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Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 67,039 bioRxiv papers from 295,099 authors.

Most tweeted bioRxiv papers, last 24 hours

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

361: A resource of targeted mutant mouse lines for 5,061 genes
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Posted to bioRxiv 22 Nov 2019

A resource of targeted mutant mouse lines for 5,061 genes
1 tweet genetics

Marie-Christine Birling, Atsushi Yoshiki, David J. Adams, Shinya Ayabe, Arthur L. Beaudet, Joanna Bottomley, Allan Bradley, Steve D.M Brown, Antje B&uumlrger, Wendy Bushell, Francesco Chiani, Hsian-Jean Genie Chin, Skevoulla Christou, Gemma F Codner, Francesco J DeMayo, Mary Dickinson, Brendan Doe, Leah Rae Donahue, Martin D Fray, Alessia Gambadoro, Xiang Gao, Marina Gertsenstein, Alba Gomez-Segura, Leslie O. Goodwin, Jason D. Heaney, Yann H&eacuterault, Martin Hrabe de Angelis, Si-Tse Jiang, Monica J. Justice, Petr Kasparek, Ruairidh E King, Ralf K&uumlhn, Ho Lee, Young Jae Lee, Zhiwei Liu, K C Kent Lloyd, Isabel Lorenzo, Ann-Marie Mallon, Colin McKerlie, Terrence F Meehan, Stuart Newman, Lauryl M.J. Nutter, Goo Taeg Oh, Guillaume Pavlovic, Ramiro Ramirez-Solis, Barry Rosen, Edward J Ryder, Luis A Santos, Joel Schick, John R. Seavitt, Radislav Sedlacek, Claudia Seisenberger, Je Kyung Seong, William C. Skarnes, Tania Sorg, Karen P Steel, Masaru Tamura, Glauco P Tocchini-Valentini, Chi-Kuang Leo Wang, Hannah Wardle-Jones, Marie Wattenhofer-Donz&eacute, Sara Wells, Brandon J Willis, Joshua A Wood, Wolfgang Wurst, Ying Xu, IMPC Consortium, Lydia Teboul, Stephen A. Murray

The International Mouse Phenotyping Consortium reports the generation of new mouse mutant strains for over 5,000 genes from targeted embryonic stem cells on the C57BL/6N genetic background. This includes 2,850 null alleles for which no equivalent mutant mouse line exists, 2,987 novel conditional-ready alleles, and 4,433 novel reporter alleles. This nearly triples the number of genes with reporter alleles and almost doubles the number of conditional alleles available to the scientific community. When combined with more than 30 years of community effort, the total mutant allele mouse resource covers more than half of the genome. The extensively validated collection is archived and distributed through public repositories, facilitating availability to the worldwide biomedical research community, and expanding our understanding of gene function and human disease.

362: The Landscape of Mutations in Fumarate Hydratase
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Posted to bioRxiv 23 Nov 2019

The Landscape of Mutations in Fumarate Hydratase
1 tweet biophysics

David Shorthouse, Michael W J Hall, Benjamin A Hall

Fumarate Hydratase (FH) is an enzyme of the citric acid (TCA) cycle that is responsible for reversibly catalysing the conversion between fumarate and malate. FH loss and subsequent buildup of the oncometabolite fumarate causes hereditary leiomyomatosis and renal cell carcinoma. We sought to explore the mutational landscape of FH in silico, to predict the functional effects of many detected mutations, and categorise detected but un-characterised mutations in human populations. Using mutational energy predicting tools such as Rosetta and FoldX we can accurately predict mutations and mutational hotspots with high disruptive capability. Furthermore, through performing molecular dynamics simulations we show that hinge regions of the protein can be stabilized or destabilized by mutations, with new mechanistic implications of the consequences on the binding affinity of the enzyme for its substrates. We can additionally categorise a large majority of mutations and potential mutations into functional groups. This allows us to predict which detected mutations in the human population are likely to be loss-of-function, and therefore predispose patients to papillary renal carcinoma through considering only mutations to the protein binding site, hinges, and those that are buried deep within the protein. We additionally link mutation data to publicly available metabolomics data, and show that we can accurately predict which mutations in cancer cell lines are functionally relevant.

