bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protein-based Immunome Wide Association Studies (PIWAS) for the discovery of significant disease-associated antigens
Authors: Haynes Winston A. , Kamath Kathy , Daugherty Patrick S. , Shon John C. 
Published: March 2020

AbstractIdentification of the antigens associated with antibodies is vital to understanding immune responses in the context of infection, autoimmunity, and cancer. Discovering antigens at a proteome scale could enable broader identification of antigens that are responsible for generating an immune response or driving a disease state. Although targeted tests for known antigens can be straightforward, discovering antigens at a proteome scale using protein and peptide arrays is time consuming and expensive. We leverage Serum Epitope Repertoire Analysis (SERA), an assay based on a random bacterial display peptide library coupled with NGS, to power the development of Protein-based Immunome Wide Association Study (PIWAS). PIWAS uses proteome-based signals to discover candidate antibody-antigen epitopes that are significantly elevated in a subset of cases compared to controls. After demonstrating statistical power relative to the magnitude and prevalence of effect in synthetic data, we apply PIWAS to systemic lupus erythematosus (SLE, n=31) and observe known autoantigens, Smith and Ribosomal P, within the 22 highest scoring candidate protein antigens across the entire human proteome. We validate the magnitude and location of the SLE specific signal against the Smith family of proteins using a cohort of patients who are positive by predicate anti-Sm tests. Collectively, these results suggest that PIWAS provides a powerful new tool to discover disease-associated serological antigens within any known proteome.Author SummaryInfection, autoimmunity, and cancer frequently induce an antibody response in patients with disease. Identifying the protein antigens that are involved in the antibody response can aid in the development of diagnostics, biomarkers, and therapeutics. To enable high-throughput antigen discovery, we present PIWAS, which leverages the SERA technology to identify antigens at a proteome- and cohort-scale. We demonstrate the ability of PIWAS to identify known autoantigens in SLE. PIWAS represents a major step forward in the ability to discover protein antigens at a proteome scale.
Comprehensive Topographical Map of the Serotonergic Fibers in the Mouse Brain
Authors: Awasthi Janak R. , Tamada Kota , Overton Eric T. N. , Takumi Toru 
Published: March 2020

AbstractIt is well established that serotonergic fibers distribute throughout the brain. Abnormal densities or patterns of serotonergic fibers have been implicated in neuropsychiatric disorders. Although many classical studies have examined the distribution pattern of serotonergic fibers, most of them were either limited to specific brain areas or had limitations in demonstrating the fine axonal morphology. In this study, we utilize transgenic mice expressing GFP under the SERT promoter to map the topography of serotonergic fibers across the rostro-caudal extent of each brain area. We demonstrate previously unreported regional density and fine-grained anatomy of serotonergic fibers. Our findings include: 1) SERT fibers distribute abundantly in the thalamic nuclei close to the midline and dorsolateral areas, in most of the hypothalamic nuclei with few exceptions such as the median eminence and arcuate nuclei, and within the basal amygdaloid complex and lateral septal nuclei, 2) the source fibers of innervation of the hippocampus traverse through the septal nuclei before reaching its destination, 3) unique, filamentous type of straight terminal fibers within the nucleus accumbens, 4) laminar pattern of innervation in the hippocampus, olfactory bulb and cortex with heterogenicity in innervation density among the layers, 5) cortical labelling density gradually decreases rostro-caudally, 6) fibers traverse and distribute mostly within the gray matter, leaving the white fiber bundles uninnervated, and 7) most of the highly labelled nuclei and cortical areas have predominant anatomical connection to limbic structures. In conclusion, we provide novel, regionally specific insights on the distribution map of serotonergic fibers using transgenic mouse.
Critical role for cold shock protein YB-1 in cytokinesis
Authors: Mehta Sunali , Algie Michael , Al-Jabri Tariq , McKinney Cushla , Kannan Srinivasaraghavan , Verma Chandra S , Ma Weini , Zhang Jessie , Bartolec Tara K. , Masamsetti V. Pragathi , Parker Kim , Henderson Luke , Gould Maree L , Bhatia Puja , Harfoot Rhodri , Chircop Megan , Kleffmann Torsten , Cohen Scott B , Woolley Adele G , Cesare Anthony J , Braithwaite Antony 
Published: March 2020

