Biology subjects

Hsu, C.-Y.

Publications and source records attributed to Hsu, C.-Y..

At least 19 recordsLinked to original sources

bioRxiv2026

Targeting catecholate siderophore systems enables precision depletion of gut enterobacteria during colitis

Adherent-invasive Escherichia coli (AIEC) is frequently isolated from the dysbiotic gut microbiome in inflammatory bowel disease and is implicated in disease progression, highlighting its potential as a therapeutic target. Here we show that iron acquisition is essential for AIEC colonization of the inflamed gut. Mechanistically, four catecholate siderophore receptors act redundantly to support AIEC growth under iron-limited conditions and during colitis. Immunization of colitis-prone Il10-/- mice against catecholate siderophores reduced intestinal AIEC colonization, particularly its association with the mucosa, while largely preserving overall gut microbiome composition. Longitudinal metagenomic profiling identified immunization-associated shifts in Akkermansiaceae and Lactobacillaceae, and experiments in gnotobiotic Il10-/- mice demonstrated that Limosilactobacillus reuteri, a member of the Lactobacillaceae, limited AIEC colonization, whereas Akkermansiaceae exacerbated disease. Our findings establish catecholate siderophore-mediated iron acquisition as a therapeutic target in AIEC and provide proof-of-principle that virulence-targeted immunization can selectively antagonize a disease-associated bacterium while preserving the gut microbiota

microbiology↗

bioRxiv2026

Autoimmune diabetes-dependent c-Maf SUMOylation licenses inflammatory bowel disease by reshaping the gut microbiota

We have previously demonstrated a critical role of c-Maf SUMOylation in the regulation of autoimmune diabetogenesis, but its physiological relevance to and potential clinical impact on gut inflammation need further elucidation. Here, integrating a 14-year population-based time-trend cohort study of 139,204 type 1 diabetes patients with experiments in non-obese diabetic mice, we illustrated that autoimmune diabetes confers resistance to colitis mediated by an impaired c-Maf SUMOylation-driven IL-21-IgA axis. Utilizing T cell-specific c-Maf SUMOylation site-mutated mice, we further demonstrated that SUMOylation-defective c-Maf enhances IL-21 expression in CD4+ T cells to promote fecal IgA production and colitis resistance via microbiota remodeling, specifically through Lactobacillus johnsonii enrichment and activating lithocholic acid (LCA)-mediated AMPK anti-inflammatory pathway. Pharmacological HDAC2 inhibition by BRD6688 promotes c-Maf-mediated IL-21 and suppresses colitis in PBMC-humanized mice. Altogether, we revealed how SUMOylation reciprocally modulates the inflammatory process between autoimmune diabetes and colitis in a T cell-restricted and single transcription factor-based manner.

immunology↗

bioRxiv2025

Commensal Escherichia coli colonization triggers Peyer's patch development

The gut microbiota plays a pivotal role in shaping mucosal immunity, yet the specific microbes contributing to lymphoid tissue development remain poorly defined. Here, we identify Escherichia coli, a pioneer commensal bacterium, as a key driver of naive B cell accumulation in gut Peyers patches and lamina propria via a CXCR2-dependent mechanism. We show that E. coli promotes B cell recruitment through the production of curli amyloid fibers, which signal via Toll-like receptor 2 (TLR2). Notably, this effect extends beyond the neonatal period, revealing a broader temporal window for microbial modulation of mucosal immune development. These findings reveal a previously unrecognized role for a defined gut commensal bacterium and its molecular products in orchestrating the formation of gut-associated lymphoid tissue and B cell recruitment.

microbiology↗

bioRxiv2025

Comparative population genomics of relictual Caribbean island Gossypium hirsutum

Gossypium hirsutum is the worlds most important source of cotton fiber, yet the diversity and population structure of its wild forms remain largely unexplored. The complex domestication history of G. hirsutum combined with reciprocal introgression with a second domesticated species, G. barbadense, has generated a wealth of morphological forms and feral derivatives of both species and their interspecies recombinants, which collectively are scattered across a large geographic range in arid regions of the Caribbean basin. Here we assessed genetic diversity within and among populations from two Caribbean islands, Puerto Rico (n = 43, five sites) and Guadeloupe (n = 25, one site), which contain putative wild and/or introgressed forms. Using whole-genome resequencing data and a phylogenomic framework derived from a broader genomic survey, we parsed individuals into feral derivatives and truly wild forms. Feral cottons display uneven levels of genetic and morphological resemblance to domesticated cottons, with diverse patterns of genetic variation and heterozygosity. These patterns are inferred to reflect a complex history of interspecific and intraspecific gene flow that is spatially highly variable in its effects. Wild cottons in both Caribbean islands appear to be relatively inbred, especially the Guadeloupe samples. Our results highlight the dynamics of population demographics in relictual wild cottons that experienced profound genetic bottlenecks associated with repeated habitat destruction superimposed on a natural ecogeographical distribution comprising widely scattered populations. These results have implications for conservation and utilization of wild diversity in G. hirsutum.