363: Molecular mechanism of microtubule nucleation from gamma-tubulin ring complex
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Posted to bioRxiv 23 Nov 2019

Molecular mechanism of microtubule nucleation from gamma-tubulin ring complex
1 tweet cell biology

Akanksha Thawani, Howard A Stone, Joshua W Shaevitz, Sabine Petry

Determining how microtubules (MTs) are nucleated is essential for understanding how the cytoskeleton assembles. Yet, half a century after the discovery of MTs and αβ-tubulin subunits and decades after the identification of the γ-tubulin ring complex (γ-TuRC) as the universal MT nucleator, the underlying mechanism largely remains a mystery. Using single molecule studies, we uncover that γ-TuRC nucleates a MT more efficiently than spontaneous assembly. The laterally interacting array of γ-tubulins on γ-TuRC facilitates the lateral association of αβ-tubulins, while longitudinal affinity between γ:αβ-tubulin is surprisingly weak. During nucleation, 3-4 αβ-tubulin dimers bind stochastically to γ-TuRC on average until two of them create a lateral contact and overcome the nucleation barrier. Although γ-TuRC defines the nucleus, XMAP215 significantly increases reaction efficiency by facilitating αβ-tubulin incorporation. In sum, we elucidate how MT initiation occurs from γ-TuRC and determine how it is regulated.

364: Microtubule Nucleation by Single Human γTuRC in a Partly Open Asymmetric Conformation
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Posted to bioRxiv 23 Nov 2019

Microtubule Nucleation by Single Human γTuRC in a Partly Open Asymmetric Conformation
1 tweet biochemistry

Tanja Consolati, Julia Locke, Johanna Roostalu, Jayant Asthana, Wei Ming Lim, Julian Gannon, Fabrizio Martino, Alessandro Costa, Thomas Surrey

The γ-tubulin ring complex (γTuRC) is the major microtubule nucleator in cells. However, the mechanism of its regulation is not understood. Here, we purified human γTuRC and quantitatively characterized its nucleation properties in a TIRF microscopy-based real-time nucleation assay. We find that microtubule nucleation by γTuRC is kinetically inhibited compared to microtubule elongation. Determining the cryo-EM structure of γTuRC at 4 Å resolution reveals an asymmetric conformation with only part of the complex in a 'closed' conformation matching the microtubule geometry. Several factors stabilise the closed conformation. One is actin in the core of the complex and others, likely MZT1 or MZT2, line the outer perimeter of the closed part of γTuRC. The opposed side of γTuRC is in an 'open', nucleation-incompetent conformation, leading to a structural asymmetry, explaining the kinetic inhibition of nucleation by human γTuRC. Our data suggest possible regulatory mechanisms for microtubule nucleation by γTuRC closure.

365: The ecology of cancer differentiation therapy I: non-spatial models
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Posted to bioRxiv 24 Nov 2019

The ecology of cancer differentiation therapy I: non-spatial models
1 tweet cancer biology

Ricard Sole, Guim Aguade

A promising, yet still under development approach to cancer treatment is based on the idea of differentiation therapy (DTH). Most tumours are characterised by poorly differentiated cell populations exhibiting a marked loss of traits associated to communication and tissue homeostasis. DTH has been suggested as an alternative (or complement) to cytotoxic-based approaches, and has proven successful in some specific types of cancer such as acute promyelocytic leukemia (APL). While novel drugs favouring the activation of differentiation therapies are being tested, several open problems emerge in relation to its efectiveness on solid tumors. Here we present a mathematical approach to DTH based on a well-known ecological model used to describe habitat loss in a logistic-growing population experiencing death. This model seems to account for some of the observed clinical and in vitro outcomes of DTH while it provides relevant insight into potential treatment scenarios. Furthermore, the same ecological approach is tested in a hierarchical model that accounts for cancer stem cells, proving that DTH might be an effective opportunity to tackle all the self-renewing cellular compartments in a tumor. We show that the lessons learnt from metapopulation ecology can help guide future developments and potential difficulties of DTH.