ABSTRACTHigh levels of the cold shock protein Y-box-binding protein-1, YB-1, are tightly correlated with increased cell proliferation and cancer progression. However, the precise mechanism by which YB-1 regulates proliferation is unknown. Here, we found that YB-1 depletion in several cell lines resulted in cytokinesis failure, multinucleation and an increase in G1transit time. Rescue experiments indicated that YB-1 was required for completion of cytokinesis. Using confocal imaging of cells undergoing cytokinesis bothin vitroand in zebrafish embryos, we found that YB-1 was critical for microtubule organization during cytokinesis. Using mass spectrometry we identified multiple novel phosphorylation sites on YB-1. We show that phosphorylation of YB-1 at multiple serine residues was essential for its function during cytokinesis. Using atomistic modelling we show how multiple phosphorylations alter YB-1 conformation, allowing it to interact with protein partners. Our results establish phosphorylated YB-1 as a critical regulator of cytokinesis, defining for the first time precisely how YB-1 regulates cell division.SUMMARYY-box-binding protein-1, YB-1, is essential for cell division, but it is not clear how it functions. Using live imaging and confocal microscopy we show that YB-1 functions only in the last step of division, specifically being required to initiate cytokinesis.
Reovirus core proteins λ1 and σ2 promote stability of disassembly intermediates and influence early replication events
Authors: Gummersheimer Stephanie , Danthi Pranav 
Published: March 2020

ABSTRACTThe capsids of mammalian reovirus contain two concentric protein shells, the core and the outer capsid. The outer capsid is comprised of µ1-σ3 heterohexamers which surround the core. The core is comprised of λ1 decamers held in place by σ2. After entry into the endosome, σ3 is proteolytically degraded and µ1 is cleaved and exposed to form ISVPs. ISVPs undergo further conformational changes to form ISVP*s, resulting in the release of µ1 peptides which facilitate the penetration of the endosomal membrane to release transcriptionally active core particles into the cytoplasm. Previous work has identified regions or specific residues within reovirus outer capsid that impact the efficiency of cell entry. We examined the functions of the core proteins λ1 and σ2. We generated a reovirus T3D reassortant that carries strain T1L derived σ2 and λ1 proteins (T3D/T1L L3S2). This virus displays a lower ISVP stability and therefore converts to ISVP*s more readily. To identify the basis for lability of T3D/T1L L3S2, we screened for hyper-stable mutants of T3D/T1L L3S2 and identified three point mutations in µ1 that stabilize ISVPs. Two of these mutations are located in the C-terminal ϕ region of µ1, which has not previously been implicated in controlling ISVP stability. Independent from compromised ISVP stability, we also found that T3D/T1L L3S2 launches replication more efficiently and produces higher yields in infected cells. In addition to identifying a new role for the core proteins in disassembly events, these data highlight that core proteins may influence multiple stages of infection.IMPORTANCEProtein shells of viruses (capsids) have evolved to undergo specific changes to ensure the timely delivery of genetic material to host cells. The 2-layer capsid of reovirus provides a model system to study the interactions between capsid proteins and the changes they undergo during entry. We tested a virus in which the core proteins were derived from a different strain than the outer capsid. We found that this mismatched virus was less stable and completed conformational changes required for entry prematurely. Capsid stability was restored by introduction of specific changes to the outer capsid, indicating that an optimal fit between inner and outer shells maintains capsid function. Separate from this property, mismatch between these protein layers also impacted the capacity of virus to initiate infection and produce progeny. This study reveals new insights into the roles of capsid proteins and their multiple functions during viral replication.
YASS: Yet Another Spike Sorter applied to large-scale multi-electrode array recordings in primate retina
Authors: Lee JinHyung , Mitelut Catalin , Shokri Hooshmand , Kinsella Ian , Dethe Nishchal , Wu Shenghao , Li Kevin , Reyes Eduardo Blancas , Turcu Denis , Batty Eleanor , Kim Young Joon , Brackbill Nora , Kling Alexandra , Goetz Georges , Chichilnisky E.J. , Carlson David , Paninski Liam 
Published: March 2020

