bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identifying US Counties with High Cumulative COVID-19 Burden and Their Characteristics
Authors: Li Daniel , Gaynor Sheila M. , Quick Corbin , Chen Jarvis T. , Stephenson Briana J.K. , Coull Brent A. , Lin Xihong 
Published: December 2020

AbstractIdentifying areas with high COVID-19 burden and their characteristics can help improve vaccine distribution and uptake, reduce burdens on health care systems, and allow for better allocation of public health intervention resources. Synthesizing data from various government and nonprofit institutions of 3,142 United States (US) counties as of 12/21/2020, we studied county-level characteristics that are associated with cumulative case and death rates using regression analyses. Our results showed counties that are more rural, counties with more White/non-White segregation, and counties with higher percentages of people of color, in poverty, with no high school diploma, and with medical comorbidities such as diabetes and hypertension are associated with higher cumulative COVID-19 case and death rates. We identify the hardest hit counties in US using model-estimated case and death rates, which provide more reliable estimates of cumulative COVID-19 burdens than those using raw observed county-specific rates. Identification of counties with high disease burdens and understanding the characteristics of these counties can help inform policies to improve vaccine distribution, deployment and uptake, prevent overwhelming health care systems, and enhance testing access, personal protection equipment access, and other resource allocation efforts, all of which can help save more lives for vulnerable communities.Significance statementWe found counties that are more rural, counties with more White/non-White segregation, and counties with higher percentages of people of color, in poverty, with no high school diploma, and with medical comorbidities such as diabetes and hypertension are associated with higher cumulative COVID-19 case and death rates. We also identified individual counties with high cumulative COVID-19 burden. Identification of counties with high disease burdens and understanding the characteristics of these counties can help inform policies to improve vaccine distribution, deployment and uptake, prevent overwhelming health care systems, and enhance testing access, personal protection equipment access, and other resource allocation efforts, all of which can help save more lives for vulnerable communities.
Celecoxib Colorectal Bioavailability and Chemopreventive Response in Familial Adenomatous Polyposis Patients
Authors: Yang Peiying , Zuo Xiangsheng , Advani Shailesh , Wei Bo , Malek Jessica , Day R. Sue , Shureiqi Imad 
Published: December 2020

ABSTRACTThe chemopreventive activity of celecoxib against colorectal cancer is limited to a proportion of familial adenomatous polyposis (FAP) patients who experience a response. The cause of this response variability and the potential mechanisms underlying these responses remain poorly understood. Preclinical studies showed that celecoxib increases the production of main oxidative metabolism product of linoleic acid, 13-S-hydroxyoctadecadienoic acid (13-S-HODE), to suppress colorectal tumorigenesis. We conducted a phase II clinical study to determine whether celecoxib increases 13-S-HODE production in colonic adenomas from FAP patients. Twenty seven FAP patients completed a 6-month oral course of 400 mg of celecoxib twice a day and had colonoscopies before and after celecoxib treatment to assess colorectal polyp tumor burden and obtain colorectal normal and polyp biopsies to measure celecoxib, 13-HODE, 15-HETE, 12-HETE, and LTB4 levels by LC/MS. Celecoxib levels in sera from those patients were also measured before treatment and 2, 4, and 6 months of treatment. Seventeen of the 27 patients experienced a response to celecoxib, with a more than 30% reduction of colonic polyp burden on the basis of a reproducible quantitative assessment of colonoscopy results. Celecoxib levels were significantly lower in polyp tissues than in normal colorectal tissues. Celecoxib levels in sera and normal colorectal tissues were correlated in patients who experienced a response to celecoxib but not in those who did not. Among the measured lipoxygenase products, only 13-HODE levels were significantly lower in polyp tissues than in normal tissues. Our findings demonstrate the differential bioavailability of celecoxib between normal and polyp tissues and its potential effects on clinical response in FAP patients.
Apoptotic cells for therapeutic use in cytokine storm associated with sepsis
Authors: van Heerden Peter Vernon , Abutbul Avraham , Sviri Sigal , Zlotnik Eitan , Nama Ahmad , Zimro Sebastian , el-Amore Raja , Shabat Yehudit , Reicher Barak , Falah Batla , Mevorach Dror 
Published: December 2020

