American Journal of Physiology-Regulatory, Integrative and Comparative Physiology

Regulation of water permeability in the collecting duct is important for osmoregulatory acclimation in teleost fish. In hyperosmotic environments such as seawater (SW), the teleost kidney functions as a site of divalent ion excretion. The collecting ducts reabsorb Na+, Cl-, and water, thereby reducing urine volume and producing small amounts of isotonic urine with high concentrations of divalent ions. In hypoosmotic environments such as freshwater (FW) or low-salinity brackish water (BW), the kidney produces large volumes of hypotonic urine and serves as a site of water excretion; under these conditions, the collecting ducts reabsorb Na+ and Cl- but not water. To identify aquaporins (Aqps) involved in regulating water permeability in the collecting ducts of teleosts, we analyzed renal Aqp expression in a euryhaline marine fish, the Japanese pufferfish (Takifugu rubripes), which possesses 16 Aqp genes in its genome, seven of which (Aqp1aa, 1ab, 3a, 4a, 7, 8bb, and 11a) are expressed in the kidney. Quantitative RT-PCR analysis showed that Aqp1aa and Aqp4a were highly expressed in collecting duct tissues, and that Aqp1aa expression was markedly reduced in fish acclimated to BW. Immunohistochemistry revealed apical localization of Aqp1aa and basolateral localization of Aqp4 in collecting duct cells, with apical Aqp1aa downregulated in BW. These results suggest that Aqp1aa and Aqp4 mediate water reabsorption in SW and that downregulation of Aqp1aa contributes to hypotonic urine production in BW. NEW & NOTEWORTHYRegulation of water permeability in the collecting duct is important for osmoregulation in teleost fish. Expression analyses of aquaporins (Aqps) in the marine pufferfish Takifugu rubripes showed that Aqp1aa and Aqp4a are highly expressed in the collecting duct and localized to the apical and basolateral membranes, respectively. Renal Aqp1aa expression was markedly reduced in fish acclimated to hypoosmotic brackish water. These results indicate that collecting duct water permeability is regulated by Aqp1aa expression.

This study aimed to investigate the dynamics of gene expression in pigs during heat stress (HS), focusing on both short-term (STHA) and long-term (LTHA) heat acclimation phases. A total of 12 castrated males were exposed to thermoneutral temperatures (24{degrees}C) for 14 days (TN) and then to a constant temperature of 30{degrees}C for 21 days. Rectal temperature measurements indicated a biphasic thermoregulatory response, with an initial peak followed by acclimation. Using whole blood transcriptome analysis at seven time points between day 5 before the initiation of HS challenge and day 13 post HS. A total of 525 genes were differentially expressed during the STHA (day 0-day 2) phase. A switch in the expression of most genes was observed around 20 hours after HS. Functional pathway enrichment analysis identified through shape-based clustering revealed the activation of the immune system, especially mediated through toll-like receptor signaling pathways. The LTHA phase (day 2-day 13) revealed 985 differentially expressed genes, with pathways associated with various metabolisms, including mitochondrial fatty acid beta-oxidation, and electron transport, ATP synthesis, and heat production by uncoupling proteins. Interestingly, oxidative phosphorylation was predicted to be activated during the LTHA, particularly in Complex V, whereas other complexes showed mixed regulation. Comparative pathway analysis indicated distinct metabolic adaptations between STHA and LTHA, with up-regulation of glucose and lipid metabolism in late STHA and down-regulation of lipid metabolism during LTHA. This study contributes to a better understanding of the time course of adaptation mechanisms in pigs to HS, underlying a coordinated regulation during STHA involving several stress-specific mechanisms (via the HSP) and metabolic variation to help pigs achieve homeothermy.

Mental imagery is known to be accompanied by autonomic responses, traditionally viewed as merely downstream consequences of imagery. Recent theoretical work has challenged this view, proposing that mental imagery requires the integration of cortical sensory representations with ascending interoceptive signals supplied by the autonomic nervous system. These two views make opposite predictions: if autonomic activity is only a consequence of imagery, then the responsiveness of the autonomic nervous system should not predict imagery vividness. If instead autonomic input shapes the generation of mental images, individuals with greater autonomic responsiveness should experience more vivid imagery. The present study tested these competing predictions by examining whether individual differences in cardiac vagal reactivity (indexed by the magnitude of HRV change in response to a paced breathing manipulation) predict self-reported visual imagery vividness. Imagery vividness was assessed using the Vividness of Visual Imagery Questionnaire (VVIQ) at a separate time point from the paced breathing protocol, ensuring that any observed relationship between cardiac vagal capacity cannot reflect autonomic activation driven by imagery itself. The key result was that cardiac vagal reactivity (indexed by RMSSD change normalized by mean R-R interval), significantly predicted higher VVIQ scores (r = .30, p = .031). These findings demonstrate that vividness of mental imagery is not exclusively central in origin but also shaped by the capacity of the autonomic nervous system to enter a high-parasympathetic state. Imagery thus likely involves bidirectional autonomic-cortical interaction, with descending pathways triggering the intention to generate an image and ascending interoceptive signals contributing to its generation.

