American Journal of Physiology-Regulatory, Integrative and Comparative Physiology

Introduction: With global warming, heatwaves are increasing in severity, affecting species worldwide. Recent studies show associations between heat exposure in pregnancy and adverse birth outcomes such as preterm birth, low birthweight and stillbirth across multiple species. This suggests potentially conserved mechanisms such as maternal inflammation, dehydration and changes in placental physiology in response to heat exposure. Moreover, the gestational timing of antenatal heat likely impacts the type and severity of outcome, yet this is not fully understood. Methods: We conducted a scoping review of studies on heat exposure and pregnancy outcomes in humans and other animals, to identify common mechanisms and temporal dynamics of effects. Temperature-, trimester- and species- specific patterns were reviewed across 197 studies and ten species (human, cow, sheep, pig, goat, rat, mouse, guinea pig, lizard and rabbit). Results: Qualitative trends indicate that high temperatures are associated with adverse birth outcomes. In particular, third trimester exposure increases risk of preterm birth and low birthweight. Many studies emphasise placental involvement in adverse outcomes and point to potential aberrations in placental physiology or cortisol signaling pathways. Conclusions: Overall, literature presents that heat exposure increases risk of adverse birth outcomes across studies, and taxa. Understanding the relationship between heat exposure and adverse birth outcomes, as well as the mechanisms and timing, is vital for informing public health policies and creating mitigating strategies for expecting mothers.

Aldosterone is a key regulator of systemic sodium, potassium, and fluid homeostasis. Chronic elevation of aldosterone, as observed in primary aldosteronism, chronic heart and kidney diseases, promotes cardiac hypertrophy, inflammation, fibrosis, and heart failure, which are further enhanced in aging. Although these pathological effects are primarily attributed to the mineralocorticoid receptor (MR), emerging evidence suggests roles for nonclassical G protein-coupled receptor (GPCR) signaling. We identified lysophosphatidic acid receptor 2 (LPAR2) as a novel GPCR candidate that mediates aldosterone signaling in cardiomyocytes. Using AC16 human cardiomyocyte cells and reporter gene assays, we demonstrate that aldosterone activates a Gi/o-dependent GPCR pathway. Pharmacological inhibition of LPAR2 internalization confirms its specific reaction to aldosterone. Functional studies revealed that aldosterone-induced cardiomyocyte injury requires both MR and LPAR2, where specific antagonists to both receptors reduced the ability of aldosterone to induce collagen expression and cell death markers. These findings uncover a previously unrecognized non-classical mechanism of aldosterone action in the heart and highlight LPAR2 as a promising therapeutic target for aldosterone-driven cardiovascular disease.

Axonal action potential propagation critically depends on tightly regulated intra and extracellular electrolyte concentrations and acid base homeostasis. Experimental studies have demonstrated that changes in extracellular sodium, potassium, and calcium concentrations alter axonal excitability and conduction properties. However, it remains unknown whether small variations in electrolyte concentrations within the physiological range are associated with measurable changes in nerve conduction velocity in humans. In this study, data from neurologically healthy children who underwent both nerve conduction studies and blood gas analysis were analyzed to investigate the relationship between electrolyte concentrations and median motor nerve conduction velocity. Nerve conduction velocity was significantly negatively correlated with ionized calcium concentration and positively correlated with sodium concentration, whereas no significant correlation was observed for potassium. In an a priori defined multiple linear regression model, ionized calcium, sodium, and bicarbonate remained significantly associated with nerve conduction velocity after correction for multiple testing. These findings indicate that even small variations in electrolyte concentrations within the physiological range are associated with measurable differences in peripheral nerve conduction velocity and suggest an additional contribution of acid base status to nerve conduction.

