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Hematopoietic aging is associated with decreased hematopoietic stem cell (HSC) self-renewal capacity and myeloid skewing. We report that culture of bone marrow (BM) HSCs from aged mice with epidermal growth factor (EGF) suppressed myeloid skewing, increased multipotent colony formation, and increased HSC repopulation in primary and secondary transplantation assays. Mice transplanted with aged, EGF-treated HSCs displayed increased donor cell engraftment within BM HSCs and systemic administration of EGF to aged mice increased HSC self-renewal capacity in primary and secondary transplantation assays. Expression of a dominant negative EGFR in Scl/Tal1+ hematopoietic cells caused increased myeloid skewing and depletion of long term-HSCs in 15-month-old mice. EGF treatment decreased DNA damage in aged HSCs and shifted the transcriptome of aged HSCs from genes regulating cell death to genes involved in HSC self-renewal and DNA repair but had no effect on HSC senescence. These data suggest that EGFR signaling regulates the repopulating capacity of aged HSCs.

Synchronization is common in both nature and human physiology, often used to illustrate nonlinear dynamics. Interestingly, one can initiate their comprehension of this phenomenon from pure linear systems. In this Tutorial, we begin with a theoretical exploration of coupled oscillators' dynamic behavior, enabling us to discern and contrast the unique attributes of dissipative coupling as opposed to commonly observed coherent coupling. We then examine synchronization in two dissipative coupled linear systems: one with two pendulums mutually linked via the Lenz effect and the other with two RLC oscillators coupled via a resistor. This Tutorial is designed to serve as a concise starting point for researchers interested in exploring synchronization phenomena using a simplified model driven solely by dissipative coupling. [ABSTRACT FROM AUTHOR]

Since it was inspired by Bernard and developed and named by Cannon, the concept of homeostasis has been invoked by many as the central theoretical framework for physiology. It has also been the target of numerous criticisms that have elicited the introduction of a plethora of alternative concepts. We argue that many of the criticisms actually target the more restrictive account of homeostasis advanced by the cyberneticists. What was crucial to Bernard and Cannon was a focus on the maintenance of the organism as the goal of physiological regulation. We analyse how Bernard's and Cannon's broad conception of what was required to maintain the organism was narrowed to negative feedback, characterized in terms of setpoints, by the cyberneticists and demonstrate how many of the alternative concepts challenge the role of setpoints – treating them as variable in light of circumstances or in anticipation of future circumstances, or as dispensable altogether. To support our analysis, we draw on the experimental and theoretical work on thermoregulation, a phenomenon that has been considered as a paradigmatic example of homeostasis and has been a common focus of those advancing alternative concepts. To integrate the insights advanced by the original proponents of homeostasis and the theorists proposing replacement notions we advance a framework in which regulation is viewed from the perspective of maintaining the organism. [ABSTRACT FROM AUTHOR]

Heparosan (Hep), an unsulfated glycosaminoglycan (GAG), has a chemical structure closely resembling that of hyaluronic acid (HA). However, Hep has not been utilized in injectable dermal fillers as HA has been. In this article, injectable Hep crosslinked hydrogels were fabricated using 1,4-butanediol diglycidyl ether (BDDE) as the crosslinking agent. The physicochemical properties of the Hep crosslinked hydrogel, including pH and osmolality, were verified to be compatible with human physiology. The Hep crosslinked hydrogels exhibit higher viscoelasticity and a longer in vitro lifespan compared to HA crosslinked hydrogels. Furthermore, biocompatibility and safety assessments supported their potential use as injectable dermal fillers. [ABSTRACT FROM AUTHOR]

Galactic cosmic radiation (GCR) is one of the most serious risks posed to astronauts during missions to the Moon and Mars. Experimental models capable of recapitulating human physiology are critical to understanding the effects of radiation on human organs and developing radioprotective measures against space travel exposures. The effects of systemic radiation are studied using a multi‐organ‐on‐a‐chip (multi‐OoC) platform containing engineered tissue models of human bone marrow (site of hematopoiesis and acute radiation damage), cardiac muscle (site of chronic radiation damage) and liver (site of metabolism), linked by vascular circulation with an endothelial barrier separating individual tissue chambers from the vascular perfusate. Following protracted neutron radiation, the most damaging radiation component in deep space, a greater deviation of tissue function is observed as compared to the same cumulative dose delivered acutely. Further, by characterizing engineered bone marrow (eBM)‐derived immune cells in circulation, 58 unique genes specific to the effects of protracted neutron dosing are identified, as compared to acutely irradiated and healthy tissues. It propose that this bioengineered platform allows studies of human responses to extended radiation exposure in an "astronaut‐on‐a‐chip" model that can inform measures for mitigating cosmic radiation injury. [ABSTRACT FROM AUTHOR]