Perinatal opioid exposure is a prevalent clinical concern linked to respiratory instability and adverse infant outcomes. The opioid buprenorphine is prescribed as a medication for opioid use disorder during pregnancy and used to treat neonatal opioid withdrawal syndrome, yet its direct effects on neonatal control of breathing have not been examined. Here, we asked how acute buprenorphine exposure affects breathing at rest, and during chemoreceptor stimulation. Using dual-chamber head-out plethysmography, we measured pulmonary ventilation rate ([V]I) and metabolic rate in awake male and female Sprague-Dawley neonatal rats on postnatal days 4-5 (P4-5) during eupnea and a hypoxic-hypercapnic (HH) challenge. The effects of buprenorphine and two opioid receptor antagonists, naloxone hydrochloride, or peripherally restricted naloxone methiodide, were assessed using a repeated measures design. [V]I during eupnea and HH were markedly depressed following buprenorphine administration. Buprenorphine reduced [V]O2 and [V]CO2 and produced ventilatory equivalents for O2 and CO2 consistent with frank hypoventilation, driven by reduced breathing frequency and tidal volume (VT). When administered after buprenorphine, neither naloxone hydrochloride nor naloxone methiodide could rescue the buprenorphine-mediated hypoventilation in eupnea or during HH. In contrast, pre-treatment with either naloxone hydrochloride or naloxone methiodide attenuated buprenorphine-induced hypoventilation by preserving VT. These findings demonstrate that neonatal protective chemoreceptor reflexes are depressed by buprenorphine and suggest that pre-treatment with a peripheral opioid receptor antagonist could mitigate buprenorphine-induced hypoventilation without inducing opioid withdrawal. Key PointsO_LIAcute buprenorphine exposure significantly depressed pulmonary ventilation rate ([V]I) during eupnea and hypoxic hypercapnia (HH) in awake neonatal rats. C_LIO_LIBuprenorphine-induced hypoventilation was driven by reduced tidal volume (VT) and breathing frequency. C_LIO_LIBuprenorphine also reduced oxygen consumption ([V]O2) and carbon dioxide production ([V]CO2). C_LIO_LINaloxone given after buprenorphine failed to reverse hypoventilation. C_LIO_LIIn contrast, pre-treatment with either naloxone hydrochloride or peripherally restricted naloxone methiodide mitigated buprenorphine-induced hypoventilation by preserving VT. C_LI

Mice housed at room temperature (RT, 25{degrees}C) experience chronic mild cold stress compared with those housed at thermoneutrality (TN, 30{degrees}C). We hypothesized that cold stress suppresses circadian transcript expression in peripheral tissues. RNA-seq of hearts, livers, and diaphragms collected every 4 hours over 48 hours in constant darkness identified mRNA transcripts exhibiting {approx}24-hour rhythms (REGs). TN produced tissue-specific changes in REG number, identity, and phase without altering core circadian clock transcript levels. Cardiac REGs increased 4-fold, diaphragm REGs 1.5-fold, and hepatic REG identity shifted substantially. GO analysis revealed coordinated reorganization of rhythmic metabolic programs in the heart and liver. These data demonstrate that ambient housing temperature has tissue-specific effects on the number, identity, and temporal organization of rhythmically expressed transcripts in the heart, liver, and diaphragm.

