bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differences in Declines in Pediatric ED Utilization During the Covid19 Pandemic by Socioeconomic Disadvantage
Authors: Sen Bisakha , Brisendine Anne , Ghosh Pallavi 
Published: April 2021

AbstractBackgroundThere is growing evidence that the early months of the COVID19 pandemic saw substantial declines in pediatric Emergency Department (ED) utilization in the U.S. However, less is known about whether utilization changed differentially for children who are socio-economically disadvantaged. We examined how changes pediatric ED visits during the early months of the COVID19 pandemic differed by two markers of socio-economic disadvantage, minoritized race and being publicly insured.MethodsThis retrospective observational study used electronic medical records from a large pediatric ED in a Deep South state for January-June 2020. Three time-periods ╌ pre-COVID19 (TP0), COVID19 with restrictions like stay-at-home (TP1), and COVID19 with restrictions relaxed (TP2) in 2020 were compared with the corresponding time-periods in 2019. Changes in overall visits, visits for minoritized race (MR) versus non-Hispanic white (NHW) children, and Medicaid-enrolled versus privately-insured children were considered, and changes in acuity-mix of ED visits and share of visits resulting in inpatient admits were inspected.ResultsCompared to 2019, total ED visits declined in TP1 and TP2 of 2020 (54.3%, 48.9%). Declines were larger for MR children (57.3%, 57.8%) compared to NHW children (50.5%, 39.3%), and Medicaid enrollees (56.5%, 52.0%) compared to the privately insured (48.3%, 39.0%). Particularly, MR children saw steeper percentage declines in high-acuity visits and visits resulting in inpatient admissions compared to NHW children. The mix of pediatric patients by race and insurance-status, as well as the share of high-acuity visits and visits with inpatient admissions differed between TP1 and TP2 of 2019 and 2020 (p<0.05 for all cases). In contrast, there was little evidence of difference between TP0 of 2019 and 2020.ConclusionThe role of socioeconomic disadvantage and the potential impacts on pediatric ED visits during COVID19 in the Deep South of the United States changes is understudied. We find evidence of steeper declines in visits among MR and Medicaid-enrolled children, including for high-acuity conditions, than their NHW and privately-insured counterparts. Since disadvantaged children sometimes lack access to a usual source of care, this raises concerns about unmet health needs, and worsening health disparities, in a region that already has poor health indicators.
Drug Sensitivity Prediction From Cell Line-Based Pharmacogenomics Data: Guidelines for Developing Machine Learning Models
Authors: Sharifi-Noghabi Hossein , Jahangiri-Tazehkand Soheil , Smirnov Petr , Hon Casey , Mammoliti Anthony , Nair Sisira Kadambat , Mer Arvind Singh , Ester Martin , Haibe-Kains Benjamin 
Published: April 2021

ABSTRACTThe goal of precision oncology is to tailor treatment for patients individually using the genomic profile of their tumors. Pharmacogenomics datasets such as cancer cell lines are among the most valuable resources for drug sensitivity prediction, a crucial task of precision oncology. Machine learning methods have been employed to predict drug sensitivity based on the multiple omics data available for large panels of cancer cell lines. However, there are no comprehensive guidelines on how to properly train and validate such machine learning models for drug sensitivity prediction. In this paper, we introduce a set of guidelines for different aspects of training gene expression-based predictors using cell line datasets. These guidelines provide extensive analysis of the generalization of drug sensitivity predictors, and challenge many current practices in the community including the choice of training dataset and measure of drug sensitivity. Application of these guidelines in future studies will enable the development of more robust preclinical biomarkers.
Symptoms network analysis of serious mental illness: A cross disasters comparison
Authors: Levin Yafit , Rahel Bachem , Goodwin Robin , Ben-Ezra Menachem 
Published: April 2021