Background: Prone cardiopulmonary resuscitation (CPR) may be necessary when turning a prone patient supine would delay chest compressions. Although prone compressions can generate arterial pressures comparable with or greater than supine CPR, the pathway of pressure transmission is uncertain. We examined synchronized intrathoracic, intra-abdominal, and central arterial pressures in both supine and prone positions. Methods: Two thawed fresh-frozen adult cadavers underwent three, 2-minute mechanical CPR trials per position in a counterbalanced crossover sequence. Solid-state catheters recorded pleural, peritoneal, and central arterial pressures simultaneously. Trial-level outcomes included peak pressure, mean pressure, pressure-time area, and the mean peritoneal-to-pleural pressure gradient. Exploratory fixed-effects models included position, cadaver, and their interaction. Results: Prone CPR increased peak intrathoracic pressure by 7.04 mmHg, peak intra-abdominal pressure by 21.69 mmHg, and peak arterial pressure by 15.40 mmHg. Mean intra-abdominal and arterial pressures increased by 16.22 and 9.90 mmHg, respectively. The mean peritoneal-to-pleural gradient reversed direction from -8.46 mmHg supine to 4.85 mmHg prone. Intrathoracic pressure-time area increased 3.4-fold, from 1.62 to 5.46 mmHg{middle dot}s, and arterial pressure-time area increased 2.2-fold, from 2.96 to 6.42 mmHg{middle dot}s. Conclusions: Compared to supine, prone mechanical CPR generated higher arterial pressures and reversed the pressure relationship across the thoracoabdominal boundary in both cadavers. Higher abdominal pressure coincided with a larger intrathoracic pressure-time area, a pattern compatible with reduced caudal pressure dissipation.

Background: Loss- and gain-of-function variants in SCN5A, encoding the cardiac sodium channel Nav1.5, are major causes of inherited cardiac channelopathies. Their pathophysiology has almost exclusively been attributed to altered cardiomyocyte excitability and cardiac conduction. However, growing evidence indicates that autonomic dysfunction contributes to these disorders, raising the possibility that Nav1.5 dysfunction may also affect the intrinsic cardiac nervous system. Objectives: We investigated whether Nav1.5 is functionally expressed in murine intrinsic cardiac neurons and evaluated its contribution to neuronal excitability. Methods: Scn5a expression was investigated by digital PCR and immunocytochemistry in isolated murine intracardiac neurons. Whole-cell patch-clamp recordings were used to characterize sodium currents and action potential properties in wild-type and Scn5a+/- mice. Results: Scn5a transcripts and Nav1.5 protein were detected in intrinsic cardiac neurons. Voltage-clamp recordings identified a tetrodotoxin-resistant sodium current accounting for approximately 8% of the total sodium current and displaying pharmacological and biophysical properties consistent with Nav1.5. Activation and inactivation analyses indicated that Nav1.5 is the predominant sodium conductance available at most polarized membrane potentials. Accordingly, Scn5a haploinsufficiency selectively altered action potential threshold, maximal upstroke velocity, overshoot and duration in neurons resting below -60 mV, whereas more depolarized neurons were essentially unaffected. No structural or neurochemical remodeling of intrinsic cardiac ganglia was detected. Conclusion: Nav1.5 is a functional determinant of intrinsic cardiac neuronal excitability. These findings identify the intrinsic cardiac nervous system as a new cellular target of SCN5A dysfunction and suggest that inherited cardiac sodium channelopathies could involve alterations in both myocardial and intrinsic neuronal electrophysiology.

