Biology subjects

Lush, M.

Publications and source records attributed to Lush, M..

4 recordsLinked to original sources

bioRxiv2026

Sex-Specific Pathophysiological Signatures in Allometric Dosing-Controlled Bleomycin Acute Lung Injury Model

IntroductionIn acute lung injury (ALI), clinical data show that while mortality rates are similar between sexes, women require shorter ventilation times and intensive care unit stays than men, yet preclinical studies show conflicting sex-specific vulnerabilities. We reasoned that a hidden dosing bias may explain the inconsistency, as intratracheal bleomycin is scaled to body weight, even though lung mass grows more slowly than total body mass, so age-matched males, whose body mass outpaces lung growth, inevitably receive more drug per gram of lung than females. MethodsWe compared age-matched (12-week) and body-weight-matched ([~]300g) Sprague-Dawley rats receiving intratracheal bleomycin (2.5mg/kg) or saline. Both cohorts underwent functional assessments (plethysmography, lung mechanics, arterial gases, histology) at day 7; weight-matched animals exclusively underwent mechanistic profiling (BALF analysis, cytokine multiplex, paired mRNA/miRNA-sequencing, immunoblotting). ResultsMales developed worse hypoxemia (PaO2: age-matched p = 0.045; weight-matched p = 0.027) with higher respiratory rates (both cohorts p < 0.05). Weight-matched males showed greater compliance loss (p = 0.029), increased BALF protein (p = 0.008), and elevated IL-1{beta} (p =0.005) and TNF- (p = 0.017). RNA-sequencing identified 2,393 male versus 1,533 female differentially-expressed genes, with males activating complement-coagulation cascades while females enriched ECM-remodeling/BMP-signaling pathways. Males exhibited significant miR-672-3p suppression (p < 0.0001), inversely correlating with inflammatory targets. SERPINA3 and its upstream regulator STAT3 showed significantly higher induction in males (both p < 0.0001), whereas females exhibited higher BMPR2 protein levels (p = 0.009) and preserved IL-10 (p = 0.023). ConclusionsBody-weight matching corrects unrecognized allometric bias affecting preclinical ALI sex-difference studies. Both cohorts demonstrated male vulnerability with worse hypoxemia and increased respiratory rates. Weight-matched molecular analyses revealed distinct responses: males showed significant miR-672-3p suppression with concurrent inflammatory mediator upregulation, including higher SERPINA3, IL-1{beta}, and TNF-. In contrast, females maintained higher miR-672-3p levels alongside elevated BMPR2/IL-10, suggesting that divergent post-transcriptional regulation contributes to functional differences and may inform sex-specific therapeutic strategies.

physiology↗

bioRxiv2025

prdm1a drives a fate switch between hair cells of different mechanosensory organs

Vertebrate mechanosensory hair cells (HCs) in the ear detect sound and gravitational forces. Additionally, fish have homologous lateral line HCs in the skin that detect water vibrations for orientation and predator avoidance. HCs in fish and other non-mammalian vertebrates regenerate to restore function after damage, but mammalian HCs lack this ability, causing deafness and vestibular defects. Experimental attempts at regeneration in mice result in incomplete differentiation of immature HCs. Despite differences in regeneration, the gene regulatory networks (GRNs) driving HC maturation are highly similar across vertebrates. Here, we show that the transcription factor prdm1a plays a key role in the HC fate GRN in the zebrafish lateral line. Mutating prdm1a respecifies lateral line HCs into ear HCs, altering morphology and transcriptome. Understanding how transcription factors control diverse HC fates in zebrafish is crucial for understanding the yet unsolved regeneration of diverse HCs in mammalian ears to restore hearing and balance.

developmental biology↗

bioRxiv2019

Common breast cancer risk loci predispose to distinct tumor subtypes

BackgroundGenome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER), but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. MethodsAmong 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. ResultsEighty-five of 173 variants were associated with at least one tumor feature (false discovery rate <5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at P<0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. ConclusionThis report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.

genetics↗

bioRxiv2019

Fine-mapping of 150 breast cancer risk regions identifies 178 high confidence target genes

Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants (CCVs) in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium, and enriched genomic features to determine variants with high posterior probabilities (HPPs) of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of potentially causal variants, using gene expression (eQTL), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways, were over-represented among the 178 highest confidence target genes.

genetics↗