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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 73,081 bioRxiv papers from 318,132 authors.

Most tweeted bioRxiv papers, last 7 days

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

41: Long-term repeatability in social behaviours suggests stable social phenotypes in wild chimpanzees
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Posted to bioRxiv 13 Feb 2020

Long-term repeatability in social behaviours suggests stable social phenotypes in wild chimpanzees
27 tweets animal behavior and cognition

Patrick J Tkaczynski, Alexander Mielke, Liran Samuni, Anna Preis, Roman Wittig, Catherine Crockford

Animals living in social groups navigate challenges when competing and cooperating with other group members. Changes in demographics, dominance hierarchies or ecological factors, such as food availability or disease prevalence, are expected to influence decision-making processes regarding social interactions. Therefore, it could be expected individuals show flexibility in social behaviour over time to maximise the fitness benefits of social living. To date, research across species has shown that stable inter-individual differences in social behaviour exist, but mostly over relatively short data collection time periods. Using data spanning over 20 years, we demonstrate that multiple social behaviours are highly repeatable over the long-term in wild chimpanzees, a long-lived species occupying a complex fission-fusion society. We controlled for temporal, ecological and demographic changes, limiting pseudo-repeatability. We conclude that chimpanzees living in natural ecological settings have relatively stable long-term social phenotypes over years. Determining the functional consequences of these stable social phenotypes across the chimpanzee lifespan will benefit our broader understanding of how social tendencies emerge and shape sociality in our closest living relatives.

42: Structure and function of yeast Lso2 and human CCDC124 bound to hibernating ribosomes.
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Posted to bioRxiv 12 Feb 2020

Structure and function of yeast Lso2 and human CCDC124 bound to hibernating ribosomes.
27 tweets molecular biology

Jennifer N Wells, Robert Buschauer, Timur Mackens-Kiani, Katharina Best, Hanna Kratzat, Otto Berninghausen, Thomas Becker, Wendy V Gilbert, Jingdong Cheng, Roland Beckmann

Cells adjust to nutrient deprivation by reversible translational shut down. This is accompanied by maintaining inactive ribosomes in a hibernation state, where they are bound by proteins with inhibitory and protective functions. In eukaryotes, such a function was attributed to Stm1 (SERBP1 in mammals), and recently Lso2 (CCDC124 in mammals) was found to be involved in translational recovery after starvation from stationary phase. Here, we present cryo-electron microscopy (cryo-EM) structures of translationally inactive yeast and human ribosomes. We found Lso2/CCDC124 accumulating on idle ribosomes in the non-unrotated state, in contrast to Stm1/SERBP1-bound ribosomes, which display a rotated state. Lso2/CCDC124 bridges the decoding sites of the small with the GTPase-activating center of the large subunit. This position allows accommodation of the Dom34-dependent ribosome recycling system, which splits Lso2-containing but not Stm1-containing ribosomes. We propose a model in which Lso2 facilitates rapid translation reactivation by stabilizing the recycling-competent state of inactive ribosomes.

43: A mysterious 80 nm amoeba virus with a near-complete "ORFan genome" challenges the classification of DNA viruses
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Posted to bioRxiv 28 Jan 2020

A mysterious 80 nm amoeba virus with a near-complete "ORFan genome" challenges the classification of DNA viruses
26 tweets microbiology

Paulo V. M. Boratto, Graziele P. Oliveira, Talita B. Machado, Ana Cláudia S. P. Andrade, Jean-Pierre Baudoin, Thomas Klose, Frederik Schulz, Saïd Azza, Philippe Decloquement, Eric Chabrière, Philippe Colson, Anthony Levasseur, Bernard La Scola, Jônatas S. Abrahão

