bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lymphatic type-1 interferon responses are critical for control of systemic reovirus dissemination
Authors: Phillips Matthew B. , Zita Marcelle Dina , Howells Morgan A. , Weinkopff Tiffany , Boehme Karl W. 
Published: July 2020

ABSTRACTMammalian orthoreovirus (reovirus) spreads from the site of infection to every organ system in the body via the blood. However, mechanisms that underlie reovirus hematogenous spread remain undefined. Non-structural protein σ1s is a critical determinant of reovirus bloodstream dissemination that is required for efficient viral replication in many types of cultured cells. Here, we used the specificity of the σ1s protein for promoting hematogenous spread as a platform to uncover a role for lymphatic type-1 interferon (IFN-1) responses in limiting reovirus systemic dissemination. We found that replication of a σ1s-deficient reovirus was restored to wild-type levels in cells with defective type-1 interferon a-receptor (IFNAR1) signaling.In vivo, reovirus spreads systemically following oral inoculation of neonatal mice, whereas the σ1s-null virus remains localized to the intestine. We found that σ1s enables reovirus spread in the presence of a functional IFN-1 response, as the σ1s-deficient reovirus disseminated comparably to wild-type virus in IFNAR1-/-mice. Lymphatics are hypothesized to mediate reovirus spread from the intestine to the bloodstream. IFNAR1 deletion from cells expressing lymphatic vessel endothelium receptor-1 (LYVE-1), a marker for lymphatic endothelial cells, enabled the σ1s-deficient reovirus to disseminate systemically. Together, our findings indicate that IFN-1 responses in lymphatics limit reovirus dissemination. Our data further suggest that the lymphatics are an important conduit for reovirus hematogenous spread.IMPORTANCEType-1 interferon (IFN-1) responses are a critical component of the host response to viral infections. However, the contribution of specific cell and tissue types to control of viral infections is not known. Here, we found that reoviruses lacking nonstructural protein were more sensitive to IFN-1 responses than wild-type reovirus, indicating that σ1s is important for reovirus resistance to IFN-1 responses. The σ1s protein also is a key determinant of reovirus systemic spread. We used tissue-specific IFNAR1 deletion in combination with the IFN-1-sensitive σ1s-null reovirus as a tool to identify a role for lymphatics in reovirus dissemination. We used Cre-lox technology to delete type-1 interferon a-receptor (IFNAR1) in lymphatic cells and found that the IFN-1-sensitive σ1s-deficient reovirus disseminated in mice with lymphatic endothelial cells-specific deletion of IFNAR1. Together, our results indicate that IFN-1 responses in lymphatics are critical for controlling reovirus systemic spread.
Deterministic and stochastic rules of branching govern dendritic morphogenesis of sensory neurons
Authors: Palavalli Amrutha , Tizón-Escamilla Nicolás , Rupprecht Jean-François , Lecuit Thomas 
Published: July 2020

AbstractDendrite morphology is necessary for the correct integration of inputs that neurons receive. The branching mechanisms allowing neurons to acquire their type-specific morphology remain unclear. Classically, axon and dendrite patterns were shown to be guided by molecules providing deterministic cues. However, the extent to which deterministic and stochastic mechanisms, based upon purely statistical bias, contribute to the emergence of dendrite shape is largely unknown. We address this issue using theDrosophilaclass I vpda multi-dendritic neurons. Detailed quantitative analysis of vpda dendrite morphogenesis indicates that the primary branch grows very robustly in a fixed direction while secondary branch numbers and lengths showed fluctuations characteristic of stochastic systems. Live tracking dendrites and computational modeling revealed how neuron shape emerges from few local statistical parameters of branch dynamics. We report key opposing aspects of how tree architecture feedbacks on the local probability of branch shrinkage. Child branches promote stabilization of parent branches while self-repulsion promotes shrinkage. Finally, we show that self-repulsion, mediated by the adhesion molecule Dscam1, indirectly patterns the growth of secondary branches by spatially restricting their direction of stable growth perpendicular to the primary branch. Thus, the stochastic nature of secondary branch dynamics and the existence of geometric feedback emphasizes the importance of self-organization in neuronal dendrite morphogenesis.
Ferroptosis response segregates small cell lung cancer (SCLC) neuroendocrine subtypes
Authors: Bebber Christina M. , Thomas Emily S. , Chen Zhiyi , Stroh Jenny , Androulidaki Ariadne , Schmitt Anna , Höhne Michaela N. , Stüker Lukas , de Pádua Alves Cleidson , Khonsari Armin , Dammert Marcel A. , Parmaksiz Fatma , Beleggia Filippo , Sos Martin L. , Riemer Jan , George Julie , Brodesser Susanne , Thomas Roman K. , Reinhardt H. Christian , von Karstedt Silvia 
Published: July 2020