SummaryBackgroundSepsis has no proven specific pharmacologic treatment. Reported mortality in sepsis ranges from 30%–45%. This study was designed to determine the safety preliminary efficacy of allogenic apoptotic cells administered for immunomodulation in septic patients.MethodsThe primary aim of this phase IB study was to determine the safety profile of apoptotic cell infusion in subjects presenting to the emergency room with sepsis. Sepsis was determined by clinical infections and Sequential Organ Failure Assessment (SOFA) scores >2. The secondary aims were to measure organ dysfunction, intensive care unit (ICU) and hospital stays, and mortality, that were compared to historical controls. Exploratory endpoints included measuring immune modulator agents to elucidate the mechanism of action using Luminex® analysis.FindingsTen patients were treated with apoptotic cells, administered as a single dose or two sequential doses. All 10 patients had mild-to-moderate sepsis with a SOFA score range of 2–6 upon entering the study. No serious adverse events (SAEs) and no related AEs were reported. All 10 study subjects survived while matched historical controls had a mortality rate of 27%. The study subjects exhibited rapid resolution of organ dysfunction and had significantly shorter ICU lengths of stay compared to matched historical controls (p<0·0001). All patients had both elevated pro- and anti-inflammatory cytokines, chemokines and additional immune modulators that gradually decreased following treatment.InterpretationAdministration of apoptotic cells to patients with mild-to-moderate sepsis was safe and had a significant immuno-modulating effect, leading to early resolution of the cytokine storm.Trial registrationClinicalTrials.gov Identifier: NCT03925857FundingThe study was sponsored by Enlivex Therapeutics Ltd.
In vivo Characterization of MRI-based T1w/T2w Ratios and Covariance Network in Temporal Lobe Epilepsy
Authors: Jiang Yuchao , Li Wei , Qin Yingjie , Zhang Le , Tong Xin , Xiao Fenglai , Gong Qiyong , Zhou Dong , An Dongmei , Luo Cheng , Yao Dezhong 
Published: December 2020

AbstractTemporal lobe epilepsy (TLE) is the most common type of intractable epilepsy in adults. A novel method based on the ratio of T1-weighted (T1w) and T2-weighted (T2w) magnetic resonance images can investigate brain microstructural changes and how these regional changes interact with each other. This study estimated T1w/T2w ratios in 42 left TLE (LTLE) and 42 right TLE (RTLE) patients and 41 healthy controls (HC). A T1w/T2w structural covariance network (SCN) was built by calculating correlations between any two regions across subjects and analysed by graph theory. Voxel-wise comparisons of T1w/T2w laterality were performed among the three groups. Compared to HC, both patient groups showed decreased T1w/T2w in frontotemporal regions, amygdala and thalamus; however, the LTLE showed lower T1w/T2w in left medial temporal regions than RTLE. Moreover, the LTLE exhibited decreased global efficiency compared with HC and more increased connections than RTLE. The laterality in putamen was differently altered between the two patient groups: higher laterality at posterior putamen in LTLE and higher laterality at anterior putamen in RTLE. This study demonstrated T1w/T2w reductions in frontotemporal and subcortical regions and extensive disconnections of SCN, providing evidence that TLE is a system disorder with widespread disruptions at regional and network levels. The putamen may play a transfer station role in damage spreading induced by epileptic seizures from the hippocampus.
Covid-19 Will Reduce US Life Expectancy at Birth by More Than One Year in 2020
Authors: Heuveline Patrick 
Published: December 2020