366: Rapid diagnosis of SCA36 in a three-generation family using short-read whole genome sequencing data
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Posted to bioRxiv 25 Nov 2019

Rapid diagnosis of SCA36 in a three-generation family using short-read whole genome sequencing data
1 tweet genomics

Haloom Rafehi, David J Szmulewicz, Kate Pope, Mathew Wallis, John Christodoulou, Susan M White, Martin Delatycki, Paul J. Lockhart, Melanie Bahlo

Background: Spinocerebellar ataxias (SCA) are often caused by expansions of short tandem repeats (STRs). Recent methodological advances have made repeat expansion (RE) detection with whole genome sequencing (WGS) feasible. Objectives: To determine the genetic basis of ataxia in a multigenerational Australian pedigree, with autosomal dominant inheritance. Methods and Results: WGS was performed on three affected relatives. The sequence data was screened for known pathogenic REs using two repeat expansion detection tools: exSTRa and ExpansionHunter. This screen provided a clear and rapid diagnosis (less than five days from receiving the sequencing data) of SCA36, a rare form of ataxia caused by an intronic GGCCTG RE in NOP56. Conclusions: the that diagnosis of rare ataxias caused by REs is highly feasible and cost effective with WGS. We propose that WGS be implemented as the frontline, cost effective methodology for molecular testing of individuals with a clinical diagnosis of ataxia.

367: CiteFuse enables multi-modal analysis of CITE-seq data
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Posted to bioRxiv 25 Nov 2019

CiteFuse enables multi-modal analysis of CITE-seq data
1 tweet bioinformatics

Hani Jieun Kim, Yingxin Lin, Thomas A Geddes, Jean Yee Hwa Yang, Pengyi Yang

Multi-modal profiling of single cells represents one of the latest technological advancements in molecular biology. Among various single-cell multi-modal strategies, cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) allows simultaneous quantification of two distinct species: RNA and surface marker proteins (ADT). Here, we introduce CiteFuse, a streamlined package consisting of a suite of tools for pre-processing, modality integration, clustering, differential RNA and ADT expression analysis, ADT evaluation, ligand-receptor interaction analysis, and interactive web-based visualization of CITE-seq data. We show the capacity of CiteFuse to integrate the two data modalities and its relative advantage against data generated from single modality profiling. Furthermore, we illustrate the pre-processing steps in CiteFuse and in particular a novel doublet detection method based on a combined index of cell hashing and transcriptome data. Collectively, we demonstrate the utility and effectiveness of CiteFuse for the integrative analysis of transcriptome and epitope profiles from CITE-seq data.

368: Drosophila models of pathogenic copy-number variant genes show global and non-neuronal defects during development
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Posted to bioRxiv 26 Nov 2019

Drosophila models of pathogenic copy-number variant genes show global and non-neuronal defects during development
1 tweet genomics

Tanzeen Yusuff, Matthew Jensen, Sneha Yennawar, Lucilla Pizzo, Siddharth Karthikeyan, Dagny J Gould, Avik Sarker, Yurika Matsui, Janani Iyer, Zhi-Chun Lai, Santhosh Girirajan

While rare pathogenic copy-number variants (CNVs) are associated with both neuronal and non-neuronal phenotypes, functional studies evaluating these regions have focused on the molecular basis of neuronal defects. We report a systematic functional analysis of non-neuronal defects for homologs of 59 genes within ten CNVs and 20 neurodevelopmental genes in Drosophila. Using wing-specific knockdown of 136 RNA interference lines, we identified qualitative and quantitative phenotypes in 72/79 homologs, including six lines with lethality and 21 lines with severe wing defects. Assessment of 66 lines for tissue-specific effects showed no correlation between the severity of wing and eye-specific defects. We observed disruptions in cell proliferation and apoptosis in larval wing discs for 23/27 homologs, and altered Wnt, Hedgehog and Notch signaling for 9/14 homologs, including AATF/Aatf, PPP4C/Pp4-19C, and KIF11/Klp61F. These findings were further validated with differences in human tissue-specific expression and network connectivity of CNV genes. Our findings suggest that multiple genes within each CNV differentially affect both global and tissue-specific developmental processes within conserved pathways, and that their roles are not restricted to neuronal functions.

