bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pre-existing autoimmunity is associated with increased severity of COVID-19: A retrospective cohort study using data from the National COVID Cohort Collaborative (N3C)
Authors: Yadaw Arjun S. , Afzali Behdad , Hotaling Nathan , Sidky Hythem , Pfaff Emily R , Sahner David K. , Mathé Ewy A. 
Published: February 2023

AbstractImportanceIdentifying individuals with a higher risk of developing severe COVID-19 outcomes will inform targeted or more intensive clinical monitoring and management.ObjectiveTo examine, using data from the National COVID Cohort Collaborative (N3C), whether patients with pre-existing autoimmune disease (AID) diagnosis and/or immunosuppressant (IS) exposure are at a higher risk of developing severe COVID-19 outcomes.Design, setting and participantsA retrospective cohort of 2,453,799 individuals diagnosed with COVID-19 between January 1st, 2020, and June 30th, 2022, was created from the N3C data enclave, which comprises data of 15,231,849 patients from 75 USA data partners. Patients were stratified as those with/without a pre-existing diagnosis of AID and/or those with/without exposure to IS prior to COVID-19.Main outcomes and measuresTwo outcomes of COVID-19 severity, derived from the World Health Organization severity score, were defined, namely life-threatening disease and hospitalization. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using logistic regression models with and without adjustment for demographics (age, BMI, gender, race, ethnicity, smoking status), and comorbidities (cardiovascular disease, dementia, pulmonary disease, liver disease, type 2 diabetes mellitus, kidney disease, cancer, and HIV infection).ResultsIn total, 2,453,799 (16.11% of the N3C cohort) adults (age> 18 years) were diagnosed with COVID-19, of which 191,520 (7.81%) had a prior AID diagnosis, and 278,095 (11.33%) had a prior IS exposure. Logistic regression models adjusted for demographic factors and comorbidities demonstrated that individuals with a prior AID (OR = 1.13, 95% CI 1.09 - 1.17;p=2.43E-13), prior exposure to IS (OR= 1.27, 95% CI 1.24 - 1.30;p=3.66E-74), or both (OR= 1.35, 95% CI 1.29 - 1.40;p=7.50E-49) were more likely to have a life-threatening COVID-19 disease. These results were confirmed after adjusting for exposure to antivirals and vaccination in a cohort subset with COVID-19 diagnosis dates after December 2021 (AID OR = 1.18, 95% CI 1.02 - 1.36;p=2.46E-02; IS OR= 1.60, 95% CI 1.41 - 1.80;p=5.11E-14; AID+IS OR= 1.93, 95% CI 1.62 - 2.30;p=1.68E-13). These results were consistent when evaluating hospitalization as the outcome and also when stratifying by race and sex. Finally, a sensitivity analysis evaluating specific IS revealed that TNF inhibitors were protective against life-threatening disease (OR = 0.80, 95% CI 0.66-0.96;p=1.66E-2) and hospitalization (OR = 0.80, 95% CI 0.73 - 0.89;p=1.06E-05).Conclusions and RelevancePatients with pre-existing AID, exposure to IS, or both are more likely to have a life-threatening disease or hospitalization. These patients may thus require tailored monitoring and preventative measures to minimize negative consequences of COVID-19.
Membranous Nephropathy in the UK Biobank
Authors: Hamilton Patrick , Blaikie Kieran , Roberts Stephen A. , Gittins Matthew , Downie Mallory L. , Gupta Sanjana , Voinescu Catalin , Kanigicherla Durga , Stanescu Horia , Kleta Robert , Brenchley Paul 
Published: February 2023

AbstractBackgroundDespite MN being one of the most common causes of nephrotic syndrome worldwide, its biological and environmental determinants are poorly understood in large-part due to it being a rare disease. Making use of the UK Biobank, a unique resource holding a clinical dataset and stored DNA, serum and urine for ∼500,000 participants, this study aims to address this gap in understanding.MethodsThe primary outcome was putative MN as defined by ICD-10 codes occurring in the UK Biobank. Univariate relative risk regression modelling was used to assess the associations between the incidence of MN and related phenotypes with sociodemographic, environmental exposures, and previously described increased-risk SNPs.Results502,507 patients were included in the study of whom 100 were found to have a putative diagnosis of MN; 36 at baseline and 64 during the follow-up. Prevalence at baseline and last follow-up were 72 and 199 cases/million respectively. At baseline, as expected, the majority of those previously diagnosed with MN had proteinuria, and there was already evidence of proteinuria in patients diagnosed within the first 5 years of follow-up. The highest incidence rate for MN in patients was seen in those homozygous for the high-risk alleles (9.9/100,000 person-years).ConclusionIt is feasible to putatively identify patients with MN in the UK Biobank and cases are still accumulating. This study shows the chronicity of disease with proteinuria present years before diagnosis. Genetics plays an important role in disease pathogenesis, with the at-risk group providing a potential population for recall.
Acceptability of Community Midwives in rural communities of Pakistan: A qualitative exploratory study
Authors: Khowaja Bakhtawar Muhammad Hanif , Feroz Anam Shahil , Rani Musarrat , Khowaja Quratulain , Khowaja Mehmooda Afroz Ali , Abrejo Farina , Saleem Sarah 
Published: February 2023