Several different mechanisms of regeneration have been proposed to explain repair of the endometrial luminal epithelium (LE) following menstrual/estrous cyclicity, parturition or other damaging insults to the uterine mucosa. These include activity of an as-yet unidentified epithelial stem cell population, mesenchymal transdifferentiation, or integration of bone marrow-derived cells. Here, we used a novel Cag-Flox-STOP-Flox-Pgrmc2-3XFlag (Pgrmc2-3XFlag) reporter mouse coupled with a recently developed GE-specific cre recombinase mouse (Prss29-Cre) to determine if and to what extent the GE contributes to regeneration of the LE following parturition and during aging in nulliparous mice. To initiate regeneration in the endometrium, control (Pgrmc2-3XFlag) and reporter (Prss29-Cre;Pgrmc2-3XFlag) mice were placed with males for one pregnancy. Postpartum (pp) uterine tissues were then collected 5 days (1x5dpp), 3-weeks (1x3wpp) and 7-weeks (1x7wpp) later. A fourth set of uterine tissues was collected 3-weeks after three pregnancies (3x3wpp). The number of glands did not change at any time point. Indelibly marked FLAG+ GE cells were detected by immunohistochemistry and immunofluorescence in GE as expected. As demonstrated in serial uterine sections of uteri from all four treatment groups, GE cells migrated toward the LE and formed junctional points (JP) where GE cells transitioned from cuboidal GE cells to pseudostratified columnar LE cells. Transitioning cells at junctional points expressed markers of both GE (i.e., FOXA2) and LE (i.e., CALB1) tissues. Following transition, GE-derived LE cells expressed PGR and ESR1 consistent with surrounding developmentally-derived LE cells. About 17 FLAG+ LE cell islands were also observed in 1x5dpp 4 mm longitudinal sections at sites distant from GE-LE junctional points. Interestingly, the number of islands did not change from 1x5dpp to 1x7wpp. However, the total number of GE-derived FLAG+ LE cells observed in each island decreased from 1x5dpp to 1x3wpp, but then tended (p=0.07) to increase by 1x7wpp. There was no difference in the number of GE-LE junctional points or GE-derived FLAG+ LE islands between 1x3wpp and 3x3wpp tissues. However, a significant increase in the total (p=0.02) and average (p=0.02) number of FLAG+ LE cells was observed in 3x3wpp LE islands highlighting the proliferative expansion of these cells over the intervening ~80 days. GE-LE junctional points were also observed in 5-month old nulliparous Prss29-Cre;Pgrmc2-3XFlag mice at diestrus, but not in younger 6-week old mice. Collectively, these findings establish the GE as a quantifiable cellular source for LE regeneration during postpartum involution and as part of normal LE cell turnover during the estrous cycle in nulliparous mice. We propose a mechanism whereby GE cells within glandular structures are not terminally differentiated, but rather are stably differentiated to perform glandular function. However, when needed and based on the level of endometrial damage, GE cells can dedifferentiate, become integrated in to LE tissue and then reprogram to take on an LE phenotype as part of the regenerative process following parturition and during estrous cyclicity over time.

Stressful events are associated with long-term adverse health impacts, but the causal mechanisms linking these exposures to subsequent disease remain poorly understood. One plausible mechanism is persistent changes to hormonal signaling that regulate metabolic homeostasis. Here, we examine the long-term impacts of stress associated with exposure to the 2004 Indian Ocean tsunami on levels of free triiodothyronine (FT3), a circulating measure of biologically active thyroid hormone, using data from the Study of Tsunami Aftermath and Recovery. We measure biomarkers 20 years after the tsunami in a population-representative sample age 35y+ in 2024 who, at the time of the tsunami, were living along the coast of Aceh, Indonesia, the most affected part of the Indian Ocean Basin. Because respondents were first interviewed before the tsunami and subsequently tracked regardless of migration, the sample avoids a major source of selection bias common in long-term disaster studies. We identify the causal effect of tsunami exposure using variation in community-level tsunami mortality, comparing communities within the same sub-district. We find that greater tsunami exposure reduced levels of FT3 20 years later. Exposure also altered relationships between FT3, body composition, and cortisol and increased cardiometabolic risk. These findings identify persistent alteration of thyroid hormone physiology as a potential pathway linking severe stressful exposures to long-term cardiometabolic disease risk.

