bluuebunny/crossref_metadata_2025_split huggingface dataset:
Birth history is associated with whole-blood and T-cell methylation patterns in relapse onset multiple sclerosis
Authors: Campagna Maria Pia , Xavier Alexandre , Stankovich Jim , Maltby Vicki , Slee Mark , Kilpatrick Trevor , Scott Rodney J , Butzkueven Helmut , Lechner-Scott Jeannette , Lea Rodney , Jokubaitis Vilija 
Published: March 2022

AbstractBackgroundPregnancy in women with multiple sclerosis (MS) is associated with a reduction of long-term disability progression. The mechanism that drives this effect is unknown, but converging evidence suggests a role for epigenetic mechanisms altering immune and/or central nervous system function.ObjectivesWe aimed to identify whole blood and immune cell-specific DNA methylation patterns associated with parity in relapse-onset multiple sclerosis.MethodsWe compared whole-blood methylation patterns between 96 matched pairs of nulligravida and parous females with MS (n=192). Parity was defined as at least one term or pre-term birth, and nulligravida was defined as no prior pregnancies. Methylation was measured with Illumina EPIC arrays, and data was pre-processed and statistically analysed using theChAMPpackage. Cell-type proportions were estimated using theEpiDISHpackage, and cell-specific analysis conducted using linear regression. Gene-set enrichment analysis (GSEA) was performed with ToppGene API and GOmeth. Methylation age was calculated with themethyAgepackage. Methylation age acceleration (MAA) was calculated by regressing methylation age on chronological age. FDR<0.05 was used to assess significance.ResultsThe median time from last pregnancy to blood collection was 16.66 years (range = 1.45 – 44.42 years). We identified 903 differentially methylated positions (DMPs) in whole blood; 365 were hypomethylated and 528 were hypermethylated in parous women. We further identified two differentially methylated regions (DMRs) inCRYGNon Chromosome 7 and an intergenic region on Chromosome 15. There were four and eight cell type specific DMPs in CD4+ and CD8+ cells, respectively. Differentially methylated genes were enriched in neuronal plasticity pathways. Parity was associated with reduced MAA by a mean of 1.44 to 2.27 years using the PhenoAge (p = 0.002) and GrimAge (p = 0.005) algorithms.ConclusionWhole-blood methylation patterns are associated with birth history in females with relapse-onset multiple sclerosis. We found enrichment of differentially methylated genes encoding neuronal processes and reduced MAA in parous women. These methylation changes could mediate the long-term benefit of pregnancy for disease progression in multiple sclerosis.
Temporal coordination between chromosome mobility and homologous recombination
Authors: Joseph Fraulin , Lee So Jung , Bryant Eric Edward , Reid Robert J. D. , Sunjevaric Ivana , Rothstein Rodney 
Published: March 2022

AbstractHomologous recombination (HR), a principal cellular pathway for double-strand break (DSB) repair, is linked to changes in chromosome movement. Although increased chromosome mobility in response to a DSB has been observed in a variety of species, its precise role in HR remains controversial. Here, we find that end resection, the recruitment of recombination proteins, increased chromosome mobility, the pairing of homologs and gene conversion are temporally linked in response to a DSB. In mre11Δ mutant cells, which exhibit a delay in the initial processing of a DSB, chromosome mobility and all subsequent recombination events are also delayed. Overexpression of the Dna2 nuclease suppresses the mre11Δ delay in end resection and restores the original timing of chromosome mobility and all subsequent downstream HR events. Thus, changing the timing of chromosome mobility results in a corresponding change in essential downstream HR events, reinforcing its mechanistic role in the DNA repair process.
Distinct Neurexin-Cerebellin Complexes Control AMPA- and NMDA-Receptor Responses in a Circuit-Dependent Manner
Authors: Dai Jinye , Liakath-Ali Kif , Golf Samantha , Südhof Thomas C. 
Published: March 2022

