Biology subjects

Lester, M.

Publications and source records attributed to Lester, M..

3 recordsLinked to original sources

bioRxiv2025

ALDH2 Deficiency Drives Proliferative Mammary Morphogenesis and Epithelial Cell Stemness via Oxidative Stress and Estrogen Receptor Activation

Alcohol consumption has been linked to breast cancer, partly due to the accumulation of toxic aldehydes like acetaldehyde, a carcinogenic byproduct of ethanol metabolism. ALDH2, a key mitochondrial enzyme, detoxifies acetaldehyde and other harmful aldehydes that drive oxidative stress, DNA damage, and hormonal dysregulation, key factors in carcinogenesis. Despite the possible link between alcohol consumption and breast cancer risk, little is known about how ALDH2 deficiency itself, independent of alcohol exposure, affects mammary gland biology and cancer susceptibility. Genetic variants leading to ALDH2 deficiency are highly prevalent in East Asian populations, where individuals carrying inactive ALDH2 alleles experience impaired aldehyde detoxification. While these individuals are at increased risk for alcohol-related cancers, the impact of ALDH2 deficiency on mammary gland development and homeostasis in the absence of alcohol exposure remains unexplored. To address this, we utilized a C57BL/6-based ALDH2 knockout (Aldh2-/-) mouse model to investigate its effects on mammary proliferation and development. Our findings revealed that Aldh2-/- mice exhibited hyperproliferative mammary glands, characterized by increased epithelial cell density, ductal expansion, and elevated Ki67+ cells. Flow cytometry analysis demonstrated a rise in luminal and basal epithelial subpopulations, alongside enhanced mammary epithelial stemness, as evidenced by increased mammosphere formation and colony-forming efficiency. At the molecular level, ALDH2 deficiency activated oxidative stress pathways, marked by elevated 8-OHdG, p38 MAPK, NF-{kappa}B, and Nrf2 signaling, alongside DNA damage responses involving p53 and H2A.X. Importantly, we also identified a previously unrecognized upregulation of RANKL in Aldh2-/- mammary glands, implicating the RANK/RANKL axis as a critical mediator linking aldehyde stress to NF-{kappa}B/p38 MAPK activation and enhanced mammary stemness. Furthermore, hormonal dysregulation was observed, with a significant increase in ER and PR expression and phosphorylation. Dysregulated ER signaling was further linked to enhanced erbB3 activation and downstream signaling, including the cyclin D1-pRb-E2F1 axis. Our results suggest that the accumulation of endogenous aldehydes, independent of alcohol exposure, profoundly alters mammary morphogenesis, epithelial repopulation, and stemness. Mechanistically, this occurs through oxidative stress activation and DNA damage pathways, leading to metabolic changes and upregulation of estrogen receptor and receptor tyrosine kinase signaling. This study highlights for the first time the potential role of ALDH2 deficiency in increasing mammary tissue susceptibility to oncogenic factors and breast cancer risk.

cancer biology↗

bioRxiv2025

Courtship vocalizations in male ducks: spectral composition and resonance of the syringeal bulla

Ducks display a unique and dramatic sexual dimorphism in their vocal organ, the syrinx. Males have a left-sided bulla that is not present in females and that has been long hypothesized to play a role in courtship vocalizations, though this connection has never been tested. The large, hollow morphology of the bulla and its proximity to the sound-producing vocal folds introduce the possibility that it may work as a Helmholtz resonator, which makes it possible to predict the resonance frequencies enhanced by this structure. We find that during early ontogeny, the distribution of energy across the harmonic spectrum of contact calls is not different between males and females. We then used micro-CT scans of duck syrinxes to estimate resonance frequencies of the bullae and compared these to spectral features of their vocalizations. This comparison overall supports the idea that the bulla resonance may specifically enhance aspects of courtship vocalizations, especially in species that have a tonal courtship whistle. We also see potential influence in non-courtship vocalizations, which could be explored further with a greater understanding of the input of other vocal tract features that influence vocalization. We observed that bulla size is positively correlated with bird body mass with the largest exception in the Common Eider, which had a small bulla for its body mass and for which we saw no evidence of bulla-input to its vocalizations. This study found support for the long-held hypothesis that the adult male duck bulla influences resonance frequencies, in particular in courtship vocalizations.

physiology↗

bioRxiv2023

Delivery of mRNA encoding an anti-Tau monoclonal antibody and engineered scFv intrabody results in functional antibody expression in SH-SY5Y cells

Monoclonal antibodies have emerged as a leading therapeutic agent for the treatment of disease, including Alzheimers disease. In the last year, two anti-amyloid monoclonal antibodies, lecanemab and aducanumab, have been approved in the USA for the treatment of Alzheimers disease, whilst several tau-targeting monoclonal antibodies are currently in clinical trials. Such antibodies, however, are expensive and timely to produce and require frequent dosing regimens to ensure disease-modifying effects. Synthetic in vitro-transcribed mRNA encoding antibodies for endogenous protein expression holds the potential to overcome many of the limitations associated with protein antibody production. Here, we have generated synthetic in vitro-transcribed mRNA encoding a tau specific monoclonal antibody as a full-sized IgG and as a single chain variable fragment (scFv). In vitro transfection of human neuroblastoma SH-SY5Y cells demonstrated the ability of the synthetic mRNA to be translated into functional tau-specific antibodies. Furthermore, we show that the translation of the tau-specific scFv as an intrabody results in the specific engagement of intracellular tau. This work highlights the utility of mRNA for the delivery of antibody therapeutics, including intrabodies, for the targeting of tau in tauopathies.

neuroscience↗