Here we report the discovery of Yaravirus, a new lineage of amoebal virus with a puzzling origin and phylogeny. Yaravirus presents 80 nm-sized particles and a 44,924 bp dsDNA genome encoding for 74 predicted proteins. More than 90% (68) of Yaravirus predicted genes have never been described before, representing ORFans. Only six genes had distant homologs in public databases: an exonuclease/recombinase, a packaging-ATPase, a bifunctional DNA primase/polymerase and three hypothetical proteins. Furthermore, we were not able to retrieve viral genomes closely related to Yaravirus in 8,535 publicly available metagenomes spanning diverse habitats around the globe. The Yaravirus genome also contained six types of tRNAs that did not match commonly used codons. Proteomics revealed that Yaravirus particles contain 26 viral proteins, one of which potentially representing a novel capsid protein with no significant homology with NCLDV major capsid proteins but with a predicted double-jelly roll domain. Yaravirus expands our knowledge of the diversity of DNA viruses. The phylogenetic distance between Yaravirus and all other viruses highlights our still preliminary assessment of the genomic diversity of eukaryotic viruses, reinforcing the need for the isolation of new viruses of protists.

44: Respiratory syncytial virus sequesters NF-κB subunit p65 to cytoplasmic inclusion bodies to inhibit innate immune signalling
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Posted to bioRxiv 12 Feb 2020

Respiratory syncytial virus sequesters NF-κB subunit p65 to cytoplasmic inclusion bodies to inhibit innate immune signalling
26 tweets microbiology

Fatoumatta Jobe, Jennifer Simpson, Philippa Hawes, Efrain Guzman, Dalan Bailey

Viruses routinely employ strategies to prevent the activation of innate immune signalling in infected cells. RSV is no exception, encoding two accessory proteins (NS1 and NS2) which are well established to block Interferon signalling. However, RSV-encoded mechanisms for inhibiting NF-KB signalling are less well characterised. In this study we identified RSV-mediated antagonism of this pathway, independent of the NS1 and NS2 proteins, and indeed distinct from other known viral mechanisms of NF-KB inhibition. In both human and bovine RSV infected cells we demonstrated that the P65 subunit of NF-KB is rerouted to perinuclear puncta in the cytoplasm, puncta which are synonymous with viral inclusion bodies (IBs), the site for viral RNA replication. Captured P65 was unable to translocate to the nucleus or transactivate a NF-KB reporter following TNF-α stimulation, confirming the immune-antagonistic nature of this sequestration. Subsequently, we used correlative light electron microscopy (CLEM) to colocalise RSV N protein and P65 within bRSV IBs; granular, membraneless regions of cytoplasm with liquid organelle-like properties. Additional characterisation of bRSV IBs indicated that although they are likely formed by liquid-liquid phase separation (LLPS), they have a differential sensitivity to hypotonic shock proportional to their size. Together, these data identify a novel mechanism for viral antagonism of innate immune signalling which relies on sequestration of the NF-KB subunit p65 to a biomolecular condensate - a mechanism conserved across the Orthopneumovirus genus and not host-cell specific. More generally they provide additional evidence that RNA virus IBs are important immunomodulatory complexes within infected cells.

45: Pantoea ananatis defeats Allium chemical defenses with a plasmid-borne virulence gene cluster
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Posted to bioRxiv 13 Feb 2020

Pantoea ananatis defeats Allium chemical defenses with a plasmid-borne virulence gene cluster
25 tweets plant biology

Shaun P Stice, Kyle K Thao, Chang Hyun Khang, David A. Baltrus, Bhabesh Dutta, Brian H. Kvitko

Onion ( Allium. cepa L ), garlic ( A. sativum L.), and other members of the Allium genus produce volatile antimicrobial thiosulfinates upon cellular damage. Allicin has been known since the 1950s as the primary antimicrobial thiosulfinate compound and odorant produced by garlic. However, the roles of endogenous thiosulfinate production in host-bacterial pathogen interactions have not been described. The bacterial onion pathogen Pantoea ananatis , which lacks both the virulence Type III and Type II Secretion Systems, induces necrotic symptoms and extensive cell death in onion tissues dependent on a proposed secondary metabolite synthesis chromosomal gene cluster. We found strong correlation between the genetic requirements for P. ananatis to colonize necrotized onion tissue and its capacity for tolerance to the thiosulfinate allicin based on the presence of an eleven gene, plasmid-borne, virulence cluster of sulfur/redox genes. We have designated them " alt " genes for allicin tolerance. We show that allicin and onion thiosulfinates restrict bacterial growth with similar kinetics. The alt gene cluster is sufficient to confer allicin tolerance and protects the glutathione pool during allicin treatment. Independent alt genes make partial phenotypic contributions indicating that they function as a collective cohort to manage thiol stress. Our work implicates endogenous onion thiosulfinates produced during cellular damage as mediators of interactions with bacteria. The P. ananatis -onion pathosystem can be modeled as a chemical arms race of pathogen attack, host chemical counter-attack, and pathogen resistance.

