bluuebunny/crossref_metadata_2025_split huggingface dataset:
GWAS of serum ALT and AST reveals an association ofSLC30A10Thr95Ile with hypermanganesemia symptoms
Authors: Ward Lucas D. , Tu Ho-Chou , Quenneville Chelsea B. , Tsour Shira , Flynn-Carroll Alexander O. , Parker Margaret M. , Deaton Aimee M. , Haslett Patrick A. J. , Lotta Luca A. , Verweij Niek , Ferreira Manuel A. R. ,   Regeneron Genetics Center, Geisinger-Regeneron DiscovEHR Collaboration, Baras Aris , Hinkle Gregory , Nioi Paul 
Published: May 2020

AbstractTo investigate mechanisms of hepatocellular damage, we performed genome-wide association studies (GWAS) on alanine aminotransferase (ALT) and aspartate aminotransferase (AST) serum activities across 411,048 subjects from four ancestry groups in the UK Biobank, and found 100 loci associating with both enzymes. The rare missense variantSLC30A10Thr95Ile (rs188273166) associates with a larger elevation in ALT and AST than any other variant tested and this association also replicates in the DiscovEHR study. SLC30A10 excretes manganese from the liver to the bile duct, and rare homozygous loss of function causes the syndrome hypermanganesemia with dystonia-1 (HMNDYT1) which involves cirrhosis. Consistent with hematological symptoms of hypermanganesemia,SLC30A10Thr95Ile carriers have increased hematocrit and risk of iron deficiency anemia. Carriers also have increased risk of extrahepatic bile duct cancer. These associations suggest that genetic variation inSLC30A10adversely affects more individuals than patients with diagnosed HMNDYT1.
Rapid Tilt-Series Method for Cryo-Electron Tomography: Characterizing Stage Behavior During FISE Acquisition
Authors: Chreifi Georges , Chen Songye , Jensen Grant J. 
Published: May 2020

ABSTRACTWe and others recently developed rapid tilt-series acquisition methods for cryo-electron tomography on a Titan Krios G3i equipped with a single axis holder and a K-series direct electron detector and showed that one of these, the fast-incremental single exposure (FISE) method, significantly accelerates tilt-series acquisition when compared to traditional methods while preserving the quality of the images. Here, we characterize the behavior of our single axis holder in detail during a FISE experiment to optimally balance data quality with speed. We explain our methodology in detail so others can characterize their own stages, and conclude with recommendations for projects with different resolution goals.
Selective role of the translin/trax RNase complex in hippocampal synaptic plasticity
Authors: Park Alan Jung , Shetty Mahesh Shivarama , Baraban Jay M. , Abel Ted 
Published: May 2020

AbstractActivity-dependent local protein synthesis is critical for synapse-specific, persistent plasticity. Abnormalities in local protein synthesis have been implicated in psychiatric disorders. We have recently identified the translin/trax microRNA-degrading enzyme as a novel mediator of protein synthesis at activated synapses. Additionally, mice lacking translin/trax exhibit some of the behavioral abnormalities found in a mouse model of fragile X syndrome. Therefore, identifying signaling pathways interacting with translin/trax to support persistent synaptic plasticity is a translationally relevant goal. Here, as a first step to achieve this goal, we have assessed the requirement of translin/trax for multiple hippocampal synaptic plasticity paradigms that rely on distinct molecular mechanisms. We found that mice lacking translin/trax exhibited selective impairment in a form of persistent hippocampal plasticity, which requires postsynaptic PKA activity. In contrast, enduring forms of plasticity that are dependent on presynaptic PKA were unaffected. Furthermore, these mice did not display exaggerated metabotropic glutamate receptor-mediated long-term synaptic depression, a hallmark of the mouse model of fragile X syndrome. Taken together, these findings demonstrate that translin/trax mediates long-term synaptic plasticity that is dependent on postsynaptic PKA signaling.
The Southern Bluefin Tuna mucosal microbiome is influenced by husbandry method, net pen location, and anti-parasite treatment
Authors: Minich Jeremiah J , Power Cecilia , Melanson Michaela , Knight Rob , Webber Claire , Rough Kirsten , Bott Nathan J. , Nowak Barbara , Allen Eric E 
Published: May 2020