AbstractIntroductionThe Government of Pakistan initiated the Community Midwifery program in 2006 to provide skilled birth attendance to women living in rural areas. However, the acceptability of midwives and what impact these community midwives have made on overall maternal morbidity and mortality remains an unanswered question. We explored the perceptions of health officials, midwifery students, midwives and community women about the factors that influence the acceptability of community midwives’ services in the rural district Thatta, Pakistan.Materials and MethodsA qualitative exploratory study was conducted in the rural district Thatta of Pakistan. In-depth interviews were conducted with health officials, midwifery students who were currently enrolled in the midwifery program of the district; community midwives providing services in district Thatta, and trained community midwives who are not practicing. Interviews were also conducted with community women. Data were analyzed using the qualitative thematic analysis approach and the deductive analysis method.ResultsTwo overarching themes were identified: (I) community acceptance and support; and (II) dynamics between CMWs and other health care providers. The major hindering factors to CMWs acceptance included their young age challenging social acceptability, patronizing behavior of doctors, high acceptance of traditional birth attendants working in rural areas, and the community’s reluctance towards referral services. The facilitating factors included clients’ privacy maintained at birth stations and the affordability of community midwives’ services.ConclusionThere are deep-rooted challenges related to the acceptability of midwifery services at the community level and with other competing healthcare providers which need advocacy to support and accept their services at the community level and by other professionals.
Cultivation of the polyextremophileCyanidioschyzon merolae10D during summer conditions on the coast of the Red Sea and its adaptation to hypersaline sea water
Authors: Villegas Melany V. , González-Portela Ricardo E. , de Freitas Bárbara Bastos , Al Jahdali Abdulaziz , Romero-Villegas Gabriel I. , Malibari Raghdah , Kapoore Rahul Vijay , Fuentes-Grünewald Claudio , Lauersen Kyle J. 
Published: February 2023

AbstractThe west coast of Saudi Arabia borders the Red Sea, which maintains high average temperatures and increased salinity compared to other seas or oceans. Summer conditions in the Arabian Peninsula may exceed the temperature tolerance of most currently cultivated microalgae. The Cyanidiales are polyextremophilic red algae whose native habitats are at the edges of acidic hot springs.Cyanidioschyzon merolae10D has recently emerged as an interesting model organism capable of high-cell density cultivation on pure CO2with optimal growth at 42 °C and low pH between 0.5-2.C. merolaebiomass has an interesting macromolecular composition, is protein rich, and contains valuable bio-products like heat-stable phycocyanin, carotenoids, β-glucan, and starch. Here, photobioreactors were used to modelC. merolae10D growth performance in simulated environmental conditions of the mid-Red Sea coast across four seasons, it was then grown at various scales outdoors in Thuwal, Saudi Arabia during the Summer of 2022. We show thatC. merolae10D is amenable to cultivation with industrial-grade nutrient and CO2inputs outdoors in this location and that its biomass is relatively constant in biochemical composition across culture conditions. We also show the adaptation ofC. merolae10D to high salinity levels of those found in Red Sea waters and conducted further modeled cultivations in nutrient enriched local sea water. It was determined that salt-water adaptedC. merolae10D could be cultivated with reduced nutrient inputs in local conditions. The results presented here indicate this may be a promising alternative species for algal bioprocesses in outdoor conditions in extreme desert summer environments.
Dual MAPK Inhibition Triggers Pro-inflammatory Signals and Sensitizes BRAFV600EGlioma to T Cell-Mediated Checkpoint Therapy
Authors: Xing Yao Lulu , Grossauer Stefan , Park Jong-Whi , Nasajpour Emon , Bui Brandon , Morales Daniella , Panovska Dena , Nirschl Jeffrey J. , Feng Zhi-Ping , Wei Ruolun , Koeck Katharina , Thomason Wes , Xiu Joanna , Harter Patrick N. , Filipski Katharina , Mahaney Kelly , Ji Xuhuai , Mulcahy Levy Jean M. , Grant Gerald A. , Prolo Laura M. , Walsh Kyle M. , Lim Michael , Hambardzumyan Dolores , Petritsch Claudia K. 
Published: February 2023

