Biology subjects

Connor, T.

Publications and source records attributed to Connor, T..

3 recordsLinked to original sources

bioRxiv2023

Afanc: a Metagenomics Tool for Variant Level Disambiguation of NGS Datasets

Genomics is amongst the most powerful tools available for mounting a clinical response to infectious disease. The accurate and precise taxonomic evaluation of pathogens is essential when building a picture of pathogenicity, virulence, transmission, and drug resistance. Carrying out such profiling in a high throughput manner necessitates the development of reliable bioinformatic tools. Here we present Afanc, a novel metagenomic profiler which is sensitive down to species and strain level taxa, and capable of elucidating the complex pathogen profile of compound datasets. We compared Afanc against currently available cutting edge profilers using 3 datasets: single species read sets simulated from the full Mycobacteriaceae taxonomic landscape; compound read sets containing multiple Mycobacteriaceae species and variants; and real data covering the majority of the M. tuberculosis lineage taxonomic space. Afanc outperformed all profilers, both generic and Mycobacteriaceae specific, across all tested fields. As a species agnostic profiler, we predict that Afanc will be of great utility when carrying out highly specific and sensitive pathogen profiling of clinical datasets. Such analyses are essential in advising both the clinical response to an individual disease case, and in forming the foundation of epidemiological surveys.

bioinformatics↗

bioRxiv2022

Class IIa HDACs reprogram mitochondrial metabolism to inhibit apoptosis and ferroptosis in response to lipotoxicity

Lipotoxicity, the accumulation of lipids in non-adipose tissues, alters the metabolic transcriptome and mitochondrial metabolism in skeletal muscle. The mechanisms involved remain poorly understood. Here we show that lipotoxicity increased histone deacetylase 4 (HDAC4) and histone deacetylase 5 (HDAC5), which reduced the expression of metabolic genes and oxidative metabolism in skeletal muscle, resulting in increased non-oxidative glucose metabolism. This metabolic reprogramming was also associated with impaired apoptosis and ferroptosis responses, and preserved muscle cell viability in response to lipotoxicity. Mechanistically, increased HDAC4 and 5 decreased acetylation of p53 at K120, a modification required for transcriptional activation of apoptosis. Redox drivers of ferroptosis derived from oxidative metabolism were also reduced. The relevance of this pathway was demonstrated by overexpression of loss-of-function HDAC4 and HDAC5 mutants in skeletal muscle of obese db/db mice, which enhanced oxidative metabolic capacity, increased apoptosis and ferroptosis and reduced muscle mass. This study identifies HDAC4 and HDAC5 as repressors of skeletal muscle oxidative metabolism, which is linked to inhibition of cell death pathways and preservation of muscle integrity in response to lipotoxicity.

cell biology↗

bioRxiv2022

Amyloid beta 42 alters cardiac metabolism and impairs cardiac function in obesity

There are epidemiological associations between obesity and type 2 diabetes, cardiovascular disease and Alzheimers disease. While some common aetiological mechanisms are known, the role of amyloid beta 42 (A{beta}42) in these diverse chronic diseases is obscure. Here we show that adipose tissue releases A{beta}42, which is increased from adipose tissue of obese mice and is associated with higher plasma A{beta}42. Increasing circulating A{beta}42 levels in non-obese mice had no effect on systemic glucose homeostasis but had obesity-like effects on the heart, including reduced cardiac glucose clearance and impaired cardiac function. These effects on cardiac function were not observed when circulating levels of the closely related A{beta}40 isoform were increased. Administration of an A{beta} neutralising antibody prevented obesity-induced cardiac dysfunction and hypertrophy. Furthermore, A{beta} neutralising antibody administration in established obesity prevented further deterioration of cardiac function. Multi-contrast transcriptomic analyses revealed that A{beta}42 impacted pathways of mitochondrial metabolism and exposure of cardiomyocytes to A{beta}42 inhibited mitochondrial function. These data reveal a role for systemic A{beta}42 in the development of cardiac disease in obesity and suggest that therapeutics designed for Alzheimers disease could be effective in combating obesity-induced heart failure.

physiology↗