AbstractAquaculture is the fastest growing primary industry worldwide. Marine finfish culture in open ocean net pens, or pontoons, is one of the largest growth areas and is currently the only way to rear high value fish such as bluefin tuna. Ranching involves catching wild juveniles, stocking in floating net pens and fattening for four to eight months. Tuna experience several parasite-induced disease challenges in culture that can be mitigated by application of praziquantel (PZQ) as a therapeutic. In this study, we characterized the microbiome of ranched southern Bluefin Tuna,Thunnus maccoyii, across four anatomic sites (gill, skin, digesta, and anterior kidney) and evaluated environmental and pathological factors that influence microbiome composition, including the impact of PZQ treatment on microbiome stability. Southern bluefin tuna gill, skin, and digesta microbiome communities are unique and potentially influenced by husbandry practices, location of pontoon growout pens, and treatment with the antiparasitic PZQ. There was no significant relationship between the fish mucosal microbiome and incidence or abundance of adult blood fluke in the heart or fluke egg density in the gill. An enhanced understanding of microbiome diversity and function in high-value farmed fish species such as bluefin tuna is needed to optimize fish health and improve aquaculture yield. Comparison of the bluefin tuna microbiome to other fish species, includingSeriola lalandi(yellowtail kingfish), a common farmed species from Australia, andScomber japonicus(Pacific mackerel), a wild caught Scombrid relative of tuna, showed the two Scombrids had more similar microbial communities compared to other families. The finding that mucosal microbial communities are more similar in phylogenetically related fish species exposes an opportunity to develop mackerel as a model for tuna microbiome and parasite research.
DNA from dried blood spots yields high quality sequences for exome analysis
Authors: Sunderam Uma , Adhikari Aashish N. , Kundu Kunal , Puck Jennifer M. , Currier Robert , Kwok Pui-Yan , Brenner Steven E. , Srinivasan Rajgopal 
Published: May 2020

AbstractBackgroundDNA sequencing of archived dried blood spots (DBS) collected by newborn screening programs constitutes a potential health resource to study newborn disorders and understand genotype-phenotype relationships. However, its essential to verify that sequencing reads from DBS derived DNA are suitable for variant discovery.ResultsWe explored 16 metrics to comprehensively assess the quality of sequencing reads from 180 DBS and 35 whole blood (WB) samples. These metrics were used to assess a) mapping of reads to the reference genome, b) degree of DNA damage, and c) variant calling. Reads from both sets mapped with similar efficiencies, had similar overall DNA damage rates, measured by the mismatch rate with the reference genome, and produced variant calls sets with similar Transition-Transversion ratios. While evaluating single nucleotide changes that may have arisen from DNA damage, we observed that the A>T and T>A changes were more frequent in DNA from DBS than from WB. However, this did not affect the accuracy of variant calling, with DBS samples yielding a comparable count of high quality SNVs and indels in samples with at least 50x coverage.ConclusionsOverall, DBS DNA provided exome sequencing data of sufficient quality for clinical interpretation.
Reproducible and accessible analysis of transposon insertion data at scale
Authors: Larivière Delphine , Wickham Laura , Keiler Kenneth C. , Nekrutenko Anton 
Published: May 2020

ABSTRACTSignificant progress has been made in advancing and standardizing tools for human genomic and biomedical research, yet the field of next generation sequencing (NGS) analysis for microorganisms (including multiple pathogens) remains fragmented, lacks accessible and reusable tools, is hindered by local computational resource limitations, and does not offer widely accepted standards. One of such “problem areas” is the analysis of Transposon Insertion Sequencing (TIS) data. TIS allows perturbing the entire genome of a microorganism by introducing random insertions of transposon-derived constructs. The impact of the insertions on the survival and growth provides precise information about genes affecting specific phenotypic characteristics. A wide array of tools has been developed to analyze TIS data and among the variety of options available, it is often difficult to identify which one can provide a reliable and reproducible analysis. Here we sought to understand the challenges and propose reliable practices for the analysis of TIS experiments. Using data from two recent TIS studies we have developed a series of workflows that include multiple tools for data de-multiplexing, promoter sequence identification, transposon flank alignment, and read count repartition across the genome. Particular attention was paid to quality control procedures such as the determination of the optimal tool parameters for the analysis and removal of contamination. Our work provides an assessment of the currently available tools for TIS data analysis and offers ready to use workflows that can be invoked by anyone in the world using our public Galaxy platform (https://usegalaxy.org). To lower the entry barriers we have also developed interactive tutorials explaining details of TIS data analysis procedures athttps://bit.ly/gxy-tis.ImportanceA wide array of tools has been developed to analyze TIS data and among the variety of options available, it is often difficult to identify which one can provide a reliable and reproducible analysis. Here we sought to understand the challenges and propose reliable practices for the analysis of TIS experiments. Using data from two recent TIS studies we have developed a series of workflows that include multiple tools for data de-multiplexing, promoter sequence identification, transposon flank alignment, and read count repartition across the genome. Particular attention was paid to quality control procedures such as the determination of the optimal tool parameters for the analysis and removal of contamination. Our work democratizes the TIS data analysis by providing open workflows supported by public computational infrastructure.
Type I and Type III IFN Restrict SARS-CoV-2 Infection of Human Airway Epithelial Cultures
Authors: Vanderheiden Abigail , Ralfs Philipp , Chirkova Tatiana , Upadhyay Amit A. , Zimmerman Matthew G. , Bedoya Shamika , Aoued Hadj , Tharp Gregory M. , Pellegrini Kathryn L. , Lowen Anice C. , Menachery Vineet D. , Anderson Larry J. , Grakoui Arash , Bosinger Steven E. , Suthar Mehul S. 
Published: May 2020

