bluuebunny/crossref_metadata_2025_split huggingface dataset:
DisPhaseDB, an integrative database of diseases related variations in liquid-liquid phase separation proteins
Authors: Navarro Alvaro , Orti Fernando , Martínez-Pérez Elizabeth , Simonetti Franco , Iserte Javier , Marino-Buslje Cristina 
Published: February 2022

AbstractMotivationProteins involved in liquid-liquid phase separation (LLPS) and membraneless organelles (MLOs) are recognized to be decisive for many biological processes and also responsible for several diseases. The recent explosion of research in the area still lacks tools for the analysis and data integration among different repositories. Currently, there is not a comprehensive and dedicated database that collects all disease-related variations in combination with the protein location, biological role in the MLO and all the metadata available for each protein and disease. Disease related protein variants and additional features are dispersed and the user has to navigate many databases, with different focus, formats and often not user friendly.ResultsWe present DisPhaseDB, a database dedicated to disease related variants of LLPS proteins and/or are involved in MLOs. It integrates 10 databases, contains 5.741 proteins, 1.660.059 variants and 4.051 disease terms. It also offers intuitive navigation and an informative display. It constitutes a pivotal starting point for further analysis, encouraging the development of new computational tools.Availability and ImplementationThe database is freely available at http://disphasedb.leloir.org.ar.Contactjiserte@leloir.org.ar and cmb@leloir.org.arGraphical abstract
Tau seeding without tauopathy
Authors: LaCroix Michael S. , Hitt Brian D. , Beaver Joshua D. , Estill-Terpack Sandi-Jo , Gleason Kelly , Tamminga Carol A. , Evers Bret M. , White Charles L. , Diamond Marc I. 
Published: February 2022

AbstractNeurodegenerative tauopathies such as Alzheimer’s disease (AD) are caused by brain accumulation of tau assemblies. Evidence suggests tau functions as a prion, and cells and animals efficiently propagate unique tau assemblies. This suggests a dedicated cellular replication machinery, with normal physiologic function for tau seeds. Consequently, we hypothesized that healthy control brains would have seeding activity. We recently developed a novel monoclonal antibody (MD3.1) specific for tau seeds. We used this antibody to immunopurify tau from the parietal and cerebellar cortices of 19 healthy subjects ranging 19-65 years. We detected seeding in the parietal cortex, but not in the cerebellum, or in wild-type or human tau knockin mice, suggesting that cellular/genetic context dictates development of seed-competent tau. Seeding did not correlate with subject age or brain tau levels. Dot blot analyses revealed no AT8 immunoreactivity above background levels in parietal and cerebellar extracts and <1/100 of that present in AD. Based on binding to a panel of antibodies, the conformational characteristics of control seeds differed from AD, suggesting a unique underlying assembly, or structural ensemble. Tau’s ability to adopt self-replicating conformations under non-pathogenic conditions may reflect normal function that goes awry in disease states.
Using multiple sampling strategies to estimate SARS-CoV-2 epidemiological parameters from genomic sequencing data
Authors: Inward Rhys P. D. , Parag Kris V. , Faria Nuno R. 
Published: February 2022

ABSTRACTSARS-CoV-2 virus genomes are currently being sequenced at an unprecedented pace. The choice of viral sequences used in genetic and epidemiological analysis is important as it can induce biases that detract from the value of these rich datasets. This raises questions about how a set of sequences should be chosen for analysis, and which epidemiological parameters derived from genomic data are sensitive or robust to changes in sampling. We provide initial insights on these largely understudied problems using SARS-CoV-2 genomic sequences from Hong Kong, China, and the Amazonas State, Brazil. We consider sampling schemes that select sequences uniformly, in proportion or reciprocally with case incidence and which simply use all available sequences (unsampled). We apply Birth-Death Skyline and Skygrowth methods to estimate the time-varying reproduction number (Rt) and growth rate (rt) under these strategies as well as related R0 and date of origin parameters. We compare these to estimates from case data derived from EpiFilter, which we use as a reference for assessing bias. We find that both Rt and rt are sensitive to changes in sampling whilst R0 and the date of origin are relatively robust. Moreover, we find that analysis using unsampled datasets, which reflect an opportunistic sampling scheme, result in the most biased Rt and rt estimates for both our Hong Kong and Amazonas case studies. We highlight that sampling strategy choices may be an influential yet neglected component of sequencing analysis pipelines. More targeted attempts at genomic surveillance and epidemic analyses, particularly in settings with limited sequencing capabilities, are necessary to maximise the informativeness of virus genomic datasets.
N-glycans mannosylation controls T-cell development by reprogramming thymocyte commitment, fate and repertoire
Authors: Vicente Manuel M , Alves Inês , Fernandes Ângela , Dias Ana M , Pérez-Anton Elena , Correia Alexandra , Almeida Afonso R M , Rabinovich Gabriel A , Vilanova Manuel , Sousa Ana E , Pinho Salomé S 
Published: February 2022

