Pregnancies affected with placental insufficiency and fetal growth restriction (FGR) are characterized by reduced umbilical blood flow, decreased nutrient and oxygen supply to the fetus, and impaired fetal skeletal muscle growth. Vascular development within FGR skeletal muscle has not been well described. We hypothesized that chronic placental insufficiency impairs microvascular architecture in FGR fetal skeletal muscle, resulting in decreased vascularity. We used a sheep model of placental insufficiency-induced FGR by exposing pregnant ewes to elevated temperature. Four muscles from the hindlimb were obtained in late gestation from FGR and control fetal sheep for histological and molecular analyses. The proportion of slow-twitch oxidative fibers was 22% lower in the tibialis anterior (TA) and 32% lower in the extensor digitorum longus (EDL) muscles in FGR fetuses compared with controls. Total cross-sectional area was 20%-45% lower in biceps femoris (BF), TA, EDL, and soleus (SOL) muscles. The capillary number per myofiber was 34% lower in BF, 51% lower in TA, and 21% lower in SOL FGR muscles compared with controls. Capillary area was also 44% lower in the FGR TA muscle. Taken together, late gestation fetuses with placental insufficiency-induced FGR had smaller myofibers, fewer slow-twitch oxidative myofibers, and defects in angiogenesis and capillary formation. Pregnancies affected by placental insufficiency-induced FGR result in fewer slow-twitch oxidative myofibers and lower capillary number per myofiber in fetal skeletal muscle by late gestation.

Major depressive disorder (MDD) often first emerges during young adulthood and is associated with an increased risk of future hypertension, but our understanding of blood pressure (BP) regulation in young adults with MDD who are otherwise clinically healthy remains limited. We tested the hypothesis that beat-to-beat BP variability (BPV) would be greater in young unmedicated adults with MDD compared with nondepressed healthy adults (HA). Because the arterial baroreflex is essential for beat-to-beat BP regulation, we also hypothesized that ) sympathetic baroreflex sensitivity would be reduced in young adults with MDD and ) positively related to BPV. Beat-to-beat BP (finger photoplethysmography), heart rate (ECG), and muscle sympathetic nerve activity (MSNA; peroneal microneurography) were measured during 10-20 min of supine rest in 40 young adults with MDD (unmedicated; = 19 females) and 27 HA ( = 17 females). There were no group differences in either resting BP (116 ± 10/73 ± 6 HA vs. 113 ± 9/74 ± 6 mmHg MDD; both > 0.05) or MSNA (26 ± 11 vs. 24 ± 13 bursts/100 heartbeats MDD; = 0.50). Neither beat-to-beat BPV (e.g., systolic BP standard deviation: 5.8 ± 2.1 HA vs. 5.9 ± 1.6 mmHg MDD, = 0.47) nor sympathetic baroreflex sensitivity (e.g., burst incidence gain: -3.8 ± 1.3 HA vs. -3.4 ± 1.5 bursts/100 beats/mmHg MDD, = 0.34) was different in MDD compared to HA. In adults with MDD, sympathetic baroreflex sensitivity was related to BPV ( = 0.52, = 0.01). Traditional measures of beat-to-beat cardiac output and total peripheral resistance variability were likewise not different between groups (all > 0.05). These data demonstrate that both beat-to-beat BPV and sympathetic baroreflex sensitivity are preserved in young unmedicated adults suffering from MDD. This study investigated beat-to-beat blood pressure variability (BPV) in young unmedicated adults with major depressive disorder (MDD). The results demonstrated that both BPV and sympathetic baroreflex sensitivity were preserved in young unmedicated adults with MDD compared with healthy nondepressed young adults.

