The initiating cellular events in cystic fibrosis (CF) hepatobiliary disease are not well characterized, in part due to the lack of accessibility of primary tissues. However, enhanced longevity due to highly effective modulator therapies has generated renewed interest in the key aspects of liver and gallbladder disease, and how these might be treated in people with cystic fibrosis (pwCF). To extend the CF hepatobiliary knowledge base, we performed a transcriptomic analysis of liver and gallbladder development in the wild-type (WT) and sheep. Bulk RNA was extracted from each tissue at specific timepoints through gestation (from 50 days to term) and used for RNA sequencing (RNA-seq). Differentially expressed genes between the timepoints within each genotype and between WT and sheep at each timepoint were identified and then used in gene ontology process enrichment analysis to reveal altered biological processes. We find that at the molecular level, the gallbladder in the animals is both structurally and functionally compromised by midgestation, consistent with the observed microgallbladder phenotype. In the liver, many aspects of differentiation are apparently well-established early in gestation. However, we find functional immaturity in the liver at term, where genes associated with many key metabolic processes do not show the upregulation seen at term in the WT liver. We also show that the regulatory mechanisms for the gene in ovine gallbladder cells are highly conserved with those elucidated at the human locus, further enhancing the relevance of these data to advance understanding of hepatobiliary disease in pwCF. We use a physiological genomics approach to further understand the etiology of cystic fibrosis gallbladder and liver disease by using a large animal (sheep) model of organ development. We find that the gallbladder in the animals is both structurally and functionally compromised by midgestation. We also observe functional immaturity in the liver at term, where genes associated with many key metabolic processes do not show the upregulation seen at term in wild-type liver.

(PG) published its first issue in July 1999, with the goal of providing a forum for scientists to exchange ideas and scientific results related to the linkage between genetic information and physiological function. In this review, past and present editors reflect on 's role in the scientific community, the founding of the journal and the historical context in which it was formed within the American Physiological Society (APS). The editors reflect on a critical conference that united physiologists and geneticists and their determination for APS to take the lead in integrating these communities. In the past 25 years, key technologies for linking genes to physiology including methods for DNA sequencing, connecting genotype with phenotype, and monitoring gene expression, metabolites, and microbiota have all been revolutionized, creating a dynamic scientific environment that has resulted in highly impactful research across a wide range of fields. As methods, technologies, and data analysis tools have developed, has been a consistent forum for sharing cutting-edge research on the latest advances in the rapidly evolving field of linking molecular data to physiological function. This article highlights the key technological advances related to the connection between genes and physiology. The contribution of the journal to the scientific community during the time periods of each of the five Editors-in-Chief are summarized, illuminating key technological approaches featured in PG and scientific questions that were addressed. The article ends with a look forward, describing what the authors anticipate for the future of PG.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine-metabolic disorder that adversely affects reproductive, metabolic, and cardiovascular health in females, leading to menstrual irregularities and an increased risk of endometrial malignancies. Emerging research evidence suggests that the gut and extra gastrointestinal microbiome dysbiosis may play a significant role in the pathophysiology of PCOS. This systematic review aims to elucidate the microbiome dysbiosis patterns in patients with PCOS compared with healthy controls. A systematic search was conducted across PubMed, Scopus, and Web of Science from inception until February 28, 2025, encompassing all original cross-sectional, cohort, or case-control studies that examined the gut, oral, blood, and lower genital tract (LGT) microbiomes of patients with PCOS (cases) against healthy females (controls). Of the 4,377 studies identified, 64 were assessed for eligibility through full-text screening, and ultimately, 29 studies met inclusion criteria and were included into the systematic review. The results revealed inconsistent patterns in alpha and beta diversity, with reports of increased, decreased, or unchanged microbial diversity across studies. Key alterations were observed at different taxonomic levels, such as phylum, family, genus, and species. The most significant bacterial alterations include changes in the relative abundance of various bacterial taxa such as and . These findings indicate that complex dysbiotic microbial shifts may be involved in the pathogenesis of PCOS. As per the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) assessment, the quality of evidence is low for most of the studies. This systematic review supports the role of microbial dysbiosis in PCOS pathogenesis; however, additional research is required to elucidate these interactions to guide the development of therapeutic strategies in the future.

