Biology subjects

Pua, C. J.

Publications and source records attributed to Pua, C. J..

5 recordsLinked to original sources

bioRxiv2025

Cardiac Adaptations in the Cave Nectar Bat Eonycteris spelaea: Insights into Metabolic Resilience and Stress Response

AimsBats are unique mammals with remarkable adaptations, including powered flight, which demands significant energy expenditure. While previous studies have documented basic structural characteristics of bat hearts, a comprehensive understanding of their response to physiological stress remains unexplored. This study investigates the cardiac adaptations of the cave nectar bat Eonycteris spelaea to elucidate the mechanisms underlying their unique physiological capabilities. Methods and ResultsWe performed RNA sequencing to analyse the cardiac gene expression profile of E. spelaea and 6 other bat species in comparison to mouse and human hearts, revealing enriched transcriptomic signatures related to oxidative phosphorylation and fatty acid metabolism across multiple bat species. Metabolomic profiling compared acylcarnitine metabolites and tricarboxylic acid (TCA) cycle intermediates between bat and mouse hearts, indicating a distinct acylcarnitine profile and increased levels of TCA cycle intermediates in bats, suggesting enhanced metabolic capacity. Structural adaptations were assessed through anatomical and histological analyses on cardiac tissues, showing thicker left ventricular walls and increased vascular density in bats without pathological hypertrophy. Functional characteristics were evaluated using dobutamine stress echocardiography, demonstrating superior cardiac reserve in bats with significant increases in ejection fraction, stroke volume, and cardiac output under stress conditions. Additionally, isolated cardiomyocytes were treated with Angiotensin II (Ang II) to assess stress responses. Bat cardiomyocytes displayed resistance to Ang II-induced hypertrophy and mitochondrial dysfunction compared to mice, further highlighting their resilience to stress-induced damage. ConclusionThe unique adaptations observed in bat hearts, including enhanced metabolic pathways, structural remodelling, and cellular resilience contribute to their ability to meet the high energy demands of powered flight while maintain cardiac function under stress. These insights into bat cardiac physiology provide valuable information on cardioprotective mechanisms that could be applicable to other species. Translational PerspectiveBats exhibit remarkable cardiac adaptations that sustain the high energy demands of powered flight while resisting stress-induced damage. These insights into evolutionarily conserved cardioprotective mechanisms highlight potential therapeutic pathways for preventing heart failure, including resistance to hypertrophy and mitochondrial dysfunction under stress. Studying non-model organisms like bats may offer innovative approaches to enhance metabolic and stress resilience in human hearts, paving the way for translational research in cardiovascular disease management and treatment.

systems biology↗

bioRxiv2023

Inhibition of an immunometabolic axis of mTORC1 activation extends mammalian healthspan

Human ageing is associated with metabolic dysfunction, sarcopenia and frailty that taken together reduce healthspan. For age-associated diseases and lifespan, ERK, AMPK and mTORC1 represent critical pathways, across species1-7. Here we examined the hypothesis that IL11, recently shown to regulate ERK/mTORC1, is an inflammaging factor important for healthspan. As mice age, IL11 is progressively upregulated in liver, skeletal muscle, and fat to stimulate an ERK/AMPK/mTORC1 axis of cellular, tissue- and organismal-level ageing pathologies. In old mice, deletion of Il11 or Il11ra1 protects against metabolic multi-morbidity, sarcopenia, and frailty. Administration of anti-IL11 therapy to elderly mice for six months reactivates an age-repressed program of white fat beiging, reverses metabolic dysfunction, restores muscle function, and reduces frailty. Across studies, inhibition of IL11 lowers epigenetic age, reduces telomere attrition, and preserves mitochondrial function. Towards clinical translation, we generated, humanised, and engineered a neutralising, high-affinity IL11 antibody. These studies identify IL11 as a key inflammaging factor and therapeutic target for mammalian healthspan.

molecular biology↗

bioRxiv2022

Interleukin-11 causes alveolar type 2 cell dysfunction and prevents alveolar regeneration