Older adults have both lower pulmonary function and impaired thermoregulation compared with younger adults. In addition, epidemiological evidence suggests that extreme heat exposure increases the incidence of pulmonary complications in older adults. However, the impact of extreme heat exposure on pulmonary function in healthy older and younger adults is not well described. To assess this question, spirometry was performed at baseline in a thermoneutral environment and at the end of a 3-h heat exposure in a DRY (47°C and 15% humidity) and HUMID (41°C and 40% humidity) environment. Fifteen younger (7 female; 30 ± 5 yr) and 15 older (8 female; 72 ± 5 yr) adults completed the study. In the DRY condition, the younger adults had no change in forced vital capacity (FVC) from baseline (4.34 ± 0.55 L) to end-heating (4.31 ± 0.62 L; = 0.72). In contrast, FVC in the older adults was increased from baseline (3.17 ± 0.72 L) to end-heating (3.29 ± 0.65 L; = 0.02) in the DRY condition. Forced expiratory volume in 1 s (FEV) in the younger and older adults increased similarly from baseline (3.55 ± 0.47 and 2.38 ± 0.60 L, respectively) to end-heating (3.70 ± 0.50 and 2.51 ± 0.54 L, respectively; = 0.003) in the DRY condition. The HUMID condition resulted in similar changes in FVC and FEV in both age groups. In summary, the younger adults had an increase in expiratory airflow following heat exposure, indicative of some degree of bronchodilation, whereas the older adults had improved airflow in addition to increased FVC that could be indicative of altered pulmonary system compliance. Pulmonary function increases in younger and older adults following 3 h of extreme heat exposure to a DRY (47°C and 15% humidity) and HUMID (41°C and 40% humidity) environment. Specifically, when hydration is maintained, FEV increases as a result of heat-induced bronchodilation in both younger and older adults, whereas FVC increases in only the older adults due to potential improvements in pulmonary system compliance.

The pressure-generating capacity of the diaphragm is generally thought to be compromised at high lung volume either due to loss of curvature or loss of its membrane tension. At a state of hyperinflation during airway occlusion at total lung capacity, the diaphragmatic muscle is forced to contract from an initial shorter length, the zone of apposition narrows, insertional force on the chest wall is reduced, and abdominal compliance falls. We hypothesize that these altered mechanical conditions at high lung volume lead to a loss of the pressure-generating capacity that is mediated by excessive muscle shortening rather than loss of curvature of its muscle fibers. Using a biplane fluoroscopy, locations of radiopaque markers attached to the diaphragm muscle fibers and the lower three ribs of 10 beagle dogs weighing between 7 and 10.5 kg were determined. Such measurements were conducted during quiet spontaneous breathing and during forceful inspiratory efforts against an occluded airway at three lung volumes spanning the vital capacity from functional residual capacity (FRC) to total lung capacity (TLC). Our data show that transdiaphragmatic pressure (Pdi) at TLC was reduced by nearly 80% and surface area of the midcostal diaphragm muscle at contracted state during airway occlusion at TLC reduced by nearly 35% from its value at end of expiration. In addition, muscle fiber curvature was essentially maintained during the entire vital capacity of airway occlusion. Our data demonstrate that during airway occlusion at high lung volume, the pressure-generating capacity of the diaphragm is compromised primarily due to a mechanism that involved a combined mechanical effect of hyperinflation and excessive muscle contraction rather than a significant loss of curvature of its muscle fibers. Data from the current study support the hypothesis that the pressure-generating capacity of the diaphragm at high lung volume is compromised primarily due to a mechanism that involves a combined mechanical effect of hyperinflation and substantial muscle contraction rather than a significant loss of its muscle fiber curvature.