Retinal neurons rely on continuous oxygen supply to maintain function, yet some species, like goldfish, withstand prolonged hypoxia due to adaptations that remain unclear. Horizontal cells (HCs) are inhibitory interneurons of the retina that express ionotropic glutamate receptors (iGluRs) and secrete gama-aminobutyric acid (GABA), allowing them to shape visual signalling by feeding back to photoreceptors. We investigated whether iGluRs in dissociated goldfish HCs are suppressed during hypoxia, and whether this process is mediated by oxygen-sensitive activation of mitochondrial ATP-sensitive K+ (mKATP) channels. Through perforated patch-clamp electrophysiology, we determined that 20 min of hypoxia reduced peak inward current density associated with glutamate application by ~25% (P = 0.0059). When mKATP channels were selectively blocked with 100 microM glibenclamide, hypoxic suppression of iGluRs was abolished. Inhibiting mitochondrial Ca2+ uptake via the mitochondrial Ca2+ uniporter with ruthenium red, or blocking Ca2+ release through ryanodine receptors in the endoplasmic reticulum, also abolished the hypoxia-induced suppression. Similarly, inhibition of calmodulin with calmidazolium, or of protein phosphatase 1 and 2A (PP1/PP2A) activity with calyculin A, prevented the hypoxia-induced suppression of iGluRs. Taken together, these results indicate that mKATP activation is required to mediate an intracellular Ca2+ signal that downregulates iGluR activity during hypoxia. Through the reduction of iGluR activity, HCs may lower their metabolic demand, allowing them to maintain cell function during hypoxia. Additionally, GABA release from HCs, as measured by mass spectrometry, was not affected by hypoxia, and we propose that downregulation of iGluR may account for hypoxic suppression of the retina in hypoxia-tolerant organisms.

Objectives: To describe associations between peripheral arterial disease (PAD) and bladder health (BH) and lower urinary tract symptoms (LUTS) among a subset of women in the Coronary Artery Risk Development In Young Adults (CARDIA) study. Methods: Women from CARDIA at Birmingham, AL and Minneapolis, MN were eligible if they completed a questionnaire about bladder symptoms in 2022-23, an ancillary study post-year 35 called CARDIA-PLUS, including the global BH scale (possible range, 0-100) and the LURN-SI 10 (0-38) and the AUASI (0-35). A subset (n=216) completed an in-person examination, including the ankle brachial index (ABI) procedure (n=194). ABI scores were clinically categorized as normal (1.00-1.40), borderline abnormal (0.91-0.99), and abnormal (</=;0.90; evidence of PAD). Continuous BH and LUTS variables were regressed on ABI category, adjusting for sociodemographics, obstetric/gynecologic variables, co-morbidities, and physical activity. Key Results: Among women who completed BH/LUTS questionnaires and the ABI (n=192), the mean age was 63+/-4 years and racial composition was 47% Black and 53% White. ABI results were normal (74%), borderline abnormal (20%), and abnormal (6%). After adjusting for covariates, women with abnormal ABI scores had higher LURN-SI scores (4.1 points, 95% CI 0.7, 7.5) and did not have higher AUASI scores (1.4 points, 95% CI -3.1, 5.7) or lower BH scores (-9.6 points, 95% CI -24.0, 4.9) compared to women with normal ABI scores. Borderline abnormal ABI was not associated with BH or LUTS. Discussion/Conclusion: In this cohort, PAD was associated with greater LUTS severity. PAD and LUTS may share common etiologies and risk factors that need additional research.

Sepsis mimics resemble sepsis clinically but may require different treatments. We evaluated whether inflammatory protein profiles could distinguish these conditions in a retrospective case-control study using 4 prospective Japanese cohorts. The study included 34 adults with sepsis and 46 with sepsis mimics. We measured 92 proteins using Olink, assessed between-group differences with false discovery rate (FDR) adjustment, and evaluated 3 prediction models using repeated nested cross-validation. No protein met the FDR threshold; the lowest FDR-adjusted P value was 0.345. The primary elastic-net model had an area under the receiver operating characteristic curve of 0.442 (95% confidence interval, 0.315-0.574), based on cross-validation predictions averaged for each participant. Random forest and gradient boosting also showed no clear evidence of discrimination above chance. Confidence intervals included chance performance in both the all-serum and quality-control-Pass sensitivity analyses. In this cohort, a single measurement of an inflammation-focused protein panel showed limited discrimination between sepsis and sepsis mimics. Integration with clinical information and longitudinal measurements warrants further investigation.

