Biology subjects

Lee, S.-G.

Publications and source records attributed to Lee, S.-G..

9 recordsLinked to original sources

bioRxiv2026

An openly licensed benchmark and per-gene calibration map for missense pathogenicity predictors on activating cancer drivers

Missense pathogenicity predictors such as AlphaMissense are increasingly used in clinical variant interpretation, yet they are trained on germline labels dominated by loss-of-function (LOF) variants. Using an openly licensed, reproducible benchmark of 768 Cancer Gene Census genes scored with 49 predictors (labels from CIViC, COSMIC, cancerhotspots, ClinVar and gnomAD), we show that 42 of 49 tools (86%) score oncogene, gain-of-function (GOF) variants worse than tumour-suppressor variants. This under-scoring is mechanistically characterized: missed drivers occupy low-conservation, solvent-exposed, non-destabilizing positions (phyloP 2.51 versus 7.89; relative solvent accessibility 0.671 versus 0.185; gene-clustered p = 4.8x10-{superscript 2} and 2.3x10-3), and, counter-intuitively, the unsupervised and protein-language models now entering clinical use are the most affected. Per-gene oncogenic thresholds span 0.07-0.99, so a single global cut-off is mis-calibrated for most genes; we provide a per-gene calibration map. A cancer-calibrated stack (OncoCal) modestly improves discrimination over the best single tool (AUROC {approx} 0.93 versus 0.87), rescues drivers such as JAK2 V617F (0.334[->]0.57), and generalizes to independent deep mutational scanning data. We provide an openly licensed framework to interpret and recalibrate these tools in the somatic setting rather than a replacement predictor.

bioinformatics↗

bioRxiv2026

Microbiome-Targeted Reduction of Circulating Trimethylamine N-Oxide Mitigates Ischemic Stroke Risk

Elevated plasma trimethylamine N-oxide (TMAO) is an independent predictor of major adverse cardiovascular events and ischemic stroke. While inhibition of microbial TMA production has been explored, concerns regarding off-target effects and limited efficacy in complex microbial ecosystems have hindered clinical translation. Here, we report a microbiome-based therapeutic strategy based on the direct enzymatic degradation of intestinal TMA by Paracoccus aminovorans BM109. Through targeted screening, we identified BM109 as a commensal strain harboring a comprehensive set of enzymes capable of metabolizing TMA and TMAO into non-toxic end products under both aerobic and anaerobic conditions. In a chronic high-choline diet murine model, oral administration of BM109 resulted in a 38% reduction in systemic TMAO levels. In a rat model of transient middle cerebral artery occlusion (tMCAO), short-term pre-treatment reduced cerebral infarct size by 58% and significantly improved neurological outcomes. These effects were accompanied by favorable safety observations, including the absence of hemolytic activity and intestinal tissue damage. Collectively, our findings establish BM109 as a promising live biotherapeutic product that targets the gut microbiome-host metabolic axis. By reducing the systemic TMAO burden, BM109 represents a potential strategy for modulating cardiometabolic and cerebrovascular risk.

microbiology↗

bioRxiv2025

Comparative analysis of naked mole-rat thermogenesis and its potential to maintain euthermia in response to cold

The naked mole-rat (NMR) is a subterranean rodent known for its unique thermal biology, exceptional longevity and resistance to cancer and hypoxia. However, its thermal biology remains controversial, with various reports describing NMRs as poikilotherms, heterotherms, mesotherms or partial homeotherms. Here, we investigated whether the thermogenic potential of NMR brown adipose tissue and its UCP1 differ from those in mice and whether the lack of thermal insulation causes extreme changes in NMR body temperature upon cold exposure. Through longitudinal molecular, thermal, metabolic, and behavioral measurements, we found that NMRs initiated non-shivering thermogenesis and elevated body temperature but could not sustain it due to excessive heat loss and limits to substrate availability. Our results suggest that NMRs represent a unique thermoregulatory category that doesnt fit neatly into traditional classifications. In vitro and in vivo experiments showed that the NMR UCP1 is functional and can be activated and inhibited as expected for most other mammals. We further demonstrated that artificial insulation can partially restore thermoregulatory capabilities in NMRs. This study employs an advanced methodology to characterize the thermal biology of NMRs and helps resolve a long-standing controversy in the field. Significance StatementThis study provides critical insights into the thermal biology of naked mole-rats (NMRs), resolving long-standing controversies regarding their thermoregulatory strategies. We highlight the unique adaptations and limitations of NMR physiology by demonstrating that NMRs possess functional non-shivering thermogenesis and UCP1 but fail to maintain homeothermy due to excessive heat loss. Our findings suggest that artificial insulation can partially restore their thermoregulatory capabilities, offering a new perspective on the evolutionary and ecological significance of fur loss in NMRs. This research advances our understanding of mammalian thermal biology and presents an updated model for NMRs, bridging gaps between previous conflicting reports.