ABSTRACTAt mature CA1→subiculum synapses, alternatively spliced SS4+ variants of neurexin-1 (Nrxn1SS4+) and neurexin-3 (Nrxn3SS4+) enhance NMDA- and suppress AMPA-receptors, respectively. Both Nrxn1SS4+and Nrxn3SS4+act by binding to secreted cerebellin-2 (Cbln2) that in turn activates postsynaptic GluD1, which is homologous to AMPA- and NMDA-receptors. Whether neurexin-Cbln2-GluD1 signaling complexes have additional functions in synapse formation besides regulating NMDA- and AMPA-receptors, and whether they perform similar roles at other synapses, remains unknown. Using constitutiveCbln2deletions, we here demonstrate that at CA1→subiculum synapses,Cbln2performs no additional developmental functions besides regulating AMPA- and NMDA-receptors. Moreover, we show that low-level expression of Cbln1, which is functionally redundant with Cbln2, does not compensate for a synapse-formation function of Cbln2 at CA1→subiculum synapses. In exploring the generality of these findings, we found that in prefrontal cortex, Nrxn1SS4+-Cbln2 signaling selectively regulates NMDA-receptors, whereas Nrxn3SS4+-Cbln2 signaling has no apparent role. In contrast, in the cerebellum Nrxn3SS4+-Cbln1 signaling regulates AMPA-receptors, whereas now Nrxn1SS4+-Cbln1 signaling has no manifest effect. Thus, Nrxn1SS4+- and Nrxn3SS4+-Cbln1/2 signaling complexes generally control NMDA- and AMPA-receptors in different synapses without regulating synapse formation, but these signaling complexes are differentially active in diverse neural circuits.
A nuclear receptor facilitates differentiation of human PSCs into more mature hepatocytes
Authors: Ma Haiting , de Zwaan Esmée , Guo Yang Eric , Cejas Paloma , Thiru Prathapan , van de Bunt Martijn , Jeppesen Jacob F. , Syamala Sudeepa , Dall’Agnese Alessandra , Abraham Brian J. , Fu Dongdong , Garrett-Engele Carrie , Lee Tony , Long Henry W , Griffith Linda G. , Young Richard A. , Jaenisch Rudolf 
Published: March 2022

SummaryThe capacity to generate functional hepatocytes from renewable human pluripotent stem cells (hPSCs) could address limited supplies of primary human hepatocytes. However, hepatocytes differentiated from hPSCs in vitro are functionally immature. To understand mechanisms regulating maturation of in vitro derived hepatocytes, we developed a 3D spheroid differentiation system and compared gene regulatory elements in uncultured human primary hepatocytes with those in hepatocytes that were differentiated in 2D or 3D conditions from human PSCs by RNA-seq, ATAC-seq, and H3K27Ac ChIP-seq. Three-dimensional differentiation improved enhancer activity and expression of transcription factor ONECUT1, but was insufficient to upregulate human-specific mature hepatocytes marker gene CYP3A4 or super-enhancer regulated transcription factor gene NFIC. Regulome comparisons showed reduced enrichment of thyroid receptor THRB motifs in accessible chromatin and in active enhancers without reduced transcription of THRB, suggesting the regulation at the level of THRB ligands in PSC-differentiated hepatocytes. Addition of thyroid hormone T3 to the PSC-differentiated hepatocytes increased CYP3A4 expression. T3 increased binding of THRB to the CYP3A4 proximal enhancer and restored the super-enhancer status and gene expression of NFIC and reduced expression of AFP. The resultant hPSC-hepatocytes showed gene expression, epigenetic status and super-enhancer landscape closer to primary hepatocytes and activated regulatory regions including non-coding SNPs associated with liver-related diseases. Transplanting the 3D PSC-hepatocytes into immunocompromised mice resulted in engraftment of human hepatocytes in the mouse liver parenchyma without disrupting normal liver histology at 6 months after transplantation. This work provides insights into the functions of nuclear receptor THRB and highlights the importance of the environmental factors-nuclear receptors axis in regulating maturation of human PSC-differentiated cell types.
Neural responses to biological motion distinguish autistic and schizotypal traits in the general population
Authors: Hudson Matthew , Santavirta Severi , Putkinen Vesa , Seppälä Kerttu , Sun Lihua , Karjalainen Tomi , Karlsson Henry K. , Hirvonen Jussi , Nummenmaa Lauri 
Published: March 2022

