bluuebunny/crossref_metadata_2025_split huggingface dataset:
BinomiRare: A carriers-only test for association of rare genetic variants with a binary outcome for mixed models and any case-control proportion
Authors: Sofer Tamar , Lee Jiwon , Kurniansyah Nuzulul , Jain Deepti , Laurie Cecelia A. , Gogarten Stephanie M. , Conomos Matthew P. , Heavner Ben , Hu Yao , Kooperberg Charles , Haessler Jeffrey , Vasan Ramachandran S. , Cupples L. Adrienne , Coombes Brandon J. , Seyerle Amanda , Gharib Sina A. , Chen Han , O’Connell Jeffrey R. , Zhang Man , Gottlieb Daniel , Psaty Bruce M. , Longstreth W.T. , Rotter Jerome I. , Taylor Kent D. , Rich Stephen S. , Guo Xiuqing , Boerwinkle Eric , Morrison Alanna C. , Pankow James S. , Johnson Andrew D. , Pankratz Nathan ,   NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Reiner Alex P. , Redline Susan , Smith Nicholas L. , Rice Kenneth M. , Schifano Elizabeth D. 
Published: January 2021

AbstractWhole genome and exome sequencing studies have become increasingly available and are being used to identify rare genetic variants associated with health and disease outcomes. Investigators routinely use mixed models to account for genetic relatedness or other clustering variables (e.g. family or household) when testing genetic associations. However, no existing tests of the association of a rare variant association with a binary outcome in the presence of correlated data controls the Type 1 error where there are (1) few carriers of the rare allele, (2) a small proportion of cases relative to controls, and (3) covariates to adjust for. Here, we address all three issues in developing the carriers-only test framework for testing rare variant association with a binary trait. In this framework, we estimate outcome probabilities under the null hypothesis, and then use them, within the carriers, to test variant associations. We extend the BinomiRare test, which was previously proposed for independent observations, and develop the Conway-Maxwell-Poisson (CMP) test, and study their properties in simulations. We show that the BinomiRare test always controls the type 1 error, while the CMP test sometimes does not. We then use the BinomiRare test to test the association of rare genetic variants in target genes with small vessel disease stroke, short sleep, and venous thromboembolism, in whole-genome sequence data from the Trans-Omics for Precision Medicine program.
Mathematical Model of a Personalized Neoantigen Cancer Vaccine and the Human Immune System: Evaluation of Efficacy
Authors: Messan Marisabel Rodriguez , Yogurtcu Osman N. , McGill Joseph R. , Nukala Ujwani , Sauna Zuben E. , Yang Hong 
Published: January 2021

AbstractCancer vaccines are an important component of the cancer immunotherapy toolkit enhancing immune response to malignant cells by activating CD4+ and CD8+ T cells. Multiple successful clinical applications of cancer vaccines have shown good safety and efficacy. Despite the notable progress, significant challenges remain in obtaining consistent immune responses across heterogeneous patient populations, as well as various cancers. We present as a proof of concept a mechanistic mathematical model describing key interactions of a personalized neoantigen cancer vaccine with an individual patient’s immune system. Specifically, the model considers the vaccine concentration of tumor-specific antigen peptides and adjuvant, the patient’s major histocompatibility complexes I and II copy numbers, tumor size, T cells, and antigen presenting cells. We parametrized the model using patient-specific data from a recent clinical study in which individualized cancer vaccines were used to treat six melanoma patients. Model simulations predicted both immune responses, represented by T cell counts, to the vaccine as well as clinical outcome (determined as change of tumor size). These kinds of models have the potential to lay the foundation for generating in silico clinical trial data and aid the development and efficacy assessment of personalized cancer vaccines.Author summaryPersonalized cancer vaccines have gained attention in recent years due to the advances in sequencing techniques that have facilitated the identification of multiple tumor-specific mutations. This type of individualized immunotherapy has the potential to be specific, efficacious, and safe since it induces an immune response to protein targets not found on normal cells. This work focuses on understanding and analyzing important mechanisms involved in the activity of personalized cancer vaccines using a mechanistic mathematical model. This model describes the interactions of a personalized neoantigen peptide cancer vaccine, the human immune system and tumor cells operating at the molecular and cellular level. The molecular level captures the processing and presentation of neoantigens by dendritic cells to the T cells using cell surface proteins. The cellular level describes the differentiation of dendritic cells due to peptides and adjuvant concentrations in the vaccine, activation, and proliferation of T cells in response to treatment, and tumor growth. The model captures immune response behavior to a vaccine associated with patient specific factors (e.g., different initial tumor burdens). Our model serves as a proof of concept displaying its utility in clinical outcomes prediction, lays foundation for developing in silico clinical trials, and aids in the efficacy assessment of personalized vaccines.
An Augmented SEIR Model with Protective and Hospital Quarantine Dynamics for the Control of COVID-19 Spread
Authors: Rohith G. 
Published: January 2021

