Biology subjects

Nguyen, U.

Publications and source records attributed to Nguyen, U..

8 recordsLinked to original sources

bioRxiv2025

Trabecular structure correlates with leaping distance in tamarins

ObjectivesThe intricate trabecular architecture of long-bone epiphyses underpins functional adaptations for diverse mammalian locomotion. Despite extensive study in other mammals, tamarin trabecular structure and fine-grained differences among leaping taxa remain poorly characterized. Materials and MethodsWe examined humeral and tibial trabecular networks in four tamarin species representing short- and long-distance leapers using {micro}CT-scans and a whole-epiphysis approach. We quantified network complexity with topological indices (node density, tortuosity, trabecular length, fractal dimension) alongside traditional metrics (degree of anisotropy [DA], bone volume fraction [BV/TV]) to capture both geometric and topological features. ResultsLong leapers exhibit significantly higher node density in both humeral and tibial epiphyses and increased trabecular tortuosity in the distal humerus. Elevated node density localizes beneath the humero-scapular joint, within the proximal humerus, and in variable regions across other epiphyses. Other parameters (DA, BV/TV, trabecular length, fractal dimension) showed no leaping-related differences, instead correlating with sex and captivity. DiscussionIncreased mechanical strain during longer leaps likely drives higher node density and, to a lesser extent, tortuosity in humeral and tibial epiphyses, with node density showing the strongest functional signal. While sex and captivity influence other trabecular traits, patterns in these key metrics support locomotor adaptation. Integrating whole-epiphysis analyses with novel topological indices enhances detection of subtle functional signals and complements VOI-based and traditional frameworks in comparative trabecular bone studies.

zoology↗

bioRxiv2023

Defense-related callose synthase PMR4 promotes root hair callose deposition and adaptation to phosphate deficiency in Arabidopsis thaliana

Plants acquire phosphorus (P) primarily as inorganic phosphate (Pi) from the soil. Under Pi deficiency, plants induce an array of physiological and morphological responses, termed phosphate starvation response (PSR), thereby increasing Pi acquisition and use efficiency. However, the mechanisms by which plants adapt to Pi deficiency remain to be elucidated. Here, we report that deposition of a {beta}-1,3-glucan polymer called callose is induced in Arabidopsis thaliana root hairs under Pi deficiency, in a manner independent of PSR-regulating PHR1/PHL1 transcription factors and LPR1/LPR2 ferroxidases. Genetic studies revealed PMR4 (GSL5) callose synthase being required for the callose deposition in Pi-depleted root hairs. Loss of PMR4 also reduces Pi acquisition in shoots and plant growth under low Pi conditions. The defects are not recovered by simultaneous disruption of SID2, mediating defense-associated salicylic acid (SA) biosynthesis, excluding SA defense activation from the cause of the observed pmr4 phenotypes. Grafting experiments and characterization of plants expressing PMR4 specifically in root hair cells suggest that a PMR4 pool in the cell type contributes to shoot growth under Pi deficiency. Our findings thus suggest an important role for PMR4 in plant adaptation to Pi deficiency. Significance statementWe reveal that PMR4 callose synthase mediates callose deposition in root hairs under phosphate (Pi) deficiency, without requiring Pi starvation response regulators PHR1/PHL1 or LPR1/LPR2. The loss of the callose deposition is accompanied by decreases in Pi acquisition and plant growth in pmr4. Root hair cell-specific PMR4 expression restores callose deposition in root hairs and shoot growth under Pi deficiency, indicating a critical role for root hair callose in plant adaptation to Pi deficiency.

plant biology↗

bioRxiv2021

Transcriptomic and proteomic retinal pigment epithelium signatures of age-related macular degeneration.

