Biology subjects

Hsiao, A.

Publications and source records attributed to Hsiao, A..

12 recordsLinked to original sources

bioRxiv2026

Melatonin modulates habituation learning via the convergent action of two MT1-type receptors.

Melatonin is a hormone produced by the pineal gland and retina, with roles in sleep and circadian rhythms as well as other neuronal processes, including the regulation of learning and memory. Using larval zebrafish, we previously identified Melatonin as a potent modulator of habituation learning: the progressive suppression of responses to a repeated stimulus. Here we have extended these analyses and have found that Melatonin has strong effects on separate aspects of habituation learning: it potentiates habituation of response probability and latency, while simultaneously inhibiting habituation of movement amplitude and duration. We performed a systematic CRISPR mutagenesis of all six zebrafish Melatonin receptors, and found that only two MT1-type receptors (Mtnr1aa and Mtnr1al) are required for Melatonin's effects on habituation. These receptors showed a cooperative interaction, with each individual mutant showing reduced sensitivity to Melatonin, and mtnr1aa;mtnr1al double mutants showing complete insensitivity. To map where these receptors act, we used whole-brain activity mapping. Despite distinct footprints, both perturbed a shared set of brain areas, including the torus longitudinalis, cerebellum, and preoptic area, with the double mutant producing the most extensive phenotype by combining and expanding the effects seen in each single mutant. Thus, we propose that two MT1-type receptors act at overlapping circuit nodes to reinforce Melatonin's bidirectional control of learning.

neuroscience↗

bioRxiv2026

Gut Bacteria Prime Host Antibody Responses Against Ingested Dietary Fiber Glycans

Protein and glycan antigens synthesized by gut microbes stimulate circulating and secreted antibody production. Despite continuous exposure of hosts to the plant glycans that constitute dietary fiber, it remains unclear whether these foreign structures induce mucosal immune responses. We report that humans and mice generate antibodies specific for common glycans in plant foods. Oral exposure to individual fiber types induced T cell-independent, glycan-specific IgM and IgA. The induction of anti-fiber antibodies required colonization by particular microbes, since germ-free mice and mice harboring representatives of several bacterial phyla failed to respond. The OMM12 model community was sufficient to rescue antibody induction, and dietary fiber glycans were detected on the surfaces of OMM12 microbes, suggesting a route by which bacteria trigger anti-fiber immune responses. Our results reveal a direct impact of dietary fiber on the adaptive immune system with implications for host control of fiber breakdown by bacteria in the gut lumen.

immunology↗

bioRxiv2026

Social and neuroendocrine phenotypes reprogrammed by endocrine-disrupting chemicals can be mitigated by Limosilactobacillus reuteri modulation of the gut microbiome-thyroid-oxytocin axis