ABSTRACTThe newly emerged human coronavirus, SARS-CoV-2, has caused a pandemic of respiratory illness. The innate immune response is critical for protection against Coronaviruses. However, little is known about the interplay between the innate immune system and SARS-CoV-2. Here, we modeled SARS-CoV-2 infection using primary human airway epithelial (pHAE) cultures, which are maintained in an air-liquid interface. We found that SARS-CoV-2 infects and replicates in pHAE cultures and is directionally released on the apical, but not basolateral surface. Transcriptional profiling studies found that infected pHAE cultures had a molecular signature dominated by pro-inflammatory cytokines and chemokine induction, including IL-6, TNFα, CXCL8. We also identified NF-κB and ATF4 transcription factors as key drivers of this pro-inflammatory cytokine response. Surprisingly, we observed a complete lack of a type I or III IFN induction during SARS-CoV-2 infection. Pre-treatment or post-treatment with type I and III IFNs dramatically reduced virus replication in pHAE cultures and this corresponded with an upregulation of antiviral effector genes. Our findings demonstrate that SARS-CoV-2 induces a strong pro-inflammatory cytokine response yet blocks the production of type I and III IFNs. Further, SARS-CoV-2 is sensitive to the effects of type I and III IFNs, demonstrating their potential utility as therapeutic options to treat COVID-19 patients.IMPORTANCEThe current pandemic of respiratory illness, COVID-19, is caused by a recently emerged coronavirus named SARS-CoV-2. This virus infects airway and lung cells causing fever, dry cough, and shortness of breath. Severe cases of COVID-19 can result in lung damage, low blood oxygen levels, and even death. As there are currently no vaccines or antivirals approved for use in humans, studies of the mechanisms of SARS-CoV-2 infection are urgently needed. SARS-CoV-2 infection of primary human airway epithelial cultures induces a strong pro-inflammatory cytokine response yet blocks the production of type I and III IFNs. Further, SARS-CoV-2 is sensitive to the effects of type I and III IFNs, demonstrating their potential utility as therapeutic options to treat COVID-19 patients.
Loss of PKCα increases arterial medial calcification in a uremic mouse model of chronic kidney disease
Authors: Borland Samantha J , Facchi Cecilia , Behnsen Julia , Adamson Antony , Humphreys Neil E , Withers Philip J , Sherratt Michael J , Francis Sheila E , Brennan Keith , Ashton Nick , Canfield Ann E 
Published: May 2020

AbstractArterial medial calcification is an independent risk factor for mortality in chronic kidney disease. We previously reported that knock-down of PKCα expression increases high phosphate-induced mineral deposition by vascular smooth muscle cellsin vitro. This new study tests the hypothesis that PKCα regulates uremia-induced medial calcificationin vivo. Female wild-type and PKCα−/−mice underwent a two-stage subtotal nephrectomy and were fed a high phosphate diet for 8 weeks. X-ray micro computed tomography demonstrated that uremia-induced medial calcification was increased in the abdominal aorta and aortic arch of PKCα−/−mice compared to wild-types. Blood urea nitrogen was also increased in PKCα−/−mice compared to wild-types; there was no correlation between blood urea nitrogen and calcification in PKCα−/−mice. Phosphorylated SMAD2 immunostaining was detected in calcified aortic arches from uremic PKCα−/−mice; the osteogenic marker Runx2 was also detected in these areas. No phosphorylated SMAD2 staining were detected in calcified arches from uremic wild-types. PKCα knock-down increased TGF-β1-induced SMAD2 phosphorylation in vascular smooth muscle cellsin vitro, whereas the PKCα activator prostratin decreased SMAD2 phosphorylation. In conclusion, loss of PKCα increases uremia-induced medial calcification. The PKCα/TGF-β signaling axis could therefore represent a new therapeutic target for arterial medial calcification in chronic kidney disease.
Intra-host Variation and Evolutionary Dynamics of SARS-CoV-2 Population in COVID-19 Patients
Authors: Wang Yanqun , Wang Daxi , Zhang Lu , Sun Wanying , Zhang Zhaoyong , Chen Weijun , Zhu Airu , Huang Yongbo , Xiao Fei , Yao Jinxiu , Gan Mian , Li Fang , luo Ling , Huang Xiaofang , Zhang Yanjun , Wong Sook-san , Cheng Xinyi , Ji Jingkai , Ou Zhihua , Xiao Minfeng , Li Min , Li Jiandong , Ren Peidi , Deng Ziqing , Zhong Huanzi , Yang Huanming , Wang Jian , Xu Xun , Song Tie , Mok Chris Ka Pun , Peiris Malik , Zhong Nanshan , Zhao Jingxian , Li Yimin , Li Junhua , Zhao Jincun 
Published: May 2020