Brown adipose tissue (BAT) is a unique tissue with mitochondria specialized for thermogenesis via the BAT-specific uncoupling protein 1 (UCP1). Ucp1-/- mice cannot tolerate acute exposure to cold, illustrating the necessity of UCP1 for efficient mitochondrial thermogenesis. However, these mice adapt to low temperatures through a gradual acclimation process, suggesting a high degree of mitochondrial plasticity in brown and beige fat cells. This phenomenon, which remains to be fully elucidated, indicates the potential for these mitochondria to implement effective thermogenic mechanisms in the absence of uncoupling protein 1 (UCP1). Here, we investigated mitochondrial remodeling in beige and brown fat of Ucp1-/- mice to determine how they fulfill their thermogenic role. Upon gradual acclimation to a cold environment, Ucp1-/- mice exhibited body metabolic parameters and temperatures in the interscapular region similar to those of wild-type mice of BAT, highlighting effective thermogenesis. Interestingly, mitochondrial patch-clamp analysis and a mitochondrial Ca2+ swelling assay revealed a dramatic increase in Ca2+ uptake depending on the mitochondrial calcium uniporter (MCU) in BAT mitochondria from Ucp1-/- mice when robust thermogenesis was required. Mitochondrial remodeling was accompanied by markedly increased tethering between mitochondria and the endoplasmic reticulum (ER) in Ucp1-/- mice, confirming a significant restructuring of the contact sites between the ER and mitochondria, likely to adapt to a new Ca2+ homeostasis. Respiratory complexes also underwent significant reorganization, which partly led to a reduction in their assembly. Levels of ATP synthase and its F1 subcomplex increased, suggesting a major source of ATP consumption and energy expenditure. We propose a new role for MCU as a key regulator of mitochondrial plasticity, enabling efficient thermogenesis in beige and brown adipose tissues in the absence of UCP1.

This study evaluated the effects of short-term, low-dose supplementation with high-fructose corn syrup (HFS) and Momordica charantia (Mo) on pulmonary arterial hypertension (PAH) and system dynamics in hypertensive broiler chickens. Thirty male Cobb broilers were divided into three groups (n=10): HFS, Mo, and control. PAH was surgically induced at day 17, and supplementation was provided from days 20 to 37. Measurements included body weight, feed intake, heart indices, and tissue composition. A dynamic model (Yaantal fe Bro A1) using differential equations was developed and showed strong correlations with observed data (0.90 < r < 1.0). HFS increased feed intake and weight gain; Mo enhanced feed efficiency and selective tissue growth. Both supplements reduced PAH severity, with HFS being more effective. These findings support the application of system dynamics modeling in evaluating nutritional strategies for obesity-related hypertension in avian models.

Many marine invertebrates are characterized by broad and highly plastic thermal limits, though the dynamic molecular mechanisms that enable extended thermal acclimation remain poorly understood. A classic example is the green crab (Carcinus maenas), which is a prolific and damaging non-indigenous species. Using a 22-day thermal exposure to cold (5{degrees}C), ambient (13{degrees}C), or warm (30{degrees}C) temperatures, we characterized plastic shifts in C. maenas performance using respirometry and time-to-right. We then used untargeted metabolomics and lipidomics analysis of heart tissues from days 4 and 22 to identify the molecular mechanisms underpinning plastic responses over time. Crabs at 30{degrees}C exhibited higher oxygen consumption rates than counterparts at 5{degrees}C. Interestingly, oxygen consumption rate increased over time at both temperatures, indicating thermal plasticity of aerobic respiration. Temperature-dependent metabolic reprogramming was employed by crabs to sustain aerobic respiration across temperature. Catabolism of branched-chain amino acids was important for energy production at elevated temperatures, while catabolism of arginine may have sustained the minimal energy needs of crabs exhibiting metabolic depression at cold temperatures. Righting response was positively correlated with temperature, and did not exhibit any changes over time. Lipidome remodeling consistent with homeoviscous adaptation could have enabled motor activity across temperature. Higher abundances of saturated and monounsaturated lipids likely provided structural integrity to cell membranes at 30{degrees}C, while lower abundances of these compounds may have enabled membrane fluidity at 5{degrees}C. Our work demonstrates the importance of ongoing molecular reprogramming in long-term acclimation, even when whole-animal physiology remains relatively stable. Summary StatementThis study demonstrates how the highly invasive green crab regulates metabolite and lipid pathways over time to maintain physiological performance across different temperatures.