physiology↗

bioRxiv2024

STAT5B leukemic mutations, altering SH2 tyrosine 665, have opposing impacts on immune gene programs

STAT5B is a vital transcription factor for lymphocytes. Here, function of two STAT5B mutations from human T cell leukemias: one substituting tyrosine 665 with phenylalanine (STAT5BY665F), the other with histidine (STAT5BY665H) was interrogated. In silico modeling predicted divergent energetic effects on homodimerization with a range of pathogenicity. In primary T cells in vitro STAT5BY665F showed gain-of-function while STAT5BY665H demonstrated loss-of-function. Introducing the mutation into the mouse genome illustrated that the gain-of-function Stat5bY665F mutation resulted in accumulation of CD8+ effector and memory and CD4+ regulatory T-cells, altering CD8+/CD4+ ratios. In contrast, STAT5BY665H knock-in mice showed diminished CD8+ effector and memory and CD4+ regulatory T cells. In contrast to wild-type STAT5, the STAT5BY665F variant displayed greater STAT5 phosphorylation, DNA binding and transcriptional activity following cytokine activation while the STAT5BY665H variant resembled a null. The work exemplifies how joining in silico and in vivo studies of single nucleotides deepens our understanding of disease-associated variants, revealing structural determinants of altered function, defining mechanistic roles, and, specifically here, identifying a gain-of function variant that does not directly induce hematopoietic malignancy.

genetics↗

bioRxiv2023

Variant- and Vaccination-Specific Alternative Splicing Profiles in SARS-CoV-2 Infections

The COVID-19 pandemic, caused by the coronavirus SARS-CoV-2, and its subsequent variants has underscored the importance of understanding the host-viral molecular interactions to devise effective therapeutic strategies. A significant aspect of these interactions is the role of alternative splicing in modulating host responses and viral replication mechanisms. Our study sought to delineate the patterns of alternative splicing of RNAs from immune cells across different SARS-CoV-2 variants and vaccination statuses, utilizing a robust dataset of 190 RNA-seq samples from our previous studies, encompassing an average of 212 million reads per sample. We identified a dynamic alteration in alternative splicing and genes related to RNA splicing were highly deactivated in COVID-19 patients and showed variant- and vaccination-specific expression profiles. Overall, Omicron-infected patients exhibited a gene expression profile akin to healthy controls, unlike the Alpha or Beta variants. However, significantly, we found identified a subset of infected individuals, most pronounced in vaccinated patients infected with Omicron variant, that exhibited a specific dynamic in their alternative splicing patterns that was not widely shared amongst the other groups. Our findings underscore the complex interplay between SARS-CoV-2 variants, vaccination-induced immune responses, and alternative splicing, emphasizing the necessity for further investigations into these molecular cross-talks to foster deeper understanding and guide strategic therapeutic development.

bioinformatics↗

bioRxiv2021

TXNRD3 supports male fertility via the redox control of spermatogenesis

Thioredoxin/glutathione reductase (TGR, TXNRD3) is a thiol oxidoreductase of unknown function composed of thioredoxin reductase and glutaredoxin domains. This NADPH-dependent enzyme evolved by gene duplication within the Txnrd family, is expressed in the testes and can reduce both thioredoxin and glutathione in vitro. To characterize the function of TXNRD3 in vivo, we generated a strain of mice with the deletion of Txnrd3 gene. We show that Txnrd3 knockout mice are viable and without discernable gross phenotypes, but TXNRD3 deficiency leads to fertility impairment in male mice. Txnrd3 knockout animals exhibit a lower fertilization rate in vitro, a sperm movement phenotype and an altered redox status of thiols. Proteomic analyses revealed a broad range of substrates reduced by TXNRD3 during sperm maturation, presumably as a part of quality control. The results show that TXNRD3 plays a critical role in male reproduction via the thiol redox control of spermatogenesis.