Introduction: Diving in SCUBA modality modifies human physiology in many ways. These modifications have been studied since Paul Bert in a seminal work. This area of research is very sensible to technological development. At now, it is possible to record heart rate (HR) continuously while diving. The study of HR changes in SCUBA diving at different depths in a constant temperature of thermal water is the objective of the present paper. Methods: 18 healthy subjects were enrolled and HR was recorded while SCUBA diving in thermal water at a constant temperature of 33.6∘ C in the deepest Italian pool at Montegrotto (Padova, Italy). Three depths were investigated: −20, −30 and −40 meters. The HR has been recorded with a Galileo SOL diving computer. The dive was subdivided into three phases: descent (DSC), steady on depth (STD), post–dive (RSF), and average HR was evaluated in each phase. Moreover, considering the DSC and STD time duration, a statistical linear regression of HR and relative parameters, intercept and slope, were here assessed. Results: In STD phase, HR slope obtained by regression decreased with depth. A significant difference was found between the slope during STD at −20 vs. −40 m (p ≤ 0.05). Discussion: Present results emphasized different HR physiological adjustments among diving phases. Firstly, during the DSC, a rapid HR decrease is recognized as probably due to a vagal response; secondly, at STD, the inward blood redistribution requires another physiological adjustment. This latter is depth-dependent because of a reduction of cardiac variability. Present data highlight the important cardiac stress need to counteract the diving activity. [ABSTRACT FROM AUTHOR]

Objective: Ultradian rhythms are biological rhythms with periods of a few seconds to a few hours. Along with circadian rhythms, ultradian rhythms influence human physiology. However, such rhythms have not been studied as intensively as circadian rhythms. This study aimed to identify ultradian rest-activity rhythms induced by the dopamine D2/D3 agonist quinpirole in mice. Methods: We used 10 mice from the Institute of Cancer Research. Quinpirole was administered at a dose of 0.5 mg/kg. We assessed free rest-activity using infrared detectors and conducted wavelet analysis to measure the period and its variation. We also used the paired t test to compare ultradian rhythm patterns. Results: Quinpirole did not significantly change total 24-hour locomotor activity ( p = 0.065). However, it significantly increased locomotor activity during the dark phase ( p = 0.001) and decreased it during the light phase ( p = 0.016). In the continuous wavelet transform analysis, the mean period was 5.618 hours before quinpirole injection and 4.523 hours after injection. The period showed a significant decrease ( p = 0.040), while the variation remained relatively consistent before and after quinpirole injection. Conclusion: This study demonstrated ultradian rest-activity rhythms induced by quinpirole using wavelet analysis. Quinpirole-induced ultradian rhythms exhibited rapid oscillations with shortened periods and increased activity during the dark phase. To better understand these changes in ultradian rhythms caused by quinpirole, it is essential to compare them with the effects of other psychopharmacological agents. Furthermore, investigating the pharmacological impact on ultradian rest-activity rhythms may have valuable applications in clinical studies. [ABSTRACT FROM AUTHOR]

For often unclear reasons, the survival times of critically buried avalanche victims vary widely from minutes to hours. Individuals can survive and sustain organ function if they can breathe under the snow and maintain sufficient delivery of oxygen and efflux of carbon dioxide. We review the physiological responses of humans to critical avalanche burial, a model which shares similarities and differences with apnoea and accidental hypothermia. Within a few minutes of burial, an avalanche victim is exposed to hypoxaemia and hypercapnia, which have important effects on the respiratory and cardiovascular systems and pose a major threat to the central nervous system. As burial time increases, an avalanche victim also develops hypothermia. Despite progressively reduced metabolism, reduced oxygen and increased carbon dioxide tensions may exacerbate the pathophysiological consequences of hypothermia. Hypercapnia seems to be the main cause of cardiovascular instability, which, in turn, is the major reason for reduced cerebral oxygenation despite reductions in cerebral metabolic activity caused by hypothermia. 'Triple H syndrome' refers to the interaction of hypoxia, hypercapnia and hypothermia in a buried avalanche victim. Future studies should investigate how the respiratory gases entrapped in the porous snow structure influence the physiological responses of buried individuals and how haemoconcentration, blood viscosity and cell deformability affect blood flow and oxygen delivery. Attention should also be devoted to identifying strategies to prolong avalanche survival by either mitigating hypoxia and hypercapnia or reducing core temperature so that neuroprotection occurs before the onset of cerebral hypoxia. [ABSTRACT FROM AUTHOR]