General anesthetics enable invasive experimentation but can affect cardiovascular and respiratory physiology, biasing preclinical outcomes. We compared five anesthetic regimens in adult male Wistar rats, tribromoethanol (TBE, 250 mg/kg i.p.), chloral hydrate (CH, 400 mg/kg i.p.), ketamine-xylazine (KX, 80/10 mg/kg i.p.), thiopental (TP, 80 mg/kg i.p.), and isoflurane (ISO, 4% induction, 2% maintenance), to investigate integrated cardiorespiratory and biochemical markers. Femoral arterial catheterization allowed continuous blood pressure (BP) and derived heart rate (HR) recordings, while ventilation was assessed through pletysmography at baseline (awake), during induction, and recovery phases of anesthesia. Variability was evaluated in the time and frequency domains, including HR, systolic blood pressure (SBP), and spontaneous baroreflex sensitivity. In an independent cohort of rats, butyrylcholinesterase (BChE), CK-MB, cTnI, and LDH were measured. Baseline BP was unchanged by TBE and TP, whereas all anesthetics affected HR. Minute ventilation and breathing frequency were reduced with all agents, while tidal volume decreased with KX and TBE only. LDH and cTnI were unaffected, BChE was reduced by KX, TBE, and ISO, and CK-MB increased with CH and KX. Variability analysis showed that all anesthetics depressed pulse-interval and SBP variability and shifted spectral power toward higher frequencies, while baroreflex sensitivity and effectiveness were consistently reduced. During recovery, KX and TP restored most variability indices, whereas CH, TBE, and ISO showed persistent suppression. These findings highlight distinct profiles of cardiovascular depression and biomarker responses across anesthetics and underscore the importance of accounting for autonomic variability when selecting different anesthetics in experimental protocols. HighlightsO_LIFive anesthetic regimens were tested in rats. C_LIO_LIAll anesthetics reduced ventilation, and KX and TBE also reduced tidal volume. C_LIO_LICH and KX increased CKMB, while KX, TBE and ISO reduced BChE. C_LIO_LIAll anesthetics reduced blood pressure variability and baroreflex sensitivity. C_LIO_LIVariability recovered with TP and KX, whereas CH, TBE and ISO showed persistent suppression. C_LI

BackgroundChronic exposure to high-altitude hypoxia imposes sustained cardiovascular stress, yet hemodynamic adaptation among healthy high-altitude dwellers is heterogeneous and remains poorly characterized. This study aimed to identify distinct hemodynamic phenotypes in a healthy high-altitude population using unsupervised machine learning and to evaluate their association with multi-system subclinical target organ damage. MethodsThis cross-sectional study enrolled 694 healthy adults permanently residing at [&ge;]3300 m on the Qinghai-Tibet Plateau. Unsupervised K-means clustering was performed on nine hemodynamic variables, including peripheral and central blood pressures, augmentation index (AIx), pulse pressure amplification ratio (pPP/cPP), and systolic pressure amplification (pSBP-cSBP). Differences across phenotypes in carotid intima-media thickness (IMT), estimated glomerular filtration rate (eGFR), left ventricular mass index (LVMI), and pulse wave velocity (PWV) were assessed using one-way ANOVA with Bonferroni-corrected post-hoc tests. ResultsThree distinct hemodynamic phenotypes were successfully identified. The C2 (Balanced Adaptation) phenotype (n = 245) demonstrated the most favorable hemodynamic profile, characterized by the lowest blood pressure and augmentation index (AIx) values, along with the highest peripheral-to-central pulse pressure ratio (pPP/cPP). The C1 (Vascular Stress) phenotype (n = 267) presented with normal peripheral systolic blood pressure (125.9 {+/-} 11.3 mmHg) but exhibited markedly elevated wave reflection indices, including the highest heart rate-adjusted augmentation index (AIx@HR75: 31.9 {+/-} 9.7%) and the lowest pPP/cPP ratio (1.29 {+/-} 0.08). The C3 (High-Load Decompensation) phenotype (n = 182) displayed significantly elevated blood pressures and the greatest overall hemodynamic load. Regarding target organ damage, a clear gradient was observed across the three phenotypes. The C3 phenotype showed the highest carotid intima-media thickness (IMT: 1.162 {+/-} 0.23 mm) and left ventricular mass index (LVMI: 69.18 {+/-} 40.73 g/m{superscript 2}). Conversely, the C2 phenotype exhibited the highest estimated glomerular filtration rate (eGFR: 97.38 {+/-} 16.38 mL/min/1.73m{superscript 2}) and the lowest IMT (0.994 {+/-} 0.26 mm). The C1 phenotype consistently displayed intermediate values for all organ damage indicators. After Bonferroni correction, all pairwise comparisons for LVMI and pulse wave velocity (PWV) reached statistical significance (all P < 0.05). ConclusionsHealthy high-altitude individuals manifest three distinct hemodynamic phenotypes arrayed along a cardiovascular risk continuum. The novel Vascular Stress (C1) phenotype represents a "masked" high-risk state characterized by normal peripheral blood pressure but elevated arterial stiffness and wave reflection, challenging sole reliance on brachial pressure for risk assessment. This phenotype-based stratification provides a framework for precision prevention and early intervention in high-altitude populations.