IntroductionEnvironmental factors are increasingly implicated in the etiology of autism spectrum disorder (ASD). Polybrominated diphenyl ethers (PBDEs) are anthropogenic toxicants added as flame retardants to consumer products that have become ubiquitous environmental contaminants and disrupt thyroid hormone (TH) and neuroendocrine systems. We have previously shown that developmental PBDE exposure produces ASD-like traits with involvement of oxytocin (OXT)-thyroid hormone signaling. Limosilactobacillus reuteri (LR), a widely used probiotic bacterium, has been shown to improve social functioning and increase TH and OXT levels in murine models. Therefore, we tested the hypothesis that LR supplementation (LR) prevents PBDE-induced deficits in socioemotional behavior with concomitant modulation of TH signaling genes on hypothalamic OXT neurons. MethodsC57BL/6N mouse offspring were exposed to a commercial penta-mixture of PBDE congeners, DE-71, at an environmentally realistic concentration, 0.1 mg/kg/d (DE-71), or to corn oil vehicle (VEH/CON) via their mothers during gestation and lactation. Offspring received supplementation with LR ATCC PTA 6475 (107-108 CFU/mL, po) indirectly via the dam or continuation directly through adulthood. Unsupplemented controls were given saline. ResultsFecal microbiome analysis in offspring confirmed colonization of LR at postnatal day (P) 40 and depletion by P104. LR treatment increased plasma total thyroxine in DE-71 and plasma OXT in VEH/CON dams. In DE-71 offspring of both sexes, LR normalized deficient scores on social novelty preference and emotional recognition in adult females and males and deficient long-term social recognition memory (SRM) in adult DE-71 females; DE-71 males were normal. Reduced olfactory dishabituation between two social odors may partly explain the compromised socioemotional behavior produced by DE-71 in an LR-dependent manner. Multiplex RNA in situ hybridization performed on immunoreactive OXT-ergic neurons in the paraventricular hypothalamic nucleus (PVH) revealed significant upregulation of TH transporter monocarboxylate transporter 8 (Mct8) and downregulation of iodothyronine deiodinase 3 (Dio3) in DE-71 relative to VEH/CON females. This toxicant-induced reprogramming was prevented by probiotic treatment. DE-71 males expressed reduction in Mct8 and Dio3 transcripts on OXT-ergic neurons with minimal LR protection. In the female supraoptic nucleus (SON), Mct8 and Dio3 were downregulated by DE-71 and normalized in DE-71+LR; there were no group effects on transcript levels in male SON. Results of fecal 16S rRNA sequencing indicated reduced -diversity and altered {beta}-diversity in the gut bacterial community of female but not male DE-71 exposed offspring; most changes were correctable by LR. Alterations in taxa-level abundance caused by DE-71 and reversed by LR were observed in both sexes. These involved Bifidobacterium, Coprococcus, Desulfovibrio, Oscillospira, and Peptococcaceae in females and Desulfovibrionaceae, Rikenella, and Turicibacter in males. Exposed dams showed no detriment in - and {beta}-diversity while showing reduced abundance of several Firmicutes and Proteobacteria taxa that could be rescued by LR. The relative abundance of Lactobacillus was upregulated in DE-71 males and DE-71+LR males and dams. ConclusionsThese results indicate that developmental probiotic supplementation effectively mitigated organohalogen-induced ASD-like deficits in socioemotional behavior and partially corrected dysbiosis of gut bacterial communities in exposed offspring of both sexes. Concomitantly, PBDEs altered the expression of TH regulatory genes Mct8 and Dio3 in PVH OXT neurons in a sex-dependent manner, suggesting that TH regulation of OXT neuroendocrine cells may modulate the emergence of toxicant-induced ASD-relevant behavior. While LR reinstated normal behavioral outcomes in PBDE-exposed offspring of both sexes, coincident normalization of hypothalamic TH signaling transcripts occurred more broadly in females, indicating the existence of unique parallel processes influencing the preventive effects of LR on ASD-relevant behavioral deficits in both sexes.

neuroscience↗

bioRxiv2026

Allosteric Inhibition of NDM-1 by Thanatin Preserves the Di-Zinc Center While Restricting Dynamics

The New Delhi metallo-{beta}-lactamase 1 (NDM-1) is a major driver of carbapenem resistance in Gram-negative pathogens, yet the molecular basis by which antimicrobial peptides inhibit this enzyme has remained unresolved. Thanatin, a disulfide-stabilized {beta}-hairpin peptide, was previously proposed to inactivate NDM-1 by displacing catalytic Zn{superscript 2} ions, but this model lacked direct structural support. Here, we combine high-resolution NMR spectroscopy, intermolecular NOE mapping, HADDOCK-guided docking, and molecular dynamics simulations to reveal a distinct zinc-retaining dynamic allosteric mechanism. Thanatin binds adjacent to the catalytic groove, preserving the native di-zinc coordination environment while simultaneously rigidifying the L3 catalytic loop, as confirmed by Zn-bound spectral fingerprints and EDTA titration experiments. This conformational restriction explains how the peptide inhibits the enzyme while maintaining a zinc-bound but catalytically compromised state, a finding that contrasts with zinc-displacement hypotheses and reconciles prior biochemical observations with structural data. In bacterial assays, this allosteric inhibition translates to a moderate restoration of carbapenem sensitivity, resulting in a 50% reduction in viable cell output even under high-level enzyme expression. Our findings establish a mechanistic framework for designing next-generation peptide inhibitors that target the dynamic vulnerabilities of metallo-{beta}-lactamases.

biophysics↗

bioRxiv2025

Emergence and stabilisation of a neo-Y chromosome in nematode species with rare males