Alterations in the female urinary microbiome have been linked to several several common urinary conditions that increase in prevalence after menopause. Here we use sequencing and metabolomic data to compare the urinary bladder microenvironments between women who are premenopausal, postmenopausal, and postmenopausal using vaginal estrogen. While the urinary microbiome differs between pre- and postmenopausal women, at least 6 weeks of vaginal estrogen is associated with higher urinary lactobacilli and fewer opportunistic pathogens in the urinary postmenopausal microbiome, which closer approximates what is seen in the premenopausal context. Changes in urinary Lactobacillus species are correlated with vaginal pH and the same Lactobacillus species found in the vaginal microbiome tend to also be identified within the urinary bladder microbiome. Urinary metabolites differ by context (e.g., pre-, post-, and post-menopausal using vaginal estrogen), but the majority of metabolites that drive these differences are unannotated. Of the metabolites with shared associations among different Lactobacillus species, L. iners have consistently inverse relationships compared to L. crispatus, L. gasseri, or L. jensenii.

Background. Cancer cachexia is a multifactorial syndrome characterized by substantial metabolic disturbances including systemic inflammation, and muscle atrophy, which may affect the regulation of iron metabolism in patients. This study aimed to characterize this regulation in two murine models of colorectal and pancreatic cancer, both associated with a high prevalence of cachexia. Methods. Histological, biochemical and molecular analyses were performed in serum, skeletal muscle, liver, spleen and tumor from UN-KC-6141 pancreatic tumor bearing mice and from ApcMin/+ mice (colorectal cancer model), both models exhibiting variable cachexia severity. Results. Both models induce cachexia, but diverge markedly in their regulation of iron metabolism. UNKC mice display reduced plasma iron availability (-9.6% transferrin saturation, p<0.001) without concomitant anemia, while hepatic hepcidin synthesis is upregulated (+100.6%, p<0.001) by inflammation, promoting ferroportin (FPN) downregulation (-42.4%, p<0.001) and iron sequestration in the spleen (+134% total iron content, p<0.001). In the atrophied gastrocnemius, iron concentration is preserved through increased ferritin (+86.6%, p=0.010) and hemoproteins (i.e., myoglobin, CYSC, COXIV) expression. Conversely, ApcMin/+ mice exhibit anemia together with hepatic and splenic iron depletion (-48.4%, p<0.001 and -84.9%, p<0.001, respectively). Hepcidin synthesis is downregulated (-99.9%, p<0.001) despite persistent inflammation, indicating that hypoxia and/or iron-deficiency signals probably predominate over the inflammatory pathway. FPN is markedly decreased (-94.2%, p<0.001) in the iron-depleted spleen despite low hepcidin. In the atrophied quadriceps of ApcMin/+ mice, iron deficiency is associated with decreased FPN and ferritin (-87.9%, p<0.001, and -38.4%, p=0.016, respectively), and increased TfR1 expression (+305%, p=0.107). Finally, tumor iron import may play a significant role in cachexia progression, as suggested by the association between tumor weight, tumor TfR1 protein levels and body weight loss in UNKC mice. Conclusion. These findings reveal cancer type-specific signatures of iron regulation in cachexia, which appear to be more driven by cancer type specific features than by cachexia severity itself, with skeletal muscle iron metabolism impaired mainly when cachexia is associated with anemia. This suggests that the clinical management of iron metabolism in cachectic patients should be guided by the underlying cancer type.