Obesity is the most common cause of hypertension. We have previously shown that high levels of circulating leptin in diet-induced obese (DIO) mice induced hypertension by increasing expression of Transient Receptor Potential Melastatin-subfamily member 7 (TRPM7) in the carotid bodies (CB). In addition, we demonstrated in rat PC12 cells that leptin increases Trpm7 gene expression by inducing CpG site-specific demethylation within the 5 regulatory region containing a signal transducer and activator of transcription 3 (STAT3) binding site. This leptin-induced Trpm7 upregulation was prevented by inhibition of JAK-STAT3 signaling. Based on these findings, we hypothesized that reversing region-specific methylation at the Trpm7 promoter in the CB could attenuate obesity-associated hypertension. Compared with lean controls, DIO mice exhibited increased Trpm7 expression and the STAT3- binding site-specific promoter demethylation in the CB. Administration of methylated DNA oligonucleotides targeting the STAT3 binding site attenuated CpG site-specific DNA demethylation and reduced Trpm7 transcription in the CB of DIO mice. This intervention resulted in decreased carotid sinus nerve activity and reduced arterial blood pressure, especially during the light phase. Our results suggest that targeted modulation of CpG site-specific DNA methylation at the Trpm7 promoter using DNA oligonucleotide may represent a novel therapeutic strategy for obesity-induced hypertension.

Short-term heat acclimation (HA) induces cardiovascular and fluid-regulatory adaptations, but its impact on markers of renal tubular injury and acute kidney injury risk (AKI) during exercise-heat stress remains unclear. Fourteen healthy endurance athletes were randomised to five days of isothermic HA (HOT; n = 7; 32 {degrees}C, 70% relative humidity; target core temperature [&ge;]38.5 {degrees}C), or matched exercise in thermoneutral conditions (TEMP, n = 7). Heat stress tests (HST; 45 min cycling at 32 {degrees}C, 70% RH) were performed pre- and post-intervention. Blood biomarkers of kidney tubular stress (NGAL, KIM-1), fluid-regulation (copeptin, serum osmolality) and sympathetic activity (plasma normetanephrine) were measured at rest and immediately post-HST. HA reduced resting heart rate (-8 {+/-} 5 bpm, p = 0.007, d = 1.0), increased plasma volume (+7.3 {+/-} 5.1%, p = 0.022) and sweat loss (+500 {+/-} 539 mL, p = 0.018, d = 1.1). Copeptin rose during the pre-intervention HST in both groups (HOT: +11 {+/-} 6; TEMP: +12 {+/-} 13 pmol{middle dot}L-1, p < 0.05), but not post-intervention. NGAL increased only in TEMP during HST1 (+45 {+/-} 29 g{middle dot}L-1, p = 0.030), while KIM-1 remained unchanged. No group x time interactions were observed for any biomarkers (p > 0.05). Five days of HA improved cardiovascular and thermoregulatory responses but did not alter renal stress markers or fluid-regulatory responses during exercise in the heat. These findings suggest short-term HA enhances heat tolerance without reducing acute renal biomarker responses under hot, humid conditions. New & NoteworthyFive days of isothermic heat acclimation improved cardiovascular and thermoregulatory responses, related to a lower resting heart rate, plasma volume expansion, and greater sweat loss. However, these benefits did not reduce renal tubular stress markers (NGAL, KIM-1), fluid-regulatory strain (copeptin), or sympathetic activity (normetanephrine) during exercise in the heat. Short-term heat acclimation lowers cardiovascular strain but does not mitigate renal biomarker responses, suggesting kidney stress risk remains unchanged in hot, humid conditions.

