Biology subjects

Mann, G.

Publications and source records attributed to Mann, G..

6 recordsLinked to original sources

bioRxiv2026

Oxidative stress induces E. coli aryl polyene expression, sensitizing the bacterial stress response and modulating the redox environment of innate immune cells

Aryl polyenes (APEs) are specialized polyunsaturated outer membrane lipids that protect their producers from oxidative stress and contribute to biofilm formation. APEs are produced by an abundant biosynthetic gene cluster (BGC) family conserved across Gram-negative bacterial clades. The APE biosynthesis pathway involves 11 different enzymes and cumulates in the attachment of APEs to an anchor molecule in the Gram-negative outer membrane. Unlike most other small molecule BGCs, the APE BGC does not contain a dedicated regulatory gene that controls production of its metabolically costly compounds. Building from our prior observations of APEs role in acute oxidative stress protection, we here use a uropathogenic Escherichia coli (UPEC) strain to show that APE expression conveys a potential competitive advantage characterized by increased early-stage growth, sensitization of the bacterial oxidative stress response, and dampening of the redox stress of innate immune cells after in vitro infection. Our data indicate that APEs could act as a UPEC fitness factor, and in future work we aim to study their contribution to overall bacterial pathogenicity and survival, as well as how APEs could facilitate the transition from an oxygen poor environment such as the gut to the oxygen rich environment of the urinary tract. ImportanceBacterial pathogens use various mechanisms to achieve a competitive advantage under harsh conditions such as upon interaction with their host. We studied the function of aryl polyenes (APEs), specialized polyunsaturated fatty acids in the outer membrane, in the context of a uropathogenic E. coli strain. APE expression is induced by an oxidative environment and contributes to early-stage growth and sensitization of the oxidative stress response. Furthermore, APE-expressing E. coli dampens the intracellular oxidative milieu of target host phagocytes. These findings suggest a role for APEs as a fitness factor, and create opportunities to study their in vivo function, and explore them as a potential drug target.

microbiology↗

bioRxiv2025

Effect of Age and Sex on BCAA Metabolism in Mice

Increased plasma levels of branched-chain amino acids (BCAA) have been implicated in insulin resistance. This condition worsens with age, but plasma BCAA levels are downregulated in old men. The effect of age and/ sex on BCAA metabolism has been rarely studied. Thus, the objective of this study was to analyze how age and sex affect BCAA levels and their metabolism in mouse tissues. Male and female young (4-month) and old (18-months) CD2F1 mice were used. BCAA levels and relevant BCAA metabolic enzymes abundance/activity in plasma, muscle, liver, adipose tissue, and heart were analyzed. Old males exhibited greater plasma BCAA concentrations compared to young males and old females, but plasma branched-chain ketoacid (BCKA) levels were lower in old mice in both sexes. Intracellular BCAA levels were lower in skeletal muscle and heart from old mice independent of sex. There was an age-sex interaction in the lever in that reduced total BCAA was seen only in old male animals. In adipose tissue, total BCKA levels were higher in old male animals. Skeletal muscle abundance of the BCAA transporter LAT1 was reduced in old females compared to young females. In the liver, female mice had higher levels of LAT1 than male mice independent of age, while total BCKD was reduced in old females compared to old males. Pp2Cm levels were reduced in old animals independent of sex. In conclusion, while there were some changes in plasma and tissue BCAA/BCKA levels in response to age/sex, such changes were largely not consistent with changes in tissue BCAA catabolic enzyme abundance/activity. This suggests that protein levels of BCAA catabolic enzymes are preserved in aging in healthy animals and likely only become dysregulated in disease states.

physiology↗

bioRxiv2025

Sex Differences in Cachexia Outcomes and Branched-Chain Amino Acid Metabolism Following Chemotherapy in Aged Mice

Cachexia is a complex muscle wasting syndrome that affects majority of hospitalized cancer patients receiving chemotherapy. It is often unresponsive to nutritional interventions, including provision of branched-chain amino acids (BCAA: leucine, isoleucine and valine). BCAA are anabolic for skeletal muscle. We wondered whether their ineffectiveness in managing cachexia might be related to altered metabolism of these amino acids, a subject that has received minimal attention. Because estrogen limits BCAA catabolism, we hypothesized that the effects of chemotherapy on cachexia in old mice would be worse in males compared to females, and that this would be related to greater tissue release of BCAA in males. To better reflect age population for which cachexia is an issue, we treated aged male and female mice (18{+/-}2 months) with the chemotherapy drug cocktail FOLFIRI (50mg/kg 5-fluorouracil (5FU), 90mg/kg Leucovorin, and 24mg/kg CPT11) or vehicle twice per week for 6 weeks. This cocktail is used in treating colon cancer. Metabolism and concentrations of the BCAA and their metabolites were measured in plasma and tissues. There was a main effect of chemotherapy, reflected in reduced body weight, skeletal muscle, myofibrillar protein content, anabolic signalling and protein synthesis. In response to chemotherapy, males showed worsened outcomes for skeletal muscle weight and ubiquitinated proteins; they also had higher total plasma BCAA but reduced muscle BCAA. There was a main effect of chemotherapy in reducing the expression of the BCAA transporter LAT1. In response to chemotherapy, gastrocnemius muscle of males but not females had reduced inhibitory phosphorylation of BCKD-E1ser293, corresponding with increased activity of this enzyme. Chemotherapy reduced muscle and liver ketoacids of the BCAA only in females. These data suggest that sex differences in BCAA catabolism may be linked to the severity of chemotherapy-induced muscle damage and interventions against cachexia need to take this into account.