The success of modern antiretroviral therapy (ART) has increased the life expectancy of people living with HIV to levels approaching that of uninfected individuals. For women living with HIV (WLWH), this means that more will survive to undergo menopause and experience the consequences of decreased ovarian hormone levels, particularly estrogen (E2). The recent change in federal guidance for use of postmenopausal hormone therapy is increasing demand for both E2-alone and E2+progestogen formulations to control adverse symptoms of menopause. The consequences and efficacy of hormone therapy in WLWH are thus an important issue for WLWH and their healthcare providers. The role of E2 replacement in postmenopausal WLWH is a significant issue because of its potential effects on control the viral reservoir and its demonstrated beneficial metabolic effects in uninfected postmenopausal women. To address these questions, we employed a novel nonhuman primate model of postmenopausal WLWH undergoing E2 replacement. Reproductively competent female rhesus macaques were infected with simian immunodeficiency virus (SIV) and then subjected to a daily ART regimen. After complete suppression of plasma viremia, all animals were ovariectomized (OVX) and then implanted with Silastic capsules containing either cholesterol vehicle or sufficient E2 to restore pre-OVX plasma levels. Plasma and cell-associated viral dynamics, immune responses, body composition, systemic and tissue-specific metabolic parameters, cytokine profiles, and parameters of bone health were followed longitudinally from baseline through 34 weeks of E2 deficiency or replacement. We found that E2 status did not significantly affect plasma or tissue viral dynamics or overall metabolic homeostasis. However, E2 replacement exerted beneficial effects on several aspects of bone health in spite of a chronic inflammatory state that persisted following effective ART suppression of the SIV reservoir. Our findings suggest that hormone therapy, specifically E2 replacement, offers benefit to WLWH, particularly with respect to bone loss.

Menopause is a major neuroendocrine transition characterised by substantial changes in endocrine milieu, physiological, psychological, and psychosexual health. Although menopausal symptoms are common, their range and severity vary considerably between individuals, suggesting that menopause is a multifaceted process. Endocrine markers (luteinising, follicle-stimulating & anti-Mullerian hormone), together with perceived well-being, may contribute to this variability. Thus, the aim was to capture the complex impact of endocrine and well-being markers on psychosexual health and menopausal symptoms. Therefore, we first applied principal component analyses to identify individual endocrine and well-being profiles, to then assess their association with psychosexual health and menopausal symptoms in pre- and post-menopausal females. Post- compared to pre-menopausal females report reduced psychosexual health and greater urogenital and psychological menopausal symptom burden. Endocrine and well-being profiles interact with reproductive status: Post-menopausal females with lower subjective well-being and a stronger menopause-like endocrine milieu report decreased overall psychosexual health and more sexual related pain. Additionally, endocrine milieu interacted with reproductive status on urogenital symptoms: Post-menopausal females with a stronger menopause-like endocrine milieu report less urogenital symptoms. Together, these findings suggest that endocrine factors and subjective well-being jointly influence psychosexual health and menopausal symptoms after menopause. No association is seen before menopause. Therefore, females after menopause need to be considered separately in research and clinic. Multivariate analyses capture patterns that are not identified using individual biomarkers and conventional univariate approaches. Our findings highlight the value of integrative multivariate approaches for improving the assessment of menopausal health and characterising individual variability across the menopausal transition.

Capacitation is a post-ejaculatory maturation process by which sperm become hyperactive and undergo the acrosome reaction, both of which are required to fertilize an oocyte. Two key features of capacitation are increased intracellular calcium via the calcium channel CatSper and changes in mitochondrial function. In mouse spermatozoa, CatSper-dependent calcium entry promotes mitochondrial calcium uptake and mitochondrial activation, contributing to hyperactivated motility and fertilization ability. Whether this mechanism is conserved in human spermatozoa was unknown. Here, we assessed mitochondrial function and mitochondrial calcium in paired non-capacitated and capacitated human spermatozoa from normozoospermic donors. Capacitation increased mitochondrial respiratory control ratio, coupling efficiency, mitochondrial membrane potential, and mitochondrial calcium. The increase in mitochondrial calcium required extracellular calcium and was prevented by pharmacological inhibition of CatSper or the mitochondrial calcium uniporter (MCU). Inhibition of CatSper or mitochondrial calcium uniporter also attenuated the capacitation-associated increase in mitochondrial membrane potential and reduced hyperactivated motility without affecting progressive or total motility. Pharmacological disruption of mitochondrial function reduced capacitation-associated hyperactivated motility without affecting the acrosome reaction. Together, these findings support a conserved pathway in human and mouse spermatozoa in which CatSper-mediated calcium entry promotes MCU-dependent mitochondrial calcium uptake and mitochondrial activation, contributing to the acquisition of hyperactivated motility during capacitation. These findings identify mitochondrial calcium handling as a potential target for modulating human spermatozoa function.