AbstractBackgroundThe Kessler Psychological Distress Scale (K-6) has been used worldwide in community epidemiological surveys and served as a screening measure for serious mental illness in the general population. We take a novel approach by examining the symptoms network of the K-6 and the exploration of differences between three types of disasters: Nature related, Terror attacks, and COVID-19.AimsTo explore the K-6 symptoms network and its structure replication across the three types of disasters.MethodsA network analysis of psychological distress symptoms as assessed by the K-6 was conducted using data from 9,271 participants from different disaster samples: Terror (n = 5842), COVID-19 (n = 2428), and Nature related (n = 1001).ResultsWhile there were extensive connections between items across all disaster samples, network structure differed across the disaster types. While after a nature related disaster and the COVID-19 pandemic depression- and anxiety-items were interconnected, a terror attack resulted in more separated manifestations of anxiety and depression. Centrality analysis showed “depressed/no cheering up” to be the node with the highest strength centrality in all networks; in the Nature-related network, “restless or fidgety” was also highly central.ConclusionsResults provide evidence of different psychological distress structures in different disasters. Depending on the type of disaster, trauma-focused interventions may need to be augmented, with specific components directed at depression and/or anxiety.
Enhanced cell deconvolution of peripheral blood using DNA methylation for high-resolution immune profiling
Authors: Salas Lucas A , Zhang Ze , Koestler Devin C , Butler Rondi A , Hansen Helen M , Molinaro Annette M , Wiencke John K , Kelsey Karl T , Christensen Brock C 
Published: April 2021

AbstractDNA methylation microarrays can be employed to interrogate cell-type composition in complex tissues. Here, we expand reference-based deconvolution of blood DNA methylation to include 12 leukocyte subtypes (neutrophils, eosinophils, basophils, monocytes, B cells, CD4+ and CD8+ naïve and memory cells, natural killer, and T regulatory cells). Including derived variables, our method provides up to 56 immune profile variables. The IDOL (IDentifying Optimal Libraries) algorithm was used to identify libraries for deconvolution of DNA methylation data both for current and retrospective platforms. The accuracy of deconvolution estimates obtained using our enhanced libraries was validated using artificial mixtures, and whole-blood DNA methylation with known cellular composition from flow cytometry. We applied our libraries to deconvolve cancer, aging, and autoimmune disease datasets. In conclusion, these libraries enable a detailed representation of immune-cell profiles in blood using only DNA and facilitate a standardized, thorough investigation of the immune system in human health and disease.
RESIC: A tool for comprehensive adenosine to inosine RNA Editing Site Identification and Classification
Authors: Light Dean , Haas Roni , Yazbak Mahmoud , Elfand Tal , Blau Tal , Lamm Ayelet T. 
Published: April 2021

AbstractAdenosine to inosine (A-to-I) RNA editing, the most prevalent type of RNA editing in metazoans, is carried out by adenosine deaminases (ADARs) in double-stranded RNA regions. Several computational approaches have been recently developed to identify A-to-I RNA editing sites from sequencing data, each addressing a particular issue. Here we present RESIC, an efficient pipeline that combines several approaches for the detection and classification of RNA editing sites. The pipeline can be used for all organisms and can use any number of RNA-sequencing datasets as input. RESIC provides 1. The detection of editing sites in both repetitive and non-repetitive genomic regions; 2. The identification of hyper-edited regions; 3. Optional exclusion of polymorphism sites to increase reliability, based on DNA, and ADAR-mutant RNA sequencing datasets, or SNP databases. We demonstrate the utility of RESIC by applying it to human, successfully overlapping and extending the list of known putative editing sites. We further tested changes in the patterns of A-to-I RNA editing, and RNA abundance of ADAR enzymes, following SARS-CoV-2 infection in human cell lines. Our results suggest that upon SARS-CoV-2 infection, compared to mock, the number of hyper editing sites is increased, and in agreement, the activity of ADAR1, which catalyzes hyper-editing, is enhanced. These results imply the involvement of A-to-I RNA editing in conceiving the unpredicted phenotype of COVID-19 disease. RESIC code is open-source and is easily extendable.
A memetic algorithm enables efficient local and global all-atom protein-protein docking with backbone and sidechain flexibility
Authors: Varela Daniel , Karlin Vera , André Ingemar 
Published: April 2021

