Biology subjects

Kuo, S.

Publications and source records attributed to Kuo, S..

6 recordsLinked to original sources

bioRxiv2026

Selective Sugar Transport Supports Proteus mirabilis Fitness in the Urinary Tract

Proteus mirabilis is a leading cause of complicated urinary tract infections (UTIs). Prior work showed P. mirabilis metabolizes sugars during experimental UTI, yet the role of sugar import systems in pathogenesis remains poorly defined. To investigate this, we generated a panel of 47 targeted mutants in predicted sugar transporter genes and assessed their growth in vitro and fitness in vivo. Growth screening in nutrient-rich and minimal media revealed carbon source-dependent defects in several phosphotransferase system (PTS) mutants, including ptsH and ptsI. Pooled insertion sequencing (In-seq) identified xapB, ptsH, and ptsI as in vivo fitness factors, with validation in a traditional murine co-challenge model. Functional studies showed that xapB, annotated as a xanthosine permease, did not support xanthosine or guanosine uptake in P. mirabilis, suggesting misannotation. Dissection of the PTS network revealed that a triple mutant lacking scrA, ulaC, and ptsG recapitulated the ptsH phenotype in vivo. To evaluate whether increased sugar availability exacerbates these defects, we modeled glucosuria using the SGLT2 inhibitor dapagliflozin in CBA/J mice. Dapagliflozin treatment significantly increased urinary glucose and enhanced P. mirabilis colonization. There was an inverse correlation between colonization and urinary glucose, but only in untreated mice. These findings reveal limitations in genome-based transporter annotation, establish a functional link between sugar import and P. mirabilis fitness during UTI, and demonstrate that host metabolic conditions such as glucosuria can influence the severity of infection. AUTHOR SUMMARYAll living organisms require nutrients to grow, survive, and cause disease. Bacteria like Proteus mirabilis, which causes urinary tract infections, rely on specialized systems to import and metabolize sugars available in the host environment. In this study, we systematically disrupted 47 genes predicted to encode sugar transporters in P. mirabilis and tested their contribution to infection in a mouse model. We identified three key genes (xapB, ptsH, and ptsI) that were critical for colonization. Further analysis showed that many sugar transporters in P. mirabilis were misannotated, and predicted substrates like sucrose and cellobiose were not utilized by the bacterium. We also demonstrated that high sugar conditions, mimicking diabetic urine using the drug dapagliflozin, worsened infection and increased disease severity. These results highlight the importance of carbohydrate acquisition for P. mirabilis during infection and emphasize the need to experimentally validate gene function rather than rely on predictions based on other bacteria like E. coli.

microbiology↗

bioRxiv2026

Bacteroides intestinalis-Driven Arabinoxylan Fermentation Mitigates Inflammatory and Metabolic Dysfunction

Insufficient dietary fiber intake is closely linked to gut microbiome dysfunction and increased risk of noncommunicable diseases. Synergistic synbiotics, pairing defined microbes with their dietary substrates, offer a precise strategy to restore microbiome function. Here, we show that pairing the human colonic commensal Bacteroides intestinalis with insoluble wheat arabinoxylan (inWAX) yields pronounced metabolic and anti-inflammatory benefits. Using mono-associated gnotobiotic mice and high-fat diet-induced obese mice, we demonstrate that this synbiotic enhances resistance to intestinal inflammation and improves glucose homeostasis. Mechanistically, this synbiotic increases production of 6-hydroxylated bile acids with anti-diabetic and anti-steatotic effects. It also promotes microbial transformation of phenolic compounds and redirects protein metabolism toward neuroactive metabolites. These metabolic shifts are accompanied by transcriptional remodeling in the colon, spleen and liver, involving induction of genes essential for circadian rhythm, lipid metabolism, immune defense, and bile acid 6-hydroxylation. Notably, Y chromosome-linked genes associated with epigenetic regulation and protein turnover are also induced, suggesting a potential sex-specific response to synbiotics. Together, our findings establish a mechanistic framework for targeted synbiotic interventions to combat inflammatory and metabolic disorders.

microbiology↗

bioRxiv2025

Sp Transcription Factors Establish the Signaling Environment in the Neuromesodermal Progenitor Niche During Axial Elongation

Neuromesodermal competent progenitors (NMCs) are located in the caudal epiblast near the node and primitive streak and give rise to spinal cord and somitic mesoderm during trunk and tail elongation. Their self-renewal depends on an autoregulatory loop involving Wnt3a and Fgf signaling, and the Tbxt and Cdx transcription factors, but the mechanisms underlying loop formation and the establishment of the niche are poorly understood. Here, we identify the zinc-finger transcription factors Sp5 and Sp8 (Sp5/8) as essential regulators of NMC maintenance. Sp5/8 expression is controlled by Wnt, Fgf and retinoic acid signaling, and they cooperate with Tbxt, Tcf7 and Cdx2 to sustain a robust autoregulatory network that promotes high Wnt/Fgf and low retinoic acid activity in the niche. These factors bind a novel enhancer essential for Wnt3a expression and feedback-loop integrity. Mechanistically, Sp5/8 regulate the dynamic exchange of activating and repressive Tcf complexes at Wnt-responsive enhancers. Our findings define a transcriptional module centered on Sp5/8 that stabilizes niche signaling and transcriptional circuitry essential for NMC fate decisions and trunk development.

developmental biology↗

bioRxiv2024

Transcriptomic landscape of human induced pluripotent stem cell-derived osteogenic differentiation identifies a regulatory role of KLF16

