoughts, whose content predicts subsequent emotional states. In 43 young subjects, we find that imitating the arm movements of an actor alters the dynamics and the content of subsequent resting-state spontaneous thoughts. Imitation-sensitive features of spontaneous thoughts correlate with both behavioural states and salivary oxytocin levels. EEG microstate analysis reveals that global patterns of correlated neuronal activity predict imitation-induced changes in spontaneous thoughts. Thus, imitation can modulate ongoing activity in specific neural networks to change spontaneous thought patterns as a function of oxytocin levels, and to ultimately orchestrate behavioural states.

70: NanoMethViz: an R/Bioconductor package for visualizing long-read methylation data
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Posted 18 Jan 2021

NanoMethViz: an R/Bioconductor package for visualizing long-read methylation data
2 tweets bioRxiv bioinformatics

Shian Su, Quentin Gouil, Marnie E Blewitt, Dianne Cook, Peter S Hickey, Matthew E Ritchie

Motivation: A key benefit of long-read nanopore sequencing technology is the ability to detect modified DNA bases, such as 5-methylcytosine. Tools for effective visualisation of data generated by this platform to assess changes in methylation profiles between samples from different experimental groups remains a challenge. Results: To make visualisation of methylation changes more straightforward, we developed the R/Bioconductor package NanoMethViz. Our software can handle methylation calls generated from a range of different methylation callers and manages large datasets using a compressed data format. To fully explore the methylation patterns in a dataset, NanoMethViz allows plotting of data at various resolutions. At the sample-level, we use multidimensional scaling to look at the relationships between methylation profiles in an unsupervised way. We visualise methylation profiles of classes of features such as genes or CpG islands by scaling them to relative positions and aggregating their profiles. At the finest resolution, we visualise methylation patterns across individual reads along the genome using the spaghetti plot, allowing users to explore particular genes or genomic regions of interest. In summary, our software makes the handling of methylation signal more convenient, expands upon the visualisation options for nanopore data and works seamlessly with existing methylation analysis tools available in the Bioconductor project. Our software is available at https://bioconductor.org/packages/NanoMethViz.

71: Histone Deacetylase 2 (HDAC2) influences maturation and mitochondrial dynamics in human induced pluripotent stem cell derived neurons.
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Posted 18 Jan 2021

Histone Deacetylase 2 (HDAC2) influences maturation and mitochondrial dynamics in human induced pluripotent stem cell derived neurons.
2 tweets bioRxiv neuroscience

Harald Frankowski, Fred Yeboah, Bonnie Berry, Chizuru Kinoshita, Michelle Lee, Kira Evitts, Joshua Davis, Yoshito Kinoshita, Richard S. Morrison, Jessica E. Young

Histone deacetylase 2 (HDAC2) is a major HDAC protein in the adult brain and has been shown to regulate many neuronal genes. Aberrant expression of HDAC2 and subsequent dysregulation of neuronal gene expression is implicated in neurodegeneration and brain aging. Human induced pluripotent stem cell-derived neurons (hiPSC-Ns) are widely used models for studying neurodegenerative disease mechanisms, however the role of HDAC2 in hiPSC-N differentiation and maturation has not been explored. In this study, we show that levels of HDAC2 progressively decrease as hiPSCs are differentiated towards neurons. This suppression of HDAC2 inversely corresponds to an increase in neuron-specific isoforms of Endophilin-B1, a multifunctional protein involved in mitochondrial dynamics. Expression of neuron-specific isoforms of Endophilin-B1 are is accompanied by concomitant expression of a neuron-specific alternative splicing factor, SRRM4. Manipulation of HDAC2 and Endophilin-B1 using lentiviral approaches shows that knock-down of HDAC2 or overexpression of a neuron-specific Endophilin-B1 isoform promotes mitochondrial elongation and protects against cytotoxic stress in hiPSC-Ns, while HDAC2 knock-down specifically influences genes regulating mitochondrial dynamics and synaptogenesis. Furthermore, HDAC2 knock-down promotes enhanced mitochondrial respiration. Collectively, our study demonstrates a role for HDAC2 in hiPSC-neuronal differentiation, highlights neuron-specific isoforms of Endophilin-B1 as a marker of differentiating hiPSC-Ns, and demonstrates that HDAC2 regulates key neuronal and mitochondrial pathways in hiPSC-Ns.