How do sex chromosomes evolve in the transition to asexuality? So far, species that depart from canonical sexual reproduction - for example, parthenogens with rare sex, or species where the paternal genome is set aside - have been found to carry either no sex chromosomes, or sex chromosomes but no male-specific sex chromosome (i. e., no Y). Here we reveal that, in Mesorhabditis nematodes, a new Y chromosome emerged once, from sexual ancestors, in species that have transitioned into an unconventional mode of reproduction called autopseudogamy. In this reproductive system, females produce clonal females plus rare ([~]10%) males that are needed for fertilisation, but that do not contribute to the female genome. Analysing the Y chromosomes of two autopseudogamous species, we found high levels of degeneration, most likely due to loss of recombination, and two additional conserved features: i) they accumulated male-beneficial genes, and ii) they display a strong fertilisation drive, in that mainly Y-bearing sperm fertilise female oocytes. Both features are likely evolutionarily favourable in the context of autopseudogamy. Our results suggest that male-specific chromosomes can still be maintained in systems with rare, and possibly genetically useless, males.

evolutionary biology↗

bioRxiv2025

Estradiol promotes habituation learning via an unidentified target, bypassing the suppressive effects of established Estrogen Receptors

Habituating to the constant stimuli in the environment is a critical learning process conserved across species. We use a larval zebrafish visual response to sudden darkness as a model for studying habituation learning, where zebrafish reduce their responses to repeated stimulations. In this paradigm, treatment with estradiol strongly increases learning rate, resulting in more strongly suppressed responses. We used mutant lines for the Estrogen Receptors (esr1, esr2a, esr2b, gper1) in an attempt to identify the receptor(s) mediating these effects. These experiments failed to identify a necessary receptor (or combination of receptors). Surprisingly, esr1, esr2a, and gper1 mutants showed weak but consistent increases in habituation, indicating these receptors suppress habituation learning. These experiments demonstrate that estradiol is a complex modulator of learning in our model, where the learning-promoting effects are mediated by an unidentified estradiol target, and the classical Estrogen Receptors act in competition to subtly suppress learning.

neuroscience↗

bioRxiv2024

Somatosensory cortex and body representation: Updating the motor system during a visuo-proprioceptive cue conflict

The brains representation of hand position is critical for voluntary movement. Representation is multisensory, combining visual and proprioceptive cues. When these cues conflict, the brain recalibrates its unimodal estimates, shifting them closer together to compensate. Converging evidence from research in perception, behavior, and neurophysiology suggest that such updates to body representation are communicated to the motor system to keep hand movements accurate. We hypothesized that primary somatosensory cortex (SI) is crucial in this updating process due to its role in proprioception and connections with primary motor cortex. We tested this hypothesis in two experiments. We predicted that proprioceptive, but not visual, recalibration would be associated with change in short latency afferent inhibition (SAI), a measure of sensorimotor integration (influence of sensory input on motor output) (Expt. 1). We further predicted that modulating SI activity with repetitive transcranial magnetic stimulation (TMS) should affect recalibration of the proprioceptive estimate of hand position, but have no effect on the visual estimate or on the normal inverse relationship between proprioceptive and visual recalibration (Expt. 2). Our results are consistent with these predictions, supporting the idea that (1) SI is indeed a key region in facilitating motor system updates based on changes in body representation, and (2) this function is mediated by unisensory (proprioceptive) processing, separate from multisensory visuo-proprioceptive computations. Other aspects of the body representation (visual and multisensory) may be conveyed to the motor system via separate pathways, e.g. from posterior parietal regions to motor cortex. Significance StatementRepresentation of the hand, which is critical for accurate control of movement, comes from weighting and combining available proprioceptive (position sense) and visual cues. Our results suggest that when the hand representation is modified by introducing a conflict between these cues, the motor system receives updates directly from the primary somatosensory cortex (SI). These updates are specific to the change in proprioceptive representation and are absent when cues are not in conflict. This may represent a unisensory pathway to the motor system that conveys information about hand representation, acting in parallel with multisensory pathways involving posterior parietal and premotor regions.

neuroscience↗

bioRxiv2023

Microbiome induced complement synthesized in the gut protects against enteric infections