Interpersonal physiological synchrony (IPS) between interaction partners has been studied as a marker of social connectedness and coordination. However, little is known about how such interpersonal synchrony relates to the intrapersonal coordination of individuals' own autonomic systems during team interaction. The present study examined whether IPS and intrapersonal physiological synchrony (IAPS), defined as the within-person coordination of heart rate (HR), respiration, and electrodermal activity (EDA), function as competing or complementary regulatory processes. It also examined whether IAPS is state- or trait-like and whether teams high or low in both IPS and IAPS had better outcomes. Fifty five newly formed triads (N = 165; Mage = 23.87, 77% female) participated in a laboratory interaction including passive shared experiences and active collaborative tasks while continuous physiological activity was recorded. Synchrony within individuals and between team members was quantified using multidimensional recurrence quantification analysis. Across interaction segments, IAPS was positively associated with IPS in both HR and EDA, with stronger and more consistent associations during active teamwork versus during passive social contexts. These findings contradict a trade-off hypothesis and instead support a synergistic relationship between IAPS and IPS. IAPS exhibited state-like dynamics and sensitivity to features of the context, i.e., consistency within similar interaction contexts and higher in passive versus active social segments. Further, IAPS had limited associations with individual difference measures. Exploratory analyses indicated that teams characterized by both high IAPS and high IPS demonstrated more favorable outcomes, reflected in either higher objective task performance or greater perceived team efficacy depending on physiological modality. Together, these results suggest that effective team coordination is supported not only by IPS but also by the capacity to maintain coherent internal autonomic organization. They further highlight IAPS as a dynamic component of social functioning that merits exploration alongside interpersonal processes.

Objectives: The bile acid nuclear receptor Farnesoid X Receptor (FXR, NR1H4) is a major regulator of metabolism and energy homeostasis in peripheral organs. It modulates bile acid, glucose, and lipid metabolism, as well as fat mass and body weight. However, FXR is also expressed in the brain, particularly in the hypothalamus, a key center for the regulation of energy homeostasis. Although one study has demonstrated a role for brain FXR activation in energy balance, its specific hypothalamic role is still unknown. Here, we examined the role of FXR in the mediobasal hypothalamus in the regulation of energy balance. Methods: We used a genetic approach combined with metabolic phenotyping to determine the effect of FXR invalidation in the mediobasal hypothalamus on metabolic parameters involved in the central regulation of energy homeostasis. Results: Our results demonstrate that hypothalamic FXR deficiency induces a positive energy balance, resulting in a reduction in energy expenditure due to alterations in glucose metabolism accompanied by structural changes in white adipose tissues. Conclusion: This study uncovers a previously unrecognized role for hypothalamic FXR in the central homeostatic control of energy balance, providing new insights into its contribution to peripheral glucose metabolism and adipose tissue structural remodeling.