ABSTRACTBRAFV600Epediatric low-grade gliomas frequently transform into high-grade gliomas (HGG) and poorly respond to chemotherapy, resulting in high mortality. Although combined BRAF and MEK inhibition (BRAFi+MEKi) outperforms chemotherapy, ∼70% of BRAFV600EHGG patients are therapy resistant and undergo unbridled tumor progression. BRAFV600Eglioma have an immune-rich microenvironment suggesting that they could be responsive to immunotherapy but effects of BRAFi+MEKi on anti-tumor immunity are unclear. Using patient tumor tissue before and after BRAFi+MEKi, two novel syngeneic murine models of BRAFV600EHGG, and patient-derived cell lines, we examined the effects of clinically relevant BRAFi+MEKi with dabrafenib and trametinib on tumor growth, cell states, and tumor-infiltrating T cells. We find that BRAFi+MEKi treatment: i) upregulated programmed cell death protein-1 (PD-1) signaling genes and PD-1 ligand (PD-L1) protein expression in murine BRAFV600EHGG by stimulating IFNγ and IL-27, ii) attenuated T cell activity by IL-23, IL-27 and IL-32 production, which can promote the expansion of regulatory T cells, and iii) induced glial differentiation linked to a therapy-resistant PD-L1+ compartment through Galectin-3 secretion by tumor cells. Murine BRAFV600EHGG shrinkage by BRAFi+MEKi is associated with the upregulation of interferon-gamma response genes, MHC class I/II expression, and antigen presentation and processing programs, indicative of increased anti-tumor immunity. Combined BRAFi+MEKi with therapeutic antibodies inhibiting the PD-1 and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) immune checkpoints re-activate T cells and provide a survival benefit over single therapy in a T cell-dependent manner. The quadruple treatment overcame BRAFi+MEKi resistance by invigorating T cell-mediated anti-tumor immunity in murine BRAFV600EHGG. PD-L1 expression was elevated in human BRAF-mutant versus BRAF-wildtype glioblastoma clinical specimen, complementing experimental findings and suggesting translational relevance for patient care.
Leveraging type 1 diabetes human genetic and genomic data in the T1D Knowledge Portal
Authors: Kudtarkar Parul , Costanzo Maria C. , Sun Ying , Jang Dongkeun , Koesterer Ryan , Mychaleckyj Josyf C , Nayak Uma , Onengut-Gumuscu Suna , Rich Stephen S , Flannick Jason A , Gaulton Kyle J , Burtt Noël P 
Published: February 2023

AbstractTranslating genetic discoveries for type 1 diabetes (T1D) into mechanistic insight can reveal novel biology and therapeutic targets but remains a major challenge. We developed the T1D Knowledge Portal (T1DKP), a disease-specific resource of genetic and functional annotation data that enables users to develop hypotheses for T1D-based research and target discovery. The T1DKP can be used to query genes and genomic regions for genetic associations, identify epigenomic features, access results of bioinformatic analyses, and obtain expert-curated resources. The T1DKP is available athttp://t1d.hugeamp.org.
Comparative multi-omics analyses of cardiac mitochondrial stress in three mouse models of frataxin deficiency
Authors: Sayles Nicole M. , Napierala Jill S. , Anrather Josef , Diedhiou Nadège , Li Jixue , Napierala Marek , Puccio Hélène , Manfredi Giovanni 
Published: February 2023

AbstractCardiomyopathy is often fatal in Friedreich Ataxia (FA). However, the FA heart maintains adequate function until disease end stage, suggesting that it can initially adapt to the loss of frataxin (FXN). Conditional knockout mouse models with noFxnexpression show transcriptional and metabolic profiles of cardiomyopathy and mitochondrial integrated stress response (ISRmt). However, ISRmthas not been investigated in models with disease-relevant, partial decrease of FXN. We characterized the heart transcriptomes and metabolomes of three mouse models of partial FXN loss, YG8-800, KIKO-700, and FxnG127V. Few metabolites were significantly changed in YG8-800 mice and did not provide a signature of cardiomyopathy or ISRmt. Instead, several metabolites were altered in FxnG127Vand KIKO-700 hearts. Transcriptional changes were found in all models, but differentially expressed genes consistent with cardiomyopathy and ISRmtwere only identified in FxnG127Vhearts. However, these changes were surprisingly mild even at an advanced age (18-months), despite a severe decrease in FXN levels to 1% of WT. These findings indicate that the mouse heart has extremely low reliance on FXN, highlighting the difficulty in modeling genetically relevant FA cardiomyopathy.Summary statementThe mitochondrial integrated stress response in the heart of a Friedreich Ataxia mouse model is surprisingly mild, despite a severe decrease in frataxin levels below 1% of normal.
Root cap cell corpse clearance limits microbial colonization inArabidopsis thaliana
Authors: Charura Nyasha M. , Llamas Ernesto , De Quattro Concetta , Vilchez David , Nowack Moritz K. , Zuccaro Alga 
Published: February 2023

