American Journal of Physiology-Regulatory, Integrative and Comparative Physiology

Brown adipose tissue (BAT) thermogenesis is essential for cold defense, but its contribution to fever and emotionally induced hyperthermia (psychogenic fever) remains disputed. Here we address this issue using genetic, surgical, physiological, and molecular approaches in rats. We generated UCP1 knockout rats, in which classical BAT thermogenesis is abolished, and examined body temperature responses to systemic inflammation induced by lipopolysaccharide and to emotional stressors such as restraint and cage exchange. Despite profound impairment of cold-induced and {beta}3-adrenergic-induced thermogenesis, UCP1 deletion did not affect LPS- or stress-evoked elevations in core or interscapular temperature. Surgical removal of interscapular BAT in wild-type rats likewise failed to alter these hyperthermic responses. Consistent with these findings, LPS and emotional stress induced only small, strain-dependent changes in the expression of thermogenic genes in BAT and minimally affected BAT mass, in marked contrast to the robust BAT activation elicited by {beta}3-adrenergic stimulation. Notably, emotional stress induced UCP3 expression in neck muscles, suggesting a potential contribution of skeletal muscle metabolic processes to stress-induced hyperthermia. Together, these findings demonstrate that both immune-induced and psychogenic fever occur independently of BAT thermogenesis and point to non-BAT tissues - likely including skeletal muscle - as candidate peripheral effectors supporting fever and emotional hyperthermia.

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.

Disturbances of 24-hour or circadian rhythms imposed by everyday irregular work and/or social schedules have been linked to vascular disease, including ischemic stroke. Using an established shift work-like paradigm and preclinical model for ischemic stroke, we have shown that environment-induced circadian dysregulation exacerbates stroke outcomes differentially to a greater extent in male than female rats. Because more severe stroke outcomes and circadian rhythm disturbances have been linked to gut pathophysiology, present study examined the effects of chronic LD cycle shifting on gut cytoarchitecture, microbiota composition, metabolites, and gut-derived inflammatory mediators. Adult (5-7mo) rats were divided into 2 groups and exposed for 50d to a fixed or shifted (lights-on advanced by 12hr/5d) LD 12:12 cycle. Circadian entrainment of activity rhythms was stable in all rats on the fixed LD 12:12 cycle but was severely disrupted during exposure to shifted LD cycles. Significant changes in the composition of the gut microbiome including reduced alpha diversity, shifts in beta diversity and correlations between the abundance of beneficial gut bacteria and stroke survival were observed in male but not female rats exposed to shifted LD cycles relative to fixed LD controls. This effect of circadian dysregulation on gut microbiota was accompanied by evidence of pathologic gut morphology (i.e., shorter and blunted villi, crypt hyperplasia disruption of tight junction proteins and gut barrier integrity), elevated serum endotoxin concentrations, decreased levels of the short-chain fatty acid (SCFA) butyrate, and increased circulating levels of the inflammatory cytokine IL-17A in shifted LD male rats. These results suggest that alterations in gut morphology, microbiota and metabolites may contribute to sex differences in the effects of shift work-related circadian dysregulation on ischemic stroke outcomes.

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.

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

Animals exhibit a diverse range of sociality from the strictly solitary to the highly social. Different forms of sociality have evolved in response to ecological constraints and selective habitat pressures, which are governed by the energetic and fitness costs to an individual. Uniquely among mammals, the clade of African mole-rats (Bathyergidae and Heterocephalidae) covers three distinct life-history forms of sociality: solitary, social and eusocial species. This variety in social structure makes them a model clade to study how metabolic traits vary between different forms of sociality. Resting metabolic rates (RMR) of seven African mole-rat species, ranging from solitary to eusocial, were measured using open-flow respirometry. Results were combined with published data, enabling the inclusion and statistical analysis of 16 species in total. We identified distinct allometric scaling of RMR, with eusocial species exhibiting a considerably greater rise in RMR with increases in body mass. This is likely attributable to reproductive and behavioural divisions of labour, and mass-dependent colony roles in eusocial species. Phylogenetically-informed analyses further identified that sociality, in addition to select bioclimatic traits - diurnal temperature range ({degrees}C) and isothermality (%) - significantly explain variation in the mass-independent RMR of African mole-rats. These findings elucidate, for the first time, that sociality can be a determinant of RMR, and calls for further study to identify the wider significance of sociality on mammalian metabolism, as well as exploring the allometric scaling of metabolic rate with respect to mammalian sociality.

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.

