Biology subjects

Bradshaw, A.

Publications and source records attributed to Bradshaw, A..

4 recordsLinked to original sources

bioRxiv2025

Multicenter HFpEF study identifies sex disparity linked with two discrete cardiac proteomic signatures

Heart failure with preserved ejection fraction (HFpEF) is epidemic, with an incidence exceeding that of heart failure with reduced ejection fraction (HFrEF). Sex differences in HFpEF phenotype have been observed, particularly linked to aging and metabolic comorbidities in women. Here, we report a multi-centre proteomic analysis of HFpEF and HFrEF cardiac samples. Using tissues and clinical data derived from multiple institutional biobanks, in-depth characterization of the proteome of ventricular samples was undertaken. Relative to HFrEF, the HFpEF cohort exhibited minimal proteome composition overlap and pronounced heterogeneity. A key finding of this investigation is that sex per se did not confer a distinctive proteomic HFpEF signature. Rather, two HFpEF proteomic profiles were identified, differing significantly in sex ratios. The identification of two Clusters revealed that HFpEF has two predominant proteomic signatures at the molecular level, marked by differences in the extent and nature of structural and contractile machinery and by local cellular and ECM communications. Upstream regulator analysis identified various molecular leads to be pursued in defining these two HFpEF profiles. Our findings offer specific opportunities for new exploration of therapeutic options to target the spectrum of HFpEF proteomic diversity and identify potential drug targeting prospects.

molecular biology↗

bioRxiv2025

Enterocloster citroniae and related gut microbiome species modulate Vibrio cholerae biofilm formation through the production of bioactive small molecules

Cholera is a diarrheal disease that affects millions of people globally. Although the causative agent, Vibrio cholerae, has been extensively studied in isolation, investigation of its interactions with the gut microbiota started relatively recently. We and others previously showed that microbiota-derived metabolites significantly influence V. cholerae behavior. By investigating how an organic extract of human feces affects V. cholerae gene expression, we showed that gut metabolites strongly suppress swimming motility, a trait important for host colonization. Interestingly, extracts of pure cultures of a gut commensal, Enterocloster citroniae, recapitulated this inhibition. Here, we present a comprehensive examination of the effect of small molecules produced by E. citroniae and related species on V. cholerae behavior. We show that E. citroniae small molecules inhibit motility by various V. cholerae strains, and that several phylogenetically related species produce this activity, although the magnitude of the effect varies between strains. Using biofilm formation assays in static and flow conditions, we show that V. cholerae strongly induces biofilm formation in response to E. citroniae metabolites. Transcriptome and reporter analyses showed that several genes involved in synthesis of an extracellular polysaccharide are induced by E. citroniae metabolites. Lastly, we show that V. cholerae interactions with host cells are also modulated by this commensal. These findings advance our understanding of microbiome-pathogen interactions and how commensal bacteria influence V. cholerae virulence through the production of small molecules. In the future, this knowledge may be used to design novel microbiome-based therapeutic approaches to combat cholera and other infections. ImportanceThe human gut is home to a dense and rich community of microbes termed microbiota. This community has critical functions for host health, including protection against enteric pathogens. Despite this important role, we have only recently scratched the surface of the interactions that occur between members of the microbiota and pathogenic invaders. Cholerae is a disease that still causes significant morbidity and mortality worldwide. Studying how the causative agent, Vibrio cholerae, interacts with the microbiota will have implications not only for our understanding of this important microbial community, but may also lead to the development of new therapeutic strategies against cholera and potentially other infectious diseases.

microbiology↗

bioRxiv2023

Phylogenomics, biogeography, and trait evolution of the Boletaceae (Boletales, Agaricomycetes, Basidiomycota)

The species-rich porcini mushroom family Boletaceae is a widespread and well-known group of ectomycorrhizal (ECM) mushroom-forming fungi that has eluded intrafamilial phylogenetic resolution despite many attempts using morphological traits and multi-locus molecular datasets. In this study, we present a genome-wide molecular dataset of 1764 single-copy gene families from a global sampling of 418 Boletaceae specimens. The resulting phylogenetic analysis has strong statistical support for most branches of the tree, including the first statistically robust backbone. The enigmatic Phylloboletellus chloephorus from non-ECM Argentinian subtropical forests was recovered as an early diverging lineage within the Boletaceae. Time-calibrated branch lengths estimate that the family first arose in the early- to mid-Cretaceous and underwent a rapid radiation in the Eocene, possibly when the ECM nutritional mode arose with the emergence and diversification of ECM angiosperms. Biogeographic reconstructions reveal a complex history of vicariance and episodic long-distance dispersal correlated with historical geologic events, including Gondwanan origins and cladogenesis patterns that parallel its fragmentation. Ancestral state reconstruction of sporocarp morphological traits predicts that the ancestor of the Boletaceae was lamellate with ornamented basidiospores, contrary to most contemporary "bolete" morphologies. Transition rates indicated that the lamellate hymenophore and sequestrate sporocarp are reversible traits. Together, this study represents the most comprehensively sampled, data-rich molecular phylogeny of the Boletaceae to date, enabling robust inferences of trait evolution and biogeography in the group.

evolutionary biology↗

bioRxiv2019

Transforming growth factor-beta signaling via ALK1 and ALK5 regulates distinct functional pathways in vein graft intimal hyperplasia

RationaleTransforming growth factor-beta (TGF{beta}) is tightly regulated at multiple levels, with regulation at the receptor level now recognized as a key determinant of the cellular response to this pleiotropic cytokine. TGF{beta} promotes saphenous vein graft neointima formation after coronary artery bypass graft (CABG) surgery, inducing smooth muscle cell (SMC) hyperplasia and fibrosis by signaling via activin receptor-like kinase 5(ALK5). However, the role of the alternate TGF{beta} receptor ALK1 remains completely unknown. ObjectiveTo define the receptor pathways activated by TGF{beta} in SMCs and their mechanistic importance during CABG neointima formation. Methods and resultsRadioligand co-IP assays revealed direct interactions between TGF{beta}, ALK5 and ALK1 in primary saphenous vein graft SMC (HSVSMC) from patients undergoing CABG. Knockdown and pharmacological inhibition of ALK5 or ALK1 in HSVSMC significantly attenuated TGF{beta}-induced phosphorylation of receptor-regulated (R)-Smads 2/3 and 1/5, respectively. Microarray profiling followed by qRT-PCR validation showed that TGF{beta} induced distinct transcriptional networks downstream of ALK5 or ALK1, associated with HSVSMC contractility and migration, respectively and confirmed using migration assays as well as qRT-PCR and western blot assays of contractile SMC markers. scRNAseq analysis of TGF{beta}-treated HSVSMC identified distinct subgroups of cells showing ALK5 or ALK1 transcriptional responses, while RNA velocity analyses indicated divergence in differentiation towards ALK5 or ALK1-dominant lineages. ALK1, ALK5 and their downstream effectors pSmad1/5 and pSmad2/3 were localized to SMA+ neointimal SMCs in remodelled mouse vein grafts. Pharmacological inhibition or genetic ablation of Smad1/5 substantially reducing neointima formation following acute vascular injury. Notably, expression and activation of ALK1, ALK5 and their respective downstream R-Smads was already evident in hyperplastic saphenous veins prior to grafting. ConclusionsWhilst canonical TGF{beta} signaling via ALK5 promotes a contractile HSVSMC phenotype, transactivation of ALK1 by TGF{beta} induces neointima formation by driving cell migration. Restoring the balance between ALK1 and ALK5 in HSVSMC may represent a novel therapeutic strategy for vein graft failure.

cell biology↗