AbstractDifficulties in social interactions are common to both autism and schizophrenia, and contribute to correlated autistic and schizotypal traits in the neurotypical population. It remains unresolved whether this represents a shared etiology or a superficial phenotypic overlap. Both conditions are associated with atypical neural activity in response to the perception of social stimuli, and also decreased neural synchronization between individuals that may prohibit establishing shared experiences. This study sought to establish if neural activity and neural synchronization associated with biological motion perception are differentially associated with autistic and schizotypal traits in the neurotypical population. Participants watched an audiovisual montage of naturalistic social interactions whilst hemodynamic brain activity was measured with fMRI. A separate sample of participants provided a continuous measure of the extent of biological motion, which was used to predict hemodynamic activity. General Linear Model analysis revealed that biological motion perception was associated with neural activity across the action-observation network. However, inter-subject phase synchronization analysis revealed that neural activity synchronized between individuals in occipital and parietal areas, but de-synchronized in temporal and frontal regions. Autistic traits were associated with a decrease in neural activity (precuneus, middle cingulate gyrus) and schizotypal traits were associated with a decrease in neural synchronization (middle and inferior frontal gyri). Biological motion perception elicits convergent and divergent patterns of neural activity and neural synchronization, and are differentially associated with shared traits related with autism and schizophrenia in the general population, suggesting that they originate from different neural mechanisms.
A comparison of the genes and genesets identified by EWAS and GWAS of fourteen complex traits
Authors: Battram Thomas , Gaunt Tom R. , Relton Caroline L. , Timpson Nicholas J. , Hemani Gibran 
Published: March 2022

AbstractIdentifying the genes, properties of these genes and pathways to understand the underlying biology of complex traits responsible for differential health states in the population is a common goal of epigenome-wide and genome-wide association studies (EWAS and GWAS). GWAS identify genetic variants that effect the trait of interest or variants that are in linkage disequilibrium with the true causal variants. EWAS identify variation in DNA methylation, a complex molecular phenotype, associated with the trait of interest. Therefore, while GWAS in principle will only detect variants within or near causal genes, EWAS can also detect genes that confound the association between a trait and a DNA methylation site, or are reverse causal. Here we systematically compare association EWAS and GWAS results of 14 complex traits (N > 4500). A small fraction of detected genomic regions were shared by both EWAS and GWAS (0-9%). We evaluated if the genes or gene ontology terms flagged by GWAS and EWAS overlapped, and after a multiple testing correction, found substantial overlap for diastolic blood pressure (gene overlap P = 5.2×10−6, term overlap P = 0.001). We superimposed our empirical findings against simulated models of varying genetic and epigenetic architectures and observed that in a majority of cases EWAS and GWAS are likely capturing distinct genesets, implying that genes identified by EWAS are not generally causally upstream of the trait. Overall our results indicate that EWAS and GWAS are capturing different aspects of the biology of complex traits.
Multilevel Correlates of Abdominal Obesity in Adolescents and Youth Living with HIV in peri-urban Cape Town, South Africa.
Authors: Kamkuemah Monika , Gausi Blessings , Oni Tolu , Middelkoop Keren 
Published: March 2022

Background

Chronic non-communicable disease comorbidities are a major problem faced by people living with HIV (PLHIV). Obesity is an important factor contributing to such comorbidities and PLHIV face an elevated risk of obesity. However, there is data paucity on the intersection of obesity and HIV in adolescents and youth living with HIV (AYLHIV) in sub-Saharan Africa. We therefore aimed to investigate the prevalence of abdominal obesity and associated multilevel factors in AYLHIV in peri-urban Cape Town, South Africa.Methods

We conducted a cross-sectional study enrolling AYLHIV aged 15 – 24 years attending primary healthcare facilities in peri-urban Cape Town in 2019. All measures, except for physical examination measures, were obtained via self-report using a self-administered electronic form. Our outcome of interest was abdominal obesity (waist-to-height ratio >= 0.5). We collected individual-level data and data on community, built and food environment factors. Data was summarized using descriptive statistics, stratified by sex. Multilevel logistic regression was conducted to investigate factors associated with abdominal obesity, adjusted for sex and age.Findings

A total of 87 participants were interviewed, 76% were female and the median age was 20.7 (IQR 18.9-23.0) years. More than two fifths had abdominal obesity (41%; 95% CI: 31.0- 51.7%), compared to published rates for young people in the general population (13.7- 22.1%). In multilevel models, skipping breakfast (aOR= 5.42; 95% CI: 1.32 – 22.25) was associated with higher odds of abdominal obesity, while daily wholegrain consumption (aOR= 0.20; 95% CI: 0.05 – 0.71) and weekly physical activity (aOR = 0.24; 95% CI: 0.06 – 0.92) were associated with lower odds of abdominal obesity. Higher anticipated stigma was associated with reduced odds of obesity (aOR= 0.58; 95% CI: 0.33 – 1.00). Land-use mix diversity (aOR= 0.52; 95% CI: 0.27 – 0.97), access to recreational places (aOR= 0.37; 95% CI: 0.18 – 0.74), higher perceived pedestrian and traffic safety (aOR= 0.20; 95% CI: 0.05 – 0.80) and having a non-fast-food restaurant within walking distance (aOR= 0.30; 95% CI: 0.10 – 0.93) were associated with reduced odds of abdominal obesity. The main limitations of the study were low statistical power and possible reporting bias from self-report measures.Conclusions