72: Morphometry of SARS-CoV and SARS-CoV-2 particles in ultrathin plastic sections of infected Vero cell cultures.
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Posted 21 Aug 2020

Morphometry of SARS-CoV and SARS-CoV-2 particles in ultrathin plastic sections of infected Vero cell cultures.
1 tweet bioRxiv microbiology

Michael Laue, Anne Kauter, Tobias Hoffmann, Lars Moeller, Janine Michel, Andreas Nitsche

SARS-CoV-2 is the causative of the COVID-19 disease, which has spread pandemically around the globe within a few months. It is therefore necessary to collect fundamental information about the disease, its epidemiology and treatment, as well as about the virus itself. While the virus has been identified rapidly, detailed ultrastructural analysis of virus cell biology and architecture is still in its infancy. We therefore studied the virus morphology and morphometry of SARS-CoV-2 in comparison to SARS-CoV as it appears in Vero cell cultures by using conventional thin section electron microscopy and electron tomography. Both virus isolates, SARS-CoV Frankfurt 1 and SARS-CoV-2 Italy-INMI1, were virtually identical at the ultrastructural level and revealed a very similar particle size distribution with a median of about 100 nm without spikes. Maximal spike length of both viruses was 23 nm. The number of spikes per virus particle was about 30% higher in the SARS-CoV than in the SARS-CoV-2 isolate. This result complements a previous qualitative finding, which was related to a lower productivity of SARS-CoV-2 in cell culture in comparison to SARS-CoV.

73: Lamellar cells in Pacinian and Meissner corpuscles are touch sensors
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Posted 24 Aug 2020

Lamellar cells in Pacinian and Meissner corpuscles are touch sensors
1 tweet bioRxiv physiology

Yury A Nikolaev, Viktor V Feketa, Evan O Anderson, Elena O Gracheva, Sviatoslav N Bagriantsev

The skin covering the human palm and other specialized tactile organs contains a high density of mechanosensory corpuscles tuned to detect transient pressure and vibration. These corpuscles comprise a sensory afferent neuron surrounded by lamellar cells. The neuronal afferent is thought to be the mechanical sensor within the corpuscle, whereas the function of lamellar cells is unknown. Here we show that lamellar cells within Meissner and Pacinian corpuscles detect tactile stimuli. We develop a preparation of bill skin from tactile-specialist ducks that permits electrophysiological recordings from lamellar cells and demonstrate that they contain mechanically-gated ion channels. We also show that lamellar cells from Meissner corpuscles generate mechanically-evoked action potentials using R-type voltage-gated calcium channels. These findings provide the first evidence for R-type channel-dependent action potentials in non-neuronal cells and demonstrate that lamellar cells are active detectors of touch. We propose that Meissner and Pacinian corpuscles use both neuronal and non-neuronal mechanoreception to detect mechanical signals. ### Competing Interest Statement The authors have declared no competing interest.

74: Evaluation of the antiviral effect of chlorine dioxide (ClO2) using a vertebrate model inoculated with avian coronavirus
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Posted 14 Oct 2020

Evaluation of the antiviral effect of chlorine dioxide (ClO2) using a vertebrate model inoculated with avian coronavirus
1 tweet bioRxiv microbiology

Xochitl Zambrano-Estrada, Carlos A. Dominguez-Sanchez, Marina Banuet-Martinez, Fabiola Guerrero-de la Rosa, Teresa Garcia-Gasca, Luis Prieto-Valiente, Karina Acevedo-Whitehouse

The need for safe and effective antiviral treatments is pressing given the number of viral infections that are prevalent in animal and human populations, often causing devastating economic losses and mortality. Informal accounts of anecdotal use of chlorine dioxide (ClO2), a well-known disinfectant and antiseptic, in COVID-19 patients has raised concern about potential toxicity, but also raises the question that ClO2 might elicit antiviral effects, a possibility that has never been examined in vivo in any animal model. Here, we challenged the hypothesis that ClO2 decreases the viral load and virus-induced mortality in a vertebrate model. For this, we determined viral load, virus-induced lesions and mortality in 10-day old chick embryos inoculated with 104 mean EID50/mL of attenuated Massachusetts and Connecticut avian coronavirus (IBV) strains. The ClO2 treatment had a marked impact on IBV infection. Namely, viral titres were 2.4-fold lower and mortality was reduced by half in infected embryos that were treated with ClO2. Infection led to developmental abnormalities regardless of treatment. Lesions typical of IBV infections were observed in all inoculated embryos, but severity tended to be significantly lower in ClO2-treated embryos. We found no gross or microscopic evidence of toxicity caused by ClO2 at the doses used herein. Our study shows that ClO2 could be a safe and viable way of treating and mitigating the effects of avian coronavirus infections, and raises the possibility that similar effects could be observed in other organisms. ### Competing Interest Statement The authors have declared no competing interest.