AbstractT-cell development is a major physiological process occurring in complex organisms, that ensures the formation of T-cell receptors diverse repertoire, to recognize antigens throughout the life of the organism. The thymus offers a microenvironment for efficient development, where progenitor populations go through maturation steps, which, when not regulated, are associated with disease onset, including autoimmune disorders and cancer. Glycosylation is a major post-translational modification that occurs in virtually all cells, including T lymphocytes, regulating receptor- turnover, affinity and signaling. However, there is a missing knowledge on how glycans regulate lymphocyte development and their impact in T-cell functions. We discovered stage-specific glycosylation profiles in human and murine thymocyte populations. Thereafter, we generated two glycoengineered mouse models displaying N-glycosylation pathway deficiencies, at early DN stages, lacking the Mgat1 or Mgat2 genes. We demonstrated remarkable defects in key T-cell developmental stages, such as ß- and DP-selection, natural regulatory T-cell generation, γδ T development/differentiation and thymic egression, in Mgat1-deficient thymocytes, indicating a pathogenic role of mannose N-glycans in development. We also demonstrated that a single N- glycan antenna (modelled in Mgat2-deficient thymocytes) is sufficient to rescue key developmental processes. In conclusion, we demonstrated that mannosylated thymocytes render a dysregulation in T-cell development, associated with disease.Graphical abstract
Comparison of common outcome measures for assessing independence in patients diagnosed with disorders of consciousness: A Traumatic Brain Injury Model Systems Study
Authors: Snider Samuel B. , Kowalski Robert G. , Hammond Flora , Izzy Saef , Shih Shirley L. , Rovito Craig , Edlow Brian L. , Zafonte Ross D. , Giacino Joseph T. , Bodien Yelena G. 
Published: February 2022

ABSTRACTImportancePatients with disorders of consciousness (DoC) after traumatic brain injury (TBI) recover to varying degrees of functional dependency. Dependency is difficult to measure but critical for outcome interpretation and prognostic counseling. Traditional outcome measures, like the Glasgow Outcome Scale-Extended (GOSE), are mandated by the US Food and Drug Administration for evaluating TBI clinical trial efficacy but have an unknown accuracy for measuring dependency.ObjectiveWe used the Functional Independence Measure (FIM®) as the reference standard to evaluate how accurately the GOSE and Disability Rating Scale (DRS) assess functional dependency in the world’s largest cohort of patients with DoC after TBI. We propose an alternate, data-driven, approach to measuring dependency.Design, Setting, and ParticipantsIn this cohort study, we included patients with DoC prospectively enrolled in the longitudinal Traumatic Brain Injury Model Systems National Database (TBIMS NDB). Participants were survivors of moderate/severe TBI with DoC on admission to a US inpatient rehabilitation center between 1988 and 2020, followed 1 year after injury.ExposureWe examined the classification performance of common TBI outcome measure cutpoints (GOSE ≤3 and ≤4 [Lower and Upper Severe Disability, respectively], and DRS ≥12 [Severe Disability]) in identifying subjects with functional dependency at 1 year. We compared dataderived optimal cut-points on these scales to a novel DRS-based marker of dependency, the DRSDepend.Main Outcome and MeasureTotal FIM score < 80 (FIM-dependency) at 1 year.ResultsOf 18,486 TBIMS participants, 1,483 with DoC on arrival to inpatient rehabilitation met inclusion criteria (mean [SD] age=38 [18] years; 76% male). The sensitivity of GOSE cut-points of ≤3 and ≤4 for identifying FIM-dependency were 97% and 98%, but specificities were 73% and 51%, respectively. The sensitivity of the DRS cut-point of ≥12 was 60%, but specificity was 100%. The DRSDependhad a sensitivity of 83% and a specificity of 94% for classifying FIM-dependency, with a greater AUROC than the data-derived optimal GOSE (≤3, p=0.01) and DRS (≥10, p=0.008) cut-points.Conclusions and RelevanceCommonly-used GOSE and DRS cut-points have limited sensitivity or specificity for identifying functional dependency. The DRSDependidentifies FIM-dependency more accurately than GOSE and DRS cut-points, but requires further validation.
SARS-CoV-2 Omicron symptomatic infections in previously infected or vaccinated South African healthcare workers
Authors: Nunes Marta C. , Sibanda Sthembile , Baillie Vicky L. , Kwatra Gaurav , Aguas Ricardo , Madhi Shabir A. ,   the Wits VIDA HCW Study Group
Published: February 2022

