Biology subjects

Nguyen, T. T. L.

Publications and source records attributed to Nguyen, T. T. L..

6 recordsLinked to original sources

bioRxiv2025

Multifaceted suppression of staphylococcal virulence: in vitro study of a cellular status with reduced Agr activity and impaired biofilm

Anti-quorum sensing (QS) therapy has been focused on to reduce the virulence of pathogenic bacteria. However, a series of studies have shown that suppression of the staphylococcal QS Agr system promotes biofilm formation. In this study, we found that both Agr activity and the biofilm of Staphylococcus aureus can be reduced by a sappanwood extract (SWe). The impaired biofilm in the presence of SWe exhibited reduced extracellular DNA (eDNA) and increased extracellular polysaccharides. SWe also reduced pigmentation. The RNA-seq analysis showed that SWe suppressed multiple key virulence regulators, including the Agr and SaeRS systems. SWe downregulated cell-wall-associated proteins and several Agr-regulated virulence factors such as hemolysins and phenol-soluble modulins (PSMs). The present study did not intend the clinical application of the SWe but exemplified that it is possible to achieve anti-Agr and anti-biofilm activities simultaneously, suggesting a new therapeutic concept to combat S. aureus infection.

microbiology↗

bioRxiv2025

Microglial SWELL1 Deficiency Drives Male-Specific Seizure Vulnerability but Paradoxical Neuroprotection through Impaired Phagocytosis

The discovery of genes encoding the volume-regulated anion channel (VRAC) has enabled detailed exploration of its cell type-specific roles in the brain. LRRC8A (SWELL1) is the essential VRAC subunit. We observed seizure-induced, subunit-specific changes in microglial VRAC expression and investigated its function using conditional knockout (cKO) of LRRC8A in microglia. SWELL1 cKO mice exhibited a male-specific increase in kainate-induced seizure severity yet showed paradoxical neuroprotection against seizure-associated neuronal loss. Mechanistically, SWELL1 deletion led to a cell-autonomous reduction in microglial density and decreased release of VRAC-permeable neuroactive metabolites, including taurine, GABA, and glutamate in culture. Additionally, impaired phagocytic kinetics and reduced lysosomal biogenesis contributed to the observed neuroprotection. These findings reveal novel roles for microglial VRAC in regulating seizure outcomes and microglia-neuron interactions.

neuroscience↗

bioRxiv2024

Functional dissection of complex and molecular trait variants at single nucleotide resolution

Identifying the causal variants and mechanisms that drive complex traits and diseases remains a core problem in human genetics. The majority of these variants have individually weak effects and lie in non-coding gene-regulatory elements where we lack a complete understanding of how single nucleotide alterations modulate transcriptional processes to affect human phenotypes. To address this, we measured the activity of 221,412 trait-associated variants that had been statistically fine-mapped using a Massively Parallel Reporter Assay (MPRA) in 5 diverse cell-types. We show that MPRA is able to discriminate between likely causal variants and controls, identifying 12,025 regulatory variants with high precision. Although the effects of these variants largely agree with orthogonal measures of function, only 69% can plausibly be explained by the disruption of a known transcription factor (TF) binding motif. We dissect the mechanisms of 136 variants using saturation mutagenesis and assign impacted TFs for 91% of variants without a clear canonical mechanism. Finally, we provide evidence that epistasis is prevalent for variants in close proximity and identify multiple functional variants on the same haplotype at a small, but important, subset of trait-associated loci. Overall, our study provides a systematic functional characterization of likely causal common variants underlying complex and molecular human traits, enabling new insights into the regulatory grammar underlying disease risk.

genetics↗

bioRxiv2022

Glucocorticoids Mediate Transcriptome-wide Alternative Polyadenylation: Mechanisms and Functional Implications