SummaryProtein complex formation is encoded by specific interactions at the atomic scale, but the computational cost of modeling proteins at this level often requires the use of simplified energy models and limited conformational flexibility. In particular, the use of all-atom energy functions, backbone and sidechain flexibility results in rugged energy landscapes that are difficult to explore. In this study we develop a protein-protein docking algorithm, EvoDOCK, that combine the strength of a differential evolution algorithm for efficient exploration of the global search space with the benefits of a local optimization method to refine detailed atomic interactions. EvoDOCK enabled accurate and fast local and global protein-protein docking using an all-atom energy function with side-chain flexibility. Comparison with a standard method built on Monte Carlo optimization demonstrated improved accuracy and with increases in computational speed of up to 35 times. The evolutionary algorithm also enabled efficient atomistic docking with backbone flexibility.
SLIT2-ROBO signaling in tumor-associated microglia/macrophages drives glioblastoma immunosuppression and vascular dysmorphia
Authors: Geraldo Luiz Henrique , Xu Yunling , Jacob Laurent , Fragner Laurence Pibouin , Rao Rohit , Maissa Nawal , Verreault Maïté , Lemaire Nolwenn , Knosp Camille , Lesaffre Corinne , Daubon Thomas , Dejaegher Joost , Solie Lien , Rudewicz Justine , Viel Thomas , Tavitian Bertrand , De Vleeschouwer Steven , Sanson Marc , Bikfalvi Andreas , Idbaih Ahmed , Lu Q. Richard , Souza Lima Flavia Regina , Thomas Jean-Leon , Eichmann Anne , Mathivet Thomas 
Published: April 2021

AbstractSLIT2 is a secreted polypeptide that guides migration of cells expressing ROBO1&2 receptors. Herein, we investigated SLIT2/ROBO signaling effects in gliomas. In patients with glioblastoma (GBM),SLIT2expression increased with malignant progression and correlated with poor survival and immunosuppression. Knockdown ofSLIT2in mouse glioma cells and patient derived GBM xenografts reduced tumor growth and synergized with immunotherapy to prolong survival. Tumor cellSLIT2knockdown inhibited macrophage invasion and promoted a cytotoxic gene expression profile, which improved tumor vessel function and enhanced efficacy of chemotherapy and immunotherapy. Mechanistically, SLIT2 promoted microglia/macrophage chemotaxis and tumor-supportive polarization via ROBO1&2-mediated PI3Kγ activation. MacrophageRobo1&2deletion and systemic SLIT2 trap delivery mimickedSLIT2knockdown effects on tumor growth and the tumor microenvironment (TME), revealing SLIT2 signaling through macrophage ROBOs as a novel regulator of the GBM microenvironment and a potential immunotherapeutic target for brain tumors.
Safety and efficacy of C9ORF72-repeat RNA nuclear export inhibition in amyotrophic lateral sclerosis
Authors: Castelli Lydia M. , Cutillo Luisa , Souza Cleide Dos Santos , Sanchez-Martinez Alvaro , Granata Ilaria , Myszczynska Monika A. , Heath Paul R. , Livesey Matthew R. , Ning Ke , Azzouz Mimoun , Shaw Pamela J. , Guarracino Mario R. , Whitworth Alexander J. , Ferraiuolo Laura , Milo Marta , Hautbergue Guillaume M. 
Published: April 2021

AbstractBackgroundLoss of motor neurons in amyotrophic lateral sclerosis (ALS) leads to progressive paralysis and death. Dysregulation of thousands of RNA molecules with roles in multiple cellular pathways hinders the identification of ALS-causing alterations over downstream changes secondary to the neurodegenerative process. How many and which of these pathological gene expression changes require therapeutic normalisation remains a fundamental question.MethodsHere, we investigated genome-wide RNA changes in C9ORF72-ALS patient-derived neurons and Drosophila, as well as upon neuroprotection taking advantage of our gene therapy approach which specifically inhibits the SRSF1-dependent nuclear export of pathological C9ORF72-repeat transcripts. This is a critical study to evaluate (i) the overall safety and efficacy of the partial depletion of SRSF1, a member of a protein family involved itself in gene expression, and (ii) a unique opportunity to identify neuroprotective RNA changes.ResultsOur study demonstrates that manipulation of 362 transcripts out of 2,257 pathological changes in C9ORF72-ALS patient-derived neurons is sufficient to confer neuroprotection upon partial depletion of SRSF1. In particular, expression of 90 disease-altered transcripts is fully reverted upon neuroprotection leading to the characterisation of a human C9ORF72-ALS disease-modifying gene expression signature. These findings were further investigated in vivo in diseased and neuroprotected Drosophila transcriptomes, highlighting a list of 21 neuroprotective changes conserved with 16 human orthologues in patient-derived neurons. We also functionally validated the high therapeutic potential of one of these disease-modifying transcripts, demonstrating that inhibition of ALS-upregulated human KCNN1-3 (Drosophila SK) voltage-gated potassium channel orthologs mitigates degeneration of human motor neurons as well as Drosophila motor deficits.ConclusionsStrikingly, manipulating the expression levels of a small proportion of RNAs is sufficient to induce a therapeutic effect, further indicating that the SRSF1-targeted gene therapy approach is safe in the above preclinical models as it does not disrupt globally gene expression. The efficacy of this intervention is also validated at genome-wide level with therapeutically-induced RNA changes involved in the vast majority of biological processes affected in C9ORF72-ALS. Finally, the identification of a characteristic signature with key RNA changes modified in both the disease state and upon neuroprotection also provides potential new therapeutic targets and biomarkers.
Investigating the roles ofListeria monocytogenesperoxidases in growth and virulence
Authors: Cesinger Monica R. , Schwardt Nicole H. , Halsey Cortney R. , Thomason Maureen K. , Reniere Michelle L. 
Published: April 2021

