Biology subjects

Barnett, C.

Publications and source records attributed to Barnett, C..

5 recordsLinked to original sources

bioRxiv2026

RNA polymerase loss by nuclear rupture drives LMNA cardiomyopathy

Localized rupture of the nuclear envelope has recently been reported in various pathologies, including cancer 1,2, neurodegenerative disease 3-5, myocardial infarction 6, as well as dilated cardiomyopathy caused by Lamin A/C gene mutations (LMNA-DCM) 7. Whether and how nuclear rupture contributes to disease remains unknown. Here, we report that nuclear rupture causes global transcriptional deficiency in a mouse model of LMNA-DCM. We observed that ruptured nuclei lost RNA polymerase II, leading to downregulation of numerous genes essential for cardiomyocyte structure and function. We identified endogenous resealing of nuclear rupture as a cardioprotective mechanism in LMNA-DCM mouse hearts. Resealing involved the ESCRT-III membrane remodeling complex recruited to nuclear rupture sites. Resealed nuclei restored transcription while inhibiting ESCRT-III activity accelerated cardiomyopathy. However, resealed nuclei were short-lived: they re-ruptured at twice the rate of resealing. A kinetic model predicted progressive accumulation of ruptured nuclei despite ongoing resealing. Consistently, a human LMNA-DCM heart contained numerous ruptured nuclei at disease presentation. These findings linked nuclear rupture to organ deterioration through global transcriptional deficiency and suggested rupture resealing as a critical modifier of nuclear rupture-associated conditions.

molecular biology↗

bioRxiv2025

Lower Airway Dysbiosis in NTM+ Bronchiectasis is Associated with NET-Predominant Severe Phenotypes

RationaleThe discoveries of neutrophilic inflammation and Pseudomonas-dominant pulmonary dysbiosis have helped pave the way for host-directed therapy in bronchiectasis. Substantial knowledge gaps remain about the interplay between neutrophilic signatures and microbes in non-tuberculous mycobacterial lung disease (NTM-LD), a phenotypically diverse lung infection that is increasingly prevalent in the United States and other parts of the world. ObjectivesEvaluate the lower airway microbiota and neutrophilic traits in NTM- and NTM+ bronchiectasis. Methods16S rRNA gene sequencing, cell counts and neutrophil extracellular trap (NET) immunoassays were performed on bronchoscopic lower airway samples in 200 bronchiectasis subjects (108 NTM-, 92 NTM+). A preclinical model of oral commensal micro-aspiration and NTM infection was used to profile the murine lower airways with flow cytometry and a NET assay. Measurements and Main ResultsLower airways of NTM+ bronchiectasis patients were enriched with Mycobacterium and oral commensals (e.g., Veillonella, Prevotella). NET levels were higher in NTM+ BAL. Mycobacterium and oral commensals co-occurred with NET and neutrophils in network studies. Distinct oral commensal taxa associated with severe disease phenotypes such as cavitary disease and exacerbators. In a murine micro-aspiration model, the combination of oral commensals and Mycobacterium led to a sustained pro-inflammatory immune response marked by an increase in Th17, {gamma}8T cells, PD-1+ T lymphocytes as well as higher NET levels. ConclusionsOur analyses showed that distinct microbiome features beyond the primary pathogen can contribute to neutrophilic inflammation and severe disease phenotypes in bronchiectasis/ NTM-LD.

immunology↗

bioRxiv2021

ACE2-containing defensosomes serve as decoys to inhibit SARS-CoV-2 infection

Extracellular vesicles of endosomal origin, exosomes, mediate intercellular communication by transporting substrates with a variety of functions related to tissue homeostasis and disease. Their diagnostic and therapeutic potential has been recognized for diseases such as cancer in which signaling defects are prominent. However, it is unclear to what extent exosomes and their cargo inform the progression of infectious diseases. We recently defined a subset of exosomes termed defensosomes that are mobilized during bacterial infection in a manner dependent on autophagy proteins. Through incorporating protein receptors on their surface, defensosomes mediated host defense by binding and inhibiting pore-forming toxins secreted by bacterial pathogens. Given this capacity to serve as decoys that interfere with surface protein interactions, we investigated the role of defensosomes during infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of COVID-19. Consistent with a protective function, exosomes containing high levels of the viral receptor ACE2 in bronchioalveolar lavage fluid from critically ill COVID-19 patients was associated with reduced ICU and hospitalization times. We found ACE2+ exosomes were induced by SARS-CoV-2 infection and activation of viral sensors in cell culture, which required the autophagy protein ATG16L1, defining these as defensosomes. We further demonstrate that ACE2+ defensosomes directly bind and block viral entry. These findings suggest that defensosomes may contribute to the antiviral response against SARS-CoV-2 and expand our knowledge on the regulation and effects of extracellular vesicles during infection.

immunology↗

bioRxiv2020

Impacts of radiation on the bacterial and fungal microbiome of small mammals in the Chernobyl Exclusion Zone

Environmental impacts of the 1986 Chernobyl Nuclear Power Plant accident are much debated, but the effects of radiation on host microbiomes has received little attention to date. We present the first analysis of small mammal gut microbiome from the Chernobyl Exclusion Zone in relation to total absorbed dose rate and including caecum as well as faeces sample. The associations between microbiome communities and radiation exposure varied between host species. Associations between microbiome and radiation was different for analyses based on ambient versus total weighted absorbed dose rates. We found considerable variation between patterns for faecal and gut samples of bank voles, suggesting faecal samples are not an accurate indicator of gut composition. For bank vole guts, associations between radiation and bacterial community composition were robust against geographical and habitat variation. We found limited associations between radiation and fungal communities. Host physiological mechanisms or environmental factors may be driving these patterns.

ecology↗

bioRxiv2018

Genetic determinants of risk and survival in pulmonary arterial hypertension

BackgroundPulmonary arterial hypertension (PAH) is a rare disorder leading to premature death. Rare genetic variants contribute to disease etiology but the contribution of common genetic variation to disease risk and outcome remains poorly characterized.\n\nMethodsWe performed two separate genome-wide association studies of PAH using data across 11,744 European-ancestry individuals (including 2,085 patients), one with genotypes from 5,895 whole genome sequences and another with genotyping array data from 5,849 further samples. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. We functionally annotated associated variants and tested associations with duration of survival.\n\nFindingsA locus at HLA-DPA1/DPB1 within the class II major histocompatibility (MHC) region and a second near SOX17 were significantly associated with PAH. The SOX17 locus contained two independent signals associated with PAH. Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. PAH risk variants determined haplotype-specific enhancer activity and CRISPR-inhibition of the enhancer reduced SOX17 expression. Analysis of median survival showed that PAH patients with two copies of the HLA-DPA1/DPB1 risk variant had a two-fold difference (>16 years versus 8 years), compared to patients homozygous for the alternative allele.\n\nInterpretationWe have found that common genetic variation at loci in HLA-DPA1/DPB1 and an enhancer near SOX17 are associated with PAH. Impairment of Sox17 function may be more common in PAH than suggested by rare mutations in SOX17. Allelic variation at HLA-DPB1 stratifies PAH patients for survival following diagnosis, with implications for future therapeutic trial design.\n\nFundingUK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, Inserm, Universite Paris-Sud, and French ANR.

genetics↗