AbstractBi-allelic loss ofTP53andRB1in treatment-naïve small cell lung cancer (SCLC) suggests strong selective pressure to inactivate regulated cell death pathways prior to therapy. Yet, which regulated cell death pathways remain available in treatment-naïve SCLC is unknown. Here, through systemic analysis of cell death pathway availability, we identify non-neuroendocrine (NE) and NE SCLC subtypes to segregate by their response to ferroptosis, a recently described iron-dependent type of regulated necrosis. While we identify that in treatment-naïve SCLC extrinsic apoptosis and necroptosis are incapacitated, we find non-NE SCLC to be exquisitely sensitive to ferroptosis induced through pharmacological and genetic means. Mechanistically, non-NE SCLC as opposed to NE SCLC presents with an oxygenated lipidome priming non-NE SCLC for ferroptosis. ASCL1+ NE SCLC, in turn, is resistant to ferroptosis but acquires selective addiction to the thioredoxin (TRX) anti-oxidant pathway. Importantly, co-cultures mimicking non-NE/NE intratumoral heterogeneity selectively deplete non-NE populations upon induction of ferroptosis while eliminating NE cell populations only upon TRX pathway. As a consequence, combined induction of ferroptosis and inhibition of the TRX pathway broadly kills established non-NE and NE tumors in xenografts and genetically engineered mouse models of SCLC. Moreover, patient-derived treatment-naïve and refractory NE SCLC models are selectively killed via this regime. In SCLC, combined low expression of GPX4 and TRX reductase 1 (TXNRD1) identifies a patient subset with drastically improved overall survival. These data identify ferroptosis as an SCLC subtype-specific vulnerability and suggest repurposing ferroptosis induction with TRX pathway inhibition to specifically address intratumoral NE/non-NE heterogeneity in SCLC.One Sentence SummaryThe SCLC non-neuroendocrine subtype is sensitive to ferroptosis
Evolutionary responses to codon usage of horizontally transferred genes inPseudomonas aeruginosa
Authors: Callens Martijn , Scornavacca Celine , Bedhomme Stéphanie 
Published: July 2020

AbstractProkaryote genome evolution is characterized by the frequent gain of genes through horizontal gene transfer (HGT). For a gene, being horizontally transferred can represent a strong change in its genomic and physiological context. If the codon usage of a transferred gene deviates from that of the receiving organism, the fitness benefits it provides can be reduced due to a mismatch with the expression machinery. Consequently, transferred genes with a deviating codon usage can be selected against or elicit evolutionary responses that enhance their integration. In this study, a comparative genomics approach was used to investigate evolutionary responses after the horizontal transfer of genes with diverse degrees of codon usage mismatch inPseudomonas aeruginosa. Selection on codon usage of genes acquired through HGT was observed, with the overall codon usage converging towards that of the core genome over evolutionary time. This pattern seemed to be mainly driven by selective retention of transferred genes with an initial codon usage similar to that of the core genes. Gene amelioration, through the accumulation of synonymous mutations after HGT, did not seem to systematically affect transferred genes. Additionally, variation in the copy number of tRNA genes was often associated with the acquisition of genes for which the observed variation could enhance their expression. This provides evidence that compensatory evolution might be an important mechanism for the integration of horizontally transferred genes.
Disruption of a Hedgehog-Foxf1-Rspo2 Signaling Axis Leads to Tracheomalacia and a Loss of Sox9+ Tracheal Chondrocytes
Authors: Nasr Talia , Chaturvedi Praneet , Agarwal Kunal , Kinney Jessica L. , Daniels Keziah , Trisno Stephen L. , Ustiyan Vladimir , Shannon John M. , Wells James M. , Sinner Debora , Kalinichenko Vladimir V. , Zorn Aaron M. 
Published: July 2020