AbstractIn this work, an attempt is made to analyse the dynamics of COVID-19 outbreak mathematically using a modified SEIR model with additional compartments and a nonlinear incidence rate with the help of bifurcation theory. Existence of a forward bifurcation point is presented by deriving conditions in terms of parameters for the existence of disease free and endemic equilibrium points. The significance of having two additional compartments, viz., protective and hospital quarantine compartments, is then illustrated via numerical simulations. From the analysis and results, it is observed that, by properly selecting transfer functions to place exposed and infected individuals in protective and hospital quarantine compartments, respectively, and with apt governmental action, it is possible to contain the COVID-19 spread effectively. Finally, the capability of the proposed model in predicting/representing the COVID-19 dynamics is presented by comparing with real-time data.
Women in Health Care Experiencing Occupational Stress and Burnout during COVID-19: A Review
Authors: Sriharan Abi , Ratnapalan Savithiri , Tricco Andrea C. , Lupea Doina 
Published: January 2021

AbstractContextCOVID-19 has had an unprecedent impact on physicians, nurses, and other health professionals around the world, and a serious health care burnout crisis is emerging as a result of this pandemic.ObjectivesWe aim to identify the causes of occupational stress and burnout in women in medicine, nursing, and other health professions during the COVID-19 pandemic and interventions that can support female health professionals deal with this crisis through a rapid review.MethodsWe searched MEDLINE, Embase, CINAHL, PsycINFO, and ERIC from December 2019 through September 30, 2020. The review protocol was registered in PROSPERO and is available online. We selected all empirical studies that discussed stress and burnout in women health care workers during the COVID-19 pandemic.ResultsThe literature search identified 6148 citations. A review of abstracts led to the retrieval of 721 full-text articles for assessment, of which 47 articles were included for review. Our findings show that concerns of safety (65%), staff and resource adequacy (43%), workload and compensation (37%), job roles and security (41%) appeared as common triggers of stress in the literature.Conclusions and RelevanceThe current literature primarily focuses on self-focused initiatives such as wellness activities, coping strategies, reliance of family, friends and work colleagues to organizational led initiatives such as access to psychological support and training. Very limited evidence exists about the organizational interventions such as work modification, financial security, and systems improvement.
Pathways and signatures of mutagenesis at targeted DNA nicks
Authors: Zhang Yinbo , Davis Luther , Maizels Nancy 
Published: January 2021

AbstractNicks are the most frequent form of DNA damage and a potential source of mutagenesis in human cells. By deep sequencing, we have identified factors and pathways that promote and limit mutagenic repair at targeted nicks. BRCA2 inhibits all categories of mutational events at nicks, including indels, SNVs and HDR. DNA2 and RPA promote 5’ resection. Most insertions at nicks consist of a single C incorporated opposite the nick by the translesion polymerase REV1. DNA2 and REV3 inhibit these 1 bp insertions; and DNA2 also inhibits 1 bp deletions. Longer deletions are stimulated by DNA2, REV7 and POLQ. Strikingly, POLQ generates most SNVs at both nicks and double-strand breaks. These results identify mutagenic signatures of DNA2, REV1, REV3, REV7 and POLQ at nicks and highlight the potential for nicks to promote mutagenesis, especially in BRCA-deficient cells.
Gut microbiota ofDrosophila subobscuracontributes to its heat tolerance but is sensitive to transient thermal stress
Authors: Jaramillo Angélica , Castañeda Luis E. 
Published: January 2021