physiology↗

bioRxiv2025

Synthetic Substitutes as a Conservation Tool: Evaluating Synthetic Leopard Fur for Demand Reduction and Species Recovery

Providing synthetic substitutes is a widely promoted strategy to shift consumer demand away from wildlife products derived from threatened species. Yet, there is little evidence on whether such product substitution interventions effectively prevent illegal or unsustainable harvesting and contribute to the recovery of threatened populations. Drawing on the Furs For Life (FFL) Zambia initiative, which supplied synthetic furs known as "Heritage Furs" to replace leopard skins traditionally worn during Lozi royal ceremonies in Western Zambia, we present an evaluation designed to test both the effects and causal mechanisms of substitution. Guided by the EMMIE framework, commonly used in crime prevention evaluation, we triangulated data from semi-structured questionnaires, law enforcement patrols, court records, camera trap monitoring, and stakeholder interviews conducted between 2018 and 2024. Qualitative analysis using the General Elimination Method was employed to assess plausible alternative explanations for leopard recovery. By 2024, adoption of synthetic furs among leopard fur users exceeded 80 percent, while self-reported ownership of authentic leopard furs declined by 70 percent. At the same time, patrol detections of leopard poaching incidents decreased, and camera trap density estimates increased from an average of 2.7 to 3.8 leopards per 100 square kilometers across the focal landscape. An integrated mechanism of change, derived from stakeholder perspectives, indicates that while substitution reduced demand, concurrent and reinforcing effects of counter-poaching and counter-trafficking operations were critical to leopard recovery. This study provides the first empirical link between a demand reduction initiative based on synthetic substitutes and measurable species population recovery.

ecology↗

bioRxiv2023

The landscape of genomic structural variation in Indigenous Australians

Indigenous Australians harbour rich and unique genomic diversity. However, Aboriginal and Torres Strait Islander ancestries are historically under-represented in genomics research and almost completely missing from reference databases. Addressing this representation gap is critical, both to advance our understanding of global human genomic diversity and as a prerequisite for ensuring equitable outcomes in genomic medicine. Here, we apply population-scale whole genome long-read sequencing to profile genomic structural variation across four remote Indigenous communities. We uncover an abundance of large indels (20-49bp; n=136,797) and structural variants (SVs; [≥]50bp; n=159,912), the majority of which are composed of tandem repeat or interspersed mobile element sequences (90%) and have not been previously annotated (73%). A large fraction of SVs appear to be exclusive to Indigenous Australians (>30%) and the majority of these are found in only a single community, underscoring the need for broad and deep sampling to achieve a comprehensive catalogue of genomic structural variation across the Australian continent. Finally, we explore short-tandem repeats (STRs) throughout the genome to characterise allelic diversity at 50 known disease loci, uncover hundreds of novel repeat expansion sites within protein-coding genes, and identify unique patterns of diversity and constraint among STR sequences. Our study sheds new light on the dimensions, diversity and evolutionary trajectories of genomic structural variation within and beyond Australia.

genomics↗

bioRxiv2021

SurvBenchmark: comprehensive benchmarking study of survival analysis methods using both omics data and clinical data

Survival analysis is a branch of statistics that deals with both, the tracking of time and of the survival status simultaneously as the dependent response. Current comparisons of survival model performance mostly center on clinical data with classic statistical survival models, with prediction accuracy often serving as the sole metric of model performance. Moreover, survival analysis approaches for censored omics data have not been thoroughly investigated. The common approach is to binarise the survival time and perform a classification analysis. Here, we develop a benchmarking framework, SurvBenchmark, that evaluates a diverse collection of survival models for both clinical and omics datasets. SurvBenchmark not only focuses on classical approaches such as the Cox model, but it also evaluates state-of-art machine learning survival models. All approaches were assessed using multiple performance metrics, these include model predictability, stability, flexibility and computational issues. Our systematic comparison framework with over 320 comparisons (20 methods over 16 datasets) shows that the performances of survival models vary in practice over real-world datasets and over the choice of the evaluation metric. In particular, we highlight that using multiple performance metrics is critical in providing a balanced assessment of various models. The results in our study will provide practical guidelines for translational scientists and clinicians, as well as define possible areas of investigation in both survival technique and benchmarking strategies. Contactjean.yang@sydney.edu.au

bioinformatics↗