AbstractSpike sorting is a critical first step in extracting neural signals from large-scale multi-electrode array (MEA) data. This manuscript presents several new techniques that make MEA spike sorting more robust and accurate. Our pipeline is based on an efficient multi-stage “triage-then-cluster-then-pursuit” approach that initially extracts only clean, high-quality waveforms from the electrophysiological time series by temporarily skipping noisy or “collided” events (representing two neurons firing synchronously). This is accomplished by developing a neural network detection and denoising method followed by efficient outlier triaging. The denoised spike waveforms are then used to infer the set of spike templates through nonparametric Bayesian clustering. We use a divide-and-conquer strategy to parallelize this clustering step. Finally, we recover collided waveforms with matching-pursuit deconvolution techniques, and perform further split-and-merge steps to estimate additional templates from the pool of recovered waveforms. We apply the new pipeline to data recorded in the primate retina, where high firing rates and highly-overlapping axonal units provide a challenging testbed for the deconvolution approach; in addition, the well-defined mosaic structure of receptive fields in this preparation provides a useful quality check on any spike sorting pipeline. We show that our pipeline improves on the state-of-the-art in spike sorting (and outperforms manual sorting) on both real and semi-simulated MEA data with > 500 electrodes; open source code can be found athttps://github.com/paninski-lab/yass.
Dppa2/4 promotes zygotic genome activation by binding to GC-rich region in signaling pathways
Authors: Li Hanshuang , Long Chunshen , Xiang Jinzhu , Liang Pengfei , Zuo Yongchun 
Published: March 2020

AbstractDevelopmental pluripotency associated 2 (Dppa2) and Dppa4 as positive drivers were helpful for transcriptional regulation of ZGA. Here, we systematically assessed the cooperative interplay between Dppa2 and Dppa4 in regulating cell pluripotency of three cell types and found that simultaneous overexpression of Dppa2/4 can make induced pluripotent stem cells closer to embryonic stem cells. Compared with other pluripotency transcription factors (TFs), Dppa2/4 tends to bind on GC-rich region of proximal promoter (0-500bp). Moreover, there was more potent effect of Dppa2/4 regulation on signaling pathways than other TFs, in which 75% and 85% signaling pathways were significantly activated by Dppa2 and Dppa4, respectively. Notably, Dppa2/4 also can dramatically trigger the decisive signaling pathways for facilitating ZGA, including Hippo, MAPK and TGF-beta signaling pathways and so on. At last, we found that Alkaline phosphatase placental-like 2 (Alppl2) was significantly activated at the 2-cell stage in mouse embryos and 4-8 cell stage in human embryos, further predicted that Alppl2 was directly regulated by Dppa2/4 as a candidate driver of ZGA to regulate pre-embryonic development.
RRBP1 rewires cisplatin resistance in Oral Squamous Cell Carcinoma by regulating YAP-1
Authors: Shriwas Omprakash , Arya Rakesh , Mohanty Sibasish , Kumar Sugandh , Rath Rachna , Kaushik Sandeep Rai , Thakur Mukund Chandra , Pahwa Falak , Das Majumdar Saroj Kumar , Muduly Dillip Kumar , Nanda Ranjan K , Dash Rupesh 
Published: March 2020

AbstractCisplatin-based chemotherapy still remains as one of the primary treatment modalities for OSCC. Several OSCC patients experience relapse owing to development of chemoresistance. To identify key resistance triggering molecules, we performed global proteomic profiling of human OSCC lines presenting with sensitive, early and late cisplatin resistance patterns. From the proteomic profiling study, human RRBP1 was identified to be upregulated in both early and late cisplatin-resistant cells with respect to the sensitive counterpart. Analysis of OSCC patient sample indicates that RRBP1 expression is elevated in chemotherapy-non-responder tumors as compared to chemotherapy-naïve tumors. Knocking out RRBP1 resulted in restoring cisplatin mediated cell death in chemoresistant lines and patient derived cells (PDC). Mechanistically, RRBP1 regulates YAP-1 to induce chemoresistance in OSCC. The chemoresistant PDC xenograft data suggests that knock out of RRBP1 induces cisplatin mediated cell death and facilitates a significant reduction of tumor burden. We also found Radezolid, a novel oxazolidinone antibiotic represses the expression of RRBP1 and restores cisplatin-induced cell death in chemoresistant OSCC. This unique combinatorial approach needs further clinical investigation to target advanced OSCC. Here with for the first time, we uncover the novel role of RRBP1 as potential modulator of cisplatin resistance in advanced OSCC.
A framework for identifying regional outbreak and spread of COVID-19 from one-minute population-wide surveys
Authors: Rossman Hagai , Keshet Ayya , Shilo Smadar , Gavrieli Amir , Bauman Tal , Cohen Ori , Balicer Ran , Geiger Benjamin , Dor Yuval , Segal Eran 
Published: March 2020