Alternative polyadenylation (APA) is a common genetic regulatory mechanism that generates distinct 3' ends for RNA transcripts. Changes in APA have been associated with multiple biological processes and disease phenotypes. However, the role of hormones and their drug analogs in APA remains largely unknown. In this study, we investigated transcriptome-wide the impact of glucocorticoids on APA in 30 human B-lymphoblastoid cell lines. We found that glucocorticoids could regulate APA of a subset of genes, possibly by changing the expression of 142 RNA-binding proteins, some with known APA-regulating properties. Interestingly, genes with glucocorticoid-mediated APA were enriched in viral translation-related pathways, while genes with glucocorticoid-mediated expression were enriched in interferon and interleukin pathways, suggesting that glucocorticoid-mediated APA might result in functional consequences distinct from gene expression. Glucocorticoid-mediated APA was also cell-type-specific, suggesting an action of glucocorticoids that may be unique to immune regulation. We also observed evidence for genotype-dependent glucocorticoid-mediated APA, providing potential functional mechanisms for a series of common genetic variants that had previously been associated with immune disorders, but without a clear mechanism. In summary, this study reports a series of novel observations regarding the impact of glucocorticoids on APA, suggesting novel avenues for mechanistic studies of hormonal biology.

genomics↗

bioRxiv2021

Glucocorticoids Unmask Silent Non-Coding Genetic Risk Variants for Common Diseases

Understanding the function of non-coding genetic variants represents a formidable challenge for biomedicine. We previously identified genetic variants that influence gene expression only after exposure to a hormone or drug. Using glucocorticoid signaling as a model system, we have now demonstrated, in a genome-wide manner, that exposure to glucocorticoids triggered disease risk variants with previously unclear function to influence the expression of genes involved in autoimmunity, metabolic and mood disorders, osteoporosis and cancer. Integrating a series of pharmacogenomic and pharmacoepigenomic datasets, we identified the cis-regulatory elements and 3-dimensional interactions underlying the ligand-dependent associations between those genetic variants and distant risk genes. These observations increase our understanding of mechanisms of non-coding genetic variant-chemical environment interactions and advance the fine-mapping of disease risk and pharmacogenomic loci.

genomics↗

bioRxiv2018

Demographic features and mortality risks in smallholder poultry farms of the Mekong river delta region

This study describes the demographic structure and dynamics of small scale poultry farms of the Mekong river delta region, one of the worlds highest-risk regions for avian influenza outbreaks. Fifty farms were monitored over a 20-month period, with farm sizes, species, age, arrival/departure of poultry, and farm management practices recorded monthly. The history of poultry flocks in the sampled farms was recovered using a flock-matching algorithm. Median flock population sizes were 16 for chickens (IQR: 10 - 40), 32 for ducks (IQR: 18 - 101) and 11 for Muscovy ducks (IQR: 7 - 18); farm size distributions for the three species were heavily right-skewed. There was substantial flock overlap on almost all farms, with only one farm practicing an all-in-all-out management system. The rate of interspecific contacts was high, with two out of three farms housing at least two bird species. Among poultry species, demographic dynamics varied. Muscovy ducks were kept for long periods, in small numbers and outdoors, while chickens and ducks were farmed in larger numbers, indoors or in pens, with more rapid flock turnover. Most chicks were sold young to be fattened on other farms, and broiler and layer ducks had a short production period and higher degree of specialization. The rate of mortality due to disease did not differ much among species, with birds being less likely to die from disease at older ages, but frequency of disease symptoms differed by species. Time series of disease-associated mortality and population size were correlated for Muscovy ducks (Kendalls coefficient {tau} = 0.49, p value < 0.01).\n\nImpacts O_LIThe structure and dynamics of poultry populations kept in small scale farms in the Mekong river delta were accurately described.\nC_LIO_LIPoultry farms mix poultry of different species, ages, and production types, with multiple overlapping flocks present on a farm at all times. This promotes the persistence of pathogens.\nC_LIO_LIThe three main farmed poultry species of poultry (chickens, ducks and Muscovy ducks) are managed differently and have different demographic characteristics.\nC_LI

epidemiology↗