evolutionary biology↗

bioRxiv2024

Exploring The Formation And Permeability Of Plasmodesmata In The Liverwort, Marchantia polymorpha

Plasmodesmata are cell-wall-embedded channels that evolved in the common ancestor of land plants to increase cell-to-cell communication. Whether all the fundamental properties of plasmodesmata emerged and were inherited in all land plants at the same time is unknown. Here we show that the bryophyte Marchantia polymorpha (a non-vascular plant) forms mostly simple plasmodesmata in early-developing gemmae. The complexity of plasmodesmata increases during gemma maturation, and complex plasmodesmata with enlarged cavities are majorly observed in thalli. In contrast to vascular plants, whose simple plasmodesmata can transport monomeric fluorescent proteins, plasmodesmata in Marchantia polymorpha limited their permeability before the juvenile-to-adult transition. In support, callose, a known polysaccharide regulating plasmodesmata permeability in vascular plants, accumulated in most of the Marchantia polymorpha tissues examined. Furthermore, we found that in the apical meristematic region, plasmodesmata allowed the transport of monomeric fluorescent proteins, and this relaxation might correlate with the lower accumulation of callose. Taken together, our study suggests that certain plasmodesmata properties, such as complexity progression and callose accumulation, may have evolved before the divergence between vascular and non-vascular plants.

plant biology↗

bioRxiv2024

Assessment of the Genetic Diversity of Atlantic Bottlenose Dolphin (Tursiops truncatus) Strandings in the Mississippi Sound (USA)

The common bottlenose dolphin (Tursiops truncatus) is a key marine mammal species in the northern Gulf of Mexico, playing an essential role as a top predator. This study focuses on the genetic diversity and population structure of bottlenose dolphins stranded in the Mississippi Sound from 2010 to 2021. A total of 511 tissue samples (muscle, liver, lung, kidney, and brain) were collected from stranded dolphins, and mitochondrial DNA (mtDNA) was extracted for analysis. Using high-throughput sequencing methods, 417 samples were successfully amplified and sequenced, producing 386 complete mitogenomes. Genetic diversity metrics, such as nucleotide and haplotype diversity, were calculated, and population structure was inferred for both mitochondrial control region (mtCR) and whole mitogenome sequences. Using the whole mitogenome, the study identified four genetically distinct populations within the Mississippi Sound, demonstrating regional variation in dolphin populations. Notably, some individuals likely originated from populations outside the sampled area. The use of whole mitogenomes allowed for improved resolution of genetic diversity and population differentiation compared to previous studies using partial mtDNA sequences. These findings provide critical insights into the genetic structure of bottlenose dolphins in the region and highlight the value of using stranded animals for population genetic studies.

genomics↗

bioRxiv2024

Pathogenic Bacteroides fragilis strains can emerge from gut-resident commensals

Bacteroides fragilis is a prominent member of the human gut microbiota, playing crucial roles in maintaining gut homeostasis and host health. Although it primarily functions as a beneficial commensal, B. fragilis can become pathogenic. To determine the genetic basis of its duality, we conducted a comparative genomic analysis of 813 B. fragilis strains, representing both commensal and pathogenic origins. Our findings reveal that pathogenic strains emerge across diverse phylogenetic lineages, due in part to rapid gene exchange and the adaptability of the accessory genome. We identified 16 phylogenetic groups, differentiated by genes associated with capsule composition, interspecies competition, and host interactions. A microbial genome-wide association study identified 44 genes linked to extra-intestinal survival and pathogenicity. These findings reveal how genomic diversity within commensal species can lead to the emergence of pathogenic traits, broadening our understanding of microbial evolution in the gut.

microbiology↗

bioRxiv2023

Pangenome comparison of Bacteroides fragilis genomospecies unveil genetic diversity and ecological insights