AbstractOn December 3rd, 2020, the cumulative number of U.S. Covid-19 deaths tallied by Johns Hopkins University (JHU) online dashboard reached 275,000, surpassing the number at which life table calculations show Covid-19 mortality will lower the U.S. life expectancy at birth (LEB) for 2020 by one full year. Such an impact on the U.S. LEB is unprecedented since the end of World War II. With additional deaths by the year end, the reduction in 2020 LEB induced by Covid-19 deaths will inexorably exceed one year. Factoring the expected continuation of secular gains against other causes of mortality, the U.S. LEB should still drop by more than a full year between 2019 and 2020. By comparison, the opioid-overdose crisis led to a decline in U.S. LEB averaging .1 year annually, from 78.9 years in 2014 to 78.6 years in 2017. At its peak, the HIV epidemic reduced the U.S. LEB by .3 year in a single year, from 75.8 years in 1992 to 75.5 years in 1993. As of now, the US LEB is expected to fall back to the level it first reached in 2010. In other words, the impact of Covid-19 on U.S. mortality can be expected to cancel a decade of gains against all other causes of mortality combined.
Ca2+-dependent mechanism of membrane insertion and destabilization by the SARS-CoV-2 fusion peptide
Authors: Khelashvili George , Plante Ambrose , Doktorova Milka , Weinstein Harel 
Published: December 2020

ABSTRACTCell penetration after recognition of the SARS-CoV-2 virus by the ACE2 receptor, and the fusion of its viral envelope membrane with cellular membranes, are the early steps of infectivity. A region of the Spike protein (S) of the virus, identified as the “fusion peptide” (FP), is liberated at its N-terminal site by a specific cleavage occurring in concert with the interaction of the receptor binding domain of the Spike. Studies have shown that penetration is enhanced by the required binding of Ca2+ions to the FPs of corona viruses, but the mechanisms of membrane insertion and destabilization remain unclear. We have predicted the preferred positions of Ca2+binding to the SARS-CoV-2-FP, the role of Ca2+ions in mediating peptide-membrane interactions, the preferred mode of insertion of the Ca2+-bound SARS-CoV-2-FP and consequent effects on the lipid bilayer from extensive atomistic molecular dynamics (MD) simulations and trajectory analyses. In a systematic sampling of the interactions of the Ca2+-bound peptide models with lipid membranes SARS-CoV-2-FP penetrated the bilayer and disrupted its organization only in two modes involving different structural domains. In one, the hydrophobic residues F833/I834 from the middle region of the peptide are inserted. In the other, more prevalent mode, the penetration involves residues L822/F823 from the LLF motif which is conserved in CoV-2-like viruses, and is achieved by the binding of Ca2+ions to the D830/D839 and E819/D820 residue pairs. FP penetration is shown to modify the molecular organization in specific areas of the bilayer, and the extent of membrane binding of the SARS-CoV-2 FP is significantly reduced in the absence of Ca2+ions. These findings provide novel mechanistic insights regarding the role of Ca2+in mediating SARS-CoV-2 fusion and provide a detailed structural platform to aid the ongoing efforts in rational design of compounds to inhibit SARS-CoV-2 cell entry.STATEMENT OF SIGNIFICANCESARS-CoV-2, the cause of the COVID-19 pandemic, penetrates host cell membranes and uses viral-to-cellular membrane fusion to release its genetic material for replication. Experiments had identified a region termed “fusion peptide” (FP) in the Spike proteins of coronaviruses, as the spearhead in these initial processes, and suggested that Ca2+is needed to support both functions. Absent structure and dynamics-based mechanistic information these FP functions could not be targeted for therapeutic interventions. We describe the development and determination of the missing information from analysis of extensive MD simulation trajectories, and propose specific Ca2+-dependent mechanisms of SARS-CoV-2-FP membrane insertion and destabilization. These results offer a structure-specific platform to aid the ongoing efforts to use this target for the discovery and/or of inhibitors.
A Quantitative Hematopoietic Stem Cell Reconstitution Protocol: Accounting for Recipient Variability, Tissue Distribution and Cell Half-Lives
Authors: Rajendiran Smrithi , Boyer Scott W. , Forsberg E. Camilla 
Published: December 2020