Osteogenic differentiation is essential for bone development, metabolism, and repair; however, the underlying regulatory relationships among genes remain poorly understood. To elucidate the transcriptomic changes and identify novel regulatory genes involved in osteogenic differentiation, we differentiated mesenchymal stem cells (MSCs) derived from 20 human iPSC lines into preosteoblasts (preOBs) and osteoblasts (OBs). We then performed transcriptome profiling of MSCs, preOBs and OBs. The iPSC-derived MSCs and OBs showed similar transcriptome profiles to those of primary human MSCs and OBs, respectively. Differential gene expression analysis revealed global changes in the transcriptomes from MSCs to preOBs, and then to OBs, including the differential expression of 840 genes encoding transcription factors (TFs). TF regulatory network analysis uncovered a network comprising 451 TFs, organized into five interactive modules. Multiscale embedded gene co-expression network analysis (MEGENA) identified gene co-expression modules and key network regulators (KNRs). From these analyses, KLF16 emerged as an important TF in osteogenic differentiation. We demonstrate that overexpression of Klf16 in vitro inhibited osteogenic differentiation and mineralization, while Klf16+/- mice exhibited increased bone mineral density, trabecular number, and cortical bone area. Our study underscores the complexity of osteogenic differentiation and identifies novel regulatory genes such as KLF16, which plays an inhibitory role in osteogenic differentiation both in vitro and in vivo.

molecular biology↗

bioRxiv2019

A simple mass-action model predicts protein timecourses from mRNA trajectories during a dynamic response in two strains of S. cerevisiae

Although mRNA is a necessary precursor to protein, several studies have argued that the relationship between mRNA and protein levels is often weak. This claim undermines the functional relevance of conclusions based on quantitative analyses of mRNA levels, which are ubiquitous in modern biology from the single gene to the whole genome scale. Furthermore, if post-translational processes vary between strains and species, then comparative studies based on mRNA alone would miss an important driver of diversity. However, gene expression is dynamic, and most studies examining relationship between mRNA and protein levels at the genome scale have analyzed single timepoints. We measure yeast gene expression after pheromone exposure and show that, for most genes, protein timecourses can be predicted from mRNA timecourses through a simple, gene-specific, generative model. By comparing model parameters and predictions between strains, we find that while mRNA variation often leads to protein differences, evolution also manipulates protein-specific processes to amplify or buffer transcriptional regulation.

genomics↗

bioRxiv2019

Polygenic Risk for Alcohol Misuse is Moderated by Romantic Partnerships: Primarily in Men

ImportanceProblematic alcohol use remains a leading influence on preventable mortality and morbidity across the globe. Those in committed relationships consistently report lower levels of alcohol misuse and problems. ObjectiveTo determine 1) whether genetic risk for alcohol misuse is moderated by romantic relationships (gene-environment interaction; GxE), and 2) whether GxE results are consistent across sex. DesignData came from the young adult wave of the Finnish Twin Study (FinnTwin12), a nationally representative sample of twins. Predictors included genome-wide polygenic scores (GPS), derived from a recent genome-wide association study (GWAS) of alcohol consumption in ~1 million participants; and participant reports of relationship status. SettingFinland ParticipantsAn intensively studied subset of FinnTwin12 received a diagnostic interview during the young adult phase (1,312 of 1,347 individuals provided genotypic data). The analytic sample includes those with complete interview and genetic data (N=1,201, 54% female). ExposureSelf-reported involvement in a romantic partnership. Main Outcomes and MeasuresDrinking frequency, intoxication frequency, and DSM-IV alcohol dependence (AD) symptoms from a diagnostic interview. ResultsGPS predicted drinking frequency (b = 0.109; 95% CI = 0.051, 0.167), intoxication frequency (b = 0.111; 95% CI = 0.054, 0.168), and AD symptoms (b = 0.123; 95% CI = 0.064, 0.182). Relationship moderated the association between GPS and drinking frequency (b = -0.105; 95% CI = -0.211, -0.001), intoxication frequency (b = -0.118; 95% CI = -0.220, -0.015), and AD symptoms (b = -0.119; 95% CI = -0.229, -0.010). The interaction for drinking frequency was not significant after correcting for covariates. There was a 3-way interaction between sex, relationship status, and GPS for intoxication frequency (b = 0.223; 95% CI = 0.014, 0.432), with the two-way interaction of relationship status and PRS on intoxication frequency being significant only in men. Conclusions and RelevanceBeing in a relationship reduced the association between genetic predisposition and high risk drinking. Part of the protective effect of committed partnerships on alcohol misuse observed in epidemiological research may be in limiting genetic liability. However, this protective effect was largely limited to males, mapping onto earlier findings suggesting that males benefit more from romantic partnerships. Key PointsO_ST_ABSQuestionC_ST_ABSDo romantic relationships moderate polygenic risk on alcohol misuse in young adulthood? FindingsInvolvement in romantic relationships moderated the polygenic risk on frequency of intoxication and DSM-IV alcohol dependence symptoms, such that polygenic associations with alcohol misuse were stronger among those not in a romantic relationship. Males experienced a stronger protective effect of romantic relationship in limiting the manifestation of genetic predispositions toward intoxication frequency. MeaningThe interplay between genes and environment is important in understanding etiology of problematic alcohol use, and romantic relationships appear to buffer genetic risk for alcohol misuse in young adulthood. Findings underscore how social relationships may alter the risk posed by genetic predispositions.

epidemiology↗