46: Thousands of novel unannotated proteins expand the MHC I immunopeptidome in cancer
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Posted to bioRxiv 13 Feb 2020

Thousands of novel unannotated proteins expand the MHC I immunopeptidome in cancer
24 tweets cancer biology

Tamara Ouspenskaia, Travis Law, Karl R. Clauser, Susan Klaeger, Siranush Sarkizova, Francois Aguet, Bo Li, Elena Christian, Binyamin A. Knisbacher, Phuong M. Le, Christina R Hartigan, Hasmik Keshishian, Annie Apffel, Giacomo Oliveira, Wandi Zhang, Yuen Ting Chow, Zhe Ji, Sachet A. Shukla, Pavan Bachireddy, Gad Getz, Nir Hacohen, Derin B. Keskin, Steven A. Carr, Catherine J Wu, Aviv Regev

Tumor epitopes - peptides that are presented on surface-bound MHC I proteins - provide targets for cancer immunotherapy and have been identified extensively in the annotated protein-coding regions of the genome. Motivated by the recent discovery of translated novel unannotated open reading frames (nuORFs) using ribosome profiling (Ribo-seq), we hypothesized that cancer-associated processes could generate nuORFs that can serve as a new source of tumor antigens that harbor somatic mutations or show tumor-specific expression. To identify cancer-specific nuORFs, we generated Ribo-seq profiles for 29 malignant and healthy samples, developed a sensitive analytic approach for hierarchical ORF prediction, and constructed a high-confidence database of translated nuORFs across tissues. Peptides from 3,555 unique translated nuORFs were presented on MHC I, based on analysis of an extensive dataset of MHC I-bound peptides detected by mass spectrometry, with >20-fold more nuORF peptides detected in the MHC I immunopeptidomes compared to whole proteomes. We further detected somatic mutations in nuORFs of cancer samples and identified nuORFs with tumor-specific translation in melanoma, chronic lymphocytic leukemia and glioblastoma. NuORFs thus expand the pool of MHC I-presented, tumor-specific peptides, targetable by immunotherapies.

47: Functional specialization of human salivary glands and origins of proteins intrinsic to human saliva
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Posted to bioRxiv 13 Feb 2020

Functional specialization of human salivary glands and origins of proteins intrinsic to human saliva
24 tweets developmental biology

Marie Saitou, Eliza Gaylord, Duo Xu, Lubov Neznanova, Sara Nathan, Anissa Grawe, Jolie Chang, William Ryan, Stefan Ruhl, Sarah M. Knox, Omer Gokcumen

Salivary proteins facilitate food perception and digestion, maintain the integrity of the mineralized tooth and oral epithelial surfaces, and shield the oro-digestive tract from environmental hazards and invading pathogens. Saliva, as one of the easiest to collect body fluids, also serves in diagnostic applications, with its proteins providing a window to body health. However, despite the availability of the human saliva proteome, the origins of individual proteins remain unclear. To bridge this gap, we analyzed the transcriptomes of 27 tissue samples derived from the three major types of human adult and fetal salivary glands and integrated these data with the saliva proteome and the proteomes and transcriptomes of 28+ other human organs, with tissue expression confirmed by 3D microscopy. Using these tools, we have linked saliva proteins to their source for the first time, an outcome with significant implications for basic research and diagnostic applications. Furthermore, our study represents the first comparative transcriptomic analysis of human adult and fetal exocrine organs, providing evidence that functional specialization occurs late in salivary gland development, and is driven mainly by the transcription of genes encoding secreted saliva proteins. Moreover, we found that dosage of abundant saliva proteins secreted by the salivary glands is primarily regulated at the transcriptional level, and that secreted proteins can be synthesized by distinct subsets of serous acinar cells, revealing hitherto unrecognized heterogeneity in the acinar cell lineage. Our results reveal the functional underpinnings of these secretory organs, paving the way for future investigations into saliva biology and pathology.