AbstractHematopoietic stem and progenitor cell (HSPC) transplantation is the paradigm for stem cell therapies. The protocol described here enables quantitative assessment of the body-wide HSPC reconstitution of different mature hematopoietic cells in mice based on their presence in circulating blood. The method determines donor-derived mature cell populations per mouse, over time, by quantitatively obtaining their absolute numbers in the peripheral blood and utilizing previously assessed tissue-distribution factors. A Markov-based birth/death computational model accounts for the drastic differences in mature cell half-lives. By quantifying the number of cells produced and eliminating host variability, the protocol can be used to directly compare the lineage output of different types of HSPCs on a per cell basis, thereby clarifying the lineage potential and expansion capacity of different cell populations. These protocols were developed for hematopoiesis, but can readily be extended to other contexts by simply replacing the cell types and distributions.HighlightsQuantitative assessment of stem and progenitor cell reconstitution capacityElimination of cell-specific recipient variability for accurate donor cell potentialDirectly comparable lineage output within and between stem and progenitor cellsBlood-based absolute quantification of whole-body repopulation over timeMarkov modelling-based consideration of differential mature cell half-lives
Aperture: Accurate detection of structural variations and viral integrations in circulating tumor DNA using an alignment-free algorithm
Authors: Liu Hongchao , Yin Huihui , Li Guangyu , Li Junling , Wang Xiaoyue 
Published: December 2020

AbstractBackgroundThe identification of structural variations (SV) and viral integrations in circulating tumor DNA (ctDNA) is a key step in precision oncology that may assist clinicians for treatment selection and monitoring. However, it is challenging to accurately detect low frequency SVs or SVs involving complex junctions in ctDNA sequencing data due to the short fragment size of ctDNA.ResultsHere, we describe Aperture, a new fast SV caller that applies a unique strategy ofk-mer based searching, breakpoint detection using binary labels and candidates clustering to detect SVs and viral integrations in high sensitivity, especially when junctions span repetitive regions, followed by a barcode-based filter to ensure specificity. We evaluated the performance of Aperture in stimulated, reference and real datasets. Aperture demonstrates superior sensitivity and specificity in all tests, especially for low dilution test, compared with existing methods. In addition, Aperture is able to predict sites of viral integration and identify complex SVs involving novel insertions and repetitive sequences in real patient data.ConclusionsUsing a novel alignment-free algorithm, Aperture achieves sensitive, specific and fast detection of structural variations and viral integrations, which may enhance the diagnostic value of ctDNA in clinical application. The executable file and source code are freely available athttps://github.com/liuhc8/Aperture.
Aborting meiosis overcomes hybrid sterility
Authors: Mozzachiodi Simone , Tattini Lorenzo , Llored Agnes , Irizar Agurtzane , Škofljanc Neža , D’Angiolo Melania , De Chiara Matteo , Barré Benjamin P. , Yue Jia-Xing , Lutazi Angela , Loeillet Sophie , Laureau Raphaelle , Marsit Souhir , Stenberg Simon , Albaud Benoit , Persson Karl , Legras Jean-Luc , Dequin Sylvie , Warringer Jonas , Nicolas Alain , Liti Gianni 
Published: December 2020

AbstractHybrids between species or diverged lineages contain fundamentally novel genetic combinations but an impaired meiosis often makes them evolutionary dead ends. Here, we explored to what extent and how an aborted meiosis followed by a return-to-growth (RTG) promotes recombination across a panel of 20 yeast diploid backgrounds with different genomic structures and levels of sterility. Genome analyses of 284 clones revealed that RTG promoted recombination and generated extensive regions of loss-of-heterozygosity in sterile hybrids with either a defective meiosis or a heavily rearranged karyotype, whereas RTG recombination was reduced by high sequence divergence between parental subgenomes. The RTG recombination preferentially occurred in regions with local sequence homology and in meiotic recombination hotspots. The loss-of-heterozygosity had a profound impact on sexual and asexual fitness, and enabled genetic mapping of phenotypic differences in sterile lineages where linkage or association analyses failed. We propose that RTG gives sterile hybrids access to a natural route for genome recombination and adaptation.One sentence summaryAborting meiosis followed by a return to mitotic growth promotes evolution by genome wide-recombination in sterile yeast hybrids.
Online biophysical predictions for SARS-CoV-2 proteins
Authors: Kagami Luciano , Roca-Martínez Joel , Gavaldá-García Jose , Ramasamy Pathmanaban , Feenstra K. Anton , Vranken Wim 
Published: December 2020