AbstractGlobal warming impacts the animal’s fitness, leading to increasing extinction risk in ectotherm species. Gut microbiota can contribute to host physiology leading to an increase of resistance to abiotic stress conditions. Temperature has profound effects on ectotherms and gut microbiota can influence cold and heat tolerance of ectotherm species. Additionally, the gut microbiota is sensitive to environmental temperature, which induces changes in its composition and diversity. Here, we investigated the role of the gut microbiota on heat tolerance ofDrosophila subobscura, comparing the knockdown time between conventional and axenic, and we also assessed the impact of heat stress on the diversity and community structure of the gut microbiota, comparing non-stressed and heat-stressed flies. Our findings provide evidence that gut microbiota influences heat tolerance, and that heat stress modifies the gut microbiota at taxonomical and structural levels. These results demonstrate that gut microbiota contributes to heat tolerance but it is also highly sensitive to transient heat stress, which could have important effects on host fitness, population risk extinction, and vulnerability of ectotherms to current and future climatic conditions.
FLAgellum Member 8 modulates extravascular trypanosome distribution in the mammalian host
Authors: Alvarez Estefanía Calvo , Travaillé Christelle , Crouzols Aline , Rotureau Brice 
Published: January 2021

SummaryThe African trypanosome flagellum is an essential organelle in multiple aspects of the parasites’ development. Here, we investigated the role of a flagellar protein termed FLAgellar Member 8 (FLAM8) that is specifically distributed along the entire flagellum in trypanosomes stages of the vertebrate host. Analyses of knockdown and knockout trypanosomes demonstrated that FLAM8 is not essentialin vitrofor survival, growth, motility and slender to stumpy differentiation. Functional investigations in experimental infections showed thatFLAM8-deprived trypanosomes are able to establish and maintain the infection in the blood circulation, and to differentiate into insect transmissible forms. However, quantitative bioluminescence imaging revealed thatFLAM8-null parasites exhibit an impaired dissemination in the extravascular compartment, that is partially restored by the addition of a single rescue copy ofFLAM8. Interestingly, among all dissected organs scrutinized individually, only the skin of mice infected withFLAM8-deprived parasites showed a significant reduction in extravascular trypanosome population as compared to mice infected with parental controls. To our knowledge, FLAM8 is the first example of a flagellar protein that modulatesT. bruceiparasite distribution in the host tissues, contributing to the maintenance of extravascular parasite populations in mammalian anatomical niches, especially in the skin.Take awayFLAM8 is dispensablein vitrofor survival, growth, motility and differentiation ofT. brucei.FLAM8 depletion does not affect parasitemia and bloodstream form differentiationin vivo.FLAM8 modulates the extravascular dissemination of trypanosomes in the mammalian host, especially in the skin.
Towards the restoration of ancient hominid craniofacial anatomy: Chimpanzee morphology reveals covariation between craniometrics and facial soft tissue thickness
Authors: Campbell Ryan M , Vinas Gabriel , Henneberg Maciej 
Published: January 2021