48: Classifyber, a robust streamline-based linear classifier for white matter bundle segmentation
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Posted to bioRxiv 12 Feb 2020

Classifyber, a robust streamline-based linear classifier for white matter bundle segmentation
23 tweets neuroscience

Giulia Bertò, Daniel Bullock, Pietro Astolfi, Siochi Hayashi, Luca Zigiotto, Luciano Annicchiarico, Francesco Corsini, Alessandro De Benedictis, Silvio Sarubbo, Franco Pestilli, Paolo Avesani, Emanuele Olivetti

Virtual delineation of white matter bundles in the human brain is of paramount importance for multiple applications, such as pre-surgical planning and connectomics. A substantial body of literature is related to methods that automatically segment bundles from diffusion Magnetic Resonance Imaging (dMRI) data indirectly, by exploiting either the idea of connectivity between regions or the geometry of fiber paths obtained with tractography techniques or, directly, through the information in volumetric data. Despite the remarkable improvement in automatic segmentation methods over the years, their segmentation quality is not yet satisfactory, especially when dealing with datasets with very diverse characteristics, such as different tracking methods, bundle sizes or data quality. In this work, we propose a novel, supervised streamline-based segmentation method, called Classifyber, which combines information from atlases, connectivity patterns, and the geometry of fiber paths into a simple linear model. With a wide range of experiments on multiple datasets that span from research to clinical domains, we show that Classifyber substantially improves the quality of segmentation as compared to other state-of-the-art methods and, more importantly, that it is robust across very diverse settings. We provide an implementation of the proposed method as open source code, as well as web service.

49: Epigenomic translocation of H3K4me3 broad domains following super-enhancer hijacking
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Posted to bioRxiv 12 Feb 2020

Epigenomic translocation of H3K4me3 broad domains following super-enhancer hijacking
22 tweets genomics

Aneta Mikulasova, Marco Trevisan-Herraz, Kent Fung, Cody Ashby, Nefeli Karataraki, Gareth J. Morgan, Anne Corcoran, Sophie Hambleton, Brian A. Walker, Daniel Rico, Lisa J Russell

Chromosomal translocations are important drivers of haematological malignancies whereby proto-oncogenes are activated by juxtaposition with super-enhancers, often called super-enhancer hijacking. We analysed the epigenomic consequences of rearrangements between the enhancers of the immunoglobulin heavy chain locus (IGH) and proto-oncogene CCND1 that are common in B-cell malignancies. By integrating BLUEPRINT epigenomic data with DNA breakpoint detection, we characterised the normal chromatin landscape of the human IGH locus and its dynamics after pathological genomic rearrangement. We detected an H3K4me3 broad domain (BD) within the IGH locus of healthy B-cells that was absent in samples with IGH-CCND1 translocations. The appearance of H3K4me3-BD over CCND1 in the latter was associated with overexpression and extensive chromatin accessibility of this locus. We observed similar cancer-specific H3K4me3-BDs associated with super-enhancer hijacking of other common oncogenes in B-cell (MAF, MYC and FGFR3) and in T-cell malignancies (LMO2, TLX3 and TAL1). Our analysis suggests that H3K4me3-BDs are created by super-enhancers and supports the new concept of epigenomic translocation, where the relocation of H3K4me3-BDs accompanies the translocation of super-enhancers.