Defective postprandial glucagon suppression contributes to chronic hyperglycemia in type 2 diabetes. Although insulin action and secretion have been extensively and quantitatively studied in the literature, less effort has been made to quantify the glucagon stimulatory effect on endogenous glucose production (EGP). This study aims to model the glucagon effect on EGP in healthy humans, capturing the decline of its action following sustained hyperglucagonemia. We analyzed data from 54 nondiabetic individuals studied on two occasions, where they received a glucose, labeled with [3-H]-glucose, and an insulin infusion, mimicking systemic appearance after an oral glucose challenge, whereas endogenous hormone secretion was suppressed by somatostatin. Glucagon was infused at a rate of 0.65 ng/kg/min starting at 0 min (nonsuppressed occasion) or 120 min to mimic postprandial glucagon suppression (suppressed occasion). Plasma glucose, insulin, and glucagon concentrations were frequently measured for 300 min, and model-independent estimates of EGP were obtained from tracer specific activity. Several physiological models describing the EGP time course as a function of plasma glucose, insulin, and glucagon concentrations were developed and compared, each implementing a different hypothesis for the evanescence of glucagon effect. The best model successfully described EGP using the glucagon-to-insulin ratio and over-basal glucose to account for the waning glucagon effect. The model precisely estimated hepatic glucagon and insulin sensitivities. However, the glucose effect was excessively delayed, likely reflecting a cascade of other biological signals rather than the direct effect of hyperglycemia on the liver. The model can be used to quantify hepatic glucagon and insulin sensitivity, accounting also for glucagon evanescence over time. The ability to quantify glucagon effects on postprandial glucose metabolism will further our understanding of its role in the onset and progression of type 2 diabetes. These findings can also be used in the design of novel glucagon-based therapies where accurate modeling of glucagon action is required to meet efficacy and safety standards.

The vagal nerves in mice run ventrally and dorsally below their diaphragm. They form four branches (common hepatic, R1; ventral gastric, R2; dorsal gastric, L1; celiac, L2) that project into the abdominal organs, such as the stomach, small intestine, and liver. To identify the vagal afferents that receive inputs from these organs, we examined the neural responses to the gastrointestinal and portal injection of capsaicin, a known stimulant of vagal afferents. The afferent fibers of the three branches (R1, R2, and L1) were activated following the intragastric (IG) injection of capsaicin in anesthetized mice. Moreover, the injection of a wheat germ agglutinin tracer into the stomach enabled the detection of positive cells in the nodose ganglion of intact mice, but not in vagotomized (VG) mice with transected R1, R2, and L1 branches. Capsaicin administered into the duodenum or portal vein activated the afferent neural activities of the R1 and L2 or R1, R2, and L1 branches, respectively. Moreover, IG injection of capsaicin increased the efferent sympathetic outflows to the brown adipose tissue and the kidney. The sympathetic response of the brown adipose tissue, but not the kidney, was abolished in the VG mice. In addition, an anorexigenic response to capsaicin was also abolished in the VG mice. Finally, increased vagal afferents were observed in diet-induced obese mice, which were comparable with the responses observed with capsaicin treatment of control mice. Thus, vagal afferents activated by capsaicin may contribute to the suppression of diet-induced obesity through efferent sympathoexcitation and appetite reduction. In a mouse study, we identified input patterns from the gastrointestinal organs and liver to vagal afferents, with physiological evidence that there is no one-to-one correspondence between nerve branches and organs; multiple nerve branches receive inputs from a single organ. This new discovery is important as it contributes to elucidating the mechanisms of physiological function based on the vagal afferent pathway affected by nutrition, osmotic pressure, and hormones.

Allostatic load, a maladaptive biological process wherein physiological stability ("allostasis") fails owing to chronic stress exposure, is traditionally measured by the allostatic load index (ALI). Whether ALI is associated with wearable-assessed physiological responses remains unknown. We aimed to determine the association between ALI and wearable-assessed physiological responses during a 10-wk military training course. Twenty-five participants (12 women) with ALI and suitable wearable data [84.31% complete data (range: 64.71%-97.56%)] were included. ALI (0-8) was calculated using biomarker components from neuroendocrine, autonomic, and immune systems. Device variables included total energy expenditure (TEE), energy expenditure during physical activity (PAEE), daytime heart rate (HR), sleeping HR, nonlinear HR variability (detrended fluctuation analysis, DFA-α), and sleep architecture. Flux was calculated as raw (Δ) or absolute difference (|Δ|) in average values between days and nights. Generalized linear mixed effect models assessed the association between high allostatic load (ALI > 4) and responses (α = 0.05). Twelve (4 women) participants experienced ALI > 4. High allostatic load was associated with TEE (β = 0.658, standard error (SE) = 0.002, odds ratio (OR) = 1.931, < 0.001), Δ in relative PAEE (β = 0.472, SE = 0.002, OR = 1.602, < 0.001), daytime HR (β = 0.189, SE = 0.002, OR = 1.208, < 0.001), |Δ| in relative daytime HR (β = 0.262, SE = 0.001, OR = 1.298, < 0.001), and |Δ| in relative sleeping HR (β = -0.048, SE = 0.001, OR = 0.953, < 0.001). Every one-standard-deviation increase in absolute TEE, flux in relative PAEE, daytime HR, flux in daytime HR, and reduced flux in sleeping HR increased the risk of high allostatic load by 5%-90%. Chronically elevated and variable cardiometabolic activity with blunted night-to-night variation in sleeping HR may be a digital phenotype of high allostatic load in military personnel. This investigation for the first time observed an association between the traditional measurement of allostatic load, the allostatic load index, and wearable-assessed physiological responses to strenuous military training stress. We found a novel digital phenotype of allostatic load characterized by chronically elevated and variable cardiometabolic activity with blunted variation in heart rate during sleep. This phenotype may serve as an at-risk profile of high allostatic load and prompt in-training modifications to enhance posttraining readiness.