ABSTRACTBacteria have necessarily evolved a protective arsenal of proteins to contend with peroxides and other reactive oxygen species generated in aerobic environments.Listeria monocytogenesencounters an onslaught of peroxide both in the environment and during infection of the mammalian host, where it is the causative agent of the foodborne illness listeriosis. Despite the importance of peroxide for the immune response to bacterial infection, the strategy by whichL. monocytogenesprotects against peroxide toxicity has yet to be illuminated. Here, we investigated the expression and essentiality of all the peroxidase-encoding genes duringL. monocytogenesgrowthin vitroand during infection of murine cells in tissue culture. We found thatchdCandkatwere required for aerobic growthin vitro, andfriandahpAwere each required forL. monocytogenesto survive acute peroxide stress. Despite increased expression offri, ahpA, andkatduring infection of macrophages, onlyfriproved necessary for cytosolic growth and intercellular spread. In contrast, the proteins encoded bylmo0367, lmo0983, tpx, lmo1609, andohrAwere dispensable for aerobic growth, acute peroxide detoxification, and infection. Together, our results provide insight into the multifacetedL. monocytogenesperoxide detoxification strategy and demonstrate thatL. monocytogenesencodes a functionally diverse set of peroxidase enzymes.
Tissue-resident FOLR2+macrophages associate with tumor-infiltrating CD8+T cells and with increased survival of breast cancer patients
Authors: Ramos Rodrigo Nalio , Missolo-Koussou Yoann , Gerber-Ferder Yohan , Bromley Christian , Bugatti Mattia , Núñez Nicolas Gonzalo , Tosello Jimena Boari , Richer Wilfrid , Denizeau Jordan , Sedlik Christine , Caudana Pamela , Kotsias Fiorella , Niborski Leticia Laura , Viel Sophie , Bohec Mylène , Lameiras Sonia , Baulande Sylvain , Lesage Laëtitia , Nicolas André , Meseure Didier , Vincent-Salomon Anne , Reyal Fabien , Dutertre Charles-Antoine , Ginhoux Florent , Vimeux Lene , Donnadieu Emmanuel , Buttard Bénédicte , Galon Jérôme , Zelenay Santiago , Vermi William , Guermonprez Pierre , Piaggio Eliane , Helft Julie 
Published: April 2021

SUMMARYMacrophage infiltration is a hallmark of solid cancers and overall macrophage infiltration is correlated with lower patient survival and resistance to therapy. However, tumor-associated macrophages are phenotypically and functionally heterogeneous. Specific tumor-associated macrophage subsets might be endowed with antagonistic role on cancer progression and on the development of anti-tumor immunity. For instance, monocyte-derived TREM2+tumor-associated macrophages have pro-tumorigenic and immunosuppressive functions. Here, we identify a discrete population of FOLR2+tumor-associated macrophages positively correlating with patient survival in breast cancer. FOLR2+macrophages are evolutionarily conserved across species and populate human and murine healthy mammary gland. Moreover, FOLR2+macrophages co-localize with lymphoid aggregates containing CD8+T cells in breast cancer and across ten other types of cancers. This study highlights antagonistic roles for tumor-associated macrophage subsets and paves the way for subset-specific therapeutic interventions in macrophages-based cancer therapies.
Public-good driven release of heterogeneous resources leads to genotypic diversification of an isogenic yeast population in melibiose
Authors: Mahilkar Anjali , Alugoju Phaniendra , Kavatalkar Vijendra , Rajeshkannan E. , Bhat Paike Jayadeva , Saini Supreet 
Published: April 2021