369: A fully phased accurate assembly of an individual human genome
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Posted to bioRxiv 26 Nov 2019

A fully phased accurate assembly of an individual human genome
1 tweet bioinformatics

David Porubsky, Peter Ebert, Peter A. Audano, Mitchell R. Vollger, William T. Harvey, Katherine M. Munson, Melanie Sorensen, Arvis Sulovari, Marina Haukness, Maryam Ghareghani, Human Genome Structural Variation Consortium, Peter M. Lansdorp, Benedict Paten, Scott E. Devine, Ashley D. Sanders, Charles Lee, Mark J.P. Chaisson, Jan O. Korbel, Evan E Eichler, Tobias Marschall

The prevailing genome assembly paradigm is to produce consensus sequences that "collapse" parental haplotypes into a consensus sequence. Here, we leverage the chromosome-wide phasing and scaffolding capabilities of single-cell strand sequencing (Strand-seq) and combine them with high-fidelity (HiFi) long sequencing reads, in a novel reference-free workflow for diploid de novo genome assembly. Employing this strategy, we produce completely phased de novo genome assemblies separately for each haplotype of a single individual of Puerto Rican origin (HG00733) in the absence of parental data. The assemblies are accurate (QV > 40), highly contiguous (contig N50 > 25 Mbp) with low switch error rates (0.4%) providing fully phased single-nucleotide variants (SNVs), indels, and structural variants (SVs). A comparison of Oxford Nanopore and PacBio phased assemblies identifies 150 regions that are preferential sites of contig breaks irrespective of sequencing technology or phasing algorithms.

370: Neutrophil swarming in damaged tissue is orchestrated by connexin-dependent calcium signals
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Posted to bioRxiv 26 Nov 2019

Neutrophil swarming in damaged tissue is orchestrated by connexin-dependent calcium signals
1 tweet cell biology

Hugo Poplimont, Antonios Georgantzoglou, Morgane Boulch, Caroline Coombs, Foteini Papaleonidopoulou, Milka Sarris

Neutrophils are major inflammatory cells that rapidly infiltrate injured tissues to provide antimicrobial functions. A key step in their response is the paracrine release of the attractant LTB4, which switches the migration mode from exploratory patrolling to coordinated swarming. This leads to dense clusters that may further disrupt tissue architecture. The coordination mechanism underpinning neutrophil swarms is elusive. Here we show that neutrophils swarms require mutual reinforcement of damage signalling at the wound core. New biosensors and live imaging in zebrafish revealed that neutrophil chemoattractant synthesis is triggered by a sustained calcium flux upon contact with necrotic tissue and sensing of the damage signal ATP. This calcium alarm signal propagates in the nascent neutrophil cluster through connexin-43 hemichannels, which allow release of intracellular ATP. This enables rapid assembly of a centralised, supracellular chemoattractant source, which is instrumental for coordinated recruitment and maximal cell gathering.

371: Extracellular electron transfer-dependent anaerobic oxidation of ammonium by anammox bacteria
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Posted to bioRxiv 26 Nov 2019

Extracellular electron transfer-dependent anaerobic oxidation of ammonium by anammox bacteria
1 tweet microbiology

Dario R. Shaw, Muhammad Ali, Krishna P. Katuri, Jeffrey A Gralnick, Joachim Reimann, Rob Mesman, Laura van Niftrik, Mike S. M. Jetten, Pascal E. Saikaly

Anaerobic ammonium oxidation (anammox) by anammox bacteria contributes significantly to the global nitrogen cycle, and plays a major role in sustainable wastewater treatment. Anammox bacteria convert ammonium (NH4+) to dinitrogen gas (N2) using nitrite (NO2-) or nitric oxide (NO) as the electron acceptor. In the absence of NO2- or NO, anammox bacteria can couple formate oxidation to the reduction of metal oxides such as Fe(III) or Mn(IV). Their genomes contain homologs of Geobacter and Shewanella cytochromes involved in extracellular electron transfer (EET). However, it is still unknown whether anammox bacteria have EET capability and can couple the oxidation of NH4+ with transfer of electrons to carbon-based insoluble extracellular electron acceptors. Here we show using complementary approaches that in the absence of NO2-, freshwater and marine anammox bacteria couple the oxidation of NH4+ with transfer of electrons to carbon-based insoluble extracellular electron acceptors such as graphene oxide (GO) or electrodes poised at a certain potential in microbial electrolysis cells (MECs). Metagenomics, fluorescence in-situ hybridization and electrochemical analyses coupled with MEC performance confirmed that anammox electrode biofilms were responsible for current generation through EET-dependent oxidation of NH4+. 15N-labelling experiments revealed the molecular mechanism of the EET-dependent anammox process. NH4+ was oxidized to N2 via hydroxylamine (NH2OH) as intermediate when electrode was the terminal electron acceptor. Comparative transcriptomics analysis supported isotope labelling experiments and revealed an alternative pathway for NH4+ oxidation coupled to EET when electrode is used as electron acceptor compared to NO2- as electron acceptor. To our knowledge, our results provide the first experimental evidence that marine and freshwater anammox bacteria can couple NH4+ oxidation with EET, which is a significant finding, and challenges our perception of a key player of anaerobic oxidation of NH4+ in natural environments and engineered systems.