Acute intermittent hypoxia (AIH) is an emerging technique for enhancing neuroplasticity and motor function in respiratory and limb musculature. Thus far, AIH‐induced improvements in strength have been reported for upper and lower limb muscles after chronic incomplete cervical spinal cord injury (iSCI), but the underlying mechanisms have been elusive. We used high‐density surface EMG (HDsEMG) to determine if motor unit discharge behaviour is altered after 15 × 60 s exposures to 9% inspired oxygen, interspersed with 21% inspired oxygen (AIH), compared to breathing only 21% air (SHAM). We recorded HDsEMG from the biceps and triceps brachii of seven individuals with iSCI during maximal elbow flexion and extension contractions, and motor unit spike trains were identified using convolutive blind source separation. After AIH, elbow flexion and extension torque increased by 54% and 59% from baseline (P = 0.003), respectively, whereas there was no change after SHAM. Across muscles, motor unit discharge rates increased by ∼4 pulses per second (P = 0.002) during maximal efforts, from before to after AIH. These results suggest that excitability and/or activation of spinal motoneurons is augmented after AIH, providing a mechanism to explain AIH‐induced increases in voluntary strength. Pending validation, AIH may be helpful in conjunction with other therapies to enhance rehabilitation outcomes after incomplete spinal cord injury, due to these enhancements in motor unit function and strength. Key points: Acute intermittent hypoxia (AIH) causes increases in muscular strength and neuroplasticity in people living with chronic incomplete spinal cord injury (SCI), but how it affects motor unit discharge rates is unknown.Motor unit spike times were identified from high‐density surface electromyograms during maximal voluntary contractions and tracked from before to after AIH.Motor unit discharge rates were increased following AIH.These findings suggest that AIH can facilitate motoneuron function in people with incomplete SCI. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension are the main precapillary forms of pulmonary hypertension (PH) summarized as pulmonary vascular diseases (PVD). PVDs are characterized by exertional dyspnoea and oxygen desaturation, and reduced quality of life and survival. Medical therapies improve life expectancy and physical performance of PVD patients, of whom many wish to participate in professional work and recreational activities including traveling to high altitude. The exposure to the hypobaric hypoxic environment of mountain regions incurs the risk of high altitude adverse events (AEHA) due to severe hypoxaemia exacerbating symptoms and further increase in pulmonary artery pressure, which may lead to right heart decompensation. Recent prospective and randomized trials show that altitude‐induced hypoxaemia, pulmonary haemodynamic changes and impairment of exercise performance in PVD patients are in the range found in healthy people. The vast majority of optimally treated stable PVD patients who do not require long‐term oxygen therapy at low altitude can tolerate short‐term exposure to moderate altitudes up to 2500 m. PVD patients that reveal persistent severe resting hypoxaemia (SpO2${{S}_{{\mathrm{p}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$ <80% for >30 min) at 2500 m respond well to supplemental oxygen therapy. Although there are no accurate predictors for AEHA, PVD patients with unfavourable risk profiles at low altitude, such as higher WHO functional class, lower exercise capacity with more pronounced exercise‐induced desaturation and more severely impaired haemodynamics, are at increased risk of AEHA. Therefore, doctors with experience in PVD and high‐altitude medicine should counsel PVD patients before any high‐altitude sojourn. This review aims to summarize recent literature and clinical recommendations about PVD patients travelling to high altitude. [ABSTRACT FROM AUTHOR]

High altitude residents have a lower incidence of type 2 diabetes mellitus (T2DM). Therefore, we examined the effect of repeated overnight normobaric hypoxic exposure on glycaemic control, appetite, gut microbiota and inflammation in adults with T2DM. Thirteen adults with T2DM [glycated haemoglobin (HbA1c): 61.1 ± 14.1 mmol mol−1; aged 64.2 ± 9.4 years; four female] completed a single‐blind, randomised, sham‐controlled, cross‐over study for 10 nights, sleeping when exposed to hypoxia (fractional inspired O2 [FIO2${{F}_{{\mathrm{I}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$] = 0.155; ∼2500 m simulated altitude) or normoxic conditions (FIO2${{F}_{{\mathrm{I}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$ = 0.209) in a randomised order. Outcome measures included: fasted plasma [glucose]; [hypoxia inducible factor‐1α]; [interleukin‐6]; [tumour necrosis factor‐α]; [interleukin‐10]; [heat shock protein 70]; [butyric acid]; peak plasma [glucose] and insulin sensitivity following a 2 h oral glucose tolerance test; body composition; appetite indices ([leptin], [acyl ghrelin], [peptide YY], [glucagon‐like peptide‐1]); and gut microbiota diversity and abundance [16S rRNA amplicon sequencing]. During intervention periods, accelerometers measured physical activity, sleep duration and efficiency, whereas continuous glucose monitors were used to assess estimated HbA1c and glucose management indicator and time in target range. Overnight hypoxia was not associated with changes in any outcome measure (P > 0.05 with small effect sizes) except fasting insulin sensitivity and gut microbiota alpha diversity, which exhibited trends (P = 0.10; P = 0.08 respectively) for a medium beneficial effect (d = 0.49; d = 0.59 respectively). Ten nights of overnight moderate hypoxic exposure did not significantly affect glycaemic control, gut microbiome, appetite, or inflammation in adults with T2DM. However, the intervention was well tolerated and a medium effect‐size for improved insulin sensitivity and reduced alpha diversity warrants further investigation. Key points: Living at altitude lowers the incidence of type 2 diabetes mellitus (T2DM). Animal studies suggest that exposure to hypoxia may lead to weight loss and suppressed appetite.In a single‐blind, randomised sham‐controlled, cross‐over trial, we assessed the effects of 10 nights of hypoxia (fractional inspired O2 ∼0.155) on glucose homeostasis, appetite, gut microbiota, inflammatory stress ([interleukin‐6]; [tumour necrosis factor‐α]; [interleukin‐10]) and hypoxic stress ([hypoxia inducible factor 1α]; heat shock protein 70]) in 13 adults with T2DM.Appetite and inflammatory markers were unchanged following hypoxic exposure, but an increased insulin sensitivity and reduced gut microbiota alpha diversity were associated with a medium effect‐size and statistical trends, which warrant further investigation using a definitive large randomised controlled trial.Hypoxic exposure may represent a viable therapeutic intervention in people with T2DM and particularly those unable or unwilling to exercise because barriers to uptake and adherence may be lower than for other lifestyle interventions (e.g. diet and exercise). [ABSTRACT FROM AUTHOR]