Canonically, complement is a serum-based host defense system that protects against systemic microbial invasion. Little is known about the production and function of complement components on mucosal surfaces. Here we show gut complement component 3 (C3), central to complement function, is regulated by the composition of the microbiota in healthy humans and mice, leading to host-specific gut C3 levels. Stromal cells in intestinal lymphoid follicles (LFs) are the predominant source of intestinal C3. During enteric infection with Citrobacter rodentium or enterohemorrhagic Escherichia coli, luminal C3 levels increase significantly and are required for protection. C. rodentium is remarkably more invasive to the gut epithelium of C3-deficient mice than of wild-type mice. In the gut, C3-mediated phagocytosis of C. rodentium functions to clear pathogens. Our study reveals that variations in gut microbiota determine individuals intestinal mucosal C3 levels, dominantly produced by LF stromal cells, which directly correlate with protection against enteric infection. HighlightsO_LIGut complement component 3 (C3) is induced by the microbiome in healthy humans and mice at a microbiota-specific level. C_LIO_LIGut stromal cells located in intestinal lymphoid follicles are a major source of luminal C3 C_LIO_LIDuring enteric infections with Citrobacter rodentium or enterohemorrhagic Escherichia coli, gut luminal C3 levels increase and are required for protection. C_LIO_LIC. rodentium is significantly more invasive of the gut epithelium in C3-deficient mice when compared to WT mice. C_LIO_LIIn the gut, C3-mediated opsonophagocytosis of C. rodentium functions to clear pathogens. C_LI

immunology↗

bioRxiv2021

Diet High in Soybean Oil Increases Susceptibility to Colitis in Mice

The current American diet is high in soybean oil (SO), which consists of unsaturated fatty acids, most notably linoleic acid (LA, C18:2 omega-6). While LA is an essential fatty acid that must be obtained from the diet, high LA consumption has been linked to the development of inflammatory bowel disease (IBD) in humans. Here, we show that a high fat diet (HFD) based on soybean oil increases susceptibility to colitis in wild-type and IL10 knockout mice. It causes immune dysfunction, decreases colon and crypt length and increases intestinal epithelial barrier permeability; these effects were not observed in low LA HFDs. The SO diet also disrupts the balance of isoforms encoded by the IBD susceptibility gene Hepatocyte Nuclear Factor 4 (HNF4). Both the SO diet and an LA gavage cause gut dysbiosis: the SO diet increases the abundance of an adherent, invasive Escherichia coli (AIEC), which can use LA as a carbon source, and the LA gavage decreases the beneficial bacteria Lactobacillus murinus. Metabolomic analysis of both host-associated and cultured bacteria shows that SO increases levels of LA and oxylipins while decreasing eicosapentaenoic acid (EPA, C20:5 omega-3) and endocannabinoids. Our results suggest that excess LA, obtained from a diet high in soybean oil, increases susceptibility to colitis by alterations in intestinal HNF4, gut microbiota and bioactive metabolites.

physiology↗

bioRxiv2020

Infection with novel Bacteroides phage BV01 alters host transcriptome and bile acid metabolism in a common human gut microbe

The bacterial genus Bacteroides is among the most abundant and common taxa in the human gut, yet little is known about the phages infecting the group. Bacteroides phage BV01 (BV01) was identified as a prophage integrated on the chromosome of its host, Bacteroides vulgatus ATCC 8482. Phage BV01 is actively produced, and infects susceptible B. vulgatus hosts in the mouse gut. Infection with BV01 causes a generalized repression of the B. vulgatus transcriptome, downregulating 103 transcripts and upregulating only 12. Integration of BV01 disrupts the promoter sequence of a downstream gene encoding a putative tryptophan-rich sensory protein (tspO). Deletion of tspO and subsequent RNAseq analysis revealed that more than half of the differentially-regulated transcripts are shared with the BV01 lysogen, suggesting the transcriptomic response to BV01 is linked to tspO. Among these differentially-regulated transcripts are two encoding bile salt hydrolases. Bile acid deconjugation assays show that BV01 represses its hosts ability to hydrolyze bile acids in a tspO-dependent manner. Analysis of 256 published healthy human gut metagenomes suggests that phage integration adjacent to B. vulgatus-like tspO genes is rare within an individual, but common among humans. Finally, this work proposes a novel phage family that includes BV01, the Salyersviridae, whose host range spans the Bacteroides and is detectable in human-associated samples. Together, these findings highlight the importance of phage-host interactions to our understanding of how gut microbes sense and interact with their environment. IMPORTANCEThe links between human disease and the gut microbiome are numerous. Most mechanisms by which most gut microbes and their activities change and impact human health remain elusive. Phages, viruses that infect bacteria, are hypothesized to play a central role in modulating both community dynamics and functional activities. Here we have characterized an active prophage, BV01, which infects a pervasive and abundant human gut-associated species. BV01 infection alters its hosts transcriptional profile including its metabolism of bile acids, molecules implicated in mediating health and disease states in the gut. This highlights that prophages and other components of the variable genome should not be overlooked in bacterial genomes because they may dramatically alter host phenotypes. Furthermore, BV01 represents a new family of phages infecting human gut symbionts, providing a foundation for future investigations of phage-host interactions in these clinically-relevant but underexplored hosts.