372: Kinetochore phosphatases suppress autonomous kinase activity to control the spindle assembly checkpoint
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Posted to bioRxiv 26 Nov 2019

Kinetochore phosphatases suppress autonomous kinase activity to control the spindle assembly checkpoint
1 tweet cell biology

Marilia H Cordeiro, Richard J Smith, Adrian T Saurin

Local phosphatase regulation is critical for determining when phosphorylation signals are activated or deactivated. A typical example is the spindle assembly checkpoint (SAC) during mitosis, which regulates kinetochore PP1 and PP2A-B56 activities to switch-off signalling events at the correct time. In this case, kinetochore phosphatase activation dephosphorylates MELT motifs on KNL1 to remove SAC proteins, including the BUB complex. We show here that, surprisingly, neither PP1 or PP2A are required to dephosphorylate the MELT motifs. Instead, they remove polo-like kinase 1 (PLK1) from the BUB complex, which can otherwise maintain MELT phosphorylation in an autocatalytic manner. This is their principle role in the SAC, because both phosphatases become redundant if PLK1 is inhibited or BUB-PLK1 interaction is prevented. Therefore, phosphatase regulation is critical for the SAC, but primarily to restrain and extinguish autonomous kinase activity. We propose that these circuits have evolved to generate a semi-autonomous SAC signal that can be synchronously silenced following kinetochore-microtubule tension.

373: Whole genome sequencing analysis of the cardiometabolic proteome
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Posted to bioRxiv 27 Nov 2019

Whole genome sequencing analysis of the cardiometabolic proteome
1 tweet genetics

Arthur Gilly, Young-Chan Park, Grace Png, Thea Bjornland, Lorraine Southam, Daniel Suveges, Sonja Neumeyer, Iris Fischer, Andrei Barysenka, Nigel William Rayner, Emmanouil Tsafantakis, Maria Karaleftheri, George Dedoussis, Eleftheria Zeggini

The human proteome is a crucial intermediate between complex diseases and their genetic and environmental components, and an important source of drug development targets and biomarkers. Here, we conduct high-depth (22.5x) whole-genome sequencing (WGS) in 1,328 individuals to fully assess the genetic architecture of 257 circulating protein biomarkers of cardiometabolic relevance. We discover 132 independent sequence variant associations ( P <7.45×10−11) across the allele frequency spectrum, including 44 new cis -acting and 11 new trans- acting loci, all of which replicate in an independent cohort (n=1,605, 18.4x WGS). We identify replicating evidence for rare-variant cis -acting protein quantitative trait loci for five genes, involving both coding and non-coding variation. We find causal links between protein biomarkers and cardiovascular, inflammatory and immune-related diseases. We construct and validate polygenic risk scores that explain up to 45% of protein level variation, and find significant correlation between genetically-predicted biomarker levels and cardiovascular disease risk in UK Biobank.

374: Annotation-free Learning of Plankton for Classification and Anomaly Detection
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Posted to bioRxiv 27 Nov 2019

Annotation-free Learning of Plankton for Classification and Anomaly Detection
1 tweet bioinformatics

Vito Paolo Pastore, THOMAS ZIMMERMAN, SUJOY BISWAS, SIMONE BIANCO

The acquisition of increasingly large plankton digital image datasets requires automatic methods of recognition and classification. As data size and collection speed increases, manual annotation and database representation are often bottlenecks for utilization of machine learning algorithms for taxonomic classification of plankton species in field studies. In this paper we present a novel set of algorithms to perform accurate detection and classification of plankton species with minimal supervision. Our algorithms approach the performance of existing supervised machine learning algorithms when tested on a plankton dataset generated from a custom-built lensless digital device. Similar results are obtained on a larger image dataset obtained from the Woods Hole Oceanographic Institution. Our algorithms are designed to provide a new way to monitor the environment with a class of rapid online intelligent detectors.