Recent advances and foundational knowledge are integrated to provide a comprehensive description of brain-gut signaling relevant to colorectal motility, with an emphasis on defecation. We discuss molecular targets of therapeutic potential. We identify four levels of neural control: ) cortical and hypothalamic centers; ) pontomedullary cell groups; ) the lumbosacral defecation centers; and ) the enteric nervous system (ENS). The critical role of central nervous system (CNS) input is evidenced by the constipation that follows spinal cord injury or during Parkinson's disease. The constipation of spinal cord injury suggests that propulsive reflexes generated by the ENS require augmentation from the CNS. Conversely, the crucial role of the ENS is revealed by the failed defecation in Hirschsprung and Chagas diseases. Spinal descending pathways receive inputs from the cortex and hypothalamus, and converge on a common efferent neuronal link between the CNS and the ENS: parasympathetic preganglionic neurons (PPG neurons) that connect with ENS directly or via pelvic ganglia. CNS pathways respond to the urge to defecate, to stress or alarm, and to signals from the large intestine. The ENS responds to signals from its lumen, commonly mediated through the release of local hormones, and to signals from the CNS. PPG neurons, the CNS to ENS link, express a wide range of amine and peptide receptors that are potential targets for the treatment of constipation. Important among targets are ghrelin, dopamine, and serotonin receptors. The receptors within the colon that connect luminal signals with propulsive contractile activity also represent potential therapeutic targets.

Strenuous physical work in hot environments can impair kidney function and potentially cause acute kidney injury (AKI). Heat acclimation is recommended to reduce thermal strain but its efficacy in mitigating decrements in kidney function remains unclear. The present study tested the hypothesis that 10 days of heat acclimation attenuates increases in serum creatinine (ΔCr) during exercise heat stress. Twenty healthy adults (14 females) completed 10 days of fixed-intensity treadmill walking for 120 min in a climatic chamber (40°C) to induce heat acclimation. Kidney function was assessed as ΔCr from pre-to-post exercise on (D1) and (D10). Plasma neutrophil gelatinase-associated lipocalin (ΔNGAL) was measured to estimate the magnitude of renal ischemia. The increase in core temperature (Tc) from pre- to postexercise was attenuated on D10 (Post: 38.3 ± 0.4°C) compared with D1 (Post: 38.8 ± 0.5°C, < 0.001). Heat acclimation did not alter the increase in ΔCr and ΔNGAL to exercise heat stress ( ≥ 0.325). There was a strong correlation between ΔTc and ΔCr on D10 ( = 0.61) but no correlation on D1 ( = 0.908). There was no correlation between ΔTc and ΔNGAL on either day ( ≥ 0.480). There was a strong correlation between ΔNGAL and ΔCr on D1 ( = 0.694) but no correlation on D10 ( = 0.118). These findings indicate that heat acclimation does not alter the magnitude of increase in circulating biomarkers of kidney function following exercise heat stress. However, that ΔCr was correlated with ΔTc on D10 but not on D1 suggests that the kidneys may exhibit increased sensitivity to hyperthermia in heat-acclimated individuals. Heat acclimation provides beneficial adaptation during heat stress. The impact of heat acclimation on kidney function are not well understood. This short report provides findings that plasma neutrophil gelatinase-associated lipocalin (NGAL) and creatinine appear to be unaffected by acute heat stress before and after heat acclimation, but that the kidneys may exhibit increased sensitivity to hyperthermia in heat-acclimated individuals.