ABSTRACTAs of middle May 2020, the causative agent of COVID-19, SARS-CoV-2, has infected over 4 million people with more than 300 thousand death as official reports1,2. The key to understanding the biology and virus-host interactions of SARS-CoV-2 requires the knowledge of mutation and evolution of this virus at both inter- and intra-host levels. However, despite quite a few polymorphic sites identified among SARS-CoV-2 populations, intra-host variant spectra and their evolutionary dynamics remain mostly unknown. Here, using deep sequencing data, we achieved and characterized consensus genomes and intra-host genomic variants from 32 serial samples collected from eight patients with COVID-19. The 32 consensus genomes revealed the coexistence of different genotypes within the same patient. We further identified 40 intra-host single nucleotide variants (iSNVs). Most (30/40) iSNVs presented in single patient, while ten iSNVs were found in at least two patients or identical to consensus variants. Comparison of allele frequencies of the iSNVs revealed genetic divergence between intra-host populations of the respiratory tract (RT) and gastrointestinal tract (GIT), mostly driven by bottleneck events among intra-host transmissions. Nonetheless, we observed a maintained viral genetic diversity within GIT, showing an increased population with accumulated mutations developed in the tissue-specific environments. The iSNVs identified here not only show spatial divergence of intra-host viral populations, but also provide new insights into the complex virus-host interactions.
Algorithmic Assessment of Missense Mutation Severity in the Von-Hippel Lindau Protein
Authors: Fields Francisco R. , Suresh Niraja , Hiller Morgan , Freed Stefan D. , Haldar Kasturi , Lee Shaun W. 
Published: May 2020

AbstractVon Hippel-Lindau disease (VHL) is an autosomal dominant rare disease that causes the formation of angiogenic tumors. When functional, pVHL acts as an E3 ubiquitin ligase that negatively regulates hypoxia inducible factor (HIF). Genetic mutations that perturb the structure of pVHL result in dysregulation of HIF, causing a wide array of tumor pathologies including retinal angioma, pheochromocytoma, central nervous system hemangioblastoma, and clear cell renal carcinoma. These VHL-related cancers occur throughout the lifetime of the patient, requiring frequent intervention procedures, such as surgery, to remove the tumors. Although VHL is classified as a rare disease (1 in 39,000 to 1 in 91,000 affected) there is a large heterogeneity in genetic mutations listed for observed pathologies. Understanding how these specific mutations correlate with the myriad of observed pathologies for VHL could provide clinicians insight into the potential severity and onset of disease. Using a set of 285 ClinVar mutations in VHL, we developed a multiparametric scoring algorithm to evaluate the overall clinical severity of missense mutations in pVHL. The mutations were assessed according to eight weighted parameters as a comprehensive evaluation of protein misfolding and malfunction. Higher mutation scores were strongly associated with pathogenicity. Our approach establishes a novelin silicomethod by which VHL-specific mutations can be assessed for their severity and effect on the biophysical functions of the VHL protein.
Wnt16 Elicits a Protective Effect Against Fractures and Supports Bone Repair in Zebrafish
Authors: McGowan Lucy M. , Kague Erika , Vorster Alistair , Newham Elis , Cross Stephen , Hammond Chrissy L. 
Published: May 2020