375: The genomic landscape of intrinsic and acquired resistance to cyclin-dependent kinase 4/6 inhibitors in patients with hormone receptor positive metastatic breast cancer
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Posted to bioRxiv 28 Nov 2019

The genomic landscape of intrinsic and acquired resistance to cyclin-dependent kinase 4/6 inhibitors in patients with hormone receptor positive metastatic breast cancer
1 tweet cancer biology

Seth A Wander, Ofir Cohen, Xueqian Gong, Gabriela N. Johnson, Jorge Buendia-Buendia, Maxwell R. Lloyd, Dewey Kim, Flora Luo, Pingping Mao, Karla Helvie, Kailey J Kowalski, Utthara Nayar, Adrienne G Waks, Stephen Parsons, Ricardo Martinez, Lacey M. Litchfield, Xiang S. Ye, Chun Ping Yu, Valerie M. Jansen, John R. Stille, Patricia S. Smith, Gerald J. Oakley, Quincy Chu, Gerald Batist, Melissa Hughes, Jill D. Kremer, Levi A. Garraway, Eric P Winer, Sara M. Tolaney, Nancy U Lin, Sean Buchanan, Nikhil Wagle

Clinical resistance mechanisms to CDK4/6 inhibitors in HR+ breast cancer have not been clearly Whole exome sequencing of 59 tumors with CDK4/6i exposure revealed multiple candidate resistance mechanisms including RB1 loss, activating alterations in AKT1, RAS, AURKA, CCNE2, ERBB2, and FGFR2, and loss of ER expression. In vitro experiments confirmed that these alterations conferred CDK4/6i resistance. Cancer cells cultured to resistance with CDK4/6i also acquired RB1, KRAS, AURKA, or CCNE2 alterations, which conferred sensitivity to AURKA, ERK, or CHEK1 inhibition. Besides inactivation of RB1, which accounts for ~5% of resistance, seven of these mechanisms have not been previously identified as clinical mediators of resistance to CDK4/6 inhibitors in patients. Three of these - RAS activation, AKT activation, and AURKA activation - have not to our knowledge been previously demonstrated preclinically. Together, these eight mechanisms were present in 80% of resistant tumors profiled and may define therapeutic opportunities in patients.

376: CD300lf is the primary physiologic receptor of murine norovirus but not human norovirus
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Posted to bioRxiv 28 Nov 2019

CD300lf is the primary physiologic receptor of murine norovirus but not human norovirus
1 tweet microbiology

Vincent Graziano, Forrest C Walker, Elizabeth A. Kennedy, Jin Wei, Khalil Ettayebi, Madison S. Simões, Renata B. Filler, Ebrahim Hassan, Leon L Hsieh, Abimbola O Kolawole, Christiane E Wobus, Lisa C. Lindesmith, Ralph S. Baric, Mary Estes, Robert Orchard, Megan T Baldridge, Craig Wilen