AbstractCoronavirus infection spreads in clusters and therefore early identification of these clusters is critical for slowing down the spread of the virus. Here, we propose that daily population-wide surveys that assess the development of symptoms caused by the virus could serve as a strategic and valuable tool for identifying such clusters to inform epidemiologists, public health officials, and policy makers. We show preliminary results from a survey of over 58,000 Israelis and call for an international consortium to extend this concept in order to develop predictive models. We expect such data to allow: Faster detection of spreading zones and patients; Obtaining a current snapshot of the number of people in each area who have developed symptoms; Predicting future spreading zones several days before an outbreak occurs; Evaluating the effectiveness of the various social distancing measures taken, and their contribution to reduce the number of symptomatic people. Such information can provide a valuable tool for decision makers to decide which areas need strengthening of social distancing measures and which areas can be relieved. Preliminary analysis shows that in neighborhoods with confirmed COVID-19 patient history, more responders report on COVID-19 associated symptoms, demonstrating the potential utility of our approach for detection of outbreaks. Researchers from other countries including the U.S, India, Italy, Spain, Germany, Mexico, Finland, Sweden, Norway and several others have adopted our approach and we are collaborating to further improve it. We call with urgency for other countries to join this international consortium, and to share methods and data collected from these daily, simple, one-minute surveys.
Alcohol Screening for Women in their Childbearing Years: What are Health Care Providers doing in Canada?
Authors: Cantin Christina , Patel Tejal , Green Courtney R. , Kaminsky Kyla , Roberts Nicole , Cook Jocelynn L. 
Published: March 2020

AbstractHealth care providers (HCPs) have an important role in screening for alcohol use across the lifespan, particularly during the childbearing years, and providing brief intervention to yield optimal outcomes and prevent the potential teratogenic effects of prenatal alcohol exposure.ObjectiveThe purpose of this study was to describe the current alcohol screening practices of Canadian HCPs who care for pregnant women and women of childbearing age.MethodsAn online survey was administered in 2017 with the aim to identify current knowledge, attitudes, practices and beliefs among Canadian HCPs on screening, brief intervention and referral to treatment (SBIRT) for alcohol use for this population. The bilingual survey was disseminated by 4 national professional associations. A total of 634 interprofessional clinicians completed to the survey. Descriptive analysis was completed for the respondent’s profession and their practices related to alcohol SBIRT. Cross-tabulation analyses explored the use of different screening questionnaires.ResultsMost respondents reported asking about alcohol use; however, there was a low overall use of screening questionnaires for both women of childbearing age and those who are pregnant. Low screening rates may equate to missed opportunities for intervention. Low rates of brief intervention and referral were noted even in circumstances where at-risk drinking was identified, with only 16.4% of respondents intervening when pregnant women reported at-risk alcohol consumption.ConclusionContinued efforts are needed to improve alcohol screening practices among women’s HCPs across Canada. Priority areas for training include: understanding validated alcohol screening questionnaires; incorporating brief intervention into routine care; and developing local referral pathways.
Investigation of fascin1, a marker of mature dendritic cells, reveals a New role for IL-6 signaling in chemotaxis
Authors: Matsumura Fumio , Polz Robin , Singh Sukhwinder , Scheller Jürgen , Yamashiro Shigeko 
Published: March 2020