AbstractWe investigated Omicron infections among healthcare workers (HCW) presenting with symptoms of SARS-CoV-2 infection and evaluated the protective effect of vaccination or prior infection.Between 24th November and 31st December 2021, HCW in Johannesburg, South Africa, were tested for SARS-CoV-2 infection by Nucleic Acid Amplification Test (NAAT). Blood samples collected either at the symptomatic visit or within 3-months prior, were tested for spike protein immunoglobulin G (IgG).Overall, 433 symptomatic HCW were included in the analysis, with 190 (43.9%) having an Omicron infection; 69 (16.7%) were unvaccinated and 270 (62.4%) received a single dose of Ad26.COV.2 vaccine. There was no difference in the odds of identifying Omicron between unvaccinated and Ad26.COV.2 vaccinated HCW (adjusted odds ratio [aOR] 0.81, 95% confidence interval [CI]: 0.46, 1.43). One-hundred and fifty-four (35.3%) HCW had at least one SARS-CoV-2 NAAT-confirmed prior infection; these had lower odds of Omicron infection compared with those without past infection (aOR 0.55, 95%CI: 0.36, 0.84). Anti-spike IgG concentration of 1549 binding antibody unit/mL was suggestive of significant reduction in the risk of symptomatic Omicron infection.We found high reinfection and vaccine breakthrough infection rates with the Omicron variant among HCW. Prior infection and high anti-spike IgG concentration were protective against Omicron infection.
Epigenetic clock acceleration is linked to age-at-onset of idiopathic and LRRK2 Parkinson’s disease
Authors: Tang Xuelin , Gonzalez-Latapi Paulina , Marras Connie , Visanji Naomi P. , Yang Wanli , Sato Christine , Lang Anthony E. , Rogaeva Ekaterina , Zhang Ming 
Published: February 2022

AbstractParkinson’s disease is a clinically and genetically heterogeneous movement disorder with highly variable age-at-onset. DNA methylation (DNAm) age is an epigenetic clock that could reflect biological aging. Studies of DNAm-age acceleration (difference between DNAm-age and chronological age) are pertinent to neurodegenerative diseases (e.g., Parkinson’s disease), for which aging is the strongest risk-factor. We assessed DNAm-age in idiopathic Parkinson’s disease (n=96) and a longitudinal LRRK2 cohort at four time-points over a 3-year period (n=220), including manifesting (n=91) and non-manifesting (n=129) G2019S-carriers. A highly variable age-at-onset was observed in both the idiopathic cohort (26-77 years) and manifesting G2019S-carriers (39-79 years). Increased DNAm-age acceleration was significantly associated with younger onset in idiopathic and LRRK2-related Parkinson’s disease, suggesting that every 5-year increase in DNAm-age acceleration is linked to about 6-year earlier onset. At an individual level, DNAm-age acceleration remained steady over a 3-year period for most G2019S-carriers, indicating that it might serve as a stable biomarker of biological aging. Future studies should evaluate the stability of DNAm-age acceleration over longer time-periods, especially for phenoconverters from non-manifesting to manifesting subjects. In conclusion, DNAm-age acceleration is linked to disease onset, and could be used in disease-modifying clinical trials of prodromal Parkinson’s disease.
Human Cerebral Spheroids Undergo Activity Dependent Changes In Cellular Composition And Microrna Expression
Authors: Parmentier Thomas , James Fiona , Hewitson Elizabeth , Bailey Craig , Werry Nicholas , Sheridan Steve D. , Perlis Roy H. , Perreault Melissa , Gaitero Luis , Lalonde Jasmin , LaMarre Jonathan 
Published: February 2022