ABSTRACTCongenital tracheomalacia, resulting from incomplete tracheal cartilage development, is a relatively common birth defect that severely impairs breathing in neonates. Mutations in the Hedgehog (HH) pathway and downstream Gli transcription factors are associated with tracheomalacia in patients and mouse models; however, the underlying molecular mechanisms are unclear. Using multipleHH/Glimouse mutants including one that mimics Pallister-Hall Syndrome, we show that excessive Gli repressor activity prevents specification of tracheal chondrocytes. Lineage tracing experiments show that Sox9+ chondrocytes arise from HH-responsive splanchnic mesoderm in the fetal foregut that expresses the transcription factor Foxf1. Disrupted HH/Gli signaling results in 1) loss of Foxf1 which in turn is required to support Sox9+ chondrocyte progenitors and 2) a dramatic reduction inRspo2, a secreted ligand that potentiates Wnt signaling known to be required for chondrogenesis. These results reveal a HH-Foxf1-Rspo2 signaling axis that governs tracheal cartilage development and informs the etiology of tracheomalacia.SUMMARY STATEMENTThis work provides a mechanistic basis for tracheomalacia in patients with Hedgehog pathway mutations.
EGF signaling in bowel carcinoma cells utilizes higher order architectures of EGFR and HER2
Authors: Wollman Adam J. M. , Fournier Charlotte , Llorente-Garcia Isabel , Harriman Oliver , Hargreaves Alex L. , Shashkova Sviatlana , Zhou Peng , Liu Ta-Chun , Ouaret Djamila , Wilding Jenny , Kusumi Akihiro , Bodmer Walter , Leake Mark C. 
Published: July 2020

AbstractEpidermal growth factor (EGF) signaling regulates normal cell development, however EGF receptor (EGFR) overexpression is reported in several carcinomas. Despite structural and biochemical evidence that EGF-EGFR ligation activates signaling through monomer-dimer transitions, live cell mechanistic details remain contentious. We report single-molecule multispectral TIRF of human epithelial carcinoma cells transfected with fluorescent EGFR, and of CHO-K1 cells containing fluorescent EGFR and HER2, enabling super-resolved localization to quantify receptor architectures and spatiotemporal dynamics upon EGF ligation. Using inhibitors that block binding to EGFR, and time-dependent kinetics modelling, we find that pre-activated EGFR consist predominantly of preformed clusters that contain a mixture of EGFR and HER2, whose stoichiometry increases following EGF activation. Although complicated by EGFR internalization and recycling, our observation of an EGFR:EGF stoichiometry >1 for plasma membrane colocalized EGFR/EGF foci soon after activation may indicate preferential binding of EGF ligand to EGFR monomers, negative cooperativity and preferential ligated-unligated dimerization of monomers.
Viscoelastic relaxation of collagen networks provides a self-generated directional cue during collective migration
Authors: Clark Andrew G. , Maitra Ananyo , Jacques Cécile , Simon Anthony , Pérez-González Carlos , Trepat Xavier , Voituriez Raphaël , Vignjevic Danijela Matic 
Published: July 2020

AbstractThere is growing evidence that the physical properties of the cellular environment can impact cell migration. However, it is not currently understood how active physical remodeling of the network by cells affects their migration dynamics. Here, we study collective migration of small clusters of cells on deformable collagen-1 networks. Combining theory and experiments, we find that cell clusters, despite displaying no apparent internal polarity, migrate persistently and generate asymmetric collagen gradients during migration. We find that persistent migration can arise from viscoelastic relaxation of collagen networks, and reducing the viscoelastic relaxation time by chemical crosslinking leads to a reduction in migration persistence. Single cells produce only short range network deformations that relax on shorter timescales, which leads to lower migration persistence. This physical model provides a mechanism for self-generated directional migration on viscoelastic substrates in the absence of internal biochemical cues.
ACE2-expressing endothelial cells in aging mouse brain
Authors: Lim Su Bin , Dawson Valina L. , Dawson Ted M. , Kang Sung-Ung 
Published: July 2020