microbiology↗

bioRxiv2019

A Dysbiotic Gut Microbiome Suppresses Antibody Mediated-Protection Against Vibrio cholerae

Vibrio cholerae is the etiologic agent of cholera, a severe diarrheal disease that represents a significant burden on global health and productivity. Despite the pressing need, available preventative measures such as oral cholera vaccines exhibit highly variable protective efficacy. We hypothesized that one contributor to vaccine efficacy variability across geographical regions may be due to differences in gut microbiome, which in cholera-endemic areas is strongly and repeatedly modulated by malnutrition, cholera, and non-cholera infectious diarrhea. Here, we assemble representative model communities of either human gut microbes resembling those of healthy individuals or those of individuals recovering from diarrhea or malnutrition. We establish these communities in a murine immunization model, and show that the dysbiotic gut microbiome, commonly present in areas where malnutrition and diarrhea are common, suppresses the immune response against Vibrio cholerae through the action of CD4+ cells. Our findings suggest that the composition of the gut microbiome at time of immunization may be pivotal for providing robust immunity from oral cholera vaccines, and highlight the importance of the gut microbiome on mucosal immunization responses and vaccine development strategies.\n\nImportanceDiarrhea caused by enteric bacterial pathogens is a recurring and important issue for worldwide health. Cholera, the severe watery diarrhea caused by the bacterium Vibrio cholerae, affects millions of people annually. Currently, there is a lack of effective preventative measures for cholera, due to the uneven performance of oral cholera vaccines. Thus, it is essential to better understand the factors that may affect vaccine efficacy. One aspect may be variations in the resident community of gut microbes, the gut microbiome, across populations living in developed versus developing regions as a function of host genetics, diet, and infection. Our findings suggest that specific structures of the gut microbiome are involved in disrupting the immune responses to V. cholerae vaccination.

microbiology↗

bioRxiv2019

The Autoimmune Susceptibility Gene, PTPN2, Restricts Expansion of a Novel Mouse Adherent-Invasive E. coli

Inflammatory bowel diseases (IBD) involve genetic and environmental factors that play major roles in disease pathogenesis. Loss-of-function single-nucleotide polymorphisms (SNPs) in the protein tyrosine phosphatase non-receptor type 2 (PTPN2) gene increase the risk of IBD and are associated with altered microbiome population dynamics in IBD. Moreover, expansion of intestinal pathobionts, such as adherent-invasive E. coli (AIEC), is strongly implicated in the pathogenesis of IBD as AIEC increases pro-inflammatory cytokine production and alters tight junction protein regulation suggesting a potential mechanism of pathogen-induced barrier dysfunction and inflammation. The aim of this study was to identify if PTPN2 deficiency disturbs the composition of the intestinal microbiome to promote expansion of specific bacteria with pathogenic properties. In mice constitutively lacking Ptpn2 we identified increased abundance of a novel adherent-invasive E. coli (AIEC) that showed similar adherence and invasion of intestinal epithelial cells, but greater survival in macrophages to the IBD associated AIEC, LF82. Furthermore, we confirmed this novel mouse AIEC (mAIEC) caused disease when administered to germ-free and mice lacking segmented-filamentous bacteria (SFB). Moreover, mAIEC infection increased severity of and prevented recovery from dextran-sodium sulfate (DSS)-induced colitis. mAIEC genome sequence analysis showed >90% similarity to LF82. Interestingly, mAIEC contained distinct attachment genes not found in LF82 thereby also demonstrating the novelty of this AIEC. We show here for the first time that an IBD susceptibility gene, PTPN2, plays a key role in modulating the gut microbiome to protect against a novel pathobiont. This study generates new insights into gene-environment-microbiome interactions in IBD.

microbiology↗