During acute hypoxic exposure, cerebral blood flow (CBF) increases to compensate for the reduced arterial oxygen content (CaO2). Nevertheless, as exposure extends, both CaO2 and CBF progressively normalize. Haemoconcentration is the primary mechanism underlying the CaO2 restoration and may therefore explain, at least in part, the CBF normalization. Accordingly, we tested the hypothesis that reversing the haemoconcentration associated with extended hypoxic exposure returns CBF towards the values observed in acute hypoxia. Twenty‐three healthy lowlanders (12 females) completed two identical 4‐day sojourns in a hypobaric chamber, one in normoxia (NX) and one in hypobaric hypoxia (HH, 3500 m). CBF was measured by ultrasound after 1, 6, 12, 48 and 96 h and compared between sojourns to assess the time course of changes in CBF. In addition, CBF was measured at the end of the HH sojourn after hypervolaemic haemodilution. Compared with NX, CBF was increased in HH after 1 h (P = 0.001) but similar at all later time points (all P > 0.199). Haemoglobin concentration was higher in HH than NX from 12 h to 96 h (all P < 0.001). While haemodilution reduced haemoglobin concentration from 14.8 ± 1.0 to 13.9 ± 1.2 g·dl−1 (P < 0.001), it did not increase CBF (974 ± 282 to 872 ± 200 ml·min−1; P = 0.135). We thus conclude that, at least at this moderate altitude, haemoconcentration is not the primary mechanism underlying CBF normalization with acclimatization. These data ostensibly reflect the fact that CBF regulation at high altitude is a complex process that integrates physiological variables beyond CaO2. Key points: Acute hypoxia causes an increase in cerebral blood flow (CBF). However, as exposure extends, CBF progressively normalizes.We investigated whether hypoxia‐induced haemoconcentration contributes to the normalization of CBF during extended hypoxia.Following 4 days of hypobaric hypoxic exposure (corresponding to 3500 m altitude), we measured CBF before and after abolishing hypoxia‐induced haemoconcentration by hypervolaemic haemodilution.Contrary to our hypothesis, the haemodilution did not increase CBF in hypoxia.Our findings do not support haemoconcentration as a stimulus for the CBF normalization during extended hypoxia. [ABSTRACT FROM AUTHOR]

In eukaryotic cells, aerobic energy is produced by mitochondria through oxygen uptake. However, little is known about the early mitochondrial responses to moderate hypobaric hypoxia (MHH) in highly metabolic active tissues. Here, we describe the mitochondrial responses to acute MHH in the heart and skeletal muscle. Rats were randomly allocated into a normoxia control group (n = 10) and a hypoxia group (n = 30), divided into three groups (0, 6, and 24 h post‐MHH). The normoxia situation was recapitulated at the University of Granada, at 662 m above sea level. The MHH situation was performed at the High‐Performance Altitude Training Centre of Sierra Nevada located in Granada at 2320 m above sea level. We found a significant increase in mitochondrial supercomplex assembly in the heart as soon as the animals reached 2320 m above sea level and their levels are maintained 24 h post‐exposure, but not in skeletal muscle. Furthermore, in skeletal muscle, at 0 and 6 h, there was increased dynamin‐related protein 1 (Drp1) expression and a significant reduction in Mitofusin 2. In conclusion, mitochondria from the muscle and heart respond differently to MHH: mitochondrial supercomplexes increase in the heart, whereas, in skeletal muscle, the mitochondrial pro‐fission response is trigged. Considering that skeletal muscle was not actively involved in the ascent when the heart was beating faster to compensate for the hypobaric, hypoxic conditions, we speculate that the different responses to MHH are a result of the different energetic requirements of the tissues upon MHH. Key points: The heart and the skeletal muscle showed different mitochondrial responses to moderate hypobaric hypoxia.Moderate hypobaric hypoxia increases the assembly of the electron transport chain complexes into supercomplexes in the heart.Skeletal muscle shows an early mitochondrial pro‐fission response following exposure to moderate hypobaric hypoxia. [ABSTRACT FROM AUTHOR]

This Symposium Review examines challenges to surviving birth and infancy at high altitudes. Chronic exposure to the environmental hypoxia of high altitudes increases the incidence of maternal vascular disorders of pregnancy characterized by placental insufficiency, restricted fetal growth and preterm delivery, and impairs pulmonary vascular health during infancy. While each condition independently contributes to excess morbidity and mortality in early life, evidence indicates vascular disorders of pregnancy and infantile pulmonary vascular dysfunction are intertwined. By integrating our recent scientific and clinical observations in Bolivia with existing literature, we propose potential avenues to reduce the infant mortality burden at high altitudes and reduce pulmonary vascular disease in highland neonates, and emphasize the need for further research to address unresolved questions. [ABSTRACT FROM AUTHOR]