AbstractAngiotensin-converting enzyme 2 (ACE2) is a key receptor mediating the entry of SARS-CoV-2 into the host cell. Through a systematic analysis of publicly available mouse brain sc/snRNA-seq data, we found that ACE2 is specifically expressed in small sub-populations of endothelial cells and mural cells, namely pericytes and vascular smooth muscle cells. Further, functional changes in viral mRNA transcription and replication, and impaired blood-brain barrier regulation were most prominently implicated in the aged, ACE2-expressing endothelial cells, when compared to the young adult mouse brains. Concordant EC transcriptomic changes were further found in normal aged human brains. Overall, this work reveals an outline of ACE2 distribution in the mouse brain and identify putative brain host cells that may underlie the selective susceptibility of the aging brain to viral infection.
Identification of pathways modulating Vemurafenib resistance in melanoma cells via a genome-wide CRISPR/Cas9 screen
Authors: Jie Hui Goh Corinna , Wong Jin Huei , Farran Chadi El , Tan Ban Xiong , Coffill Cynthia , Loh Yuin-Hain , Lane David , Arumugam Prakash 
Published: July 2020

ABSTRACTVemurafenib is a BRAF kinase inhibitor (BRAFi) that is used to treat melanoma patients harbouring the constitutively active BRAF-V600E mutation. However, after a few months of treatment patients often develop resistance to vemurafenib leading to disease progression. Sequence analysis of drug-resistant tumour cells and functional genomic screens have identified several genes that regulate vemurafenib resistance. Reactivation of mitogen-activated protein kinase (MAPK) pathway is a recurrent feature of cells that develop resistance to vemurafenib. We performed a genome-scale CRISPR-based knockout screen to identify modulators of vemurafenib resistance in melanoma cells with a highly improved CRISPR sgRNA library called Brunello. We identified 33 genes that regulate resistance to vemurafenib out of which 14 genes have not been reported before. Gene Ontology enrichment analysis showed that the hit genes regulate histone modification, transcription and cell cycle. We discuss how inactivation of hit genes might confer resistance to vemurafenib and provide a framework for follow-up investigations.
ReCoNet: Multi-level Preprocessing of Chest X-rays for COVID-19 Detection Using Convolutional Neural Networks
Authors: Ahmed Sabbir , Yap Moi Hoon , Tan Maxine , Hasan Md. Kamrul 
Published: July 2020

AbstractLife-threatening COVID-19 detection from radiomic features has become a dire need of the present time for infection control and socio-economic crisis management around the world. In this paper, a novel convolutional neural network (CNN) architecture, ReCoNet (residual image-based COVID-19 detection network), is proposed for COVID-19 detection. This is achieved from chest X-ray (CXR) images shedding light on the preprocessing task considered to be very useful for enhancing the COVID-19 fingerprints. The proposed modular architecture consists of a CNN-based multi-level preprocessing filter block in cascade with a multi-layer CNN-based feature extractor and a classification block. A multi-task learning loss function is adopted for optimization of the preprocessing block trained end-to-end with the rest of the proposed network. Additionally, a data augmentation technique is applied for boosting the network performance. The whole network when pre-trained end-to-end on the CheXpert open source dataset, and trained and tested with the COVIDx dataset of 15,134 original CXR images yielded an overall benchmark accuracy, sensitivity, and specificity of 97.48%, 96.39%, and 97.53%, respectively. The immense potential of ReCoNet may be exploited in clinics for rapid and safe detection of COVID-19 globally, in particular in the low and middle income countries where RT-PCR labs and/or kits are in a serious crisis.
Serum-IgG responses to SARS-CoV-2 after mild and severe COVID-19 infection and analysis of IgG non-responders
Authors: Marklund Emelie , Leach Susannah , Axelsson Hannes , Nyström Kristina , Norder Heléne , Bemark Mats , Angeletti Davide , Lundgren Anna , Nilsson Staffan , Andersson Lars-Magnus , Yilmaz Aylin , Lindh Magnus , Liljeqvist Jan-Åke , Gisslén Magnus 
Published: July 2020