75: Oocyte spindle assembly depends on multiple interactions between HP1 and the CPC
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Posted 03 Jun 2020

Oocyte spindle assembly depends on multiple interactions between HP1 and the CPC
1 tweet bioRxiv genetics

Lin-Ing Wang, Tyler Defosse, Janet Ko Jang, Rachel Battaglia, Victoria Wagner, Kim McKim

The chromosomes in the oocytes of many animals appear to promote bipolar spindle assembly. In Drosophila oocytes, spindle assembly requires the chromosome passenger complex (CPC), which consists of INCENP, Borealin, Survivin and Aurora B. To determine what recruits the CPC to the chromosomes and its role in spindle assembly, we developed a strategy to manipulate the function and localization of INCENP, which is critical for recruiting the Aurora B kinase. We found that an interaction between Borealin and the chromatin is crucial for the recruitment of the CPC to the chromosomes and is sufficient to build kinetochores and recruit spindle microtubules. We also found that HP1 moves from the chromosomes to the spindle microtubules along with the CPC. We propose that the interaction with HP1 promotes the movement of the CPC from the chromosomes to the microtubules. In addition, within the central spindle, rather than at the centromeres, the CPC and HP1 are required for homologous chromosome bi-orientation.

76: Genome-scale identification of SARS-CoV-2 and pan-coronavirus host factor networks
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Posted 08 Oct 2020

Genome-scale identification of SARS-CoV-2 and pan-coronavirus host factor networks
1 tweet bioRxiv microbiology

William M. Schneider, Joseph M. Luna, H.-H. Hoffmann, Francisco J. Sánchez-Rivera, Andrew A Leal, Alison W. Ashbrook, Jérémie Le Pen, Eleftherios Michailidis, Inna Ricardo-Lax, Avery Peace, Ansgar F. Stenzel, Scott W. Lowe, Margaret R. MacDonald, C.M. Rice, John T Poirier

The COVID-19 pandemic has claimed the lives of more than one million people worldwide. The causative agent, SARS-CoV-2, is a member of the Coronaviridae family, which are viruses that cause respiratory infections of varying severity. The cellular host factors and pathways co-opted by SARS-CoV-2 and other coronaviruses in the execution of their life cycles remain ill-defined. To develop an extensive compendium of host factors required for infection by SARS-CoV-2 and three seasonal coronaviruses (HCoV-OC43, HCoV-NL63, and HCoV-229E), we performed parallel genome-scale CRISPR knockout screens. These screens uncovered multiple host factors and pathways with pan-coronavirus and virus-specific functional roles, including major dependency on glycosaminoglycan biosynthesis, SREBP signaling, and glycosylphosphatidylinositol biosynthesis, as well as an unexpected requirement for several poorly characterized proteins. We identified an absolute requirement for the VTT-domain containing protein TMEM41B for infection by SARS-CoV-2 and all other coronaviruses. This human Coronaviridae host factor compendium represents a rich resource to develop new therapeutic strategies for acute COVID-19 and potential future coronavirus spillover events. ### Competing Interest Statement S.W.L. is an advisor for and has equity in the following biotechnology companies: ORIC Pharmaceuticals, Faeth Therapeutics, Blueprint Medicines, Geras Bio, Mirimus Inc., PMV Pharmaceuticals, and Constellation Pharmaceuticals. CMR is a founder of Apath LLC, a Scientific Advisory Board member of Imvaq Therapeutics, Vir Biotechnology, and Arbutus Biopharma, and an advisor for Regulus Therapeutics and Pfizer. The remaining authors declare no competing interests.