Our findings demonstrate a high prevalence of abdominal obesity and highlight multilevel correlates of obesity in AYLHIV in South Africa. An intersectoral approach to obesity prevention, intervening at multiple levels is necessary to intervene at this critical life stage.
Estimating time-dependent infectious contact: a multi-strain epidemiological model of SARS-CoV-2 on the island of Ireland
Authors: Kamiya Tsukushi , Alvarez-Iglesias Alberto , Ferguson John , Murphy Shane , Sofonea Mircea T. , Fitz-Simon Nicola 
Published: March 2022

AbstractMathematical modelling plays a key role in understanding and predicting the epidemiological dynamics of infectious diseases. We construct a flexible discrete-time model that incorporates multiple viral strains with different transmissibilities to estimate the changing infectious contact that generates new infections. Using a Bayesian approach, we fit the model to longitudinal data on hospitalisation with COVID-19 from the Republic of Ireland and Northern Ireland during the first year of the pandemic. We describe the estimated change in infectious contact in the context of governmentmandated non-pharmaceutical interventions in the two jurisdictions on the island of Ireland. We take advantage of the fitted model to conduct counterfactual analyses exploring the impact of lockdown timing and introducing a novel, more transmissible variant. We found substantial differences in infectious contact between the two jurisdictions during periods of varied restriction easing and December holidays. Our counterfactual analyses reveal that implementing lockdowns earlier would have decreased subsequent hospitalisation substantially in most, but not all cases, and that an introduction of a more transmissible variant - without necessarily being more severe - can cause a large impact on the health care burden.
Understanding the role of mask-wearing during COVID-19 on the island of Ireland
Authors: Fitz-Simon Nicola , Ferguson John , Alvarez-Iglesias Alberto , Sofonea Mircea T. , Kamiya Tsukushi 
Published: March 2022

AbstractBackgroundNon-pharmaceutical interventions (NPI) play a key role in managing epidemics, yet it is challenging to evaluate their impacts on disease spread and outcomes.MethodsTo estimate the effect of a mask-wearing intervention to mitigate the spread of SARS-CoV-2 on the island of Ireland, we focused on the potential for interindividual infectious contact over time as the outcome. This is difficult to measure directly; in a companion paper we estimated it using a multi-strain epidemiological model. We used data on mask-wearing and mobility in both Northern Ireland (NI) and the Republic of Ireland (ROI) to predict independently the estimated infectious contact over time. We made counterfactual predictions of infectious contact rates and hospitalisations under a hypothetical intervention where 90% of the population were wearing masks during early 2020, when in reality few people were wearing masks in public; this was mandated in both jurisdictions on 10th August 2020.ResultsThere were 1601 hospitalisations with COVID-19 in NI between 12th March and 10th August 2020, and 1521 in ROI between 3rd April and 10th August 2020. Under the counterfactual mask-wearing scenario, we estimated 512 (95% CI 400, 730) hospitalisations in NI, and 344 (95% CI 266, 526) in ROI, during the same periods.ConclusionsWe have estimated a large effect of population mask-wearing on COVID-19 hospitalisations. This could be partly due to other factors that were also changing over time.
Acute manipulation and real-time visualization of membrane trafficking and exocytosis inDrosophila
Authors: Glashauser Jade , Camelo Carolina , Hollmann Manuel , Backer Wilko , Jacobs Thea , Sanchez Jone Isasti , Schleutker Raphael , Förster Dominique , Berns Nicola , Riechmann Veit , Luschnig Stefan 
Published: March 2022