50: PHF3 regulates neuronal gene expression through the new Pol II CTD reader domain SPOC
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Posted to bioRxiv 12 Feb 2020

PHF3 regulates neuronal gene expression through the new Pol II CTD reader domain SPOC
22 tweets biochemistry

Lisa-Marie Appel, Vedran Franke, Melania Bruno, Irina Grishkovskaya, Aiste Kasiliauskaite, Ursula E Schoeberl, Martin G Puchinger, Sebastian Kostrhon, Etienne Beltzung, Karl Mechtler, Gen Lin, Anna Vlasova, Martin Leeb, Rushad Pavri, Alexander Stark, Altuna Akalin, Richard Stefl, Carrie Bernecky, Kristina Djinovic-Carugo, Dea Slade

The C-terminal domain (CTD) of the largest subunit of RNA polymerase II (Pol II) is a regulatory hub for transcription and RNA processing. Here, we identify PHD-finger protein 3 (PHF3) as a new CTD-binding factor that negatively regulates transcription and mRNA stability. The PHF3 SPOC domain preferentially binds to CTD repeats phosphorylated on Serine-2 and PHF3 tracks with Pol II across the length of genes. PHF3 competes with TFIIS for Pol II binding through its TFIIS-like domain (TLD), thus inhibiting TFIIS-mediated rescue of backtracked Pol II. PHF3 knock-out or PHF3 SPOC deletion in human cells result in gene upregulation and a global increase in mRNA stability, with marked derepression of neuronal genes. Key neuronal genes are aberrantly expressed in Phf3 knock-out mouse embryonic stem cells, resulting in impaired neuronal differentiation. Our data suggest that PHF3 is a prominent effector of neuronal gene regulation at the interface of transcription elongation and mRNA decay.

51: MS-DIAL 4: accelerating lipidomics using an MS/MS, CCS, and retention time atlas
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Posted to bioRxiv 12 Feb 2020

MS-DIAL 4: accelerating lipidomics using an MS/MS, CCS, and retention time atlas
22 tweets bioinformatics

Hiroshi Tsugawa, Kazutaka Ikeda, Mikiko Takahashi, Aya Satoh, Yoshifumi Mori, Haruki Uchino, Nobuyuki Okahashi, Yutaka Yamada, Ipputa Tada, Paolo Bonini, Yasuhiro Higashi, Yozo Okazaki, Zhiwei Zhou, Zheng-Jiang Zhu, Jeremy Koelmel, Tomas Cajka, Oliver Fiehn, Kazuki Saito, Masanori Arita, Makoto Arita

We formulated mass spectral fragmentations of lipids across 117 lipid subclasses and included ion mobility tandem mass spectrometry (MS/MS) to provide a comprehensive lipidome atlas with retention time, collision cross section, and MS/MS information. The all-in-one solution from import of raw MS data to export of a common output format (mztabM) was packaged in MS-DIAL 4 (http://prime.psc.riken.jp/) providing an enhanced standardized untargeted lipidomics procedure following lipidomics standards initiative (LSI) semi-quantitative definitions and shorthand notation system of lipid structures with a 1~2% estimated false discovery rate, which will contribute to harmonizing lipidomics data across laboratories to accelerate lipids research.

52: Dynamics of genome architecture and chromatin function during human B cell differentiation and neoplastic transformation
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Posted to bioRxiv 10 Sep 2019

Dynamics of genome architecture and chromatin function during human B cell differentiation and neoplastic transformation
21 tweets genomics

Roser Vilarrasa-Blasi, Paula Soler-Vila, Núria Verdaguer-Dot, Núria Russiñol, Marco Di Stefano, Vicente Chapaprieta, Guillem Clot, Irene Farabella, Pol Cuscó, Xabier Agirre, Felipe Prosper, Renée Beekman, Silvia Beà, Dolors Colomer, Henk Stunnenberg, Ivo Gut, Elias Campo, Marc A. Martí-Renom, José Ignacio Martin-Subero