Exposure to an elevated state of hyperthermia is associated with heat-induced cytotoxicity, which, if left unabated, can cause tissue damage and death. Although activation of autophagy is vital to counter heat-induced cellular injury and promote cellular survival, the dose-dependent autophagic response to controlled elevations in body core temperature has yet to be evaluated in an in vivo human model. Therefore, on separate days, we evaluated cellular responses in 12 young adults [means (SD): 22 (2) yr; 6 women] who were immersed (up to the clavicle) in water set at a temperature to clamp core temperature (esophageal) at either baseline resting (control; 37°C), warm (38°C), or hot (39°C) conditions for 60 min. Autophagy was characterized in peripheral blood mononuclear cells before and after water immersion, as well as following 3 h of seated recovery in a temperate environment (∼22°C). Proteins associated with autophagy and cellular stress pathways (apoptosis, inflammation, and heat shock response) were assessed via Western blot. With increasing levels of hyperthermia, we observed increasing autophagic activation (as indexed via elevated LC3-II and decreasing p62) at end exposure to warm and hot core temperature clamps, with evidence of elevated autophagic activity up to 3 h after exposure to the hot condition. This was paired with significant end exposure elevations in cellular stress proteins including cleaved-caspase-3, TNF-α, and IL-6 in the hottest condition. Taken together, our findings suggest that autophagy is activated with increasing levels of hyperthermia and may be important in restoring cellular homeostasis when exposed to body core temperatures above 38°C in healthy young adults. Our findings suggest that autophagic regulation is stimulated in peripheral blood mononuclear cells associated with elevations in body core temperature induced through warm-to-hot water immersion. Importantly, our findings propose that autophagy may be important in restoring cellular homeostasis when exposed to body core temperatures above 38°C in healthy young adults. Therefore, the use of warm-to-hot water immersion may provide a potent model to study cellular heat stress responses in humans.

The morphology of the larynx is essential for vocalization, respiration, and airway protection, yet the sources of phenotypic variation within species are not well understood. This study investigated whether genetic background exerts a stronger influence than environmental factors on laryngeal morphology in two house mouse strains. Using geometric morphometrics, we analyzed the size and shape of 79 laryngeal specimens and examined the effects of body size, genetics, obesity, exercise, and social housing. Our results demonstrate that genetic background significantly shapes laryngeal structure. There were significant shape differences between the two genetic strains, and the inbred strain showed less phenotypic variation than the outbred mice. Although these structural differences likely arose without direct selection, they were associated with marginal differences in vocal output, suggesting functional relevance. Obesity and exercise also influenced laryngeal morphology, but their effects were secondary to genetics. Notably, leptin levels were linked to size and shape changes in the vocal organ. These findings suggest that random genetic drift and pleiotropy can be important drivers of laryngeal evolution in house mice. Overall, both genetic and environmental factors contribute to laryngeal shape, underscoring the organ's plasticity. How are voice, swallowing, and breathing shaped by genes, environment, and diet? This study in house mice shows that genetic background, obesity, exercise, and social housing all influence laryngeal structure and function. Laryngeal shape seems to be affected by pleiotropy and genetic drift. Outbred mice show greater variation than inbred ones, and leptin-deficient mice have smaller vocal organs-highlighting the larynx as a dynamic, responsive structure shaped by multiple forces.