AbstractBackgroundTo accurately interpret COVID-19 seroprevalence surveys, knowledge of serum-IgG responses to SARS-CoV-2 with a better understanding of patients who do not seroconvert, is imperative. This study aimed to describe serum-IgG responses to SARS-CoV-2 in a cohort of patients with both severe and mild COVID-19, including extended studies of patients who remained seronegative more than 90 days post symptom onset.ResultsForty-seven patients (mean age 49 years, 38% female) were included. All (15/15) patients with severe symptoms and 29/32 (90.6%) patients with mild symptoms of COVID-19 developed SARS-CoV-2-specific IgG antibodies in serum. Time to seroconversion was significantly shorter (median 11 vs. 22 days, P=0.04) in patients with severe compared to mild symptoms. Of the three patients without detectable IgG-responses after >90 days, all had detectable virus-neutralizing antibodies and in two, spike-protein receptor binding domain-specific IgG was detected with an in-house assay. Antibody titers were preserved during follow-up and all patients who seroconverted, irrespective of the severity of symptoms, still had detectable IgG levels >75 days post symptom onset.ConclusionsPatients with severe COVID-19 both seroconvert earlier and develop higher concentrations of SARS-CoV-2-specific IgG than patients with mild symptoms. Of those patients who not develop detectable IgG antibodies, all have detectable virus-neutralizing antibodies, suggesting immunity. Our results showing that not all COVID-19 patients develop detectable IgG using two validated commercial clinical methods, even over time, are vital for the interpretation of COVID-19 seroprevalence surveys and for estimating the true infection prevalence in populations.
Decreased serum levels of inflammaging marker miR-146a are associated with clinical response to tocilizumab in COVID-19 patients
Authors: Sabbatinelli Jacopo , Giuliani Angelica , Matacchione Giulia , Latini Silvia , Laprovitera Noemi , Pomponio Giovanni , Ferrarini Alessia , Baroni Silvia Svegliati , Pavani Marianna , Moretti Marco , Gabrielli Armando , Procopio Antonio Domenico , Ferracin Manuela , Bonafè Massimiliano , Olivieri Fabiola 
Published: July 2020

ABSTRACTBackgroundCurrent COVID-19 pandemic poses an unprecedented threat to global health and healthcare systems. At least in western countries, the most amount of the death toll is accounted by old people affected by age-related diseases. In this regard, we proposed that COVID-19 severity may be tightly related to inflammaging, i.e. the age-related onset of inflammation, which is responsible for age-related diseases. It has been reported that systemic hyper-inflammation may turn to be detrimental in COVID-19 patients.ObjectiveHere, we exploited a recently closed clinical trial (NCT04315480) on the anti-IL-6 drug tocilizumab to assess whether microRNAs regulating inflammaging can be assessed as biomarkers of drug response and outcome.MethodsSerum levels of miR-146a-5p, −21-5p, and −126-3p were quantified by RT-PCR and Droplet Digital PCR by two independent laboratories on 30 patients with virologically confirmed COVID-19, characterized by multifocal interstitial pneumonia confirmed by CT-scan and requiring oxygen therapy, and 29 age- and gender-matched healthy control subjects. COVID-19 patients were treated with a single-dose intravenous infusion of 8 mg/kg tocilizumab and categorized into responders and non-responders.ResultsWe showed that COVID-19 patients who did not respond to tocilizumab have lower serum levels of miR-146a-5p after the treatment (p=0.007). Moreover, among non-responders, those with the lowest serum levels of miR-146a-5p experienced the most adverse outcome (p=0.008).ConclusionOur data show that blood-based biomarkers, such as miR-146a-5p, can provide a molecular link between inflammaging and COVID-19 clinical course, thus allowing to enlarge the drug armory against this worldwide health threat.