AbstractIn modern humans, facial soft tissue thicknesses have been shown to covary with craniometric dimensions. However, to date it has not been confirmed whether these relationships are shared with non-human apes. In this study, we analyze these relationships in chimpanzees (Pan troglodytes) with the aim of producing regression models for approximating facial soft tissue thicknesses in Plio-Pleistocene hominid individuals. Using CT scans of 19 subjects, 637 soft tissue, and 349 craniometric measurements, statistically significant multiple regression models were established for 26 points on the face and head. Examination of regression model validity resulted in minimal differences between observed and predicted soft tissue thickness values. Assessment of interspecies compatibility using a bonobo (Pan paniscus) and modern human(Homo sapiens) subject resulted in minimal differences for the bonobo but large differences for the modern human. These results clearly show that (1) soft tissue thicknesses covary with craniometric dimensions inP. troglodytes, (2) confirms that such covariation is uniformly present in both extantHomoandPanspecies, and (3) suggests that chimp-derived regression models have interspecies compatibility with hominids who have similar craniometric dimensions toP. troglodytes. As the craniometric dimensions of early hominids, such as South African australopithecines, are more similar toP. troglodytesthan those ofH. sapiens, chimpanzee-derived regression models may be used for approximating their craniofacial anatomy. It is hoped that the results of the present study and the reference dataset for facial soft tissue thicknesses of chimpanzees it provides will encourage further research into this topic.
Auto-CORPus: A Natural Language Processing Tool for Standardising and Reusing Biomedical Literature
Authors: Beck Tim , Shorter Tom , Hu Yan , Li Zhuoyu , Sun Shujian , Popovici Casiana M. , McQuibban Nicholas A. R. , Makraduli Filip , Yeung Cheng S. , Rowlands Thomas , Posma Joram M. 
Published: January 2021

AbstractTo analyse large corpora using machine learning and other Natural Language Processing (NLP) algorithms, the corpora need to be standardised. The BioC format is a community-driven simple data structure for sharing text and annotations, however there is limited access to biomedical literature in BioC format and a lack of bioinformatics tools to convert online publication HTML formats to BioC. We present Auto-CORPus (Automated pipeline for Consistent Outputs from Research Publications), a novel NLP tool for the standardisation and conversion of publication HTML and table image files to three convenient machine-interpretable outputs to support biomedical text analytics. Firstly, Auto-CORPus can be configured to convert HTML from various publication sources to BioC. To standardise the description of heterogenous publication sections, the Information Artifact Ontology is used to annotate each section within the BioC output. Secondly, Auto-CORPus transforms publication tables to a JSON format to store, exchange and annotate table data between text analytics systems. The BioC specification does not include a data structure for representing publication table data, so we present a JSON format for sharing table content and metadata. Inline tables within full-text HTML files and linked tables within separate HTML files are processed and converted to machine-interpretable table JSON format. Finally, Auto-CORPus extracts abbreviations declared within publication text and provides an abbreviations JSON output that relates an abbreviation with the full definition. This abbreviation collection supports text mining tasks such as named entity recognition by including abbreviations unique to individual publications that are not contained within standard bio-ontologies and dictionaries.AvailabilityThe Auto-CORPus package is freely available with detailed instructions from Github athttps://github.com/omicsNLP/Auto-CORPus/.
Genome-scale sequencing and analysis of human, wolf and bison DNA from 25,000 year-old sediment
Authors: Gelabert Pere , Sawyer Susanna , Bergström Anders , Collin Thomas C. , Meshveliani Tengiz , Belfer-Cohen Anna , Lordkipanidze David , Jakeli Nino , Matskevich Zinovi , Bar-Oz Guy , Fernandes Daniel M. , Cheronet Olivia , Özdoğan Kadir T. , Oberreiter Victoria , Feeney Robin N. M. , Stahlschmidt Mareike C. , Skoglund Pontus , Pinhasi Ron 
Published: January 2021