Despite recent advances, the dynamics of genome architecture and chromatin function during human cell differentiation and its potential reorganization upon neoplastic transformation remains poorly characterized. Here, we integrate in situ Hi-C and nine additional omic layers to define and biologically characterize the dynamic changes in three-dimensional (3D) genome architecture across normal B cell differentiation and in neoplastic cells from different subtypes of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) patients. Beyond conventional active (A) and inactive (B) compartments, an integrative analysis of Hi-C data reveals the presence of a highly-dynamic intermediate compartment enriched in poised and polycomb-repressed chromatin. During B cell development, we detect that 28% of the compartments change at defined maturation stages and mostly involve the intermediate compartment. The transition from naive to germinal center B cells is associated with widespread chromatin activation, which mostly reverts into the naive state upon further maturation of germinal center cells into memory B cells. The analysis of CLL and MCL neoplastic cells points both to entity and subtype-specific alterations in chromosome organization. Remarkably, we observe that large chromatin blocks containing key disease-specific genes alter their 3D genome organization. These include the inactivation of a 2Mb region containing the EBF1 gene in CLL and the activation of a 6.1Mb region containing the SOX11 gene in clinically aggressive MCL. This study indicates that 3D genome interactions are extensively modulated during normal B cell differentiation and that the genome of B cell neoplasias acquires a tumor-specific 3D genome architecture.

53: A series of dual-reporter vectors for ratiometric analysis of protein abundance in plants
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Posted to bioRxiv 12 Feb 2020

A series of dual-reporter vectors for ratiometric analysis of protein abundance in plants
21 tweets plant biology

Aashima Khosla, Cecilia Rodriguez-Furlan, Suraj Kapoor, Jaimie M. Van Norman, David C. Nelson

Ratiometric reporter systems enable comparisons of the abundance of a protein of interest, or target, relative to a reference protein. Both proteins are encoded on a single transcript but are separated during translation. This arrangement bypasses the potential for discordant expression that can arise when the target and reference proteins are encoded by separate genes. We generated a set of 18 Gateway-compatible vectors termed pRATIO that combine a variety of promoters, fluorescent and bioluminescent reporters, and 2A self-cleaving peptides. These constructs are easily modified to produce additional combinations or introduce new reporter proteins. We found that mScarlet-I provides the best signal-to-noise ratio among several fluorescent reporter proteins during transient expression experiments in Nicotiana benthamiana. Firefly and Gaussia luciferase also produce high signal-to-noise in N. benthamiana. As proof of concept, we used this system to investigate whether degradation of the receptor KAI2 after karrikin treatment is influenced by its subcellular localization. KAI2 is normally found in the cytoplasm and the nucleus of plant cells. In N. benthamiana, karrikin-induced degradation of KAI2 was only observed when it was retained in the nucleus. These vectors are tools to easily monitor in vivo the abundance of a protein that is transiently expressed in plants, and will be particularly useful for investigating protein turnover in response to different stimuli.

54: Identifying states of collateral sensitivity during the evolution of therapeutic resistance in Ewings sarcoma
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Posted to bioRxiv 12 Feb 2020

Identifying states of collateral sensitivity during the evolution of therapeutic resistance in Ewings sarcoma
21 tweets evolutionary biology

Jessica A Scarborough, Erin McClure, Peter Anderson, Andrew Dhawan, Arda Durmaz, Stephen L Lessnick, Masahiro Hitomi, Jacob G. Scott

Ewings sarcoma (EWS) is the second most common primary malignant bone cancer in children. Advances in the treatment of EWS are desperately needed, particularly in the case of metastatic disease. A deeper understanding of collateral sensitivity, where the evolution of therapeutic resistance to one drug aligns with sensitivity to another drug, may improve our ability to effectively target this disease. For the first time in a solid tumor, we examine the repeatability of collateral sensitivity in EWS cell lines over time as evolutionary replicates evolve resistance to standard treatment. In doing so, we produced a temporal collateral sensitivity map that allows us to examine the evolution of collateral sensitivity and resistance in EWS. We found that the evolution of collateral sensitivity and resistance was predictable with some drugs, but had significant variation in response to other drugs. Samples that were most sensitive and most resistant to all drugs were compared using differential gene expression. Using this map of temporal collateral sensitivity in EWS, we can see that the path towards collateral sensitivity is not always repeatable, nor is there always a clear trajectory towards resistance or sensitivity. Identifying transcriptomic changes that accompany these states of transient collateral sensitivity could improve treatment planning for EWS patients.