AbstractThe SARS-CoV-2 virus, the causative agent of COVID-19, consists of an assembly of proteins that determine its infectious and immunological behavior, as well as its response to therapeutics. Major structural biology efforts on these proteins have already provided essential insights into the mode of action of the virus, as well as avenues for structure-based drug design. However, not all of the SARS-CoV-2 proteins, or regions thereof, have a well-defined three-dimensional structure, and as such might exhibit ambiguous, dynamic behaviour that is not evident from static structure representations, nor from molecular dynamics simulations using these structures. We here present a website (http://sars2.bio2byte.be/) that provides protein sequence-based predictions of the backbone and side-chain dynamics and conformational propensities of these proteins, as well as derived early folding, disorder, β-sheet aggregation and protein-protein interaction propensities. These predictions attempt to capture the ‘emergent’ properties of the proteins, so the inherent biophysical propensities encoded in the sequence, rather than context-dependent behaviour such as the final folded state. In addition, we provide an indication of the biophysical variation that is observed in homologous proteins, which give an indication of the limits of the functionally relevant biophysical behaviour of these proteins. With this website, we therefore hope to provide researchers with further clues on the behaviour of SARS-CoV-2 proteins.
Soluble FAS Ligand directs human memory B cells towards antibody-secreting cells
Authors: van Asten Saskia D. , Unger Peter-Paul , Marsman Casper , Bliss Sophie , Jorritsma Tineke , Thielens Nicole M. , van Ham S. Marieke , Spaapen Robbert M. 
Published: December 2020

AbstractDifferentiation of antigen-specific B cells into class-switched, high affinity antibody-secreting cells provides protection against invading pathogens but is undesired when antibodies target self-tissues in autoimmunity, beneficial non-self blood transfusion products or therapeutic proteins. Essential T cell factors have been uncovered that regulate T cell-dependent B cell differentiation. We performed a screen using a secreted protein library to identify novel factors that promote this process and may be used to combat undesired antibody formation. We tested the differentiating capacity of 756 secreted proteins on human naive or memory B cell differentiation in a setting with suboptimal T cell helpin vitro(suboptimal CD40L and IL-21). High-throughput flow cytometry screening and validation revealed that type I IFNs and soluble FAS ligand (sFASL) induce plasmablast differentiation in memory B cells. Furthermore, sFASL induces robust secretion of IgG1 and IgG4 antibodies, indicative of functional plasma cell differentiation. Our data suggest a mechanistic connection between elevated sFASL levels and the induction of autoreactive antibodies, providing a potential therapeutic target in autoimmunity. Indeed, the modulators identified in this secretome screen are associated with systemic lupus erythematosus and may also be relevant in other autoimmune diseases and allergy.
DeORFanizingCandida albicansGenes using Co-Expression
Authors: O’Meara Teresa R. , O’Meara Matthew J. 
Published: December 2020

AbstractFunctional characterization of open reading frames in non-model organisms, such as the common opportunistic fungal pathogenCandida albicans, can be labor intensive. To meet this challenge, we built a comprehensive and unbiased co-expression network forC. albicans, which we call CalCEN, from data collected from 853 RNA sequencing runs from 18 large scale studies deposited in the NCBI Sequence Read Archive. Retrospectively, CalCEN is highly predictive of known gene function annotations and can be synergistically combined with sequence similarity and interaction networks inSaccharomyces cerevisiaethrough orthology for additional accuracy in gene function prediction. To prospectively demonstrate the utility of the co-expression network inC. albicans, we predicted the function of under-annotated open reading frames (ORF)s and identifiedCCJ1as a novel cell cycle regulator inC. albicans. This study provides a tool for future systems biology analyses of gene function inC. albicans.We provide a computational pipeline for building and analyzing the co-expression network and CalCEN itself at (http://github.com/momeara/CalCEN).ImportanceCandida albicansis a common and deadly fungal pathogen of humans, yet the genome of this organism contains many genes of unknown function. By determining gene function, we can help identify essential genes, new virulence factors, or new regulators of drug resistance, and thereby give new targets for antifungal development. Here, we use information from large scale RNAseq studies and generate aC. albicansco-expression network (CalCEN) that is robust and able to predict gene function. We demonstrate the utility of this network in both retrospective and prospective testing, and use CalCEN to predict a role for C4_06590W/CCJ1in cell cycle. This tool will allow for a better characterization of under-annotated genes in pathogenic yeasts.