Aging is associated with cerebrovascular impairment, increasing the risk for neurovascular and degenerative diseases. Intermittent hypoxic conditioning (IHC) has been proposed as a valuable strategy to enhance vascular health. However, its effects in cerebrovascular territories remain unclear, particularly in older adults. Eighteen elderly individuals (62-79 yr, 11 males) were randomly assigned to either an IHC ( = 8) or a control group (CTL, = 10). Both groups underwent 24 sessions (3 sessions/wk) of passive moderate exposure to either intermittent hypoxia (targeted oxygen saturation by pulse oximetry = 75%-80%) or sham hypoxia. Middle cerebral artery (MCA) reactivity to hypo- (hyperventilation task) and hypercapnia (carbon dioxide ramp administration) was assessed using transcranial Doppler ultrasound. Cerebrovascular reactivity to carbon dioxide (CVR) was evaluated in both absolute and relative changes in MCA blood velocities (MCAv), before (Pre), 3-4 days after (post 1), and 2 mo after (post 2) intervention cessation. As expected, MCAv decreased during hypocapnia (CTL = -15.7 ± 7.0 cm/s; IHC = -15.9 ± 6.0 cm/s) and increased during hypercapnia (CTL = 20.7 ± 8.4 cm/s; IHC = 18.2 ± 11.1 cm/s) at all time points in both groups. However, compared with CTL, IHC did not significantly improve any CVR parameters (e.g., relative CVR to hypercapnia, Pre: CTL = 4.3 ± 1.9, IHC = 3.1 ± 2.0; post 1: CTL = 4.1 ± 1.6, IHC = 3.4 ± 1.6; post 2: CTL = 4.7 ± 2.0, IHC = 3.5 ± 1.7 cm/s/mmHg; = 0.739). The present work does not support the potential benefits of IHC on cerebrovascular function. However, future studies are required to confirm these preliminary results and may consider a more comprehensive appraisal of the cerebral hemodynamic control. This study is the first to investigate the effects of IHC on CVR over the short- and mid-term in elderly individuals. Contrary to our initial hypothesis, 8 wk of moderate IHC did not enhance CVR at any time point.

In preclinical models, the organum vasculosum of the lamina terminalis (OVLT) and subfornical organ (SFO) sense changes in serum sodium chloride (NaCl) concentration and mediate NaCl-induced changes in sympathetic nerve activity, vasopressin (AVP), thirst, and blood pressure (BP). In humans, brain imaging studies have shown that acute hypernatremia alters the activity or functional connectivity of the SFO and OVLT. However, no studies have investigated whether there are sex differences in central NaCl sensing in humans, which could underlie sex differences in neurohumoral responses to hypernatremia. Therefore, the purpose of this study was to test the hypothesis that acute relative hypernatremia would increase resting-state functional connectivity between NaCl-sensing brain regions and that these responses would be greater in men. Thirty-two young adults (17 men/15 women) underwent resting-state functional magnetic resonance imaging (fMRI) at baseline and during a 30-minute intravenous hypertonic saline infusion. We performed a seed-to-seed functional connectivity analysis. Despite similar increases in serum sodium, thirst, systolic BP, and plasma AVP between the sexes, there was a time*sex interaction (p<0.001) on SFO-OVLT functional connectivity, as SFO-OVLT functional connectivity increased in men during the late phase (15-30 minutes) of the hypertonic saline infusion (z-scores: baseline=0.21±0.20, late phase=0.29±0.21; p=0.04), but decreased in women (z-scores: baseline=0.27±0.17, late phase=0.15±0.18; p=0.004). Collectively, these results suggest that the functional coupling of the SFO and OVLT, which regulate sympathoexcitation and BP during acute hypernatremia, may be modulated by sex.