55: PCNA activates the MutLγ endonuclease to promote meiotic crossing over
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Posted to bioRxiv 13 Feb 2020

PCNA activates the MutLγ endonuclease to promote meiotic crossing over
20 tweets biochemistry

Neil Hunter, Dhananjaya S. Kulkarni, Shannon Owens, Masayoshi Honda, Masaru Ito, Ye Yang, Mary W. Corrigan, Lan Chen, Aric L. Quan

During meiosis, crossover recombination connects homologous chromosomes to direct their accurate segregation. Defects in crossing over cause infertility, miscarriage and congenital disease. Accordingly, each pair of chromosomes attains at least one crossover through processes that designate and then implement crossing over with high efficiency. At the DNA level, crossing over is implemented through the formation and biased resolution of double-Holliday Junction intermediates. A central tenet of crossover resolution is that the two Holliday junctions are resolved in opposite planes by targeting nuclease incisions to specific DNA strands. Although the endonuclease activity of the MutLγ complex has been implicated in crossover-biased resolution, the mechanisms that activate and direct strand-specific cleavage remain unknown. Here we show that the sliding clamp, PCNA, is important for crossover-biased resolution. In vitro assays with human enzymes show that hPCNA and its loader hRFC are sufficient to activate the hMutLγ endonuclease under physiological conditions. In this context, the hMutLγ endonuclease is further stimulated by a co-dependent activity of the pro-crossover factors hEXO1 and hMutSγ, the latter of which binds Holliday junctions. hMutLγ also specifically binds a variety of branched DNAs, including Holliday junctions, but canonical resolvase activity is not observed implying that the endonuclease incises adjacent to junction branch points to effect resolution. In vivo, we show that budding yeast RFC facilitates MutLγ-dependent crossing over. Furthermore, PCNA localizes to prospective crossover sites along synapsed chromosomes. These data highlight similarities between crossover-resolution and DNA mismatch repair and evoke a novel model for crossover-specific dHJ resolution during meiosis.

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

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

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

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

57: The novel coronavirus 2019 (2019-nCoV) uses the SARS-coronavirus receptor ACE2 and the cellular protease TMPRSS2 for entry into target cells
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Posted to bioRxiv 31 Jan 2020

The novel coronavirus 2019 (2019-nCoV) uses the SARS-coronavirus receptor ACE2 and the cellular protease TMPRSS2 for entry into target cells
20 tweets molecular biology

Markus Hoffmann, Hannah Kleine-Weber, Nadine Krüger, Marcel Müller, Christian Drosten, Stefan Pöhlmann

The emergence of a novel, highly pathogenic coronavirus, 2019-nCoV, in China, and its rapid national and international spread pose a global health emergency. Coronaviruses use their spike proteins to select and enter target cells and insights into nCoV-2019 spike (S)-driven entry might facilitate assessment of pandemic potential and reveal therapeutic targets. Here, we demonstrate that 2019-nCoV-S uses the SARS-coronavirus receptor, ACE2, for entry and the cellular protease TMPRSS2 for 2019-nCoV-S priming. A TMPRSS2 inhibitor blocked entry and might constitute a treatment option. Finally, we show that the serum from a convalescent SARS patient neutralized 2019-nCoV-S-driven entry. Our results reveal important commonalities between 2019-nCoV and SARS-coronavirus infection, which might translate into similar transmissibility and disease pathogenesis. Moreover, they identify a target for antiviral intervention.

58: A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer
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Posted to bioRxiv 12 Feb 2020