Murine norovirus (MNoV) is an important model of human norovirus (HNoV) and mucosal virus infection more broadly. Viral receptor utilization is a major determinant of cell tropism, host range, and pathogenesis. The bona fide receptor for HNoV is unknown. Recently, we identified CD300lf as a proteinaceous receptor for MNoV. Interestingly, its paralogue CD300ld was also sufficient for MNoV infection in vitro . Here we explored whether CD300lf is the sole physiologic receptor in vivo and whether HNoV can use a CD300 ortholog as an entry receptor. We report that both CD300ld and CD300lf are sufficient for infection by diverse MNoV strains in vitro . We further demonstrate that CD300lf is essential for both oral and parenteral MNoV infection and to elicit anti-MNoV humoral responses in vivo . In mice deficient in STAT1 signaling, CD300lf is required for MNoV-induced lethality. However, after high dose intraperitoneal challenge with MNoV in Cd300lf −/− Stat1 −/− mice a single amino acid mutation in the MNoV capsid protein emerged. This substitution did not alter receptor utilization in vitro . Finally, we demonstrate that human CD300lf (huCD300lf) is not essential for HNoV infection, nor does huCD300lf inhibit binding of HNoV virus-like particles to glycans. Thus, we report huCD300lf is not a receptor for HNoV. Author Summary Human norovirus is the leading cause of non-bacterial gastroenteritis causing up to 200,000 deaths each year. How human norovirus enters cells is unknown. Because human norovirus is difficult to grow in the laboratory and in small animals, we use mouse or murine norovirus as a model system. We recently discovered that murine norovirus can use the either CD300ld or CD300lf as a receptor in vitro . We also showed that CD300lf deficient mice were resistant to oral challenge with a single virus strain. Here we determined that CD300lf is essential for infection of diverse murine norovirus strains in cell lines and in mice with normal immune systems demonstrating it’s the primary physiologic receptor for diverse murine norovirus strains independent of infection route. However, in immunodeficient mice injected with high dose virus directly into the abdominal cavity, we observed a norovirus mutant that enabled CD300lf-independent infection. Finally, we demonstrated that human CD300lf is not the elusive receptor for human norovirus.

377: Rapid Alkalinization Factor (RALF) gene family genomic structure and transcriptional regulation during host-pathogen crosstalk in Fragaria vesca and Fragaria x ananassa strawberry
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Posted to bioRxiv 28 Nov 2019

Rapid Alkalinization Factor (RALF) gene family genomic structure and transcriptional regulation during host-pathogen crosstalk in Fragaria vesca and Fragaria x ananassa strawberry
1 tweet plant biology

Francesca Negrini, Kevin O’Grady, Marko Hyvönen, Kevin M. Folta, Elena Baraldi

Rapid Alkalinization Factor (RALF) are cysteins-rich peptides ubiquitous in plant kingdom. They play multiple roles as hormone signals, starting from root elongation, cell growth, pollen tube development and fertilization. Their involvement in host-pathogen crosstalk as negative regulator of immunity in Arabidopsis has also been recognized. In addition, RALF peptides are secreted by different fungal pathogens as effectors during early stages of infections. Campbell and Turner previously identified nine RALF genes in F. vesca v1 genome. Here, based on the recent release of Fragaria x ananassa genome and F. vesca reannotation, we aimed to characterize the genomic organization of the RALF gene family in both type of strawberry species according to tissue specific expression and homology with Arabidopsis . We reveal the presence of 13 RALF genes in F. vesca and 50 in Fragaria x ananassa, showing a non-homogenous localization of genes among the different Fragaria x ananassa subgenomes associated with their different TE element contents and genome remodeling during evolution. Fragaria x ananassa RALF genes expression inducibility upon infection with C. acutatum or B. cinerea was assessed and showed that, among fruit expressed RALF genes, FaRALF3-1 was the only one upregulated after fungal infection. In silico analysis and motif frequency analysis of the putative regulatory elements upstream of the FaRALF3 gene was carried out in order to identify distinct pathogen inducible elements. Agroinfiltration of strawberry fruit with 5’ deletion constructs of the FaRALF3-1 promoter identified a region required for FaRALF3 expression in fruit, but did not identify a region responsible for fungal induced expression.

378: FLIP(L) determines p53 induced life or death
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Posted to bioRxiv 28 Nov 2019

FLIP(L) determines p53 induced life or death
1 tweet cancer biology

Andrea Lees, ALexander J McIntyre, Fiammetta Falcone, Nyree T Crawford, Christopher McCann, Gerard P Quinn, Jamie Z Roberts, Tamas Sessler, Peter F Gallagher, Katherine McAllister, Kirsty McLaughlin, Wendy L Allen, Caitriona Holohan, Laurence J Egan, Aideen E. Ryan, Melissa Labonte-Wilson, Philip D Dunne, Mark Wappett, Vicky M Coyle, Patrick Johnston, Emma M Kerr, Daniel B Longley, Simon S McDade