SUMMARYActivity-induced neurogenesis has been extensively studied in rodents but the lack of ante mortem accessibility to human brain at the cellular and molecular levels limits studies of the process in humans. Using cerebral spheroids derived from human induced pluripotent stem cells (iPSCs), we investigated the effects of increased neuronal activity on neurogenesis. Our studies demonstrate that increasing neuronal activity with 4-aminopyridine in 3-month-old cerebral spheroids is associated with increases in the numbers of new neurons and decreases in the population of new glial cells. We also observed a significant decrease in the expression of miR-135a, which has previously been shown to be decreased in exercise-induced neurogenesis. Predicted targets of miR-135a include key participants in the SMAD2/3 and BDNF pathways. Together, our results suggest that iPSC-derived cerebral spheroids are an attractive model to study some aspects of activity-induced neurogenesis.
metaPR2: a database of eukaryotic 18S rRNA metabarcodes with an emphasis on protists
Authors: Vaulot Daniel , Hung Sim Clarence Wei , Ong Denise , Teo Bryan , Biwer Charlie , Jamy Mahwash , dos Santos Adriana Lopes 
Published: February 2022

AbstractIn recent years, metabarcoding has become the method of choice for investigating the composition and assembly of microbial eukaryotic communities, and an increasing number of environmental datasets are being published. Although unprocessed sequence files are often publicly available, processed data, i.e. sequences clustered as operational taxonomic units (OTUs) or amplicon sequence variants (ASVs) are rarely at hand in a comparable format. This hampers comparative studies between different environments and datasets, for example examining the biogeographical patterns of specific groups/species, as well analysing the micro-genetic diversity within these groups. Here, we present a newly-assembled database of processed 18S rRNA metabarcodes that are annotated with the PR2 reference sequence database. This database, called metaPR2, contains 41 datasets corresponding to more than 4,000 samples and 73,000 ASVs. The database is accessible through both a web-based interface (https://shiny.metapr2.org) and as an R package, and should prove very useful to all researchers working on protist diversity in a variety of systems.
Multiplexed Detection of Molecular Interactions with DNA Origami Engineered Cells in 3-D Collagen Matrices
Authors: Shahhosseini Melika , Beshay Peter E. , Akbari Ehsan , Avendano Alex , Song Jonathan W. , Castro Carlos E. 
Published: February 2022

AbstractThe interactions of cells with signaling molecules present in their local microenvironment maintain cell proliferation, differentiation, and spatial organization, and mediate progression of diseases such as metabolic disorders and cancer. Real-time monitoring of the interactions between cells and their extracellular ligands in a 3-D microenvironment can inform detection and understanding of cell processes and development of effective therapeutic agents. DNA-origami technology allows for the design and fabrication of biocompatible and 3-D functional nanodevices via molecular self-assembly for various applications including molecular sensing. Here, we report a robust method to monitor live cell interactions with molecules in their surrounding environment in a 3-D tissue model using a microfluidic device. We used a DNA origami Cell Sensing Platform (CSP) to detect two specific nucleic acid sequences on the membrane of B cells and dendritic cells. We further demonstrated real-time detection of biomolecules with the DNA sensing platform on the surface of dendritic cells in a 3-D microfluidic tissue model. Our results establish the integration of live cells with membranes engineered with DNA nanodevices into microfluidic chips as a highly capable biosensor approach to investigate subcellular interactions in physiologically relevant 3-D environments under controlled biomolecular transport.
Genome-microbiome interplay provides insight into the determinants of the human blood metabolome
Authors: Diener Christian , Dai Chengzhen L. , Wilmanski Tomasz , Baloni Priyanka , Smith Brett , Rappaport Noa , Hood Leroy , Magis Andrew T. , Gibbons Sean M. 
Published: February 2022