AbstractAdaptive diversification of an isogenic population, and its molecular basis has been a subject of a number of studies in the last few years. Microbial populations offer a relatively convenient model system to study this question. In this context, an isogenic population of bacteria (E. coli,B. subtilis, andPseudomonas) has been shown to lead to genetic diversification in the population, when propagated for a number of generations. This diversification is known to occur when the individuals in the population have access to two or more resources/environments, which are separated either temporally or spatially. Here, we report adaptive diversification in an isogenic population of yeast,S. cerevisiae, when propagated in an environment containing melibiose as the carbon source. The diversification is driven due to a public good, enzyme α-galactosidase, leading to hydrolysis of melibiose into two distinct resources, glucose and galactose. The diversification is driven by a mutations at a single locus, in theGAL3gene in the GAL/MEL regulon in the yeast.
Preservation of collagen in the soft tissues of frozen mammoths
Authors: Hattori Shunji , Kiriyama-Tanaka Tomomi , Kusubata Masashi , Taga Yuki , Ebihara Testuya , Imai Katsuyuki , Miura Mitsutaka , Mezaki Yoshihiro , Tikhonov Alexei , Senoo Haruki 
Published: April 2021

AbstractWe investigated the characteristics of extracellular matrix (ECM) in the soft tissue of two frozen baby woolly mammoths (Mammuthus primigenius) that died and were buried in Siberian permafrost approximately 40,000 years ago. Morphological and biochemical analyses of mammoth lung and liver demonstrated that those soft tissues were preserved at the gross anatomical and histological levels. The ultrastructure of ECM components, namely a fibrillar structure with a collagen-characteristic pattern of cross-striation, was clearly visible with transmission and scanning electron microscopy. Type I and type IV collagens were detected by immunohistochemical observation. Quantitative amino acid analysis of liver and lung tissues of the baby mammoths indicated that collagenous protein is selectively preserved in these tissues as a main protein. Type I and type III collagens were detected as major components by means of liquid chromatography–mass spectrometry analysis after digestion with trypsin. These results indicate that the triple helical collagen molecule, which is resistant to proteinase digestion, has been preserved in the soft tissues of these frozen mammoths for 40,000 years.
The Seroprevalence of SARS-CoV-2 in Europe: A Systematic Review
Authors: Vaselli Natasha Marcella , Hungerford Daniel , Shenton Ben , Khashkhusha Arwa , Cunliffe Nigel A. , French Neil 
Published: April 2021

AbstractBackgroundA year following the onset of the COVID-19 pandemic, new infections and deaths continue to increase in Europe. Serological studies, through providing evidence of past infection, can aid understanding of the population dynamics of SARS-CoV-2 infection.ObjectivesThis systematic review of SARS-CoV-2 seroprevalence studies in Europe was undertaken to inform public health strategies including vaccination, that aim to accelerate population immunity.MethodsWe searched the databases Web of Science, MEDLINE, EMBASE, SCOPUS, Cochrane Database of Systematic Reviews and grey literature sources for studies reporting seroprevalence of SARS-CoV-2 antibodies in Europe published between 01/12/2019 - 30/09/20. We provide a narrative synthesis of included studies. Studies were categorized into subgroups including healthcare workers (HCWs), community, outbreaks, pregnancy and children/school. Due to heterogeneity in other subgroups, we only performed a random effects meta-analysis of the seroprevalence amongst HCWs stratified by their country.Results109 studies were included spanning 17 European countries, that estimated the seroprevalence of SAR-CoV2 from samples obtained between November 2019 – August 2020. A total of 53/109 studies included HCWs with a reported seroprevalence among HCWs ranging from 0.7% to 45.3%, which did not differ significantly by country. In community studies significant heterogeneity was reported in the seroprevalence among different age groups and the majority of studies reported there was no significant difference by gender.ConclusionThis review demonstrates a wide heterogeneity in reported seroprevalence of SARS-CoV-2 antibodies between populations. Continued evaluation of seroprevalence is required to understand the impact of public health measures and inform interventions including vaccination programmes.