Sympathoexcitation is a hallmark of hypoxic exposure, occurring acutely, as well as persisting in acclimatised lowland populations and with generational exposure in highland native populations of the Andean and Tibetan plateaus. The mechanisms mediating altitude sympathoexcitation are multifactorial, involving alterations in both peripheral autonomic reflexes and central neural pathways, and are dependent on the duration of exposure. Initially, hypoxia‐induced sympathoexcitation appears to be an adaptive response, primarily mediated by regulatory reflex mechanisms concerned with preserving systemic and cerebral tissue O2 delivery and maintaining arterial blood pressure. However, as exposure continues, sympathoexcitation is further augmented above that observed with acute exposure, despite acclimatisation processes that restore arterial oxygen content (CaO2${C_{{\mathrm{a}}{{\mathrm{O}}_{\mathrm{2}}}}}$). Under these conditions, sympathoexcitation may become maladaptive, giving rise to reduced vascular reactivity and mildly elevated blood pressure. Importantly, current evidence indicates the peripheral chemoreflex does not play a significant role in the augmentation of sympathoexcitation during altitude acclimatisation, although methodological limitations may underestimate its true contribution. Instead, processes that provide no obvious survival benefit in hypoxia appear to contribute, including elevated pulmonary arterial pressure. Nocturnal periodic breathing is also a potential mechanism contributing to altitude sympathoexcitation, although experimental studies are required. Despite recent advancements within the field, several areas remain unexplored, including the mechanisms responsible for the apparent normalisation of muscle sympathetic nerve activity during intermediate hypoxic exposures, the mechanisms accounting for persistent sympathoexcitation following descent from altitude and consideration of whether there are sex‐based differences in sympathetic regulation at altitude. [ABSTRACT FROM AUTHOR]

Periodic breathing during sleep at high altitude is almost universal among sojourners. Here, in the context of acclimatization and adaptation, we provide a contemporary review on periodic breathing at high altitude, and explore whether this is an adaptive or maladaptive process. The mechanism(s), prevalence and role of periodic breathing in acclimatized lowlanders at high altitude are contrasted with the available data from adapted indigenous populations (e.g. Andean and Tibetan highlanders). It is concluded that (1) periodic breathing persists with acclimatization in lowlanders and the severity is proportional to sleeping altitude; (2) periodic breathing does not seem to coalesce with poor sleep quality such that, with acclimatization, there appears to be a lengthening of cycle length and minimal impact on the average sleeping oxygen saturation; and (3) high altitude adapted highlanders appear to demonstrate a blunting of periodic breathing, compared to lowlanders, comprising a feature that withstands the negative influences of chronic mountain sickness. These observations indicate that periodic breathing persists with high altitude acclimatization with no obvious negative consequences; however, periodic breathing is attenuated with high altitude adaptation and therefore potentially reflects an adaptive trait to this environment. [ABSTRACT FROM AUTHOR]

Acute hypoxia increases pulmonary arterial (PA) pressures, though its effect on right ventricular (RV) function is controversial. The objective of this study was to characterize exertional RV performance during acute hypoxia. Ten healthy participants (34 ± 10 years, 7 males) completed three visits: visits 1 and 2 included non‐invasive normoxic (fraction of inspired oxygen (FiO2${F_{{\mathrm{i}}{{\mathrm{O}}_{\mathrm{2}}}}}$) = 0.21) and isobaric hypoxic (FiO2${F_{{\mathrm{i}}{{\mathrm{O}}_{\mathrm{2}}}}}$ = 0.12) cardiopulmonary exercise testing (CPET) to determine normoxic/hypoxic maximal oxygen uptake (V̇O2max${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$). Visit 3 involved invasive haemodynamic assessments where participants were randomized 1:1 to either Swan–Ganz or conductance catheterization to quantify RV performance via pressure–volume analysis. Arterial oxygen saturation was determined by blood gas analysis from radial arterial catheterization. During visit 3, participants completed invasive submaximal CPET testing at 50% normoxic V̇O2max${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ and again at 50% hypoxic V̇O2max${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ (FiO2${F_{{\mathrm{i}}{{\mathrm{O}}_{\mathrm{2}}}}}$ = 0.12). Median (interquartile range) values for non‐invasive V̇O2max${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ values during normoxic and hypoxic testing were 2.98 (2.43, 3.66) l/min and 1.84 (1.62, 2.25) l/min, respectively (P < 0.0001). Mean PA pressure increased significantly when transitioning from rest to submaximal exercise during normoxic and hypoxic conditions (P = 0.0014). Metrics of RV contractility including preload recruitable stroke work, dP/dtmax, and end‐systolic pressure increased significantly during the transition from rest to exercise under normoxic and hypoxic conditions. Ventricular–arterial coupling was maintained during normoxic exercise at 50% V̇O2max${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$. During submaximal exercise at 50% of hypoxic V̇O2max${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$, ventricular–arterial coupling declined but remained within normal limits. In conclusion, resting and exertional RV functions are preserved in response to acute exposure to hypoxia at an FiO2${F_{{\mathrm{i}}{{\mathrm{O}}_{\mathrm{2}}}}}$ = 0.12 and the associated increase in PA pressures. Key points: The healthy right ventricle augments contractility, lusitropy and energetics during periods of increased metabolic demand (e.g. exercise) in acute hypoxic conditions.During submaximal exercise, ventricular–arterial coupling decreases but remains within normal limits, ensuring that cardiac output and systemic perfusion are maintained.These data describe right ventricular physiological responses during submaximal exercise under conditions of acute hypoxia, such as occurs during exposure to high altitude and/or acute hypoxic respiratory failure. [ABSTRACT FROM AUTHOR]