PurposeSepsis-associated immunothrombosis significantly contributes to high mortality, yet the role of N-glycosylation in this process remains poorly understood. This study aimed to comprehensively profile the plasma N-glycosylation landscape in sepsis and elucidate how its specific reprogramming in the complement and coagulation cascades influences immunothrombotic balance and patient outcomes. MethodsWe performed in-depth 4D-DIA proteomic and N-glycomic analyses on plasma from 43 sepsis patients and 9 healthy controls. Differential expression, weighted gene co-expression network analysis (WGCNA), and protein-glycosylation correlation analyses were used to characterize molecular features. Clinical relevance was assessed via correlation and survival analyses. ResultsExtensive N-glycosylation reprogramming was observed in sepsis plasma,with marked enrichment in complement and coagulation pathways(KEGG p=7.76x10- {superscript 2}{superscript 1}).Pro-coagulant proteins(eg,vWF,fibrinogen)showed increased abundance together with enhanced site-specific glycosylation,potentially amplifying their activity.In contrast,key anticoagulant proteins(eg,SERPINC1)displayed unchanged glycosylation at critical sites despite abundance changes,which may impair function.Survival analysis revealed distinct prognostic values of glycoproteins and specific glycosylation sites.For instance,high vWF protein levels predicted mortality(HR=2.83),whereas elevated glycosylation at vWF N211 was associated with improved survival(HR=0.135),suggesting a negative regulatory role.These glycosylation markers correlated closely with disease severity and prognosis,representing potential early-warning biomarkers independent of current clinical coagulation indicators. ConclusionOur study demonstrates widespread reprogramming of the plasma proteome and N-glycome in sepsis.We propose that decoupling of protein function from abundance through N-glycosylation in the complement-coagulation network contributes to immunothrombotic imbalance.Specific N-glycosylation sites may serve as novel prognostic biomarkers,offering new perspectives for early risk stratification and glycosylation-targeted therapies in sepsis. Key PointsO_LISepsis plasma exhibits specific N-glycosylation reprogramming overwhelmingly focused on the complement and coagulation cascade. C_LIO_LIA dominant "glycosylation-dominated co-upregulation" mode in procoagulant factors, coupled with a "silent" glycosylation state in key anticoagulants, drives prothrombotic imbalance. C_LIO_LISite-specific N-glycosylation levels provide prognostic information distinct from, and often superior to, their carrier protein abundance, offering novel early-risk biomarkers. 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.

Pacific salmon (Oncorhynchus spp.) undergo intricate physiological changes during maturation as they migrate to spawning beds and breed before succumbing to a programmed senescence (semelparous life cycle). Research into the physiological mechanisms of semelparity in salmon has identified a clear and progressive rise in sex and stress hormone levels throughout their migration, which correlates with the emergence of morphological traits, as well as changes in behavioral patterns. We examined transcriptional changes in three critical tissues (gonads, head kidney, and skeletal muscle) across the spawning migration in male and female Pink salmon (Oncorhynchus gorbuscha) to capture the molecular changes occurring in these tissues during maturation and senescence. Major transcriptional changes occurred around the time of spawning, while only modest transcriptional changes were found as the fish migrated between saltwater and freshwater. Examination of enriched biological pathways identified the signatures of semelparous catabolic processes in all tissues and a strong immune response in somatic tissues. Evidence of shifts in lipid energy mobilization were also seen in somatic tissues. A closer investigation of the expression patterns of endocrine hormone receptors showed that many endocrine pathways prioritized expression of specific dominant ohnologs to orchestrate much of the hormone response in the analyzed tissues. Our characterization of the transcriptional profiles in migrating pink salmon adds critical context to link the molecular changes occurring in tissues to the physiological transitions that define semelparous maturation in Pacific salmon. NEW & NOTEWORTHYLarge transcriptional changes occurred in the gonads, head kidney, and skeletal muscle of pink salmon during the final stages of their spawning migration. Across the tissues and sexes, spawning was marked by coordinated activation of catabolic programs (autophagy, proteolysis, cell death), and a strong immune response in somatic tissues, alongside lipid mobilization. Endocrine receptor expression analyses revealed that the response to hormones was primarily mediated by a limited number of dominant ohnologs.

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.

AimThe mammalian tracheal epithelium is composed by different cell types unevenly distributed along the proximal-distal axis. Nevertheless, variations in expression and function of ion channels and transporters participating in fluid absorption and secretion had never been studied separately in proximal and distal sections of the mouse trachea. In this work, we aim to characterize basal and stimulated absorption and secretion of fluid obtained from proximal and distal trachea from the same animal. MethodsUssing chamber experiments were performed using a custom-made tissue slider that allowed the mounting small tracheal sections, where response to agonists and blockers was recorded. The role of the NKCC1 co-transporter was studied using the Slc12a2-/- mouse. A genetically tomato-induced mouse model was used to assess co-expression of NKCC1 and ASCL3 by immunofluorescence. Animals were instilled with different interleukins (ILs) to determine changes in absorption, secretion and mucus properties. ResultsProximal trachea didnt participate in sodium absorption but exhibited higher cAMP- and succinate-induced anion secretion than the distal section. NBCe1-dependent bicarbonate and TMEM16A-driven chloride secretion was significantly higher in the distal section. NKCC1+ cells were found in the submucosal glands (SMGs) and abundant patches of NKCC1+ cells in the distal region. Isolated NKCC1+ cells co-expressing ASCL3 were also detected. ILs treatment changed the electrophysiological properties of the distal but not the proximal trachea. ConclusionsOur experiments determined that the mouse trachea organizes its functions differentially in the proximal and distal sections, based in the functional distribution of channels, transporters and receptors. While the distal trachea drastically changed its responses to agonists inducing anion secretion the proximal trachea was unperturbed by the action of ILs.