The menopausal transition is associated with an increased obesity risk, which can be ameliorated by hormone replacement therapy. However, the independent and interactive effects of obesity and menopause on the gut microbiota, along with the influence of hormone therapy, remain poorly understood. To address this, this study employed a mouse model using sham-operated and ovariectomized mice, with or without high-fat diet-induced obesity, to disentangle the roles of menopause and obesity. Ovariectomized mice on a high-fat diet were further treated with estradiol to assess the regulatory effects of hormone supplementation on the gut microbiota. The results showed that obesity and ovariectomy altered the relative abundances of 29 and 7 genera, and 243 and 99 amplicon sequence variants, respectively, indicating a stronger impact of obesity on gut microbial composition. Notably, ovariectomy increased the abundance of and enriched microbial taxa capable of producing estrogen-metabolizing enzymes, including and species, as well as the predicted abundance of the estrobolome enzyme β-glucuronidase. Estradiol supplementation increased the relative abundance of and decreased , both of which possess distinct β-glucuronidase subtypes. It also reduced the species that positively associated with adiposity. Together, these findings highlight the distinct and significant impacts of obesity and menopause on the gut microbiota and suggest that estrogen supplementation modulates microbial features linked to metabolic health. These results further implicate the potential of modulating the gut microbiota to improve postmenopausal health outcomes.

The heart undergoes significant molecular and functional adaptations throughout postnatal development. However, our understanding of these dynamic changes in the human heart is limited. Advances in pediatric cardiac research are often hindered by the lack of preclinical models. Guinea pigs may serve as a useful model for human cardiac research, as the guinea pig and human myocardium have similar ion channel expression and cardiovascular drug responsiveness. Yet, gene expression patterns during postnatal heart development have not been comprehensively investigated. In this study, we first characterized transcriptional changes in neonatal, juvenile, and adult guinea pig hearts. Neonatal hearts overexpressed cell-cycle (e.g., , ) and glycogen energy metabolism genes (e.g., , ), whereas adults overexpressed calcium signaling genes (e.g., , ). Second, we compared the transcriptional profile of right atria and left ventricular tissue; atrial maturation was enriched for sinoatrial node and conduction system pathways, while ventricular maturation was enriched for sarcomere organization and action potential regulation. Finally, we conducted a cross-species comparison of the right atrial transcriptome between humans and guinea pigs. This identified conserved maturation markers, including , suggesting shared temporal gene expression programs during postnatal cardiac development. Our findings provide a molecular framework for understanding age- and chamber-specific cardiac development, supporting the guinea pig as a promising preclinical model for studying human heart maturation. By identifying conserved gene programs and developmental markers across species, this study lays the groundwork for age-specific pharmacological strategies and computational models that can help to refine treatment decisions for pediatric patients.

Dorsal root ganglia (DRG) are essential for transmitting sensory information from visceral organs to the central nervous system. Sensory neuronal hyperactivity and glial reactivity have been reported in DRG in animal models of chronic pain, yet the molecular mechanisms contributing to the pathogenesis of visceral pain remain unclear. In this study, we performed transcriptome profiling of lumbosacral DRG in a mouse model of chronic pelvic pain, focusing on mapping the gene and signaling pathway changes associated with visceral hypersensitivity in lumbosacral DRG transmitting bladder afferent signals. Using bulk-RNA sequencing (RNA-seq) method, we identified differentially expressed genes in lumbosacral DRG between control mice and mice exhibiting visceral pain symptoms, with striking sex differences in identified genes. Hierarchical gene clustering analysis and Ingenuity Pathways Analysis both revealed sex-specific signaling pathway activation associated with visceral pain conditions, including glial activation and nociceptive sensitization in males and heightened immune activation in females. Interestingly, our data also showed enriched gene expression linked to extracellular matrix and immune functions in female control animals comparing to male control animals, suggesting molecular sexual dimorphism in sensory ganglia. Lastly, our data identified common gene and signaling pathway changes involved in visceral hypersensitivity in both sexes. This study is the first molecular and signaling pathway characterization in lumbosacral DRG in the context of bladder-origin visceral pain. The sex differences in the molecular profile of lumbosacral DRG in healthy animals and in animals exhibiting visceral pain symptoms suggest sex-specific visceral pain etiology, despite similar symptoms.