Hypoxia at high altitude facilitates changes in ventilatory control that can lead to nocturnal periodic breathing (nPB). Here, we introduce a placebo‐controlled approach to prevent nPB by increasing inspiratory CO2 and used it to assess whether nPB contributes to the adverse effects of hypoxia on sleep architecture. In a randomized, single‐blinded, crossover design, 12 men underwent two sojourns (three days/nights each, separated by 4 weeks) in hypobaric hypoxia corresponding to 4000 m altitude, with polysomnography during the first and third night of each sojourn. During all nights, subjects' heads were encompassed by a canopy retaining exhaled CO2, and CO2 concentration in the canopy (i.e. inspiratory CO2 concentration) was controlled by adjustment of fresh air inflow. Throughout the placebo sojourn inspiratory CO2 was ≤0.2%, whereas throughout the other sojourn it was increased to 1.76% (IQR, 1.07%–2.44%). During the placebo sojourn, total sleep time (TST) with nPB was 54.3% (37.4%–80.8%) and 45.0% (24.5%–56.5%) during the first and the third night, respectively (P = 0.042). Increased inspiratory CO2 reduced TST with nPB by an absolute 38.1% (28.1%–48.1%), the apnoea–hypopnoea index by 58.1/h (40.1–76.1/h), and oxygen desaturation index ≥3% by 56.0/h (38.9.1–73.2/h) (all P < 0.001), whereas it increased the mean arterial oxygen saturation in TST by 2.0% (0.4%–3.5%, P = 0.035). Increased inspiratory CO2 slightly increased the percentage of N3 sleep during the third night (P = 0.045), without other effects on sleep architecture. Increasing inspiratory CO2 effectively prevented hypoxia‐induced nPB without affecting sleep macro‐architecture, indicating that nPB does not explain the sleep deterioration commonly observed at high altitudes. Key points: Periodic breathing is common during sleep at high altitude, and it is unclear how this affects sleep architecture.We developed a placebo‐controlled approach to prevent nocturnal periodic breathing (nPB) with inspiratory CO2 administration and used it to assess the effects of nPB on sleep in hypobaric hypoxia.Nocturnal periodic breathing was effectively mitigated by an increased inspiratory CO2 fraction in a blinded manner.Prevention of nPB did not lead to relevant changes in sleep architecture in hypobaric hypoxia.We conclude that nPB does not explain the deterioration in sleep architecture commonly observed at high altitude. [ABSTRACT FROM AUTHOR]

