Biology subjects

Walsh, J. T.

Publications and source records attributed to Walsh, J. T..

8 recordsLinked to original sources

bioRxiv2026

Human Gut Bacteria Convert Endogenous Steroids into Host Cortisol Shuttle Inhibitors

11{beta}-hydroxysteroid dehydrogenase 2 (HSD11B2) protects the mineralocorticoid receptor from glucocorticoid overstimulation by inactivating cortisol. HSD11B2 inhibition can drive receptor overactivation and contribute to hypertension; however, endogenous inhibitors remain poorly defined. Glycyrrhetinic acid-like factors (GALFs) are steroid-like metabolites that inhibit HSD11B2. Given the capacity of gut bacteria to metabolize host steroids, we hypothesized that the gut microbiome could generate GALF-like inhibitors. Here, we identify two 11-oxygenated steroid metabolites that potently inhibit human HSD11B2 in colonic cells and organoids, enabling cortisol-dependent mineralocorticoid receptor activation. We identify gut bacteria and enzymes that produce these compounds and show that their levels are markedly reduced in antibiotic-treated humans. One metabolite is elevated during pregnancy, and both are higher in individuals with stage 2 hypertension-range blood pressure. These findings reveal a bacterial route to altered host cortisol signaling and suggest a potential link between microbiome-derived GALFs and blood pressure regulation.

microbiology↗

bioRxiv2026

Macrophage immunosenescence prolongs intraocular inflammation in aged mice via impaired induction of regulatory T cells

Immune-mediated intraocular inflammation, called uveitis, is a leading cause of global blindness, with the highest burden of visual impairment falling on older individuals. Immunosenescence, the functional changes in immune cells with aging, impacts the age-associated immune response, but how immunosenescence and the molecular regulators of the age-associated immune response affect the clinical course of uveitis remains unclear. In the murine model of experimental autoimmune uveitis (EAU), aged mice demonstrated a delayed onset and peak of intraocular inflammation compared to young mice. In contrast to the canonical monophasic inflammation that rapidly resolves in young mice, aged mice developed persistent, chronic inflammation. Transcriptomic and flow-cytometric analyses of immune cells and the receptor-ligand interactome revealed a dominant macrophage-CD4+ T cell signature. This signaling pathway was functionally altered on both ends: macrophages from aged mice had an impaired capacity to generate peripherally induced regulatory T cells (pTreg) through an IL-6 regulated pathway, while CD4+ T cells co-cultured with aged macrophages demonstrated increased proliferation. Our study establishes aging as a key regulator of the effector immune response in uveitis. Regulatory T cells, specifically pTreg, are essential for resolving inflammation in uveitis and an impaired ability to induce pTreg led to a sustained, chronic inflammatory uveitis phenotype in old mice, thereby linking immunosenescence to persistent neuroinflammation. These findings highlight potential therapeutic avenues for vision-threatening uveitis, especially in older patients.

immunology↗

bioRxiv2025

High-resolution comparative single-cell transcriptomics of doublesex-expressing neurons reveals evolutionary conservation and diversity of sexual circuits in Drosophila

Understanding how the cellular and molecular composition of neural circuits change during evolution is essential for deciphering how behavior evolves. Male sexual behaviors in Drosophila species are remarkably diverse, and the underlying sexual circuits are specified by sex determination genes. Here, we employed single-cell transcriptomics to systematically characterize and compare neuron cell types that express the sex determination gene doublesex in adult males across Drosophila species with divergent sexual behaviors. High-resolution profiling to delineate cellular diversity revealed a largely conserved set of cell types across four species, with minimal evolutionary gain or loss and potentially more prevalent changes in cell type abundance. In-depth comparisons between D. melanogaster and D. yakuba showed that transcriptomic conservation and differentially expressed genes between species are highly cell-type-specific, suggesting that cell types evolve as highly independent units. We identified widespread species differences in gene expression, particularly in the neuromodulatory signaling pathway, while preserving a conserved circuit layout in sexual identity and neurotransmitter properties. We further generated a female dataset in D. melanogaster to define sex differences in cell types and examine species divergence in relation to sex differences. Finally, we reported marker gene combinations that uniquely define each cell type, providing a foundational resource that enables the design of cell -type-specific genetic reagents. Overall, our study provides fundamental insights into the cellular diversity of sexual circuits and how evolution shapes cell types and gene expression in behavioral adaptations.

evolutionary biology↗

bioRxiv2024

Changes in the cellular makeup of motor patterning circuits drive courtship song evolution in Drosophila

How evolutionary changes in genes and neurons encode species variation in complex motor behaviors are largely unknown. Here, we develop genetic tools that permit a neural circuit comparison between the model species Drosophila melanogaster and the closely-related species D. yakuba, who has undergone a lineage-specific loss of sine song, one of the two major types of male courtship song in Drosophila. Neuroanatomical comparison of song patterning neurons called TN1 across the phylogeny demonstrates a link between the loss of sine song and a reduction both in the number of TN1 neurons and the neurites serving the sine circuit connectivity. Optogenetic activation confirms that TN1 neurons in D. yakuba have lost the ability to drive sine song, while maintaining the ability to drive the singing wing posture. Single-cell transcriptomic comparison shows that D. yakuba specifically lacks a cell type corresponding to TN1A neurons, the TN1 subtype that is essential for sine song. Genetic and developmental manipulation reveals a functional divergence of the sex determination gene doublesex in D. yakuba to reduce TN1 number by promoting apoptosis. Our work illustrates the contribution of motor patterning circuits and cell type changes in behavioral evolution, and uncovers the evolutionary lability of sex determination genes to reconfigure the cellular makeup of neural circuits.