AbstractVariation in the blood metabolome is intimately related to human health. Prior work has shown that host genetics and gut microbiome composition, combined, explain sizable, but orthogonal, components of the overall variance in blood metabolomic profiles. However, few details are known about the interplay between genetics and the microbiome in explaining variation on a metabolite-by-metabolite level. Here, we performed analyses of variance for each of the 945 blood metabolites that were robustly detected across a cohort of 2,049 individuals, while controlling for a number of relevant covariates, like sex, age, and genetic ancestry. Over 60% of the detected blood metabolites were significantly associated with either host genetics or the gut microbiome, with more than half of these associations driven solely by the microbiome and around 30% under hybrid genetic-microbiome control. The variances explained by genetics and the microbiome for each metabolite were indeed largely additive, although subtle, but significant, non-additivity was detected. We found that interaction effects, where a metabolitemicrobe association was specific to a particular genetic background, were quite common, albeit with modest effect sizes. The outputs of our integrated genetic-microbiome regression models provide novel biological insights into the processes governing the composition of the blood metabolome. For example, we found that unconjugated secondary bile acids were solely associated with the microbiome, while their conjugated forms were under strong host genetic control. Overall, our results reveal which components of the blood metabolome are under strong genetic control, which are more dependent on gut microbiome composition, and which are dependent upon both. This knowledge will help to guide targeted interventions designed to alter the composition of the blood metabolome.
Dopamine transporter and synaptic vesicle sorting defects initiate auxilin-linked Parkinson’s disease
Authors: Vidyadhara D J , Somayaji Mahalakshmi , Wade Nigel , Yücel Betül , Zhao Helen , Shashaank N , Ribaudo Joseph , Gupta Jyoti , Lam TuKiet T. , Sames Dalibor , Greene Lois E. , Sulzer David L. , Chandra Sreeganga S. 
Published: February 2022

SUMMARYAuxilin participates in the uncoating of clathrin-coated vesicles (CCVs), thereby facilitating synaptic vesicle (SV) regeneration at presynaptic sites. Auxilin (DNAJC6/PARK19) loss-of- function mutations cause early-onset Parkinson’s disease (PD). Here, we utilized auxilin-knockout (KO) mice to elucidate the mechanisms through which auxilin deficiency and clathrin-uncoating deficits lead to PD. We demonstrate that auxilin KO mice display the cardinal features of PD, including progressive motor deficits, α-synuclein pathology, nigral dopaminergic loss, and neuroinflammation. Through unbiased proteomic and neurochemical analyses, we demonstrate that dopamine homeostasis is disrupted in auxilin KO brains, including via slower dopamine reuptake kinetics in vivo, an effect associated with dopamine transporter misrouting into axonal membrane deformities in the dorsal striatum. We also show that elevated macroautophagy and defective SV protein sorting contribute to ineffective dopamine sequestration and homeostasis, ultimately leading to neurodegeneration. This study advances our knowledge of how presynaptic endocytosis deficits lead to dopaminergic vulnerability and pathogenesis of PD.
Genetic and genomic analysis of oxygen consumption in mice
Authors: Ogawa Shinichiro , Darhan Hongyu , Suzuki Keiichi 
Published: February 2022

AbstractWe estimated genetic parameters of oxygen consumption (OC), OC per metabolic body weight (OCMBW), and body weight at three through eight weeks of age in divergently selected mice populations, with an animal model considering maternal genetic, common litter environmental, and cytoplasmic inheritance effects. Cytoplasmic inheritance was considered based on maternal lineage information. For OC, estimated direct heritability was moderate (0.32) and estimated maternal heritability and proportion of the variance of cytoplasmic inheritance effects to the phenotypic variance were very low (both <0.03), implying that causal genes for OC could be located on autosomes. To assess this hypothesis, we attempted to identify possible candidate causal genes by performing pool-seq using pooled DNA samples from mice in high and low OC lines and selective signature detection. We made a list of possible candidate causal genes for OC, including those relating to electron transport chain and ATP-binging proteins (Ndufa12, Sdhc, Atp10b, etc.),Prr16encoding Largen protein,Cry1encoding a key component of the circadian core oscillator, and so on. The results could contribute to elucidate the genetic mechanism of OC, an indicator for maintenance energy requirement and therefore feed efficiency.