Biology subjects

Wang, M.-J.

Publications and source records attributed to Wang, M.-J..

3 recordsLinked to original sources

bioRxiv2026

Efflux Pump Activation Confers Mupirocin Resistance and Enhances Rhizosphere Fitness in Pseudomonas

Mupirocin (Mup) is a polyketide antibiotic for clinical MRSA treatment and agricultural biocontrol, acting by binding to IleRS to inhibit protein synthesis. Here, we demonstrate that Pseudomonas viciae 11K1 acquires resistance to mupirocin not through canonical mutations in ileS, the gene encoding the drug target, but via single nucleotide polymorphisms (SNPs) of EmhR, a transcriptional repressor. These SNPs attenuate EmhRs DNA-binding ability, resulting in derepression of the resistance-nodulation-division (RND) efflux pump EmhABC. This leads to a 7-fold (to 800 g/mL) increase in the mupirocin minimum inhibitory concentration (MIC), and confers cross-resistance to multiple other antibiotics. Critically, 11K1 strains harboring EmhR mutations exhibit enhanced competitive fitness in colonizing wheat rhizospheres against the mupirocin-producing Pseudomonas bijieensis 2P24. The conservation of this regulatory mechanism in Pseudomonas aeruginosa, mediated by the EmhR ortholog NalD, underscores its broader biological significance. Our findings establish a direct link between efflux pump regulation and ecological adaptation, highlighting a key mechanism contributing to environmental antimicrobial resistance with important implications for the clinical and agricultural use of mupirocin. IMPORTANCEMupirocin and its producing Pseudomonas strains are widely used in both clinical and agricultural contexts, making mupirocin resistance a significant concern for public health and food security. While canonical mupirocin resistance is primarily attributed to mutations in ileS, the gene encoding the drug target isoleucyl-tRNA synthetase (IleRS), our study identifies a novel resistance mechanism in Pseudomonas viciae strain 11K1 mediated by SNPs in the transcriptional repressor EmhR. These SNPs derepress the RND efflux system EmhABC, and reduce intracellular mupirocin levels. This mechanism not only enhances tolerance to mupirocin but also confers cross-resistance to multiple antimicrobial agents, raising the risk of multidrug-resistant strain spread. EmhR-mutant 11K1 strains exhibit enhanced rhizosphere competitiveness in the presence of mupirocin-producing Pseudomonas bijieensis strain 2P24, indicating an ecological fitness advantage that could promote resistant population expansion in agriculture environments. The same regulatory pathway is conserved in human pathogen Pseudomonas aeruginosa PAO1 via the functional ortholog NalD, suggesting that this mechanism may be widespread in Pseudomonas. These findings fill a critical gap in understanding non-target-based mupirocin resistance, clarify the ecological drivers of antimicrobial resistance (AMR), and offer practical insight for improving mupirocin application to limit the emergence and spread of resistant pathogens.

microbiology↗

bioRxiv2018

Testing Causal Bidirectional Influences between Physical Activity and Depression using Mendelian Randomization

BackgroundBurgeoning evidence from randomized controlled trials and prospective cohort studies suggests that physical activity protects against depression, pointing to a potential modifiable target for prevention. However, the direction of this inverse association is not clear: physical activity may reduce risk for depression, and/or depression may result in decreased physical activity. Here, we used bidirectional two-sample Mendelian randomization (MR) to test causal influences between physical activity and depression.\n\nMethodsFor genetic instruments, we selected independent top SNPs associated with major depressive disorder (MDD, N = 143,265) and two physical activity phenotypes--self-reported (N = 377,234) and objective accelerometer-based (N = 91,084)--from the largest available, non-overlapping genome-wide association results. We used two sets of genetic instruments: (1) only SNPs previously reported as genome-wide significant, and (2) top SNPs meeting a more relaxed threshold (p < 1x10-7). For each direction of influence, we combined the MR effect estimates from each instrument SNP using inverse variance weighted (IVW) meta-analysis, along with other standard MR methods such as weighted median, MR-Egger, and MR-PRESSO.\n\nResultsWe found evidence for protective influences of accelerometer-based activity on MDD (IVW odds ratio (OR) = 0.74 for MDD per 1 SD unit increase in average acceleration, 95% confidence interval (CI) = 0.59-0.92, p =.006) when using SNPs meeting the relaxed threshold (i.e., 10 versus only 2 genome-wide significant SNPs, which provided insufficient data for sensitivity analyses). In contrast, we found no evidence for negative influences of MDD on accelerometer-based activity (IVW b = 0.04 change in average acceleration for MDD versus control status, 95% CI = -0.43-0.51, p =.87). Furthermore, we did not see evidence for causal influences between self-reported activity and MDD, in either direction and regardless of instrument SNP criteria.\n\nDiscussionWe apply MR for the first time to examine causal influences between physical activity and MDD. We discover that objectively measured--but not self-reported--physical activity is inversely associated with MDD. Of note, prior work has shown that accelerometer-based physical activity is more heritable than self-reported activity, in addition to being more representative of actual movement. Our findings validate physical activity as a protective factor for MDD and point to the importance of objective measurement of physical activity in epidemiological studies in relation to mental health. Overall, this study supports the hypothesis that enhancing physical activity is an effective prevention strategy for depression.

genetics↗

bioRxiv2018

Prospective Study of Polygenic Risk, Protective Factors, and Incident Depression Following Combat Deployment in US Army Soldiers

BackgroundWhereas genetic susceptibility increases risk for major depressive disorder (MDD), non-genetic protective factors may mitigate this risk. In a large-scale prospective study of US Army soldiers, we examined whether trait resilience and/or unit cohesion could buffer against the onset of MDD following combat deployment, even in soldiers at high polygenic risk.\n\nMethodsData were analyzed from 4,182 soldiers of European ancestry assessed before and after their deployment to Afghanistan. Incident MDD was defined as no MDD episode at predeployment, followed by a MDD episode following deployment. Polygenic risk scores were constructed from the largest available MDD genome-wide association study. We first examined main effects of the MDD PRS and each protective factor on incident MDD. We then tested effects of each protective factor on incident MDD across strata of polygenic risk.\n\nResultsPolygenic risk showed a dose-response relationship to depression, such that soldiers at high polygenic risk had greatest odds for incident MDD. Both unit cohesion and trait resilience were prospectively associated with reduced risk for incident MDD. Notably, the protective effect of unit cohesion persisted even in soldiers at highest polygenic risk.\n\nConclusionsPolygenic risk was associated with new-onset MDD in deployed soldiers. However, unit cohesion--an index of perceived support and morale--was protective against incident MDD even among those at highest genetic risk, and may represent a potent target for promoting resilience in vulnerable soldiers. Findings illustrate the value of combining genomic and environmental data in a prospective design to identify robust protective factors for mental health.

genetics↗