AbstractProgrammed cell death occurring during plant development (dPCD) is a fundamental process integral for plant growth and reproduction. Here, we investigate the connection between developmentally controlled PCD and fungal accommodation inArabidopsis thalianaroots, focusing on the root cap-specific transcription factor ANAC033/SOMBRERO (SMB) and the senescence-associated nuclease BFN1. Mutations of both dPCD regulators increase colonization by the beneficial fungusSerendipita indica, primarily in the differentiation zone.smb-3mutants additionally exhibit hypercolonization around the meristematic zone and a delay ofS. indica-induced root-growth promotion. This demonstrates that root cap dPCD and rapid post-mortem clearance of cellular corpses represent a physical defense mechanism restricting microbial invasion of the root. Additionally, reporter lines and transcriptional analysis revealed thatBFN1expression is downregulated duringS. indicacolonization in mature root epidermal cells, suggesting a transcriptional control mechanism that facilitates the accommodation of beneficial microbes in the roots.Key findings in bullet pointsThe process of programmed cell death in root development (dPCD) influences the extent and outcomes of fungal symbiosisFungal colonization of the root tip and differentiation zone is restricted by SMB-mediated clearance of dead cells, which preserves the meristem and regulates symbiosisExpression of plant nucleaseBFN1, which is associated with senescence, is modulated to facilitate root accommodation of beneficial microbes
Comprehensive and Comparative Transcriptional Profiling of the Cell Wall Stress Response inBacillus subtilis
Authors: Zhang Qian , Cornilleau Charlene , Müller Raphael R. , Meier Doreen , Flores Pierre , Guérin Cyprien , Wolf Diana , Fromion Vincent , Carballido-Lopez Rut , Mascher Thorsten 
Published: February 2023

AbstractThe bacterial cell wall (CW) is an essential protective barrier and the frontline of cellular interactions with the environment and also a target for numerous antimicrobial agents. Accordingly, its integrity and homeostasis are closely monitored and rapid adaptive responses by transcriptional reprogramming induce appropriate counter-measures against perturbations. Here, we report a comprehensive and comparative transcriptional profiling of the primary cell envelope stress responses (CESR), based on combining RNAseq and high-resolution tiling array studies of the Gram-positive model bacteriumBacillus subtilisexposed to a range of antimicrobial compounds that interfere with cytoplasmic, membrane-coupled or extracellular steps of peptidoglycan (PG) biosynthesis. It revealed the complexity of the CESR ofB. subtilisand unraveled the contribution of extracytoplasmic function sigma factors (ECFs) and two-component signal transduction systems (TCSs) to protect the cell envelope. While membrane-anchored steps are tightly controlled, early cytoplasmic and late extracellular steps of PG biosynthesis are hardly monitored at all. The ECF σ factors σWand particularly σMprovide a general CESR, while σVis almost exclusively induced by lysozyme, against which it provides specific resistance. Remarkably, σXwas slightly repressed by most antibiotics, pointing towards a role in envelope homeostasis rather than CESR. It shares this role with the WalRK TCS, which balances CW growth with controlled autolysis. In contrast, all remaining TCSs are envelope stress-inducible systems. LiaRS is induced by a wide range of PG synthesis inhibitors, while the three paralogous systems BceAB, PsdRS and ApeRS are more compound-specific detoxification modules. Induction of the CssRS TCS by all antibiotics interfering with membrane-anchored steps of PG biosynthesis points towards a physiological link between CESR and secretion stress. Based on the expression signatures, a suite of CESR-specificB. subtiliswhole cell biosensors were developed and carefully evaluated. This is the first comprehensive transcriptomic study focusing exclusively on the primary effects of envelope perturbances that shall provide a reference point for future studies on Gram-positive CESR.
Lost inHELLS: disentangling the mystery ofSALNRexistence in senescence cellular models
Authors: Consiglio Arianna , Venturin Marco , Briguglio Sabrina , Rossi Clara , Grillo Giorgio , Bellosta Stefano , Cattaneo Maria Grazia , Licciulli Flavio , Battaglia Cristina 
Published: February 2023