A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer
20 tweets genetics

E Lopez de Maturana, JA Rodriguez, L Alonso, O Lao, E Molina-Montes, IA Martin-Antoniano, P Gomez-Rubio, RT Lawlor, A Carrato, M Hidalgo, M Iglesias, X Molero, M Lohr, CW Michalski, J Perea, M O'Rorke, VM Barbera, A Tardon, A Farre, L Munoz-Bellvis, T Crnogorac-Jurcevic, E Dominguez-Munoz, T Gress, W Greenhaf, L Sharp, L Arnes, L Cecchini, J Balsells, E Costello, L Ilzarbe, J Kleeff, B Kong, M Marquez, J Mora, D O'Driscoll, A Scarpa, W Ye, J Yu, PanGenEU Investigators, Montserrat García-Closas, M Kogevinas, N Rothman, D Silverman, SBC/EPICURO Investigators, D Albanes, AA Arslan, L Beane-Freeman, PM Bracci, P Brennan, B Bueno-de-Mesquita, J Buring, F Canzian, M Du, S Gallinger, JMM Gaziano, PJ Goodman, M Gunter, l LeMarchand, D Li, RE Neale, U Peters, GM Petersen, HA Risch, MJ Sanchez, XO Shu, MD Thornquist, M Visvanathan, W Zheng, S Chanock, D Easton, BM Wolpin, RZ Stolzenberg-Solomon, AP Klein, LT Amundadottir, MA Marti-Renom, F.X Real, N. Malats

Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. To-date, 40 GWAS hits have been associated with PC risk in individuals of European descent, explaining 4.1% of the phenotypic variance. Here, we complemented a classical new PC GWAS (1D) with spatial autocorrelation analysis (2D) and Hi-C maps (3D) to gain additional insight into the inherited basis of PC. In-silico functional analysis of public genomic information allowed prioritization of potentially relevant candidate variants. We replicated 17/40 previous PC-GWAS hits and identified novel variants with potential biological functions. The spatial autocorrelation approach prioritized low MAF variants not detected by GWAS. These were further expanded via 3D interactions to 54 target regions with high functional relevance. This multi-step strategy, combined with an in-depth in-silico functional analysis, offers a comprehensive approach to advance the study of PC genetic susceptibility and could be applied to other diseases.

59: Intracellular Lipid Droplet Accumulation Occurs Early Following Viral Infection and Is Required for an Efficient Interferon Response
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Posted to bioRxiv 13 Feb 2020

Intracellular Lipid Droplet Accumulation Occurs Early Following Viral Infection and Is Required for an Efficient Interferon Response
19 tweets microbiology

Ebony A. Monson, Keaton M. Crosse, Erika Duan, Weisan Chen, Ross D O'Shea, Linda M Wakem, Donna R. Whelan, Karla J. Helbig

Lipid droplets (LDs) are increasingly recognized as critical organelles in signalling events, transient protein sequestration and inter-organelle interactions. However, the role LDs play in antiviral innate immune pathways remains unknown. Here we demonstrate that induction of LDs occurs as early as 2 hours post viral infection, is transient, and returns to basal levels by 72 hours. This phenomenon occurred following viral infections, both in vitro and in vivo. Virally driven LD induction was type-I interferon (IFN) independent, however, was dependent on EGFR engagement, offering an alternate mechanism of LD induction in comparison to our traditional understanding of their biogenesis. Additionally, LD induction corresponded with enhanced cellular type-I and -III IFN production in infected cells, with enhanced LD accumulation decreasing viral replication of both HSV-1 and Zika virus (ZIKV). Here, we demonstrate for the first time, that LDs play vital roles in facilitating the magnitude of the early antiviral immune response specifically through the enhanced modulation of IFN following viral infection, and control of viral replication. By identifying LDs as a critical signalling organelle, this data represents a paradigm shift in our understanding of the molecular mechanisms which coordinate an effective antiviral response.

60: BANDITS: Bayesian differential splicing accounting for sample-to-sample variability and mapping uncertainty
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Posted to bioRxiv 29 Aug 2019

BANDITS: Bayesian differential splicing accounting for sample-to-sample variability and mapping uncertainty
19 tweets bioinformatics

Simone Tiberi, Mark D. Robinson

Alternative splicing is a biological process during gene expression that allows a single gene to code for multiple proteins. However, splicing patterns can be altered in some conditions or diseases. Here, we present BANDITS, a R/Bioconductor package to perform differential splicing, at both gene and transcript-level, based on RNA-seq data. BANDITS uses a Bayesian hierarchical structure to explicitly model the variability between samples, and treats the transcript allocation of reads as latent variables. We perform an extensive benchmark across both simulated and experimental RNA-seq datasets, where BANDITS has extremely favorable performance with respect to the competitors considered.

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