AbstractIntracellular trafficking of secretory proteins plays key roles in animal development and physiology, but tools for investigating dynamics of membrane trafficking have been limited to cultured cells. Here we present a system that enables acute manipulation and real-time visualization of membrane trafficking through reversible retention of proteins in the endoplasmic reticulum (ER) in living multicellular organisms. By adapting the “retention using selective hooks” (RUSH) approach toDrosophila, we show that trafficking of GPI-linked, secreted, and transmembrane proteins can be controlled with high temporal precision in intact animals and cultured organs. We demonstrate the potential of this approach by analyzing the kinetics of ER exit and apical secretion and the spatiotemporal dynamics of tricellular junction assembly in epithelia of living embryos. Furthermore, we show that controllable ER-retention enables tissue-specific depletion of secretory protein function. The system is broadly applicable to visualize and manipulate membrane trafficking in diverse cell typesin vivo.
NAb-seq: an accurate, rapid and cost-effective method for antibody long-read sequencing in hybridoma cell lines and single B cells
Authors: Subas Satish Hema Preethi , Zeglinski Kathleen , Uren Rachel T. , Nutt Stephen L. , Ritchie Matthew E. , Gouil Quentin , Kluck Ruth M. 
Published: March 2022

ABSTRACTDespite their common use in research, monoclonal antibodies are currently not systematically sequenced. This can lead to issues with reproducibility and the occasional loss of antibodies with loss of cell lines. Hybridoma cell lines have been the primary means of generating monoclonal antibodies from immunized animals including mice, rats, rabbits and alpacas. Excluding therapeutic antibodies, few hybridoma-derived antibody sequences are known. Sanger sequencing has been “the gold standard” for antibody gene sequencing but relies on the availability of species-specific degenerate primer sets for amplification of light and heavy antibody genes, in addition to lengthy and expensive cDNA preparation. Here we leveraged recent improvements in long-read Oxford Nanopore Technologies (ONT) sequencing to develop NAb-seq: a three-day, species-independent, and cost-effective workflow to characterize paired full-length immunoglobulin light and heavy chain genes from hybridoma cell lines. When compared to Sanger sequencing of two hybridoma cell lines, long-read ONT sequencing was highly accurate, reliable, and amenable to high throughput. We further show that the method is applicable to single cells, allowing efficient antibody discovery in rare populations such as memory B cells. In summary, NAb-seq promises to accelerate identification and validation of hybridoma antibodies as well as antibodies from single B cells used in research, diagnostics and therapeutics.
Human neutrophils direct epithelial cell extrusion to enhance intestinal epithelial host defense duringSalmonellainfection
Authors: Lawrence Anna-Lisa E. , Berger Ryan P. , Hill David R. , Huang Sha , Yadagiri Veda K. , Bons Brooke , Fields Courtney , Sule Gautam J. , Knight Jason S. , Wobus Christiane E. , Spence Jason R. , Young Vincent B. , O’Riordan Mary X. , Abuaita Basel H. 
Published: March 2022

AbstractInfection of the human gut bySalmonella entericaTyphimurium (STM) results in a localized inflammatory disease that is not mimicked in murine infections. To determine mechanisms by which neutrophils, as early responders to bacterial challenge, direct inflammatory programming of human intestinal epithelium, we established a multi-component human intestinal organoid (HIO) model of STM infection. HIOs were micro-injected with STM and then seeded with primary human polymorphonuclear leukocytes (PMN-HIOs), specifically neutrophils and analyzed for bacterial growth and host cell survival. Surprisingly, PMNs did not affect luminal colonization ofSalmonella,but their presence reduced intraepithelial bacterial burden. Adding PMNs to infected HIOs resulted in substantial accumulation of shed intestinal epithelial cells that could be blocked by Caspase-1 or Caspase-3 inhibition. Cleaved Caspase-3 was present in epithelial cells, but expression of the inflammasome adaptor, ASC, was only detected in PMNs. Caspase inhibition also increased bacterial burden in the epithelium of the PMN-HIO, suggesting PMNs enhance activation of cell death pathways in human intestinal epithelial cells as a protective response to infection. These data support a critical function for neutrophils beyond their antimicrobial role whereby they amplify cell death and extrusion of epithelial cells from theSalmonella-infected intestinal monolayer.Significance statementNeutrophils are early responders toSalmonellaintestinal infection, but how they influence infection progression and outcome is unknown. Here we use a co-culture model of human intestinal organoids and human primary neutrophils to study the contribution of human neutrophils toSalmonellainfection of the intestinal epithelium. We found that neutrophils markedly enhanced epithelial defenses, including enhancing cell extrusion to reduce intraepithelial burden ofSalmonellaand association with the epithelium, rather than directly killingSalmonellain the HIO lumen. These findings reveal a novel role for neutrophils in the gut beyond killing invading pathogens and illuminate how neutrophils can reprogram cells in the gut environment to enhance antimicrobial defenses.