AbstractMigration of mature dendritic cells (DCs) to lymph nodes is critical for the initiation of adaptive immunity. While CCR7, a a G-protein-coupled receptor for CCL19/21 chemokines, is known to be essential for chemotaxis of mature DCs, the molecular mechanism linking inflammation to chemotaxis remains unclear. We previously demonstrated that fascin1, an actin-bundling protein, increases chemotaxis of mature DCs. In this paper we showed that fascin1 enhanced Interleukin (IL)-6 secretion and signaling. Furthermore, we demonstrated that IL-6 signaling is required for chemotaxis. Blockage of IL-6 signaling in WT DCs with an anti-IL-6 receptorα (IL-6Rα) antibody inhibited chemotaxis toward CCL19. Likewise, knockout (KO) of IL-6Rα inhibited chemotaxis of BMDCs. The addition of soluble IL-6Rα and IL-6 rescued chemotaxis of IL-6Rα KO BMDCs, underscoring the role of IL-6 signaling in chemotaxis. We found that IL-6 signaling is required for internalization of CCR7, the initial step of CCR7 recycling. CCR7 recycling is known to be essential for CCR7-mediated chemotaxis, explaining why IL-6 signaling is needed for chemotaxis of mature DCs. Our results have identified IL-6 signaling as a new regulatory pathway for CCR7/CCL19-mediated chemotaxis, and suggest that rapid migration of mature DCs to lymph nodes depends on inflammation-associated IL-6 signaling.
A semi-automated approach to dense segmentation of 3D white matter electron microscopy
Authors: Kleinnijenhuis Michiel , Johnson Errin , Mollink Jeroen , Jbabdi Saad , Miller Karla L. 
Published: March 2020

ABSTRACTPurposeNeuroscience methods working on widely different scales can complement and inform each other. At the macroscopic scale, magnetic resonance imaging methods that estimate microstructural measures have much to gain from ground truth validation and models based on accurate measurement of that microstructure. We present an approach to generate rich and accurate geometric models of white matter microstructure through dense segmentation of 3D electron microscopy (EM).MethodsVolumetric data of the white matter of the genu of the corpus callosum of the adult mouse brain were acquired using serial blockface scanning electron microscopy (SBF-SEM). A segmentation pipeline was developed to separate the 3D EM data into compartments and individual cellular and subcellular constituents, making use of established tools as well as newly developed algorithms to achieve accurate segmentation of various compartments.ResultsThe volume was segmented into six compartments comprising myelinated axons (axon, myelin sheath, nodes of Ranvier), oligodendrocytes, blood vessels, mitochondria, and unmyelinated axons. The myelinated axons had an average inner diameter of 0.56 μm and an average outer diameter of 0.87 μm. The diameter of unmyelinated axons was 0.43 μm. A mean g-ratio of 0.61 was found for myelinated axons, but the g-ratio was highly variable between as well as within axons.ConclusionThe approach for segmentation of 3D EM data yielded a dense annotation of a range of white matter compartments that can be interrogated for their properties and used forin silicoexperiments of brain structure. We provide the resulting dense annotation as a resource to the neuroscience community.
The microRNA, miR-133b, functions to slow Duchenne muscular dystrophy pathogenesis
Authors: Taetzsch Thomas , Shapiro Dillon , Eldosougi Randa , Myers Tracey , Settlage Robert , Valdez Gregorio 
Published: March 2020

AbstractDuchenne muscular dystrophy (DMD) is characterized by progressive degeneration of skeletal muscles. To date, there are no treatments available to slow or prevent the disease. Hence, it remains essential to identify molecular factors that promote muscle biogenesis since they could serve as therapeutic targets for treating DMD. While the muscle enriched microRNA, miR-133b, has been implicated in the biogenesis of muscle fibers, its role in DMD remains unknown. To assess the role of miR-133b in DMD-affected skeletal muscles, we genetically ablated miR-133b in themdxmouse model of DMD. In the absence of miR-133b, the tibialis anterior muscle of juvenile and adultmdxmice is populated by small muscle fibers with centralized nuclei, exhibits increased fibrosis, and thickened interstitial space. Additional analysis revealed that loss of miR-133b exacerbates DMD-pathogenesis partly by altering the number of satellite cells and levels of protein-encoding genes, including previously identified miR-133b targets as well as genes involved in cell proliferation and fibrosis. Altogether, our data demonstrate that skeletal muscles utilize miR-133b to mitigate the deleterious effects of DMD.