77: Cognitive boundary signals in the human medial temporal lobe shape episodic memory representation
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Posted 16 Jan 2021

Cognitive boundary signals in the human medial temporal lobe shape episodic memory representation
1 tweet bioRxiv neuroscience

Jie Zheng, Andrea Gomez Palacio Schjetnan, Mar Yebra, Clayton P. Mosher, Suneil Kalia, Taufik A Valiante, Adam Mamelak, Gabriel Kreiman, Ueli Rutishauser

While experience unfolds continuously, memories are organized as a set of discrete events that bind together the "where", "when", and "what" of episodic memory. This segmentation of continuous experience is thought to be facilitated by the detection of salient environmental or cognitive events. However, the underlying neural mechanisms and how such segmentation shapes episodic memory representations remain unclear. We recorded from single neurons in the human medial temporal lobe while subjects watched videos with different types of embedded boundaries and were subsequently evaluated for memories of the video contents. Here we show neurons that signal the presence of cognitive boundaries between subevents from the same episode and neurons that detect the abstract separation between different episodes. The firing rate and spike timing of these boundary-responsive neurons were predictive of later memory retrieval accuracy. At the population level, abrupt neural state changes following boundaries predicted enhanced memory strength but impaired order memory, capturing the behavioral tradeoff subjects exhibited when recalling episodic content versus temporal order. Successful retrieval was associated with reinstatement of the neural state present following boundaries, indicating that boundaries structure memory search. These findings reveal a neuronal substrate for detecting cognitive boundaries and show that cognitive boundary signals facilitate the mnemonic organization of continuous experience as a set of discrete episodic events.

78: The Genetic History of France
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Posted 23 Jul 2019

The Genetic History of France
1 tweet bioRxiv genetics

Aude Saint Pierre, Joanna Giemza, Matilde Karakachoff, Isabel Alves, Philippe Amouyel, Jean-François Dartigues, Christophe Tzourio, Martial Monteil, Pilar Galan, Serge Hercberg, Richard Redon, Emmanuelle Génin, Christian Dina

The study of the genetic structure of different countries within Europe has provided significant insights into their demographic history and their actual stratification. Although France occupies a particular location at the end of the European peninsula and at the crossroads of migration routes, few population genetic studies have been conducted so far with genome-wide data. In this study, we analyzed SNP-chip genetic data from 2 184 individuals born in France who were enrolled in two independent population cohorts. Using FineStructure, six different genetic clusters of individuals were found that were very consistent between the two cohorts. These clusters match extremely well the geography and overlap with historical and linguistic divisions of France. By modeling the relationship between genetics and geography using EEMS software, we were able to detect gene flow barriers that are similar in the two cohorts and corresponds to major French rivers or mountains. Estimations of effective population sizes using IBDNe program also revealed very similar patterns in both cohorts with a rapid increase of effective population sizes over the last 150 generations similar to what was observed in other European countries. A marked bottleneck is also consistently seen in the two datasets starting in the fourteenth century when the Black Death raged in Europe. In conclusion, by performing the first exhaustive study of the genetic structure of France, we fill a gap in the genetic studies in Europe that would be useful to medical geneticists but also historians and archeologists.

79: Multi-platform discovery of haplotype-resolved structural variation in human genomes
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Posted 23 Sep 2017

Multi-platform discovery of haplotype-resolved structural variation in human genomes
1 tweet bioRxiv genomics