biochemistry↗

bioRxiv2021

Epigenetic clocks reveal a rejuvenation event during embryogenesis followed by aging

The notion that germline cells do not age goes back to the 19th century ideas of August Weismann. However, being in a metabolically active state, they accumulate damage and other age-related changes over time, i.e., they age. For new life to begin in the same young state, they must be rejuvenated in the offspring. Here, we developed a new multi-tissue epigenetic clock and applied it, together with other aging clocks, to track changes in biological age during mouse and human prenatal development. This analysis revealed a significant decrease in biological age, i.e. rejuvenation, during early stages of embryogenesis, followed by an increase in later stages. We further found that pluripotent stem cells do not age even after extensive passaging and that the examined epigenetic age dynamics is conserved across species. Overall, this study uncovers a natural rejuvenation event during embryogenesis and suggests that the minimal biological age (the ground zero) marks the beginning of organismal aging.

developmental biology↗

bioRxiv2020

COVID-19 patients upregulate toll-like receptor 4-mediated inflammatory signaling that mimics bacterial sepsis

Observational studies of the ongoing coronavirus disease 2019 (COVID-19) outbreak suggest that a cytokine storm is involved in the pathogenesis of severe illness. However, the molecular mechanisms underlying the altered pathological inflammation in COVID-19 are largely unknown. We report here that toll-like receptor (TLR) 4-mediated inflammatory signaling molecules are upregulated in peripheral blood mononuclear cells (PBMCs) from COVID-19 patients, compared with healthy controls. Among the most highly increased inflammatory mediators in severe/critically ill patients, S100A9, an alarmin and TLR4 ligand, was found as a noteworthy biomarker, because it inversely correlated with the serum albumin levels. These data support a link between TLR4 signaling and pathological inflammation during COVID-19 and contribute to develop therapeutic approaches through targeting TLR4-mediated inflammation.

immunology↗

bioRxiv2018

Olfactory Projection Neurons From the Moth Antennal Lobe Lateral Cluster Exhibit Diverse Morphological and Neurophysiological Characteristics

Olfactory projection neurons convey information from the insect antennal lobe (AL) to higher centers in the brain. Many studies on moths have reported excitatory projection neurons with cell bodies in the medial cell cluster (mcPNs) that predominantly send an axon from the AL to calyces of the mushroom body (CA) via the medial antennal lobe tract (mALT) and then to the lateral horn (LH) of the protocerebrum. These neurons tend to have dendritic arbors restricted to a single glomerulus (i.e. they are uniglomerular). In this study, we report on the physiological and morphological properties of a group of pheromone-responsive olfactory projection neurons with cell bodies in the moth AL lateral cell cluster (lcPNs) of two heliothine moth species. While mcPNs typically exhibit a narrow odor tuning range related to the restriction of their dendritic arbors within a single glomerulus, lcPNs exhibited an array of morphological and physiological configurations. Pheromone-responsive lcPNs varied in their associations with glomeruli (uniglomerular and multiglomerular), dendritic arborization structure and connections to higher brain centers with projections primarily through the lateral antennal lobe tract and to a lesser extent the mediolateral antennal lobe tract to a variety of protocerebral targets including ventrolateral and superior neuropils as well as LH. Physiological characterization of lcPNs also revealed a diversity of response profiles including those either enhanced by or reliant upon presentation of a pheromone blend. These responses manifested themselves as higher maximum firing rates and/or improved temporal resolution of pulsatile stimuli. lcPNs therefore participate in conveying a variety of olfactory information relating to qualitative and temporal facets of the pheromone stimulus to a more expansive number of protocerebral targets than their mcPN counterparts. The role of lcPNs in the overall scheme of olfactory processing is discussed.

neuroscience↗