Seasonal life-history events, such as migration, hibernation, and reproduction, depend on coordinated physiological changes. In vertebrates, a conserved thyroid hormone-signaling pathway in the hypothalamus is known to trigger many of these seasonal transitions. However, the broader processes and regulators modulating seasonal physiology are poorly defined. Recent research in Arctic ground squirrels (AGS, ) revealed that hypothalamic thyroid hormone signaling is activated, and markers of tanycytic remodeling are expressed in late hibernation in anticipation of springtime reproduction. We conducted RNA-sequencing on hypothalamic micropunches encompassing the arcuate nucleus, median eminence, pars tuberalis, and third ventricle in male and female AGS at early and late hibernation. We found substantial sex differences in the hypothalamic transcriptome across hibernation. Functional enrichment analysis of gene expression data revealed an upregulation of processes and pathways related to hormone transport and neurogenesis in females, whereas this was less apparent in males. Transcription factor binding site analysis of differentially expressed genes identified upstream regulators involved in glial cell differentiation, neuronal development, survival, and plasticity. Notably, many of the intersecting genes from these analyses were localized to specialized glial cells (tanycytes) lining the floor and walls of the third ventricle. Our findings support a model in which annual changes in gene expression rely on a progressive remodeling of tanycytes across hibernation. This remodeling may contribute to seasonal changes in neuronal plasticity and function of the hypothalamus, priming the brain in anticipation of shifting physiological demands upon hibernation termination. We examine how the transcriptome of hypothalamic micropunches changes across the hibernation season. Our analyses uncover sex-specific changes to regulatory processes associated with hormone transport and neurogenesis. Genes linked to these processes and regulators are strongly localized to third ventricle tanycytes, consistent with the key role these cells play in regulating seasonal physiological changes. Our study supports that using sex as a biological variable is essential for understanding the mechanisms underlying seasonal life-history transitions.

Extracellular vesicles (EVs) are small, membrane-bound vesicles that transfer biological content through the extracellular environment. The role of EVs in energy metabolism has primarily focused on EV proteins and microRNAs, with less attention on the metabolic content of EVs. This exploratory study assessed changes in the EV metabolome in response to an arduous, 16-day military training exercise. Forty male soldiers (21 ± 2 yr, 24.8 ± 2.7 kg/m) provided blood from which circulating EVs were isolated and completed assessments of body composition and lower body power on (PRE) and (POST) of a mountain training exercise (MTX). Total daily energy expenditure during the MTX was 4,187 ± 519 kcal·day. Fat mass (POST-PRE [95% confidence interval]: -0.9 [-1.3, -0.6] kg), lean body mass (-1.6 [-2.0, -1.2] kg), body fat percentage (-0.7 [-1.1, -0.3]%), and lower body power (-133 [-204, -63] W) decreased from PRE to POST ( < 0.05). Global metabolite profiling identified 81 metabolites from lipid (81%), energy (5%), cofactor and vitamin (5%), xenobiotic (4%), carbohydrate (2%), amino acid (1%), and nucleotide (1%) pathways in serum-derived EVs. After adjusting for EV concentration, 11 metabolites were different from PRE to POST ( < 0.05, < 0.20), with the largest increases in the oxidative stress-associated metabolites 5-oxoproline and benzoate. Changes in lean body mass were positively associated with changes in the energy metabolites citrate (ρ = 0.361, = 0.022) and phosphate (ρ = 0.369, = 0.019). Findings suggest that EV metabolites change in response to physiological stress and reflect increased oxidative stress, energy metabolism, and fatty acid metabolism, which may provide early indicators of stress adaptations relevant for optimizing training and sustaining military performance. EV metabolites change in response to periods of increased metabolic demand, reflecting increased oxidative stress, energy metabolism, and fatty acid metabolism, and may be associated with changes in lean body mass. This exploratory study adds to the limited existing literature by highlighting the potential of EV-derived metabolites to provide insight into metabolic responses and their contribution to stress-induced metabolic adaptations.