The contribution of persistent inward currents (PICs) to spinal motor neurons discharge rate is lower in old compared to young adults. However, whether this difference further progresses at very old age ([&ge;]80 years) and differs between males and females remains unknown. Thirty young (26 {+/-} 4 years, 15 females), thirty old (72 {+/-} 5 years, 15 females) and twenty-nine very old adults (85 {+/-} 3 years, 15 females) performed isometric dorsiflexion ramp contractions at 20% of maximal voluntary torque. Individual motor unit spike trains were identified from decomposed high-density surface electromyograms of the tibialis anterior. The paired motor unit technique was used to estimate the prolongation effect of PICs ({Delta}F and normalized {Delta}F), and the quasi-geometric approach to estimate neuromodulatory (brace height) and inhibitory pattern (attenuation slope) contributions. {Delta}F was lower in old and very old adults than in young adults, with no difference between old and very old adults regardless of sex. Compared with young adults, normalized {Delta}F was lower in both old and very old males, whereas in females it is only lower in the very old group. Brace height and attenuation slope did not differ across ages or sexes. These findings indicate that age-related changes in spinal motor neuron excitability are established by the seventh decade and do not progress further in healthy active very old adults, following a nonlinear trajectory that may differ between males and females. The absence of age-related differences in the neuromodulatory index does not support a lower monoaminergic drive in older adults.

The ovary is one of the first organs to age, with declines in oocyte quantity and quality leading to infertility and loss of endocrine function. Why the ovary ages earlier than somatic tissues has remained enigmatic but may relate to its highly dynamic physiology and substantial demand for cellular debris clearance. Each ovulation forms a corpus luteum (CL), a transient endocrine structure which supports pregnancy but regresses in its absence. Because CLs have a short functional lifespan but prolonged structural regression, they represent a substantial source of ovarian debris. We hypothesized that post-ovulatory debris clearance becomes impaired with age and contributes to ovarian fibroinflammation. Using a CL-labeling system, we demonstrated that CLs from reproductively old mice show dysregulated regression, resulting in an accumulation of persistent CLs (pCLs) which appeared concurrently with ovarian multinucleated giant cells (MNGCs). Laser capture microdissection, RNA sequencing, and histological evaluation of CLs, pCLs, and MNGCs demonstrated that pCLs were focal hotspots of proinflammatory and debris-associated signatures enriched in lipids, extracellular matrix, and immune cells. Although pCLs retained luteal features, they were transcriptionally more similar to MNGCs than CLs. Consistent with this, an ex vivo CL model acquired MNGC-associated molecular features during extended culture, suggesting that pCLs may represent sites of MNGC formation. Culture of isolated follicles or ovarian stromal organoids with factors from MNGC-enriched explants induced compartment-specific fibroinflammatory responses. These findings provide novel mechanistic insight into ovarian aging, whereby post-ovulatory debris clearance is compromised with age, leading to pCL accumulation, MNGC formation, and a fibroinflammatory milieu.

Sickle cell disease (SCD) causes heterogeneous mineral imbalances including variable degrees of hypocalcemia. The kidney controls systemic calcium by reabsorbing calcium from the glomerular filtrate via paracellular transport and transcellular transport in the nephron tubules, yet it is unknown whether these processes are modulated by genetic or environmental factors or disrupted in SCD. Using SCD mouse models and single-cell multiomics, we identify the distal convoluted tubule (DCT) as the nephron segment most susceptible to calcium reabsorption dysfunction in SCD, mainly via reduction of calcium buffer protein calbindin 1 (CALB1). We show that CALB1 and its encoding mRNA are decreased in DCT cells in SCD, alongside decreased Klotho (KL)-dependent fibroblast growth factor (FGF) 23 signaling and intracellular calcium signaling. Dietary iron restriction reduces CALB1, KL, and calcium exporter SLC8A1 levels in SCD kidneys. Loss of CALB1 shifts DCT cells toward energy-inefficient glycolysis with the metabolite 2,3-diphosphoglycerate impairing KL-dependent FGF23 signaling to create a feed-forward loop suppressing calcium reabsorption. Analysis of gene expression and protein quantitative trait loci data from kidneys of genetically diverse mice revealed that Calb1 expression levels are highly heritable and co-regulated with Slc8a1, identifying a genetic axis that dictates differential capacities for calcium buffering and trafficking toward blood in the kidney. Together, these findings support a model in which genetic variation, dietary iron status, and FGF23 signaling converge on DCT calcium buffering to reduce renal calcium reabsorption in the SCD kidney. This points to personalized, genotype- and iron-dependent strategies for managing mineral metabolism in SCD patients.