evolutionary biology↗

bioRxiv2020

The collective behavior of ant groups depends on group genotypic composition

Increasingly, researchers document variation between groups in collective behavior, but the genetic architecture of collective behavior and how the genotypic composition of groups affects collective behavior remains unclear. Social insects are ideal for studying the effects of genetic variation on collective behavior because their societies are defined by social interactions. To explore how the genetic composition of groups affects collective behavior, we constructed groups of pharaoh ants (Monomorium pharaonis) from 33 genetically distinct colonies of known pedigree. The groups consisted of either all workers from the same single colony or workers from two genetically different colonies, and we assayed the exploration and aggression of the groups. We found that collective behavior depended on the specific genotypic combination of group members, i.e. we found evidence for genotype-by-genotype epistasis for both collective behaviors. Furthermore, the observed collective behavior of groups differed from the additive genetic expectations of groups, further demonstrating the importance of genotype-by-genotype effects. Finally, the collective aggression of the groups was negatively correlated with the pairwise relatedness estimates between workers within the group. Overall, this study highlights that specific combinations of genotypes influence group-level phenotypes and the difficulty of predicting group-level phenotypes using only additive models.

evolutionary biology↗

bioRxiv2019

Ant cuticular hydrocarbons are heritable and associated with variation in colony productivity

In social insects, cuticular hydrocarbons function in nestmate recognition and also provide a waxy barrier against desiccation, but basic evolutionary genetic features, including the heritability of hydrocarbon profiles and how they are shaped by natural selection are largely unknown. We used a new pharaoh ant (Monomorium pharaonis) laboratory mapping population to estimate the heritability of individual cuticular hydrocarbons, genetic correlations between hydrocarbons, and fitness consequences of phenotypic variation in the hydrocarbons. Individual hydrocarbons had low to moderate estimated heritability, indicating that some compounds provide more information about genetic relatedness and can also better respond to natural selection. Strong genetic correlations between compounds are likely to constrain independent evolutionary trajectories, which is expected given that many hydrocarbons share biosynthetic pathways. Variation in cuticular hydrocarbons was associated with variation in colony productivity, with some hydrocarbons experiencing strong directional selection. Altogether, our study builds on our knowledge of the genetic architecture of the social insect hydrocarbon profile and demonstrates that hydrocarbon variation is shaped by natural selection.

evolutionary biology↗

bioRxiv2019

Ant collective behavior is heritable and shaped by selection

Collective behaviors are widespread in nature and usually assumed to be strongly shaped by natural selection. However, the degree to which variation in collective behavior is heritable and has fitness consequences -- the two prerequisites for evolution by natural selection -- is largely unknown. We used a new pharaoh ant (Monomorium pharaonis) mapping population to estimate the heritability, genetic correlations, and fitness consequences of three collective behaviors (foraging, aggression, and exploration) as well as body size, sex ratio, and caste ratio. Heritability estimates for the collective behaviors were moderate, ranging from 0.17 to 0.32, but lower than our estimates for the heritability of caste ratio, sex ratio, and the body size of new workers, queens, and males. Moreover, variation among colonies in collective behaviors was phenotypically correlated, suggesting that selection may shape multiple colony collective behaviors simultaneously. Finally, we found evidence for directional selection that was similar in strength to estimates of selection in natural populations. Altogether, our study begins to elucidate the genetic architecture of collective behavior and is one of the first studies to demonstrate that it is shaped by selection.

evolutionary biology↗

bioRxiv2017

Ant nurse workers exhibit behavioral and transcriptomic specialization on larval stage but not caste

Division of labor within and between the worker and queen castes is thought to underlie the tremendous success of social insects. Colonies might benefit if subsets of nurse workers specialize further in caring for larvae of a certain stage or caste, given that larval nutritional requirements depend on stage and caste. We used short- (<1 hr) and long-term (ten days) behavioral observations to determine whether nurses of the pharaoh ant (Monomorium pharaonis) exhibit such specialization. We found that nurses were behaviorally specialized based on larval instar but not on larval caste. This specialization was widespread, with 56% of nurses in the short-term and between 22-27% in the long-term showing significant specialization. Additionally, we identified [~]200 genes that were differentially expressed in nurse head and abdominal tissues between nurses feeding young versus old larvae. These included 18 genes predicted to code for secreted proteins, which may be passed from nurses to larvae via trophallaxis, as well as vitellogenin and major royal jelly protein-1, which have previously been implicated in the transfer of nutrition from nurse to larvae and the regulation of larval development and caste in social insects. Altogether, our results provide the first evidence in any social insect for a division of labor among nurse workers based on larval stage, and our study begins to elucidate the molecular mechanisms underlying this specialization.

evolutionary biology↗