We developed a novel artificial intelligence (AI) approach based on machine-learning to predict general health and food-intake parameters. This approach, named Transcriptome-driven Health-status Transversal-predictor Analysis (THTA) is relevant for markers of diabesity and is based on a non-transcriptomic, mathematics-driven approach. The prediction was based on values derived from food consumption, dietary lipids and their bioactive metabolites, peripheral blood mononuclear cell (PBMC) mRNA-based transcriptome signatures, magnetic resonance imaging (MRI), energy metabolism measurements, microbiome analyses, and baseline clinical parameters, as determined in a cohort of 72 subjects. Our novel machine learning approach incorporated transcriptome data from PBMCs as a "one-method" approach to predict 77 general health-status markers for the broad stratification of the diabesity phenotype. These markers would usually necessitate measurements using 16 different methods. The PBMC transcriptome was used to determine these 77 basic and background health markers with very high accuracy in a transversal-predictor establishment group (Pearson correlations are r = 0.98 ranging from 0.94 to 0.99). These collected variables provide valuable insides into which individual factor(s) are mainly target diabesity. Based on the "establishment group" prediction approach a further "confirmation group" prediction approach was performed, achieving a predictive potential r = 0.59 (ranging from 0.19 to 0.98) for these 77 variables. This "one-method" approach enables the simultaneous monitoring of a large number of health-status variables relevant to diabesity and may facilitate the monitoring of therapeutic and preventive strategies. In summary, this novel technique, which is based on PBMC transcriptomics from human blood, can predict a wide range of health-related markers.

The human microbiome is emerging as a key regulator of cancer biology, modulating tumor development, immune dynamics, and therapeutic responses across diverse malignancies. In this review, recent insights are synthesized regarding how microbial communities (bacterial, fungal, and viral) shape oncogenic signaling, immune checkpoint blockade (ICB) efficacy, and metabolic reprogramming in lung, pancreatic, colorectal, breast, cervical, melanoma, and gastric cancers. Mechanistic links between microbial metabolites, intratumoral colonization, and host immune phenotypes are highlighted proposing that the microbiome constitutes a programmable axis within the tumor immune-metabolic ecosystem. Drawing on multiomics integration and translational studies, a shift from associative profiling toward causal, spatially resolved, and intervention-ready frameworks is proposed. This perspective positions the microbiome not as a passive bystander, but as a coevolving participant in tumor progression and treatment response, with the potential to reshape diagnostics, prognostics, and therapeutic strategies in precision oncology.