How p53 differentially activates cell cycle arrest versus cell death remains poorly understood. Here, we demonstrate that upregulation of canonical pro-apoptotic p53 target genes in colon cancer cells imposes a critical dependence on the long splice form of the caspase-8 regulator FLIP (FLIP(L)), which we identify as a direct p53 transcriptional target. Inhibiting FLIP(L) expression with siRNA or Class-I HDAC inhibitors promotes apoptosis in response to p53 activation by the MDM2 inhibitor Nutlin-3A, which otherwise predominantly induces cell-cycle arrest. When FLIP(L) upregulation is inhibited, apoptosis is induced in response to p53 activation via a novel ligand-independent TRAIL-R2/caspase-8 complex, which, by activating BID, induces mitochondrial-mediated apoptosis. Notably, FLIP(L) depletion inhibits p53-induced expression of the cell cycle regulator p21 and enhances p53-mediated upregulation of PUMA, with the latter activating mitochondrial-mediated apoptosis in FLIP(L)-depleted, Nutlin-3A-treated cells lacking TRAIL-R2/caspase-8. Thus, we report two previously undescribed, novel FLIP(L)-dependent mechanisms that determine cell fate following p53 activation.

379: Frequent extrachromosomal oncogene amplification drives aggressive tumors
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Posted to bioRxiv 28 Nov 2019

Frequent extrachromosomal oncogene amplification drives aggressive tumors
1 tweet cancer biology

Hoon Kim, Nam Nguyen, Kristen Turner, Sihan Wu, Jihe Liu, Viraj Deshpande, Sandeep Namburi, Howard Y. Chang, Christine Beck, Paul S Mischel, Vineet Bafna, Roel GW Verhaak

Extrachromosomal DNA (ecDNA) amplification promotes high oncogene copy number, intratumoral genetic heterogeneity, and accelerated tumor evolution, but its frequency and clinical impact are not well understood. Here we show, using computational analysis of whole-genome sequencing data from 1,979 cancer patients, that ecDNA amplification occurs in at least 26% of human cancers, of a wide variety of histological types, but not in whole blood or normal tissue. We demonstrate a highly significant enrichment for oncogenes on amplified ecDNA and that the most common recurrent oncogene amplifications arise on ecDNA. EcDNA amplifications resulted in higher levels of oncogene transcription compared to copy number matched linear DNA, coupled with enhanced chromatin accessibility. Patients whose tumors have ecDNA-based oncogene amplification showed increase of cell proliferation signature activity, greater likelihood of lymph node spread at initial diagnosis, and significantly shorter survival, even when controlled for tissue type, than do patients whose cancers are not driven by ecDNA-based oncogene amplification. The results presented here demonstrate that ecDNA-based oncogene amplification plays a central role in driving the poor outcome for patients with some of the most aggressive forms of cancers.

380: Effects of Temperature on Zika Dynamics and Control
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Posted to bioRxiv 28 Nov 2019

Effects of Temperature on Zika Dynamics and Control
1 tweet ecology

Calistus N. Ngonghala, Sadie J. Ryan, Blanka Tesla, Leah R. Demakovskys, Erin A Mordecai, Courtney C Murdock, Matthew H. Bonds

When a formerly rare pathogen emerges to cause a pandemic, it is critical to understand the ecology of the disease dynamics and its potential effects on disease control. Here, we take advantage of newly available experimental data to parameterize a temperature-dependent dynamical model of Zika virus (ZIKV) transmission, and analyze the effects of temperature variability and the parameters related to control strategies on ZIKV R and the total disease burden (i.e., total number of human cases). Sensitivity analyses identified that R and disease burden were largely driven by different parameters, with the exception of temperature, which is the dominant driver of epidemic dynamics in the models. Our estimate of R had a single optimum temperature (≈ 30° C, comparable to recently published results (≈ 29°) [[1][1]]. However, the total number of human cases (“disease burden”) is maximized across a wider temperature range, from 24 to 36°C. The models indicate that the disease is highly sensitive to seasonal temperature variation. For example, although the model predicts that Zika transmission cannot occur at a constant temperature of 22°C, with seasonal variation of 5°C around a mean of 22°C, the model predicts a larger epidemic than what would occur at a constant 30°C, the temperature predicted to maximize R . This suggests that the potential geographic range of Zika is wider than indicated from static R models, underscoring the importance of climate dynamics and variation on emerging infectious diseases. [1]: #ref-1

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