BackgroundNeonatal sepsis is a major cause of infant morbidity and mortality worldwide, particularly in preterm and very low birthweight babies. Fundamental differences between neonates and adults warrant clinically relevant models of neonatal sepsis. Here, we describe a preclinical fecal-slurry (FS)-induced peritonitis model of polymicrobial sepsis in neonatal rats, along with a novel neonatal rat sepsis score (nRSS) to monitor illness severity. MethodsPeritonitis was induced in 3-day-old Sprague Dawley rats by intraperitoneal injection of various doses (0.3-1.5mg/g body weight) of fecal slurry (FS); control pups received equivalent doses of vehicle. All pups received analgesics (buprenorphine), antibiotics (ampicillin and gentamicin), and fluids (saline) to model clinical standards of sepsis treatment. Time-dependent changes in circulating cytokines (IL-6, IL-1{beta}) and biomarkers of sepsis pathology (hemoglobin, glucose, alanine transaminase [ALT] levels) were assessed and correlated with nRSS scores. ResultsFS administration caused a dose-dependent increase in severity of sepsis over time, as indicated by increases in mortality rates (based on predefined criteria for euthanasia), nRSS scores, as well as time-dependent changes in circulating glucose, hemoglobin, IL-6, IL-1{beta}, and ALT activity levels. nRSS scores correlated with all quantitative measures of sepsis pathology. Notably, females showed higher mortality and higher early NRSS scores than males at moderate to high FS doses, yet biochemical markers and time of death did not differ between sexes, suggesting that the apparent female vulnerability may reflect more conspicuous behavioral manifestations of illness rather than greater underlying physiological severity. ConclusionInduction of peritonitis in rats at postnatal day 3 produced a consistent and reproducible model of polymicrobial neonatal sepsis. Illness severity was monitored using a newly developed nRSS. By minimizing distress and incorporating standards of care, this model and scoring system may serve as a platform for future investigations into the underlying mechanisms and potential therapeutic interventions for neonatal sepsis. ImpactO_LIA clinically relevant rat model of neonatal polymicrobial sepsis was developed, incorporating standards of care (analgesics, antibiotics, and fluid resuscitation) to better reflect the clinical context in which preclinical findings must ultimately translate. C_LIO_LIA novel neonatal rat sepsis scoring system (nRSS) was developed and validated, providing a sensitive, non-invasive measure of disease severity that correlates with biochemical markers and predicts mortality. C_LIO_LIFemale pups showed higher mortality and earlier behavioral signs of illness than males despite equivalent biochemistry, highlighting that clinical scores may capture sex-dependent vulnerability not apparent in standard biochemical measures. C_LIO_LITogether, this model and scoring system offer a refined platform for mechanistic and therapeutic studies of neonatal sepsis while advancing the welfare-conscious 3Rs principles essential to rigorous preclinical research C_LI

Hypoxemia occurs in intermittent forms, such as obstructive sleep apnea, and in continuous forms, such as at high altitude, and is increasingly recognized as a modulator of cardiometabolic risk. Although hypoxemia alters postprandial glucose and lipid metabolism, its effects on ketone bodies remain unclear. Using a randomized crossover design, we examined whether six hours of normoxemia or intermittent hypoxemia (15 hypoxemic cycles/hour targeting [~]85% peripheral oxyhemoglobin saturation with 100% medical-grade nitrogen) alters plasma {beta}-hydroxybutyrate (BHB) concentrations in 12 young adult females (mean [SD]: 21 [3] years) following a high-fat meal (33% of estimated daily energy requirements; 59% of calories from fat). In a follow-up session, a subset (n = 8) completed six hours of continuous hypoxemia (fraction of inspired oxygen [~]12.0% in a normobaric chamber). Postprandial data were analyzed using baseline-adjusted linear mixed-effects models, with Bonferroni post hoc tests. A time x condition interaction (P = 0.010) indicated that BHB concentrations at 360 minutes were higher during continuous hypoxemia (0.247 mmol/L; 95% CI: 0.218-0.275) than normoxemia (0.176 mmol/L; 95% CI: 0.153-0.200; PBonferroni = 0.029) and intermittent hypoxemia (0.163 mmol/L; 95% CI: 0.139-0.186; PBonferroni = 0.002), representing increases of 13.0% and 14.2% in estimated marginal means, respectively. This response was accompanied by higher postprandial plasma glucose and triglyceride concentrations during continuous hypoxemia than during normoxemia and intermittent hypoxemia (PBonferroni [&le;] 0.002), despite similar plasma insulin and non-esterified fatty acid responses across conditions (P [&ge;] 0.081). These findings indicate that continuous hypoxemia increases late postprandial plasma BHB concentrations in young adult females. New FindingsO_ST_ABSWhat is the central question of this study?C_ST_ABSWhat are the effects of normoxemia, intermittent hypoxemia, and continuous hypoxemia on plasma {beta}-hydroxybutyrate (BHB) concentrations in young adult females after a high-fat meal? What is the main finding and its importance?Compared to normoxemia, young adult females showed higher postprandial plasma BHB concentrations during continuous hypoxemia, but not during intermittent hypoxemia, despite similar changes in plasma concentrations of two main regulators of BHB production (non-esterified fatty acids and insulin) across experimental conditions. These findings suggest that continuous hypoxemia modifies postprandial BHB concentrations through mechanisms not fully explained by circulating non-esterified fatty acids or insulin concentrations alone.