AbstractLong non-coding RNAs (lncRNAs) have emerged as key regulators of cellular senescence by transcriptionally and post-transcriptionally modulating the expression of many important genes involved in senescence-associated pathways and processes. Among the different lncRNAs associated to senescence,Senescence Associated Long Non-coding RNA(SALNR) was found to be down-regulated in different cellular models of senescence. Since its release in 2015,SALNRhas not been annotated in any database or public repository, and no other experimental data have been published. TheSALNRsequence is located on the long arm of chromosome 10, at band 10q23.33, and it overlaps the 3’ end of theHELLSgene. This investigation helped to unravel the mystery of the existence ofSALNRby analyzing publicly available short- and long-read RNA sequencing data sets and RT-PCR analysis in human tissues and cell lines. Additionally, the expression ofHELLShas been studied in cellular models of replicative senescence, bothin silicoandin vitro. Our findings, while strongly questioning the actual existence ofSALNRas an independent transcript, support the expression of a predictedHELLSisoform entirely covering theSALNRgenomic region. Furthermore, we observed a strong down-regulation ofHELLSin senescent cells versus proliferating cells, supporting its role in the senescence and aging process.Graphical abstract
5-HT4 receptor agonists treatment reduces tau pathology and behavioral deficit in the PS19 mouse model of tauopathy
Authors: Jiang Shan , Sydney Eric J. , Runyan Avery M. , Serpe Rossana , Figueroa Helen Y. , Yang Mu , Myeku Natura 
Published: February 2023

AbstractAccumulation of tau in synapses in Alzheimer’s disease (AD) has been shown to cause synaptic damage, synaptic loss, and the spread of pathology through synaptically connected neurons. Synaptic loss correlates with a decline in cognition, providing an opportunity to investigate strategies to target synaptic tau to rescue or prevent cognitive decline. One of the promising synaptic targets is the 5-HT4 receptor present post-synaptically in the brain areas involved in the memory processes. 5-HT4R activation exerts synaptogenic and pro-cognitive effects involving synapse-to-nucleus signaling essential for synaptic plasticity. However, it is not known whether 5-HT4R activation has a therapeutic effect on tauopathy. The goal of this study was to investigate the impact of stimulation of 5-HT4R in tauopathy mice. Our results show that 5-HT4R agonism led to reduced tauopathy and synaptic tau and correlated with increased proteasome activity and improved cognitive functioning in PS19 mice. Thus, stimulation of 5-HT4R offers a promising therapy to rescue synapses from toxic synaptic tau.
Genetics of continuous colour variation in a pair of sympatric sulphur butterflies
Authors: Hanly Joseph J. , Francescutti Caroline M. , Loh Ling S. , Corning Olaf B. W. H. , Long Derek J. , Nakatani Marshall A , Porter Adam H. , Martin Arnaud 
Published: February 2023

SummaryContinuous colour polymorphisms can serve as a tractable model for the genetic and developmental architecture of traits, but identification of the causative genetic loci is complex due to the number of individuals needed, and the challenges of scoring continuously varying traits. Here we investigated continuous colour variation inColias eurythemeandC. philodice, two sister species of sulphur butterflies that hybridise in sympatry. Using Quantitative Trait Locus (QTL) analysis of 483 individuals from interspecific crosses and an high-throughput method of colour quantification, we found that two interacting large effect loci explain around 70% of the heritable variation in orange-to-yellow chromaticity. Knockouts ofred Malphighian tubules(red), a candidate gene at the primary QTL likely involved in endosomal maturation, resulted in depigmented wing scales showing disorganised pterin granules. The Z sex chromosome contains a large secondary colour QTL that includes the transcription factorbric-a-brac(bab), which we show can act as a modulator of orange pigmentation in addition to its previously-described role in specifying UV-iridescence. We also describe the QTL architecture of other continuously varying traits, and that wing size maps to the Z chromosome, supporting a Large-X effect model where the genetic control of species-defining traits is enriched on sex chromosomes. This study sheds light on the genetic architecture of a continuously varying trait, and illustrates the power of using automated measurement to score phenotypes that are not always conspicuous to the human eye.ForewordThe colour phenotypes in this article involve nuanced gradations of yellow and orange that may be difficult to perceive for people who are colour vision deficient. Hue-shifted versions of all main figures are accessible online for dichromat readers (BioRxiv preprint: Supplementary Material).