Biology subjects

Cowley, M. V.

Publications and source records attributed to Cowley, M. V..

3 recordsLinked to original sources

bioRxiv2025

The T-cell receptor repertoire of wild mice

Wild animals live in a pathogen-rich environment, and are normally infected with a wide range of micro- and macro-parasites. Wild animals T cells are central to the effectiveness of their adaptive immune response in ameliorating the effect of these infections. Here we have investigated the T-cell receptor (TCR) repertoire of wild mice to investigate how it varies in animals of different ages and sex, and from different sites. We sequenced the TCR alpha and beta chains of CD4+ and CD8+ T-cells of 65 wild Mus musculus domesticus from two UK sites. We analysed repertoire richness and diversity finding that wild mice have large TCR repertoires. Repertoire richness, which measures the breadth of the repertoire, was not significantly affected by mouse age or sex, suggesting that wild mice maintain the capacity to respond to novel antigens throughout their lives. In contrast, repertoire diversity (measured by Shannons index) was affected by a mouse sex-by-age interaction. This low diversity, coupled with constant richness, points to older mice having comparatively more highly abundant clones in their repertoires, perhaps due to chronic exposure to persistent pathogens in their environment. These findings provide a novel description of the wild mouse TCR, revealing an immune system that balances maintaining a broad response capacity with developing strong, lasting responses to infections in the natural environment.

immunology↗

bioRxiv2024

Quantifying anti-DUX4 therapy for facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is an inherited skeletal myopathy with no cure. Expression of the myotoxic transcription factor double homeobox 4 (DUX4) is believed to underlie FSHD pathogenesis and many proposed therapies target DUX4 generation or function. Which of these therapies will be the most effective is unclear. Here, by constructing a Markov-chain-based mathematical model of DUX4-mediated myotoxity in FSHD, we interrogate various anti-DUX4 FSHD therapeutic strategies. We derive an analytical function for myonuclear life expectancy in terms of the parameters of DUX4 expression and function. In a biologically relevant parameter regime, therapeutically decreasing the DUX4 protein diffusion rate is, surprisingly, predicted to be more effective at increasing myonuclear life expectancy than reducing the rate of myonuclear apoptosis caused by the expression of DUX4-target genes. We find that targeting elements of DUX4 transcription/translation, such as mRNA stability via siRNA therapy, has a limited predicted impact on DUX4-meditated toxicity when performed in isolation. However, our model predicts a super-additive effect from combining transcription/translation targeting strategies with approaches that minimise DUX4 diffusion-mediated import into neighbouring myonuclei. Importantly, we provide a computational tool to test and inform therapeutic designs, enabling pre-clinical screening of FSHD treatment approaches.

cell biology↗

bioRxiv2022

An in silico FSHD muscle fibre for modelling DUX4 dynamics and predicting the impact of therapy

Facioscapulohumeral muscular dystrophy (FSHD) is an incurable myopathy linked to over-expression of the myotoxic transcription factor DUX4. Targeting DUX4 is the leading therapeutic approach, however it is only detectable in 0.1-3.8% of FSHD myonuclei. How rare DUX4 drives FSHD and the optimal anti-DUX4 strategy is unclear. We combine stochastic gene expression with compartment models of cell states, building a simulation of DUX4 expression and consequences in FSHD muscle fibres. Investigating iDUX4 myoblasts, scRNAseq and snRNAseq of FSHD muscle we estimate parameters including DUX4 mRNA degradation, transcription and translation rates and DUX4 target gene activation rates. Our model accurately recreates the distribution of DUX4 and target gene positive cells seen in scRNAseq of FSHD myocytes. Importantly we show DUX4 drives significant cell death despite expression in only 0.8% of live cells. Comparing scRNAseq of unfused FSHD myocytes to snRNAseq of fused FSHD myonuclei, we find evidence of DUX4 protein syncytial diffusion and estimate its rate via genetic algorithms. We package our model into freely available tools, to rapidly investigate consequences of anti-DUX4 therapy.

cell biology↗