Preeclampsia is a multifaceted pregnancy-associated hypertensive disorder that poses a major threat to maternal and fetal health. Though the etiology is not fully understood, syncytiotrophoblast stress is postulated to be a major driver of maternal symptomology. We previously demonstrated that regulator of G protein signaling-2 () expression decreases in human preeclamptic placenta and has a transcriptional dependence on histone deacetylase 9 () in trophoblast cells. Furthermore, experimental reductions of expression in the mouse fetoplacental unit are sufficient to induce preeclampsia-like features, including placental stress, in C57BL/6J dams. Here, we examined the hypotheses that and are both expressed within syncytiotrophoblasts, that and expression are positively correlated within these cells, and that expression of each is reduced within syncytiotrophoblasts during preeclampsia. and mRNA were localized and quantified in syncytiotrophoblast cells of human placental samples from pregnancies with and without preeclampsia, using laser-capture microdissection and in situ hybridization methods. Expression of and was similarly localized in the syncytiotrophoblast of the mouse placenta. Throughout, / and / were detected and positively correlated in syncytiotrophoblasts, but expression of each was substantially reduced during preeclampsia. These results document reduced and expression specifically in syncytiotrophoblast cells during preeclampsia and provide additional correlative support of HDAC9-mediated control of expression within this population of trophoblasts. This work provides rationale to further explore cell-specific disruptions in and control and function as a cause of syncytiotrophoblast stress and ultimately preeclampsia. Syncytiotrophoblast stress contributes to the pathogenesis of preeclampsia, but many of the underlying causes remain undetermined. Previous work has implicated the loss of placental HDAC9-mediated Rgs2 transcription in the disorder. Extending these findings, we report that HDAC9 and RGS2 were abundant and localized primarily to syncytiotrophoblast cells of the control placenta. Expression of both targets was attenuated in these cells during preeclampsia and thus may be an underappreciated source of syncytiotrophoblast stress, warranting further investigation.

Excess glucocorticoids induce skeletal muscle myopathy by changing gene expression. Advanced age augments glucocorticoid-mediated muscle phenotypes, yet the transcriptional responses underlying those augmented phenotypes are unclear. The purpose of this study was to define the glucocorticoid-responsive transcriptome in young and aged muscle following both acute and more prolonged glucocorticoid treatment. Young (4-mo-old) or aged (24-mo-old) male mice were administered either an acute injection of dexamethasone (DEX) or vehicle or daily DEX or vehicle injections for 7 days. Muscles were harvested 6.5 h after the final or only injection. The tibialis anterior (TA) was selected for RNA sequencing analysis as DEX treatment lowered TA mass specifically in aged males. In silico analyses identified enriched pathways and transcription factors predicted to regulate DEX-sensitive genes. Acute DEX altered similar numbers of genes in young (950) versus aged males (913), although aged males had greater magnitudes of fold change. After 7 days of DEX treatment, aged muscle exhibited more DEGs compared with acute exposure (1,196 vs. 913), whereas young muscle exhibited fewer DEGs than after acute exposure (599 vs. 950). In aged males, glucocorticoid-sensitive genes were consistently enriched for growth regulatory processes across both time points, a pattern that was not evident in young males. Despite those age-associated transcriptional differences, the transcription factors predicted to regulate the glucocorticoid-sensitive genes were similar in young and aged males. These data expand our understanding into how aging modifies the transcriptional response to excess glucocorticoids in skeletal muscle. Glucocorticoids promote mass loss in certain muscles with advanced age but not at younger ages. In a muscle whose mass is lost in response to elevated glucocorticoids only in advanced age in males, we show that glucocorticoids initiate a unique and exaggerated transcriptional profile after both acute exposure to the hormone and after prolonged treatment that is consistent with muscle atrophy. These findings expand our understanding of the effect primary aging has on glucocorticoid-induced atrophy in males.

Periodontal therapy leverages inter-cellular and inter-tissue interactions between epithelium and stroma, which mediate healing and regeneration. Importantly, grafting stroma from different regions elicits different healing responses: transplantation of gingival stroma can convert alveolar mucosa into keratinized gingiva, and . This striking clinical observation suggests that the stromal tissues of oral mucosa and gingiva provide distinct instructional signals. Our aims were to investigate the molecular differences between mucosa and gingiva and the impact of periodontal infection on inter-tissue interactions. We used human single cell RNA-seq data to compare gene expression patterns and inter-cellular interactions of: (a) adult oral mucosa and gingiva and (b) healthy gingiva and periodontitis-affected gingiva. Altered gene expression in junctional epithelial cells in periodontitis included not only inflammatory but also antioxidant genes, reflecting the potential of oral tissues to maintain health and resist bacterial infection. Many ligand/receptor genes were also enriched in junctional epithelium, highlighting inter-cellular interactions. Oral mucosal and gingival stroma expressed distinct genes related to signaling and extracellular matrix associated with their tissue phenotypes: for example, collagens and in gingiva, and elasticity-related in mucosa. Ligand-receptor analyses predicted endothelial cells and fibroblasts as the primary senders of signaling ligands. Notably, autocrine signaling was predicted to be prevalent within periodontitis-affected fibroblasts, suggesting potential autofeedback regulation in periodontitis. We present unbiased single-cell molecular characterizations of human oral tissues in health and periodontitis. These findings lay groundwork for future research into periodontal therapies.