Mark Chaisson, Ashley D. Sanders, Xuefang Zhao, Ankit Malhotra, David Porubsky, Tobias Rausch, Eugene J Gardner, Oscar Rodriguez, Li Guo, Ryan L. Collins, Xian Fan, Jia Wen, Robert E Handsaker, Susan Fairley, Zev N. Kronenberg, Xiangmeng Kong, Fereydoun Hormozdiari, Dillon Lee, Aaron M. Wenger, Alex Hastie, Danny Antaki, Peter Audano, Harrison Brand, Stuart Cantsilieris, Han Cao, Eliza Cerveira, Chong Chen, Xintong Chen, Chen-Shan Chin, Zechen Chong, Nelson T. Chuang, Christine C. Lambert, Deanna M Church, Laura Clarke, Andrew Farrell, Joey Flores, Timur Galeev, David Gorkin, Madhusudan Gujral, Victor Guryev, William Haynes Heaton, Jonas Korlach, Sushant Kumar, Jee Young Kwon, Jong Eun Lee, Joyce Lee, Wan-Ping Lee, Sau Peng Lee, Shantao Li, Patrick Marks, Karine Viaud-Martinez, Sascha Meiers, Katherine M. Munson, Fabio Navarro, Bradley J Nelson, Conor Nodzak, Amina Noor, Sofia Kyriazopoulou-Panagiotopoulou, Andy Pang, Yunjiang Qiu, Gabriel Rosanio, Mallory Ryan, Adrian Stütz, Diana C.J. Spierings, Alistair Ward, AnneMarie E. Welch, Ming Xiao, Wei Xu, Chengsheng Zhang, Qihui Zhu, Xiangqun Zheng-Bradley, Ernesto Lowy, Sergei Yakneen, Steven McCarroll, Goo Jun, Li Ding, Chong Lek Koh, Bing Ren, Paul Flicek, Ken Chen, Mark Gerstein, Pui-Yan Kwok, Peter M. Lansdorp, Gabor Marth, Jonathan Sebat, Xinghua Shi, Ali Bashir, Kai Ye, Scott E. Devine, Michael Talkowski, Ryan E. Mills, Tobias Marschall, Jan Korbel, Evan E. Eichler, Charles Lee

The incomplete identification of structural variants (SVs) from whole-genome sequencing data limits studies of human genetic diversity and disease association. Here, we apply a suite of long-read, short-read, and strand-specific sequencing technologies, optical mapping, and variant discovery algorithms to comprehensively analyze three human parent-child trios to define the full spectrum of human genetic variation in a haplotype-resolved manner. We identify 818,054 indel variants (<50 bp) and 27,622 SVs (≥50 bp) per human genome. We also discover 156 inversions per genome - most of which previously escaped detection. Fifty-eight of the inversions we discovered intersect with the critical regions of recurrent microdeletion and microduplication syndromes. Taken together, our SV callsets represent a sevenfold increase in SV detection compared to most standard high-throughput sequencing studies, including those from the 1000 Genomes Project. The method and the dataset serve as a gold standard for the scientific community and we make specific recommendations for maximizing structural variation sensitivity for future large-scale genome sequencing studies.

80: A comparative survey of Betacoronavirus binding dynamics relevant to the functional evolution of the highly transmissible SARS-CoV-2 variant N501Y
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Posted 11 Sep 2020

A comparative survey of Betacoronavirus binding dynamics relevant to the functional evolution of the highly transmissible SARS-CoV-2 variant N501Y
1 tweet bioRxiv biophysics

Patrick Rynkiewicz, Gregory Alan Babbitt, Feng Cui, Andre O. Hudson, Miranda L. Lynch

Comparative functional analysis of the binding interactions between various Betacoronavirus mutant strains and their potential multiple human target proteins is crucial for a more complete understanding of zoonotic spillovers of viruses that cause diseases like COVID-19. Here, employing hundreds of replicate sets of nanosecond scale GPU accelerated molecular dynamics simulations, we statistically compare atom motions of ACE2 and CD26 target proteins in both the presence and absence of different strains of the viral receptor binding domain (RBD) of the S spike glycoprotein. In all strains, we demonstrate a universally conserved functional binding signature of the viral RBD with the N-terminal helices of ACE2. We also identify a second more dynamically transient interaction of the viral N501 with the previously confirmed ACE2 K353 and two nearby novel sites, Q325 and the AAQPFLL 386-92 motif. We propose a model of the functional evolution of SARS-type zoonotic spillovers involving both (A) a conserved binding interaction with the N-terminal helices of ACE2 that is preadapted from viral interaction of the Tylonycteris bat coronavirus progenitor strain HKU4 with the SAMLI 291-5 motif in protein CD26 and (B) a more promiscuous and likely more evolvable interaction between viral N501 and the above-mentioned multiple regions of ACE2 that is preadapted from the bat viral interaction at the CD26 SS 333-4 motif. Our recent analysis of the highly transmissible N501Y lineage B.1.1.7 mutation in SARS-CoV-2 also supports this model, identifying a less promiscuous Y501 interaction with ACE2 that favors more stable functional binding with the K353 site alone.

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