We examined the extent to which apnoea‐induced extremes of oxygen demand/carbon dioxide production impact redox regulation of cerebral bioenergetic function. Ten ultra‐elite apnoeists (six men and four women) performed two maximal dry apnoeas preceded by normoxic normoventilation, resulting in severe end‐apnoea hypoxaemic hypercapnia, and hyperoxic hyperventilation designed to ablate hypoxaemia, resulting in hyperoxaemic hypercapnia. Transcerebral exchange of ascorbate radicals (by electron paramagnetic resonance spectroscopy) and nitric oxide metabolites (by tri‐iodide chemiluminescence) were calculated as the product of global cerebral blood flow (by duplex ultrasound) and radial arterial (a) to internal jugular venous (v) concentration gradients. Apnoea duration increased from 306 ± 62 s during hypoxaemic hypercapnia to 959 ± 201 s in hyperoxaemic hypercapnia (P ≤ 0.001). Apnoea generally increased global cerebral blood flow (all P ≤ 0.001) but was insufficient to prevent a reduction in the cerebral metabolic rates of oxygen and glucose (P = 0.015–0.044). This was associated with a general net cerebral output (v > a) of ascorbate radicals that was greater in hypoxaemic hypercapnia (P = 0.046 vs. hyperoxaemic hypercapnia) and coincided with a selective suppression in plasma nitrite uptake (a > v) and global cerebral blood flow (P = 0.034 to <0.001 vs. hyperoxaemic hypercapnia), implying reduced consumption and delivery of nitric oxide consistent with elevated cerebral oxidative–nitrosative stress. In contrast, we failed to observe equidirectional gradients consistent with S‐nitrosohaemoglobin consumption and plasma S‐nitrosothiol delivery during apnoea (all P ≥ 0.05). Collectively, these findings highlight a key catalytic role for hypoxaemic hypercapnia in cerebral oxidative–nitrosative stress. Key points: Local sampling of blood across the cerebral circulation in ultra‐elite apnoeists determined the extent to which severe end‐apnoea hypoxaemic hypercapnia (prior normoxic normoventilation) and hyperoxaemic hypercapnia (prior hyperoxic hyperventilation) impact free radical‐mediated nitric oxide bioavailability and global cerebral bioenergetic function.Apnoea generally increased the net cerebral output of free radicals and suppressed plasma nitrite consumption, thereby reducing delivery of nitric oxide consistent with elevated oxidative–nitrosative stress.The apnoea‐induced elevation in global cerebral blood flow was insufficient to prevent a reduction in the cerebral metabolic rates of oxygen and glucose.Cerebral oxidative–nitrosative stress was greater during hypoxaemic hypercapnia compared with hyperoxaemic hypercapnia and coincided with a lower apnoea‐induced elevation in global cerebral blood flow, highlighting a key catalytic role for hypoxaemia.This applied model of voluntary human asphyxia might have broader implications for the management and treatment of neurological diseases characterized by extremes of oxygen demand and carbon dioxide production. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnoea is characterized by chronic intermittent hypoxaemia and is independently associated with an increased risk of metabolic comorbidities (e.g. type II diabetes and ischaemic heart disease). These comorbidities could be attributable to hypoxaemia‐induced alterations in blood lipid profiles. However, it remains unclear whether intermittent hypoxaemia alters triglyceridaemia differently between biological sexes. Therefore, we used a randomized crossover design to examine whether 6 h of moderate intermittent hypoxaemia (15 hypoxaemic cycles/h, 85% oxyhaemoglobin saturation) alters plasma triglyceride levels differently between men and women after a high‐fat meal. Relative to men, women displayed lower levels of total triglycerides, in addition to denser triglyceride‐rich lipoprotein triglycerides (TRL‐TG; mainly very low‐density lipoprotein triglycerides and chylomicron remnant triglycerides) and buoyant TRL‐TG (mainly chylomicron triglycerides) during normoxia (ambient air) and intermittent hypoxaemia (sex × time: all P ≤ 0.008). Intermittent hypoxaemia led to higher triglyceride levels (condition: all P ≤ 0.016); however, this effect was observed only in men (sex × condition: all P ≤ 0.002). Compared with normoxia, glucose levels were higher in men and lower in women during intermittent hypoxaemia (sex × condition: P < 0.001). The different postprandial responses between biological sexes occurred despite similar reductions in mean oxyhaemoglobin saturation and similar elevations in insulin levels, non‐esterified fatty acid levels and mean heart rate (sex × condition: all P ≥ 0.185). These results support growing evidence showing that intermittent hypoxaemia impacts men and women differently, and they might help to explain biological sex‐related discrepancies in the rate of certain comorbidities associated with intermittent hypoxaemia. Key points: Intermittent hypoxaemia is a key characteristic of obstructive sleep apnoea and alters lipid metabolism in multiple tissues, resulting in increased circulating triglyceride levels, an important risk factor for cardiometabolic diseases.Circulating triglyceride levels are regulated differently between biological sexes, with women typically displaying much lower fasting and postprandial triglyceride levels than men, partly explaining why women of all ages experience lower mortality rates from cardiometabolic diseases.In this study, healthy young men and women consumed a high‐fat meal and were then exposed to 6 h of intermittent hypoxaemia or ambient air.We show that postprandial triglyceride levels are significantly lower in women compared with men and that intermittent hypoxaemia leads to higher postprandial triglyceride levels in men only.These results might help us to understand better why women living with obstructive sleep apnoea experience lower rates of cardiometabolic diseases (e.g. type II diabetes and ischaemic heart disease) than men living with obstructive sleep apnoea. [ABSTRACT FROM AUTHOR]

On the 70th anniversary of the first climb of Mount Everest by Edmund Hillary and Tensing Norgay, we discuss the physiological bases of climbing Everest with or without supplementary oxygen. After summarizing the data of the 1953 expedition and the effects of oxygen administration, we analyse the reasons why Reinhold Messner and Peter Habeler succeeded without supplementary oxygen in 1978. The consequences of this climb for physiology are briefly discussed. An overall analysis of maximal oxygen consumption (V̇O2max${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$) at altitude follows. In this section, we discuss the reasons for the non‐linear fall of V̇O2max${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ at altitude, we support the statement that it is a mirror image of the oxygen equilibrium curve, and we propose an analogue of Hill's model of the oxygen equilibrium curve to analyse the V̇O2max${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ fall. In the following section, we discuss the role of the ventilatory and pulmonary resistances to oxygen flow in limiting V̇O2max${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$, which becomes progressively greater while moving toward higher altitudes. On top of Everest, these resistances provide most of the V̇O2max${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ limitation, and the oxygen equilibrium curve and the respiratory system provide linear responses. This phenomenon is more accentuated in athletes with elevated V̇O2max${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$, due to exercise‐induced arterial hypoxaemia. The large differences in V̇O2max${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ that we observe at sea level disappear at altitude. There is no need for a very high V̇O2max${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ at sea level to climb the highest peaks on Earth. [ABSTRACT FROM AUTHOR]

Migraine, a common neurological disorder, impacts over a billion individuals globally. Its complex aetiology involves various signalling cascades. Hypoxia causes headaches such as high‐altitude headache and acute mountain sickness which share phenotypical similarities with migraine. Epidemiological data indicate an increased prevalence of migraine with and without aura in high‐altitude populations. Experimental studies have further shown that hypoxia can induce migraine attacks. This review summarizes evidence linking hypoxia to migraine, delves into potential pathophysiological mechanisms and highlights research gaps. [ABSTRACT FROM AUTHOR]