This study investigates the role of renal nerve afferents in sympathetic vasomotor responses during acute low-dose furosemide administration intravenously or directly in the renal pelvis. We hypothesized that furosemide activates renal nerve afferents modulating sympathetic vasomotor activity. To test this hypothesis, we conducted simultaneous recordings of renal sympathetic nerve activity (rSNA) and splanchnic sympathetic nerve activity (sSNA) in Wistar rats. The effects of intravenous furosemide infusion (1 mg/kg/hour) on mean arterial pressure (MAP), heart rate (HR), rSNA, and sSNA in control (CTRL, n=5) and afferent renal denervated rats (ARD, n=5) were investigated. In addition, we infused furosemide (from 10 to 100 μg/ml; 200 μL) directly in the renal pelvis (n=8), with simultaneous recordings of hemodynamic parameters and sympathetic nerve activity. Furosemide induced a significant reduction in rSNA (spikes/sec) but not in sSNA in the ARD compared to the CTRL group (rSNA maximal decrease of -10 ± 10 vs. -21 ± 7 spikes/s at 120 minutes, *P<0.05), as well as in the amplitude of bursts (rSNA -0,21 ± 0,072 vs 0,062 ± 0,16mVs at 120 minutes, *P<0.05). Moreover, intrapelvic furosemide infusion in CTRL rats preferentially increased rSNA (69% of maximal response induced by capsaicin) as for sSNA there was no significant difference. These findings suggest that transient receptor potential vanilloid type-1 (TRPV1)-expressing C-fiber afferents, located in the renal pelvis, are activated by furosemide, leading to a preferential change in the pattern of sympathetic activity to the kidneys, independently of blood volume depletion.

Maternal obesity increases risk of preterm delivery and rapid transition of offspring from hypoxemic environment to a normal or elevated oxygen environment, especially if the baby receives oxygen therapy. Maternal obesity may also increase offspring risk of developing hypertension. Thus, we examined whether neonatal hyperoxia (HO) leads to elevated blood pressure (BP) in offspring from lean mothers and exacerbates adverse impact of maternal obesity on offspring BP regulation. Male and female Sprague-Dawley offspring from lean and high fat diet-fed obese mothers (n=12-18 mothers/group) were exposed to room air (~21% O) or HO (80% O) between postnatal days P3-P10, and then returned to room air. At twelve weeks of age, offspring were instrumented with telemetry probes to measure BP and heart rate (HR). Contrary to our hypothesis, neonatal HO was associated with lower BP compared to control offspring from lean mothers (males: 105±1 vs. 111±1 mmHg; females: 102±0.4 vs. 108±0.4 mmHg); and also reduced BP and HR in hypertensive obese offspring from obese mothers (males: 117±1 vs. 123±1 mmHg and 351±4 vs. 358±5 bpm; females: 113±1 vs. 116±1mmHg and 376±2 vs. 390±4 bpm). In lean offspring from lean mothers, neonatal HO was associated with reduced +dP/dt, whereas in obese offspring from obese mothers, HO attenuated cardiac dysfunction when compared to obese offspring not submitted to HO. These results suggest that exposure to HO in early postnatal life is not associated with elevated BP in early adulthood and it does not exacerbate the hypertensive effects of maternal obesity on offspring BP regulation.

Diving marine mammals must allocate time between respiring at the surface and foraging underwater. Previous studies of optimal diving theory have attempted to predict such patterns, but the amount of time divers must spend at the surface before and after dives of varying durations remains difficult to assess. Here, we examined the surfacing and breathing patterns of short-finned pilot whales from biologger data to examine their use of anticipatory versus reactive strategies. We used linear mixed effects models to examine the effect of dive characteristics on surface interval (SI) durations and breathing rate. Pilot whales increased SI duration before dives of increasing duration and after dives of increasing activity. Instantaneous breathing rates (s) of pilot whales demonstrated little anticipation but rather a strong reactive pattern seen by the modulation of in response to the previous rather than upcoming dive. During typical SIs, was predicted by time since previous dive, duration of the previous dive, time until upcoming dive, and activity of the previous dive. Short-finned pilot whales in our study area exhibit both benthic and pelagic foraging which may compel anticipation when prey capture is predictable and reaction when prey capture is difficult to predict. The observed surfacing and breathing patterns therefore likely reflect a balance of the needs for blood gas homeostasis, aerobic metabolism, and the variability of foraging opportunities. An improved understanding of how animals make decisions about diving is critical for informing predictions of how they will contend with changing ocean landscapes.