The human startle reflex has primarily been characterized by its repeatable, coordinated, and temporally patterned somatomotor responses. In this study, we assessed whether startle-evoked sympathetic nervous system (SNS) responses might also constitute a repeatable, coordinated, and temporally structured output. Using a noninvasive tactile startle stimulus, we simultaneously recorded startle-evoked electrodermal activity, photoplethysmography-derived blood volume indices, heart rate, blood pressure, stroke volume, and cardiac output in healthy participants. Our results demonstrate that startle elicits a reproducible and patterned constellation of SNS responses - a multimodal SNS startle signature - with conserved temporal relationships across effector systems. The SNS startle signature was composed of robust bilateral peripheral responses, including palmar sweating, cutaneous vasoconstriction, and biphasic cutaneous venous-capillary blood volume changes, in addition to more mild central hemodynamic changes. In contrast to previous startle reflex studies, there was no influence of biological sex or cardiac-cycle gating on responses. Lastly, the SNS startle signature exhibited features of a potentially attractive diagnostic, associated with robust responder discrimination and high response reliability across repeated trials. Overall, these findings fill a critical knowledge gap and also suggest the potential utility of this multimodal signature for assessing autonomic dysfunction.

Harbour porpoises (Phocoena phocoena) in the North and Baltic Seas are increasingly impacted by anthropogenic pressures, including underwater noise, fisheries and pollution. These pressures correlate with declining population health, particularly affecting the respiratory system. Growing pathological lesions, partly resulting from high prevalence of parasitic infestations and subsequent diseases, can impair tissue function and oxygen supply to distant end-organs. In this study, we applied an integrative MultiOmics approach (proteomics, metabolomics, lipidomics) to analyse the lungs and muscles of 12 wild harbour porpoises with compromised respiratory health. Our aim was to identify dysregulated biological pathways across omics layers to advance insights into adaptive physiological responses and to define disease-associated molecular signatures that could assist health assessments. Our analysis revealed pronounced immune system and antioxidative responses in the lungs and muscles, indicated by enhanced immunoglobulins, plasmalogens and glutathione-related proteins. In the lungs, high cardiolipin levels and reduced collagen suggest impaired tissue structure and function, while tissue maintenance processes were elevated in the muscle. Both tissues exhibited metabolic alterations suggestive of energetic imbalance, including increased purine metabolism in the lung and decreased lipid metabolism in the muscle. Several dysregulated molecules were shared across tissues, pointing to pathophysiological effects. The proposed disease-associated molecular signatures included the protein SLC25A4, the metabolite O-phosphoethanolamine and the lipid TG O-16:0_16:0_20:4 for the lung, and the protein SPEG, the metabolite pipecolic acid, and the lipid BMP 18:1_22:6 in the muscle. Our findings elucidate the complexity of molecular mechanisms linking anthropogenic and environmental stressors with vulnerability and resilience in a marine sentinel species. Furthermore, this study highlights the potential of integrative omics to define disease-related marker panels, thereby supporting ongoing and future health monitoring and conservation efforts.

Pregnant women are particularly susceptible to adverse outcomes from environmental heat, yet the physiological effects of acute heat exposure during pregnancy remain poorly understood. Some physiological changes are monitored in humans; however, investigation of underlying molecular mechanisms requires invasive methods that can only be ethically applied in mammalian models. Moreover, research with animal models has largely focused on early and lethal teratogenic effects of heat exposure and lacks longitudinal physiological monitoring, detailed parameterisation of heating regimes and in-depth investigation of underlying mechanisms. Here we used a mouse model to investigate the impact of a controlled acute heat exposure at mid-gestation (E12{middle dot}5), slowly elevating core body temperature (CBT) over 210mins to raise CBT by [~]1{degrees}C. Using high-frequency ultrasound and morphological analyses, we observed delayed alterations in placental and foetal cerebral blood flow indicative of a brain-sparing response, alongside reduced placental labyrinth zone size. Additionally, maternal cardiac function was impaired, accompanied by cardiac and renal fibrosis and elevated circulating soluble Flt-1 levels, an anti-angiogenic biomarker of gestational hypertension. These findings demonstrate that brief heat stress at mid-gestation can induce lasting effects on placental function and maternal cardiovascular health in a mammalian model, highlighting potential risks for pregnancy outcomes under increasing global temperatures. Together this data suggests that an acute exposure to heat elevating core body temperature by 1{middle dot}2{degrees}C can induce a long-term impact on both placenta and maternal health in a mouse model. It will be important to understand the molecular changes which underpin the pathophysiology and whether this is translated to humans.