Bacteroides fragilis is a Gram-negative commensal bacterium commonly found in the human colon that differentiates into two genomospecies termed division I and II. We leverage a comprehensive collection of 694 B. fragilis whole genome sequences and report differential gene abundance to further support the recent proposal that divisions I and II represent separate species. In division I strains, we identify an increased abundance of genes related to complex carbohydrate degradation, colonization, and host niche occupancy, confirming the role of division I strains as gut commensals. In contrast, division II strains display an increased prevalence of plant cell wall degradation genes and exhibit a distinct geographic distribution, primarily originating from Asian countries, suggesting dietary influences. Notably, division II strains have an increased abundance of genes linked to virulence, survival in toxic conditions, and antimicrobial resistance, consistent with a higher incidence of these strains in bloodstream infections. This study provides new evidence supporting a recent proposal for classifying divisions I and II B. fragilis strains as distinct species, and our comparative genomic analysis reveals their niche-specific roles.

genomics↗

bioRxiv2023

A bacterial sialidase mediates early life colonization by a pioneering gut commensal

The early microbial colonization of the gastrointestinal tract can lead to long-term impacts in development and overall human health. Keystone species, including Bacteroides spp., play a crucial role in maintaining the structure, diversity, and function of the intestinal ecosystem. However, the process by which a defined and resilient community is curated and maintained during early life remains inadequately understood. Here, we show that a single sialidase, NanH, in Bacteroides fragilis mediates stable occupancy of the intestinal mucosa and regulates the commensal colonization program during the first weeks of life. This program is triggered by sialylated glycans, including those found in human milk oligosaccharides and intestinal mucus. After examining the dynamics between pioneer gut Bacteroides species in the murine gut, we discovered that NanH enables vertical transmission from dams to pups and promotes B. fragilis dominance during early life. Furthermore, we demonstrate that NanH facilitates commensal resilience and recovery after antibiotic treatment in a defined microbial community. Collectively, our study reveals a co-evolutionary mechanism between the host and the microbiota mediated through host-derived glycans to promote stable intestinal colonization.

microbiology↗

bioRxiv2023

A Taxonomically-informed Mass Spectrometry Search Tool for Microbial Metabolomics Data

MicrobeMASST, a taxonomically-informed mass spectrometry (MS) search tool, tackles limited microbial metabolite annotation in untargeted metabolomics experiments. Leveraging a curated database of >60,000 microbial monocultures, users can search known and unknown MS/MS spectra and link them to their respective microbial producers via MS/MS fragmentation patterns. Identification of microbial-derived metabolites and relative producers, without a priori knowledge, will vastly enhance the understanding of microorganisms role in ecology and human health.

microbiology↗

bioRxiv2023

Selective IL-27 production by intestinal regulatory T cells permits gut-specific regulation of Th17 immunity

Regulatory T (Treg) cells are instrumental in establishing immunological tolerance. However, the precise effector mechanisms by which Treg cells control a specific type of immune response in a given tissue remains unresolved. By simultaneously studying Treg cells from different tissue origins under systemic autoimmunity, here we show that IL-27 is specifically produced by intestinal Treg cells to regulate Th17 immunity. Selectively increased intestinal Th17 responses in mice with Treg cell-specific IL-27 ablation led to exacerbated intestinal inflammation and colitis-associated cancer, but also helped protect against enteric bacterial infection. Furthermore, single-cell transcriptomic analysis has identified a CD83+TCF1+ Treg cell subset that is distinct from previously characterized intestinal Treg cell populations as the main IL-27 producers. Collectively, our study uncovers a novel Treg cell suppression mechanism crucial for controlling a specific type of immune response in a particular tissue, and provides further mechanistic insights into tissue-specific Treg cell-mediated immune regulation.

immunology↗

bioRxiv2022

A high-quality chromosome-level genome assembly of rohu carp, Labeo rohita, and its utilization in SNP-based exploration of gene flow and sex determination

Labeo rohita (rohu) is a carp important to aquaculture in South Asia, with a production volume close to Atlantic salmon. While genetic improvements to rohu are ongoing, the genomic methods commonly used in other aquaculture improvement programs have historically been precluded in rohu, partially due to the lack of a high quality reference genome. Here we present a high-quality de novo genome produced using a combination of next-generation sequencing technologies, resulting in a 946 Mb genome consisting of 25 chromosomes and 2,844 unplaced scaffolds. Notably, while approximately half the size of the existing genome sequence, our genome represents 97.9% of the genome size newly estimated here using flow cytometry. Sequencing from 120 individuals was used in conjunction with this genome to predict the population structure, diversity, and divergence in three major rivers (Jamuna, Padma, and Halda), in addition to infer a likely sex determination mechanism in rohu. These results demonstrate the utility of the new rohu genome in modernizing some aspects of rohu genetic improvement programs.