SummaryArchaeological sediments have been shown to preserve ancient DNA, but so far have not yielded genome-scale information of the magnitude of skeletal remains. We retrieved and analysed human and mammalian low-coverage nuclear and high-coverage mitochondrial genomes from Upper Palaeolithic sediments from Satsurblia cave, western Georgia, dated to 25,000 years ago. First, a human female genome with substantial basal Eurasian ancestry, which was an ancestry component of the majority of post-Ice Age people in the Near East, North Africa, and parts of Europe. Second, a wolf genome that is basal to extant Eurasian wolves and dogs and represents a previously unknown, likely extinct, Caucasian lineage that diverged from the ancestors of modern wolves and dogs before these diversified. Third, a bison genome that is basal to present-day populations, suggesting that population structure has been substantially reshaped since the Last Glacial Maximum. Our results provide new insights into the late Pleistocene genetic histories of these three species, and demonstrate that sediment DNA can be used not only for species identification, but also be a source of genome-wide ancestry information and genetic history.HighlightsWe demonstrate for the first time that genome sequencing from sediments is comparable to that of skeletal remainsA single Pleistocene sediment sample from the Caucasus yielded three low-coverage mammalian ancient genomesWe show that sediment ancient DNA can reveal important aspects of the human and faunal pastEvidence of an uncharacterized human lineage from the Caucasus before the Last Glacial Maximum∼0.01-fold coverage wolf and bison genomes are both basal to present-day diversity, suggesting reshaping of population structure in both species
APOBEC1 mediated C-to-U RNA editing: target sequence and trans-acting factor contribution to 177 RNA editing events in 119 murine transcripts in-vivo
Authors: Soleymanjahi Saeed , Blanc Valerie , Davidson Nicholas O. 
Published: January 2021

ABSTRACTMammalian C-to-U RNA editing was described more than 30 years ago as a single nucleotide modification in APOB RNA in small intestine, later shown to be mediated by the RNA-specific cytidine deaminase APOBEC1. Reports of other examples of C-to-U RNA editing, coupled with the advent of genome-wide transcriptome sequencing, identified an expanded range of APOBEC1 targets. Here we analyze the cis-acting regulatory components of verified murine C-to-U RNA editing targets, including nearest neighbor as well as flanking sequence requirements and folding predictions. We summarize findings demonstrating the relative importance of trans-acting factors (A1CF, RBM47) acting in concert with APOBEC1. Using this information, we developed a multivariable linear regression model to predict APOBEC1 dependent C-to-U RNA editing efficiency, incorporating factors independently associated with editing frequencies based on 103 Sanger-confirmed editing sites, which accounted for 84% of the observed variance. Co-factor dominance was associated with editing frequency, with RNAs targeted by both RBM47 and A1CF observed to be edited at a lower frequency than RBM47 dominant targets. The model also predicted a composite score for available human C-to-U RNA targets, which again correlated with editing frequency.
Test-retest reliability of tone- and 40 Hz train-evoked gamma oscillations in female rats and their sensitivity to low-dose NMDA channel blockade
Authors: Raza Muhammad Ummear , Sivarao Digavalli V. 
Published: January 2021

AbstractRationaleSchizophrenia patients consistently show deficits in sensory-evoked broadband gamma oscillations and click-evoked entrainment at 40 Hz, called the 40 Hz auditory steady-state response (ASSR). Since such evoked oscillations depend on cortical N-methyl D-aspartic acid (NMDA)-mediated network activity, they can serve as pharmacodynamic biomarkers in the preclinical development of drug candidates engaging these circuits. However, there is little test-retest reliability data in preclinical species, a prerequisite for within-subject testing paradigms.ObjectivesWe investigated the long-term stability of these measures in a rodent model.MethodsFemale rats with chronic epidural implants were used to record tone- and 40 Hz click-evoked responses at multiple time points and across six sessions, spread over 3 weeks. We assessed reliability using intraclass correlation coefficients (ICC). Separately, we used mixed-effects ANOVA to examine time and session effects. Individual subject variability was determined using the coefficient of variation (CV). Lastly, to illustrate the importance of long-term measure stability for within-subject testing design, we used low to moderate doses of an NMDA antagonist MK801 (0.025-0.15 mg/kg) to disrupt the evoked responses.ResultsWe found that 40 Hz ASSR showed good reliability (ICC=0.60-0.75) while the reliability of tone-evoked gamma ranged from fair to good (0.33-0.67). We noted time but no session effects. Subjects showed a lower variance for ASSR over tone-evoked gamma. Both measures were dose-dependently attenuated by NMDA antagonism.ConclusionOverall, while both measures use NMDA transmission, 40 Hz ASSR showed superior psychometric properties of higher ICC and lower CV, relative to tone-evoked gamma.