ObjectivesTo develop and validate pediatric adaptations of the Venous Excess Ultrasound Score (P-VExUS) for noninvasive estimation of central venous pressure (CVP) in critically ill children. DesignProspective observational study. SettingPICU of a tertiary-care teaching hospital. PatientsFifty-six mechanically ventilated children (median age 7.4 months, median weight 6.0 kg) with central venous catheters. InterventionsNone. Measurements and Main ResultsVenous Doppler ultrasonography of the inferior vena cava, hepatic, portal, and intrarenal veins was performed at the bedside. Two P-VExUS models were tested: (1) a categorical grading system (0-III) and (2) a semiquantitative point-based score (0-7). Both models showed significant associations with CVP. For predicting elevated CVP (>12 mmHg), model 1 achieved an AUROC of 0.74 (95% CI 0.61-0.85) with 45% sensitivity and 98% specificity, while model 2 demonstrated superior accuracy with an AUROC of 0.94 (95% CI 0.84-0.98), sensitivity 82%, and specificity 91% (p < 0.001). For detecting low CVP (<7 mmHg), model 2 also outperformed model 1 (AUROC 0.80 vs. 0.69, p = 0.02). Among individual venous Doppler components, intrarenal veins had the highest discriminative ability (AUROC 0.92), followed by hepatic (0.89) and portal (0.80) veins. ConclusionsTwo pediatric-specific P-VExUS models were feasible and accurate for estimating CVP in critically ill children. The point-based model (model 2) demonstrated superior diagnostic performance, supporting its potential as a noninvasive tool to assess venous congestion at the bedside. Research in ContextO_LIVenous congestion, reflected by elevated central venous pressure (CVP), is associated with adverse outcomes in critically ill children, including mortality and renal dysfunction. C_LIO_LIThe Venous Excess Ultrasound Score (VExUS) is validated in adults, but pediatric-specific adaptations and cutoff values remain poorly defined. C_LIO_LIThere is a need for noninvasive, bedside tools to estimate CVP in children and guide fluid management in the PICU. C_LI What This Study MeansO_LIThis study validates pediatric-specific adaptations of the Venous Excess Ultrasound Score (P-VExUS) for estimating CVP in critically ill children. C_LIO_LIThe semiquantitative point-based model provided more consistent and accurate discrimination of venous congestion compared with categorical grading. C_LIO_LIThese findings highlight the feasibility and potential clinical utility of venous Doppler ultrasonography as a noninvasive bedside tool in the PICU. C_LI

Force production relies on the interaction between neural control of spinal motoneurons and the mechanical properties of the muscles. Changes in muscle length provide a useful model for exploring this interaction; however, studies typically assess these properties in the same muscle undergoing length change. This study investigated how altering the length of one muscle influences motor unit discharge behavior of its synergists. Eighteen healthy participants performed submaximal isometric knee extensions with the hip joint positioned at 90{degrees} (shortened rectus femoris, RF) and 180{degrees} (lengthened RF). At each hip position, participants followed trapezoidal force profiles at 10% and 30% of maximal voluntary contraction (MVC), while high-density surface electromyography (HDsEMG) was recorded from the synergistic vastus medialis and vastus lateralis (VL). Motor unit spike trains were decomposed from HDsEMG, tracked across hip positions, and analyzed for mean discharge rate and coefficient of variation of interspike interval (CoV-ISI). Lengthening the RF led to increased discharge rates of vasti motor units at 10% MVC, but not 30% MVC, with no changes in CoV-ISI. To further explore these force-dependent changes in discharge rate, two sets of experiments were conducted. The first showed that the discharge rate at recruitment during ramp-up contractions increased with RF lengthening, but only for vasti units recruited below 20% MVC. In the second, electrically evoked twitch contractions in the vasti revealed reduced twitches at 180{degrees} during low-frequency, but not high-frequency stimulation. These findings collectively suggest that the force-dependent changes in the vasti motor unit discharge rates are likely driven by RF-length dependent changes in the vasti muscles contractile properties.