Induced pluripotent stem cells generated from patients with geographic atrophy as well as healthy individuals were differentiated to retinal pigment epithelium (RPE) cells. By integrating transcriptional profiles of 127,659 RPE cells generated from 43 individuals with geographic atrophy and 36 controls with genotype data, we identified 439 expression Quantitative Trait (eQTL) loci in cis that were associated with disease status and specific to subpopulations of RPE cells. We identified loci linked to two genes with known associations with geographic atrophy - PILRB and PRPH2, in addition to 43 genes with significant genotype x disease interactions that are candidates for novel genetic associations for geographic atrophy. On a transcriptome-only level, we identified molecular pathways significantly upregulated in geographic atrophy-RPE including in extracellular cellular matrix reorganisation, neurodegeneration, and mitochondrial functions. We subsequently implemented a large-scale proteomics analysis, confirming modification in proteins associated with these pathways. We also identified six significant protein (p) QTL that regulate protein expression in the RPE cells and in geographic atrophy - two of which share variants with cis-eQTL. Transcriptome-wide association analysis identified genes at loci previously associated with age-related macular degeneration. Further analysis conditional on disease status, implicated statistically significant RPE-specific eQTL. This study uncovers important differences in RPE homeostasis associated with geographic atrophy.

neuroscience↗

bioRxiv2021

Village in a dish: a model system for population-scale hiPSC studies

The mechanisms by which DNA alleles contribute to disease risk, drug response, and other human phenotypes are highly context-specific, varying across cell types and under different conditions. Human induced pluripotent stem cells (hiPSCs) are uniquely suited to study these context-dependent effects, but to do so requires cell lines from hundreds or potentially thousands of individuals. Village cultures, where multiple hiPSC lines are cultured and differentiated together in a single dish, provide an elegant solution for scaling hiPSC experiments to the necessary sample sizes required for population-scale studies. Here, we show the utility of village models, demonstrating how cells can be assigned back to a donor line using single cell sequencing, and addressing whether line-specific signaling alters the transcriptional profiles of companion lines in a village culture. We generated single cell RNA sequence data from hiPSC lines cultured independently (uni-culture) and in villages at three independent sites. We show that the transcriptional profiles of hiPSC lines are highly consistent between uni- and village cultures for both fresh (0.46 < R < 0.88) and cryopreserved samples (0.46 < R < 0.62). Using a mixed linear model framework, we estimate that the proportion of transcriptional variation across cells is predominantly due to donor effects, with minimal evidence of variation due to culturing in a village system. We demonstrate that the genetic, epigenetic or hiPSC line-specific effects on gene expression are consistent whether the lines are uni- or village-cultured (0.82 < R < 0.94). Finally, we identify the consistency in the landscape of cell states between uni- and village-culture systems. Collectively, we demonstrate that village methods can be effectively used to detect hiPSC line-specific effects including sensitive dynamics of cell states.

genomics↗

bioRxiv2021

Retinal ganglion cell-specific genetic regulation in primary open angle glaucoma

To assess the transcriptomic profile of disease-specific cell populations, fibroblasts from patients with primary open-angle glaucoma (POAG) were reprogrammed into induced pluripotent stem cells (iPSCs) before being differentiated into retinal organoids and compared to those from healthy individuals. We performed single-cell RNA-sequencing of a total of 330,569 cells and identified cluster-specific molecular signatures. Comparing the gene expression profile between cases and controls, we identified novel genetic associations for this blinding disease. Expression quantitative trait mapping identified a total of 2,235 significant loci across all cell types, 58 of which are specific to the retinal ganglion cell subpopulations, which ultimately degenerate in POAG. Transcriptome-wide association analysis identified genes at loci previously associated with POAG, and analysis, conditional on disease status, implicated 54 statistically significant retinal ganglion cell-specific expression quantitative trait loci. This work highlights the power of large-scale iPSC studies to uncover context-specific profiles for a genetically complex disease.

genetics↗

bioRxiv2020

BBrowser: Making single-cell data easily accessible

BioTurings BBrowser is a software solution that helps scientists effectively analyze single-cell omics data. It combines big data with big computation and modern data visualization to create a unique platform where scientists can interact and obtain important biological insights from the massive amounts of single-cell data. BBrowser has three main components: a curated single-cell database, a big-data analytics layer, and a data visualization module. BBrowser is available for download at: https://bioturing.com/bbrowser/download.

bioinformatics↗

bioRxiv2019

Thiostrepton hijacks pyoverdine receptors to inhibit growth of Pseudomonas aeruginosa