Heat stress (HS) in cattle significantly challenges the dairy industry by reducing milk production. However, the molecular mechanism behind mammary gland responses to HS and recovery remains poorly understood. This study aimed to determine the transcriptomic changes in lactogenic-like bovine mammary epithelial (MAC-T) cells after HS and post-HS recovery. Six culture conditions were analyzed: MAC-T cells cultured in basal medium, cells in lactogenic medium to induce differentiation, differentiated cells at standard temperature (37°C) or HS (42°C) for 1 h. HS cells were collected after incubation at 37°C for either 2 or 6 h to examine the extent of recovery. A total of 1,668 differentially expressed genes were identified. Differentiated cells expressed genes associated with milk lipid synthesis, indicating lactogenic potential. HS suppressed genes involved in cellular differentiation and activated heat shock protein genes. Several transcription factors were identified as potential regulators of HS response. During recovery, chaperon-mediated protein folding genes remained elevated. Apoptosis regulation genes were induced at 2 h, and cellular homeostasis regulation genes were enriched at 6 h. Overall, these findings provide insight into the transcriptomic response of MAC-T cells to heat stress and recovery under in vitro conditions, offering a foundation for future studies on cellular responses to environmental stressors. Bovine mammary epithelial (MAC-T) cells were differentiated (D), heat stressed (HS), and recovered (R) under different conditions. Differentiated cells expressed milk lipid synthesis genes, which were repressed by HS. Further, HS upregulated heat shock protein genes and altered several transcription factors involved in HS response. Recovery after HS-induced apoptosis regulation at 2 h and cellular homeostasis regulation at 6 h.

The homocysteine-methionine cycle is involved in the critical human cellular functions, such as proliferation and epigenetic regulation. S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) metabolites are synthesized in this metabolic cycle, and their levels are finely regulated to ensure proper functioning of key enzymes controlling the cellular growth and differentiation. SAM and SAH levels were found altered in the plasma of subjects with trisomy 21 (T21), but how this metabolic dysregulation influences the clinical manifestation of T21 phenotype has not been previously described. SAM and SAH quantifications were performed in urine samples of 58 subjects with T21 and 48 controls (N) through liquid chromatography with tandem mass spectrometry. SAH resulted slightly more excreted in urine of subjects with T21 (T21/N mean ratio = 1.16, P value = 0.021), although no difference was found in SAM levels. Metabolite urine levels were compared with those previously observed in plasma, in which higher amounts of SAM and SAH were found. In addition, we examined if an association between the levels of SAM and SAH in T21 and the expression levels of genes involved in their production/utilization exists using the transcriptome map of blood samples of T21 and N subjects. The analysis showed overexpression of 44 methyltransferase genes responsible for the conversion of SAM to SAH, of two genes involved in SAH utilization, adenosylhomocysteinase-like 1, adenosylhomocysteinase-like 2, and of one gene involved in SAM utilization, adenosylmethionine decarboxylase 1. These data support the hypothesis that T21 genetic imbalance is responsible for SAM and SAH excess, which may be involved in the T21 phenotypic features. S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) are critical metabolites for the fundamental cellular functions, such as proliferation and epigenetic regulation. For the first time, their levels were quantified in the urine of subjects with trisomy 21 (T21) and compared with euploid controls (N). These dosages were compared with their plasma levels, and the expression of genes involved in SAM and SAH production/utilization was further investigated in the differential blood transcriptome map of T21 versus N samples.