genomics↗

bioRxiv2022

Scalable and model-free detection of spatial patterns and colocalization

The expeditious growth in spatial omics technologies enable profiling genome-wide molecular events at molecular and single-cell resolution, highlighting a need for fast and reliable methods to characterize spatial patterns. We developed SpaGene, a model-free method to discover any spatial patterns rapidly in large scale spatial omics studies. Analyzing simulation and a variety of spatial resolved transcriptomics data demonstrated that SpaGene is more powerful and scalable than existing methods. Spatial expression patterns by SpaGene reconstructed unobserved tissue structures. SpaGene also successfully discovered ligand-receptor interactions through their colocalization.

bioinformatics↗

bioRxiv2021

Commensal bacteria promote type I interferon signaling to maintain immune tolerance

Type I interferons (IFN) exert a broad range of biological effects important in coordinating immune responses. Host and microbial factors regulate IFN production, triggering a signaling cascade that has classically been studied in the context of pathogen clearance. In particular, commensal bacteria have been shown to induce IFN to protect against viral infections. Yet, whether immunomodulatory bacteria operate through IFN pathways to support immune tolerance remains elusive. Here, we demonstrate microbiota-dependent IFN signaling is required for priming tolerogenic T regulatory cells (Tregs) by intestinal dendritic cells (DCs). DCs deficient in IFN signaling through deletion of IFNAR-1 display dysregulated cytokine production in response to the commensal bacteria Bacteroides fragilis, resulting in blunted downstream Treg responses. Single cell RNA sequencing of gut tissues demonstrated that colonization with B. fragilis promotes a distinct type I IFN gene signature in Tregs during homeostasis and intestinal inflammation. Moreover, B. fragilis-mediated protection during experimental colitis was abrogated in IFNAR1-deficient mice. Altogether, our findings demonstrate an important role of microbiota-mediated immune tolerance via tonic type I IFN signaling.

immunology↗

bioRxiv2020

Molecular insights into substrate recognition and discrimination by the N-terminal domain of Lon AAA+ protease

The Lon AAA+ proteases (LonA) is a ubiquitous ATP-dependent proteolytic machine, which selectively degrades damaged proteins or native proteins carrying exposed motifs (degrons). Here we characterize the structural basis for substrate recognition and discrimination by the N-terminal domain (NTD) of LonA. The results reveal that the six NTDs are attached to the hexameric LonA chamber by flexible linkers such that the formers tumble independently of the latter. Further spectral analyses show that the NTD selectively interacts with unfolded proteins, protein aggregates, and degron-tagged proteins by two hydrophobic patches of its N-lobe, but not intrinsically disordered substrate, -casein. Moreover, the NTD selectively binds to protein substrates when they are thermally induced to adopt unfolded conformations. Collectively, our findings demonstrate that NTDs enable LonA to perform protein quality control to selectively degrade proteins in damaged states and suggest that substrate discrimination and selective degradation by LonA are mediated by multiple NTD interactions. Impact StatementThe N-terminal domains enable Lon protease to discriminate and capture selected protein species for degradation by exposed hydrophobic patches and flexible linkages to the hexameric core complex.

biochemistry↗

bioRxiv2019

Comprehensive molecular characterization of pediatric treatment-induced high-grade glioma: A distinct entity despite disparate etiologies with defining molecular characteristics and potential therapeutic targets