Aging from young to middle-aged and older adulthood modulates sweating differently across body regions, yet how biological aging from young adulthood to the 80s and beyond affects cholinergic sweating remains unclear. A total of 248 participants (143 males and 105 females) were grouped as young (≥18+20s), middle-aged (30s+40s+50s), older (60s+70s) adults, and elderly (80s+90s). Acetylcholine-induced sweat rate, activated sweat gland density, and sweat gland output were assessed via transdermal iontophoresis. Forearm sweat rate declined in the 30s+40s+50s and older in males and the 60s+70s and older in females, compared to the ≥18+20s group (all ≤0.006). Thigh sweat rate also declined with aging and was further reduced in the 60s+70s and 80s+90s compared to the 30s+40s+50s group in males (both ≤0.035). Sweat rate did not differ between the 60s+70s and 80s+90s groups in either region or sex (all ≥0.677). Sex differences in forearm sweat rate persisted across all age groups (all ≤0.012), but diminished on the thigh in the 60s+70s and 80s+90s groups (both ≥0.183). These changes were attributed to reductions in sweat gland output in males and combined reductions in sweat gland density and output in females. Collectively, forearm cholinergic sweating declines from the 30s+40s+50s to the 60s+70s relative to young adults but shows minimal further attenuation beyond the 70s in both sexes. Thigh cholinergic sweating function is more affected by biological aging in males. We also highlight the characteristics of sweating in two participants in their 90s, providing insights into sweating function at the end of the lifespan.

Anuran amphibians have a unique body plan characterized by a high interstitial compliance as a consequence of numerous subcutaneous lymph sacs. Anurans produce lymph at very high rates owing to 'leaky' capillaries and low capillary reflection coefficients. The copious amounts of formed lymph are stored in these lymph sacs but, owing to gravitational forces, lymph preferentially collects in the ventral lymph sacs. Lymph is returned to the circulation by dorsally located lymph hearts which pump lymph into the venous side of the circulation. The major problem for anurans is moving the lymph from ventral lymph sacs, against gravity, to the dorsal lymph hearts. Lymph movement is accomplished by three distinct mechanisms: 1) horizontal movement of lymph along the hind limbs by differential lymph sac compliance; 2) vertical movement by skeletal muscles that insert on the urostyle, skin and the margins of lymph sacs that change the compliance and pressure of lymph sacs; 3) lung ventilation and associated volume changes in the lungs are transmitted primarily to the subvertebral lymph sac overlying the lungs resulting in large negative pressures that aspirate lymph dorsally. Phylogenetic analyses reveal that lymph skeletal muscles have undergone bi-directional evolution with more terrestrial species showing greater elaboration of these muscles compared with aquatic species that have lost or reduced these muscles. More terrestrial species also have larger lung volumes and compliances than aquatic or semi-aquatic anurans which presumably enhance their ability to mobilize lymph movement in desiccating environments where maintenance of plasma volume is a greater challenge.

Nrf2 activation by sequestosome1/p62 (p62) (Ser351) phosphorylation is a pivotal signal for the exercise-mediated augmentation of antioxidant protein expression in muscle. However, the molecular mechanisms regulating this signal in response to exercise remain unclear. In this study, we demonstrate that exercise-training leads to higher levels of antioxidant proteins (e.g., CuZnSOD and EcSOD) in the mouse predominantly oxidative soleus, but not in the predominantly glycolytic white vastus lateralis muscle. We also observed that muscle-specific p62 overexpression, which leads to higher levels of phosphorylated (Ser351) p62, increases expression of these antioxidant proteins. Evidence for a cell-autonomous signal came from the observations that exercise training increased the expression of the Neighbor of BRCA1 gene 1 (NBR1) protein, which is known to stimulate p62 (Ser351) phosphorylation, in the soleus muscle, while cyclic stretch of C2C12 myotubes led to the same outcomes. Of note, both exercise training in mice and cyclic stretch in myotubes enhanced the expression of cleaved interleukin-1β (IL-1β), which is known to stimulate NBR1 expression. A key upstream role for IL-1β in this signaling was then established by daily injections of IL-1β-neutralizing antibody, which prevented exercise training-mediated increases in NBR1, phosphorylated p62 (Ser351), and EcSOD in the soleus muscle. Collectively, these findings point to IL-1β as an important upstream modulator of NBR1, p62 phosphorylation, and increased antioxidant protein expression in the exercise-trained predominantly oxidative muscle.