Following lung injury, alveolar regeneration is characterized by the transformation of alveolar type 2 (AT2) cells, via a transitional KRT8+ state, into alveolar type 1 (AT1) cells. In lung disease, dysfunctional intermediate cells accumulate, AT1 cells are diminished and fibrosis occurs. Using single cell RNA sequencing datasets of human interstitial lung disease, we found that interleukin-11 (IL11) is specifically expressed in aberrant KRT8 expressing KRT5-/KRT17+ and basaloid cells. Stimulation of AT2 cells with IL11 or TGF{beta}1 caused EMT, induced KRT8+ and stalled AT1 differentiation, with TGF{beta}1 effects being IL11 dependent. In bleomycin injured mouse lung, IL11 was increased in AT2-derived KRT8+ cells and deletion of Il11ra1 in lineage labeled AT2 cells reduced KRT8+ expression, enhanced AT1 differentiation and promoted alveolar regeneration, which was replicated in therapeutic studies using anti-IL11. These data show that IL11 maintains AT2 cells in a dysfunctional transitional state, impairs AT1 differentiation and blocks alveolar regeneration across species. TeaserInterleukin-11 stalls type 2-to-type 1 alveolar epithelial cell differentiation and prevents lung regeneration

immunology↗

bioRxiv2020

Disease-specific variant pathogenicity prediction significantly improves variant interpretation in inherited cardiac conditions

BackgroundAccurate discrimination of benign and pathogenic rare variation remains a priority for clinical genome interpretation. State-of-the-art machine learning tools are useful for genome-wide variant prioritisation but remain imprecise. Since the relationship between molecular consequence and likelihood of pathogenicity varies between genes with distinct molecular mechanisms, we hypothesised that a disease-specific classifier may outperform existing genome-wide tools. MethodsWe present a novel disease-specific variant classification tool, CardioBoost, that estimates the probability of pathogenicity for rare missense variants in inherited cardiomyopathies and arrhythmias, trained with variants of known clinical effect. To benchmark against state-of-the-art genome-wide pathogenicity classification tools, we assessed classification of hold-out test variants using both overall performance metrics, and metrics of high-confidence (>90%) classifications relevant to variant interpretation. We further evaluated the prioritisation of variants associated with disease and patient clinical outcomes, providing validations that are robust to potential mis-classification in gold-standard reference datasets. ResultsCardioBoost has higher discriminating power than published genome-wide variant classification tools in distinguishing between pathogenic and benign variants based on overall classification performance measures with the highest area under the Precision-Recall Curve as 91% for cardiomyopathies and as 96% for inherited arrhythmias. When assessed at high-confidence (>90%) classification thresholds, prediction accuracy is improved by at least 120% over existing tools for both cardiomyopathies and arrhythmias, with significantly improved sensitivity and specificity. Finally, CardioBoost improves prioritisation of variants significantly associated with disease, and stratifies survival of patients with cardiomyopathies, confirming biologically relevant variant classification. ConclusionsWe demonstrate that a disease-specific variant pathogenicity prediction tool outperforms state-of-the-art genome-wide tools for the classification of rare missense variants of uncertain significance for inherited cardiac conditions. To facilitate evaluation of CardioBoost, we provide pre-computed pathogenicity scores for all possible rare missense variants in genes associated with cardiomyopathies and arrhythmias (https://www.cardiodb.org/cardioboost/). Our results also highlight the need to develop and evaluate variant classification tools focused on specific diseases and clinical application contexts. Our proposed model for assessing variants in known disease genes, and the use of application-specific evaluations, is broadly applicable to improve variant interpretation across a wide range of Mendelian diseases.

genetics↗

bioRxiv2019

Digital phenotyping by consumer wearables identifies sleep-associated markers of cardiovascular disease risk and biological aging

Despite growing adoption of consumer wearables, the potential for sleep metrics from these devices to contribute to sleep-related biomedical research remains largely uncharacterized. Here we analyze sleep tracking data, along with questionnaire responses and multi-modal phenotypic data, generated from 482 normal volunteers. First, we provide a detailed comparison of wearable-derived and self-reported sleep metrics, particularly total sleep time (TST) and sleep efficiency (SE). We then identified demographic, socioeconomic and lifestyle factors associated with wearable-derived sleep duration. We also analyzed our multi-modal phenotypic data and showed that wearable-derived TST and SE are associated with various cardiovascular disease risk markers, whereas self-reported measures were not. Using whole-genome sequencing data, we estimated leukocyte telomere length and showed that volunteers with insufficient sleep also exhibit premature telomere attrition. Our study highlights the potential for sleep metrics generated by consumer wearables to provide novel insights into data generated from population cohort studies.

epidemiology↗