The gut ecosystem is shaped by multiple factors with the immune system being one of the major determinants in shaping its composition in health and disease. On the other hand, the immune system regulates its responses through the action of the sympathetic nervous system (SNS) in part through beta-adrenergic receptors 1/2 (ADRB1/2). In the past years, a clear link has been established between the immune system, SNS, and the modification of nutrient absorption by the gut microbiota in the development of diet-induced obesity. We have previously shown in male mice transplanted with bone marrow cells ADRB1/2 knock-out mice (KD) showed mild immunosuppression and microbiota changes. Post-recovery, mice were challenged with high-fat diet (HFD) for two weeks ad libitum. Our findings show that KD mice are protected against diet-induced adiposity and weight gain. Additionally, these mice showed an increase in residual calorific values and a decreased expression of the fatty acid transporter FAT/CD36. Suggesting a decreased absorption of lipids in the KD mice. Gut microbiota analysis showed that KD microbiota composition on a HFD remained stable with a significant enrichment in the Bacteroidetes phylum, which is depleted in obesity. This was associated with a switch from triglycerides to diglyceride fecal profile. Moreover, microbiome culture showed a decrease in triglycerides after an incubation with 0.1% of HFD lipid extract. Suggesting a potential role of the Bacteroidetes phylum in the metabolism of these lipids. Our findings demonstrate not only that the gut microbiota can modify nutrient absorption and susceptibility to diet-induced obesity but also that the immune system contributes to selective depletion of microbial members that would otherwise thrive on dietary lipids. Revealing a novel mechanism by which host immunity sculpts the gut ecosystem in ways that influence metabolic outcomes.

RationaleAutonomic dysfunction is a hallmark of sepsis pathophysiology, yet its quantification remains challenging. Multiscale entropy (MSE) derived from heart rate variability (HRV) offers a dynamic measure of physiological complexity and may serve as a biomarker of early deterioration associated with subsequent organ failure, vasopressor escalation, or mortality. ObjectiveTo determine whether MSE computed across multiple temporal scales during the first 24 hours of Intensive Care Unit (ICU) admission is associated with short-term mortality and longer-term organ dysfunction in patients with sepsis, and whether these relationships vary across vasopressor exposure. Unlike prior studies that focused on short-term HRV metrics, we applied MSE across multiple temporal scales and incorporated these features into machine learning models to evaluate their prognostic utility in septic shock. MethodsThis retrospective cohort study included adult ICU sepsis patients at Emory University Hospital from January 2016 to December 2019. Of 2,076 eligible patients, 958 were propensity matched into two cohorts: fluids-only and fluids-plus-vasopressor, with norepinephrine as the primary vasopressor. High-resolution electrocardiogram (ECG) waveforms were analyzed to compute MSE across 20 temporal scales. Machine learning models using (1) MSE features alone and (2) MSE combined with demographic and vital sign data (MSE-DV) were compared against traditional HRV measures based model and severity of illness scores for predicting outcomes. Model performance was assessed using the area under the receiver operating characteristic curve (AUROC), with a primary outcome of mortality at day 7 and secondary outcome of persistent organ dysfunction at day 28. ResultsIn the fluids-plus-vasopressor cohort, MSE-based models demonstrated superior predictive performance for 7-day mortality (AUROC 0.84) compared to severity of illness scores (AUROC 0.64). MSE-DV models also predicted organ dysfunction including 28-day renal (AUROC 0.75), neurological (AUROC 0.79), and respiratory (AUROC 0.71) dysfunction. Patients receiving second-line and third-line vasopressors and corticosteroids exhibited progressively lower MSE values, particularly at mid-range and long-range scales. ConclusionMSE features in the first 24 hours of ICU stay predict mortality and organ dysfunction with higher discrimination than traditional severity of illness scores. Future work should validate these findings, assess longitudinal MSE trends, and race-specific autonomic patterns to refine predictive models.

Variation in mitochondrial aerobic metabolism has been suggested to underlie variation in interindividual performance. Mitochondrial efficiency quantifies, directly or indirectly, the amount of adenosine triphosphate (ATP) produced relative to O2 consumption. High mitochondrial efficiency is theoretically beneficial by providing more ATP per amount of resource consumed, but may come at the cost of increased reactive oxygen species (ROS) production damaging tissues through oxidative stress. Mitochondrial efficiency is a plastic trait but how it changes through postnatal development remains unknown. We hypothesized that strong selective pressure could lead to an increased mitochondrial efficiency to support fast growth but incur an oxidative cost. We tested this hypothesis by quantifying mitochondrial aerobic metabolism, efficiency and ROS production through postnatal growth in Japanese quail (Coturnix japonica), in two highly aerobic tissues: skeletal and cardiac muscles. Mitochondrial efficiency was indeed higher during peak growth in both tissues, but this was surprisingly associated with markedly lower ROS production. This high efficiency was likely achieved via both a lower proton leak and a higher contribution of complex I to respiration. These results show that enhancing mitochondrial efficiency may be important to support growth, but suggest the presence of unexpected ROS mitigation processes during early-life growth.