Pseudomonas aeruginosa is a biofilm-forming opportunistic pathogen and intrinsically resistant to many antibiotics. In a high-throughput screen for molecules that modulate biofilm formation, we discovered that the thiopeptide antibiotic, thiostrepton (TS) - considered inactive against Gram-negative bacteria - stimulated P. aeruginosa biofilm formation in a dose-dependent manner. This phenotype is characteristic of exposure to antimicrobial compounds at sub-inhibitory concentrations, suggesting that TS was active against P. aeruginosa. Supporting this observation, TS inhibited growth of a panel of 96 multidrug-resistant (MDR) P. aeruginosa clinical isolates at low micromolar concentrations. TS also had activity against Acinetobacter baumannii clinical isolates. Expression of Tsr - a 23S rRNA-modifying methyltransferase - in trans conferred TS resistance, confirming that the drug acted via its canonical mode of action, inhibition of ribosome function. Deletion of oligopeptide permease systems used by other peptide antibiotics for uptake failed confer TS resistance. TS susceptibility was inversely proportional to iron availability, suggesting that TS exploits uptake pathways whose expression is increased under iron starvation. Consistent with this finding, TS activity against P. aeruginosa and A. baumannii was potentiated by FDA-approved iron chelators deferiprone and deferasirox. Screening of P. aeruginosa mutants for TS resistance revealed that it exploits pyoverdine receptors FpvA and FpvB to cross the outer membrane. Our data show that the biofilm stimulation phenotype can reveal cryptic sub-inhibitory antibiotic activity, and that TS has activity against select multidrug resistant Gram-negative pathogens under iron-limited growth conditions, similar to those encountered at sites of infection.

microbiology↗

bioRxiv2017

A semi-lethal CRISPR-Cas system permits DNA acquisition in Enterococcus faecalis

Antibiotic resistant bacteria are critical public health concerns. Among the prime causative factors for the spread of antibiotic resistance is horizontal gene transfer (HGT). A useful model organism for investigating the relationship between HGT and antibiotic resistance is the opportunistic pathogen Enterococcus faecalis, since the species possesses highly conjugative plasmids that readily disseminate antibiotic resistance genes and virulence factors in nature. Unlike many commensal E. faecalis strains, the genomes of multidrug-resistant (MDR) E. faecalis clinical isolates are enriched for mobile genetic elements (MGEs) and lack CRISPR-Cas genome defense systems. CRISPR-Cas systems cleave foreign DNA in a programmable, sequence-specific manner and are disadvantageous for MGE-derived genome expansion. An unexplored facet of CRISPR biology in E. faecalis is that MGEs that are targeted by native CRISPR-Cas systems can be transiently maintained. Here, we investigate the basis for this \"CRISPR tolerance.\" We observe that E. faecalis can maintain self-targeting constructs that direct Cas9 to cleave the chromosome, but at a fitness cost. Interestingly, DNA repair genes were not up-regulated during self-targeting, but integrated prophages were strongly induced. We determined that low cas9 expression contributes to this transient non-lethality and use this knowledge to develop a robust CRISPR-assisted genome editing scheme. Our results suggest that E. faecalis has maximized the potential for DNA acquisition by attenuating its CRISPR machinery, thereby facilitating acquisition of potentially beneficial MGEs that may otherwise be restricted by genome defense.\n\nImportanceCRISPR-Cas has provided a powerful toolkit to manipulate bacteria, resulting in improved genetic manipulations and novel antimicrobials. These powerful applications rely on the premise that CRISPR-Cas chromosome targeting, which leads to double-stranded DNA breaks, is lethal. In this study, we show that chromosomal CRISPR targeting in Enterococcus faecalis is transiently non-lethal. We uncover novel phenotypes associated with this \"CRISPR tolerance\" and, after determining its genetic basis, develop a genome editing platform in E. faecalis with negligible off-target effects. Our findings reveal a novel strategy exploited by a bacterial pathogen to cope with CRISPR-induced conflicts to more readily accept DNA, and our robust CRISPR editing platform will help simplify genetic modifications in this organism.

microbiology↗