SummaryBone homeostasis is a dynamic, multicellular process which is required throughout life to maintain bone integrity, prevent fracture and respond to skeletal damage.WNT16has been linked to bone fragility and osteoporosis in humans, as well as functional haematopoiesis of leukocytesin vivo, but the mechanisms by which it promotes bone health and repair are not fully understood. We used CRISPR-Cas9 to generate mutant zebrafish lacking Wnt16 (wnt16-/-) to study its effect on bone dynamically.wnt16mutants displayed variable tissue mineral density and were susceptible to spontaneous fractures and the accumulation of bone calluses at an early age. Fractures were induced in the lepidotrichia of the caudal fins ofwnt16-/-and wild type (WT) zebrafish; this model was used to probe the mechanisms by which Wnt16 regulates skeletal and immune cell-dynamicsin vivo. wnt16mutants repaired fractures more slowly compared to WT zebrafish. Osteoblast cell number was reduced at the fracture site 4 days post-injury inwnt16mutants, coinciding with prolonged activation of the canonical Wnt signalling pathway. Surprisingly, we found no evidence that the recruitment of innate immune cells to fractures was altered inwnt16mutants. This study highlights zebrafish as an emerging model for functionally validating osteoporosis-associated genes and investigating fracture repair dynamicallyin vivo. Using this model, we demonstrate that Wnt16 protects against fracture and is likely to support bone repair by attenuating the activation of the canonical Wnt signalling pathway to facilitate osteoblast recruitment and bone matrix deposition.
A Multiple Peptides Vaccine against nCOVID-19 Designed from the Nucleocapsid phosphoprotein (N) and Spike Glycoprotein (S) via the Immunoinformatics Approach
Authors: Albagi Sahar Obi Abd , Al-Nour Mosab Yahya , Elhag Mustafa , Abdelihalim Asaad Tageldein Idris , Haroun Esraa Musa , Essa Mohammed Elmujtba Adam , Abubaker Mustafa , Hassan Mohammed A. 
Published: May 2020

AbstractDue to the current COVID-19 pandemic, the rapid discovery of a safe and effective vaccine is an essential issue, consequently, this study aims to predict potential COVID-19 peptide-based vaccine utilizing the Nucleocapsid phosphoprotein (N) and Spike Glycoprotein (S) via the Immunoinformatics approach. To achieve this goal, several Immune Epitope Database (IEDB) tools, molecular docking, and safety prediction servers were used. According to the results, The Spike peptide peptides SQCVNLTTRTQLPPAYTNSFTRGVY is predicted to have the highest binding affinity to the B-Cells. The Spike peptide FTISVTTEI has the highest binding affinity to the MHC I HLA-B1503 allele. The Nucleocapsid peptides KTFPPTEPK and RWYFYYLGTGPEAGL have the highest binding affinity to the MHC I HLA-A0202 allele and the three MHC II alleles HLA-DPA1*01:03/DPB1*02:01, HLA-DQA1*01:02/DQB1- *06:02, HLA-DRB1, respectively. Furthermore, those peptides were predicted as non-toxic and non-allergen. Therefore, the combination of those peptides is predicted to stimulate better immunological responses with respectable safety.
Mitotic checkpoint protein Mad1 is required for early Nup153 recruitment to chromatin and nuclear envelope integrity
Authors: Mossaid Ikram , Chatel Guillaume , Martinelli Valérie , Vaz Marcela , Fahrenkrog Birthe 
Published: May 2020

AbstractThe nucleoporin Nup153 is a multifunctional protein and the mitotic checkpoint protein Mad1one of its many binding partners. The functional relevance of their interaction has remained elusive. Here, we have further dissected Nup153’s and Mad1’s interface and functional interplay. Byin situproximity ligation assays, we found that the presence of a nuclear envelope (NE) is prerequisite for the Nup153-Mad1 interaction. Time-lapse microscopy revealed that depletion of Mad1 delayed recruitment of Nup153 to anaphase chromatin, which was often accompanied by a prolongation of anaphase. Furthermore, as seen by electron microscopic and three-dimensional structured illumination investigations, Nup153 and Mad1 depletion led to alterations in NE architecture, characterised by a change of the membrane curvature at nuclear pore complexes (NPCs) and an expansion of the spacing between the inner and outer nuclear membranes. Nup153 depletion, but not of Mad1, caused defects in interphase NPC assembly with partial displacement of cytoplasmic nucleoporins and a reduction in NPC density. Together our results suggest that Nup153 has separable roles in NE and NPC formation: in post-mitotic NE reformation in concert with Mad1 and in interphase NPC assembly, independent of Mad1.SummaryThe mitotic checkpoint protein is required for Nup153 recruitment to anaphase chromatin and in turn post-mitotic, but not interphase nuclear pore complex assembly.