Treatment-induced high-grade gliomas (TIHGGs) are an incurable late complication of cranial radiation therapy or combined radiation/chemotherapy used to treat pediatric cancer. We assembled a cohort of 33 TIHGGs from multiple institutions. The primary antecedent malignancies were medulloblastoma, acute lymphoblastic leukemia, astrocytoma, and ependymoma. We performed methylation profiling, RNA-seq, and genomic sequencing (whole-genome or whole-exome) on TIHGG samples. Methylation profiling revealed that TIHGGs cluster primarily with the pediatric receptor tyrosine kinase I subtype (26/31 samples). Common TIHGG copy-number alterations include Chromosome (Ch.) 1p loss/1q gain, Ch. 4 loss, Ch. 6q loss, and Ch. 13 and Ch. 14 loss; focal alterations include PDGFRA and CDK4 gain and loss of CDKN2A and BCOR. Relative to de novo pediatric high-grade glioma (pHGG), BCOR loss (p=0.004) and CDKN2A loss (p=0.005) were significantly increased. Transcriptomic analysis identified two distinct TIHGG subgroups, one with a lesser mutation burden (0.12 mut/Mb), Ch. 1p loss/1q gain (5/6 samples), and stem cell characteristics, and one with a greater mutation burden (1.08 mut/Mb, p<0.0002), depletion of DNA repair pathways, and inflammatory characteristics. We observed increased chromothripsis in TIHGG versus pHGG (67% vs. 31%, p=0.036), which was associated with extrachromosomal circular DNA-mediated amplification of PDGFRA and CDK4. In vitro drug screening in one primary, patient-derived TIHGG cell line from each expression subgroup identified microtubule inhibitors/stabilizers, DNA-damaging agents, MEK inhibition, and, in the inflammatory subgroup, proteasome inhibitors as potentially effective therapies. This study provides a comprehensive molecular profile of TIHGG, including mechanistic insights to TIHGG oncogenesis, and identifies potentially effective therapeutic modalities for further investigation.

cancer biology↗

bioRxiv2018

Using the modified male osteoporosis self-assessment tool for Taiwan to predict osteoporosis onset - a sub-study of the Taiwan osteoporosis survey

PurposeTo develop a risk index by item reduction from multiple variable regression, which can identify male Taiwanese patients at risk of developing osteoporosis.\n\nMethodsTo develop the model, a risk index was identified by item reduction from multivariate regression analysis. Using receiver operating characteristic (ROC) curve analysis and their sensitivity/specificity, MOSTAi was validated in a separate cohort of Taiwanese men and its performance with compared with the National Osteoporosis Foundation recommendations (NOF 2013).\n\nResultsBetween 2008 and 2011 a total of 4,323 males were enrolled for bone mineral density (BMD) measurements. Univariate analysis identified four major risk factors for osteoporosis, including age, body weight (BW), previous fracture and body height. The ROC analysis showed the area under the curve (AUC) for the model based on the three-variable, two-variable (age and BW), and one-variable models (BW), was 0.701 (p<0.001, 95% confidence interval [CI] 0.658-0.744), 0.700 (p<0.001, 95% CI, 0.656-0.742), and 0.690 (p<0.001, 95% CI, 0.646-0.734), respectively. Using the optimal cutoff value (-2) for the OSTA, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) in the validation cohort were 64.0%, 65.7%, 26.9% and 90.2%, respectively. The ROC curves for predicting osteoporosis by MOSTAi, OSTA and NOF 2013 and the AUC for MOSTAi, OSTA and NOF 2013 was 0.706 (p<0.001, 95% CI: 0.664-0.748) and 0.697(p<0.001, 95% CI: 0.657-0.738), respectively.\n\nConclusionThe results showed that MOSTAi could be a more precise model than OSTA and NOF 2013, for identifying men in Taiwan with osteoporosis who require referrals for DXA scans. It was demonstrated that MOSTAi is a simple tool with fair sensitivity/specificity and PPV, and high NPV. MOSTAi could also be a more accurate model than OSTA for identifying men in Taiwan at risk of osteoporosis. In comparison with NOF 2013, MOSTAi is a more accurate and simpler tool for the referral of Taiwanese men for DXA scans.

immunology↗

bioRxiv2018

Stout camphor tree genome fills gaps in understanding of flowering plant genome and gene family evolution

We present reference-quality genome assembly and annotation for the stout camphor tree (SCT; Cinnamomum kanehirae [Laurales, Lauraceae]), the first sequenced member of the Magnoliidae comprising four orders (Laurales, Magnoliales, Canellales, and Piperales) and over 9,000 species. Phylogenomic analysis of 13 representative seed plant genomes indicates that magnoliid and eudicot lineages share more recent common ancestry relative to monocots. Two whole genome duplication events were inferred within the magnoliid lineage, one before divergence of Laurales and Magnoliales and the other within the Lauraceae. Small scale segmental duplications and tandem duplications also contributed to innovation in the evolutionary history of Cinnamomum. For example, expansion of terpenoid synthase subfamilies within the Laurales spawned the diversity of Cinnamomum monoterpenes and sesquiterpenes.

genomics↗