Platelets are known primarily for their role in blood clotting; however, it is becoming clear that they play diverse roles beyond that of haemostasis. Exercise has been shown to activate platelets and stimulate neurogenesis, neuroplasticity and improve cognitive function, highlighting a potentially powerful link between platelet function and brain health. Despite this clear link between platelets and the brain, very little is known about the behaviour of platelets through the cerebral circulation in humans. We examined platelet concentration across the brain in exercising humans at sea level (340 m) and high altitude (6–8 days at 3800 m; a stimulus known to modify platelet function). During intense exercise at sea level, platelet concentration increased similarly by 27 ± 17% in the arterial and internal jugular venous circulations (exercise: P < 0.001, interaction: P = 0.262), indicating no uptake or release of platelets into/from the brain. At high altitude, resting platelet concentrations were similar to sea level values in both the arterial and jugular venous circulations (P = 0.590); however, intense exercise at high altitude caused a 31 ± 35% decrease in platelet concentration across the brain (P = 0.016). This divergent response across the brain was not observed in any other haematological or metabolic variables. These data highlight a unique situation where the combination of intense exercise and high altitude hypoxia cause a decrease in platelet concentration across the cerebral circulation. The physiological implications and mechanisms that might influence platelet function across the brain during exercise at high altitude remain to be established. Key points: Platelets are known primarily for their role in blood clotting; however, it is becoming clear that they play diverse roles beyond that of haemostasis.Exercise has been shown to activate platelets, which in turn stimulate neurogenesis, neuroplasticity and improve cognitive function, highlighting a powerful link between platelet function and brain health.At sea level, platelet concentration in blood going into and out of the brain was similar at rest, during maximal exercise and in recovery from exercise.During maximal exercise at high altitude, platelet concentration was 31% lower in the blood exiting the brain; the final destination of these platelets is unknown.The physiological implications and mechanisms that might influence platelet function across the cerebral circulation during exercise at high altitude remain to be established. [ABSTRACT FROM AUTHOR]

Muscle injuries are the leading cause of sports casualties. Because of its high plasticity, skeletal muscle can respond to different stimuli to maintain and improve functionality. Intermittent hypobaric hypoxia (IHH) improves muscle oxygen delivery and utilization. Hypobaria coexists with cold in the biosphere, opening the possibility to consider the combined use of both environmental factors to achieve beneficial physiological adjustments. We studied the effects of IHH and cold exposure, separately and simultaneously, on muscle regeneration. Adult male rats were surgically injured in one gastrocnemius and randomly assigned to the following groups: (1) CTRL: passive recovery; (2) COLD: intermittently exposed to cold (4°C); (3) HYPO: submitted to IHH (4500 m); (4) COHY: exposed to intermittent simultaneous cold and hypoxia. Animals were subjected to these interventions for 4 h/day for 9 or 21 days. COLD and COHY rats showed faster muscle regeneration than CTRL, evidenced after 9 days at histological (dMHC‐positive and centrally nucleated fibre reduction) and functional levels after 21 days. HYPO rats showed a full recovery from injury (at histological and functional levels) after 9 days, while COLD and COHY needed more time to induce a total functional recovery. IHH can be postulated as an anti‐fibrotic treatment since it reduces collagen I deposition. The increase in the pSer473Akt/total Akt ratio observed after 9 days in COLD, HYPO and COHY, together with the increase in the pThr172AMPKα/total AMPKα ratio observed in the gastrocnemius of HYPO, provides clues to the molecular mechanisms involved in the improved muscle regeneration. Key points: Only intermittent hypobaric exposure accelerated muscle recovery as early as 9 days following injury at histological and functional levels.Injured muscles from animals treated with intermittent (4 h/day) cold, hypobaric hypoxia or a simultaneous combination of both stimuli regenerated histological structure and recovered muscle function 21 days after injury.The combination of cold and hypoxia showed a blunting effect as compared to hypoxia alone in the time course of the muscle recovery.The increased expression of the phosphorylated forms of Akt observed in all experimental groups could participate in the molecular cascade of events leading to a faster regeneration.The elevated levels of phosphorylated AMPKα in the HYPO group could play a key role in the modulation of the inflammatory response during the first steps of the muscle regeneration process. [ABSTRACT FROM AUTHOR]

Exposure to chronic hypobaric hypoxia imposes a significant physiological burden to more than 80 million humans living above 2500 m throughout the world. Among them, 50 000 live in the world's highest city, La Rinconada, located at 5000–5300 m in southern Peru. Expedition 5300 is the first scientific and medical programme led in La Rinconada to investigate the physiological adaptations and altitude‐related health issues in this unique population. Dwellers from La Rinconada have very high haemoglobin concentration (20.3 ± 2.4 g/dL; n = 57) and those with chronic mountain sickness (CMS) exhibit even higher concentrations (23.1 ± 1.7 g/dL; n = 150). These values are associated with large total haemoglobin mass and blood volume, without an associated iron deficit. These changes in intravascular volumes lead to a substantial increase in blood viscosity, which is even larger in CMS patients. Despite these large haematological changes, 24 h blood pressure monitoring is essentially normal in La Rinconada, but some results suggest impaired vascular reactivity. Echocardiography revealed large right heart dilatation and high pulmonary arterial pressure as well as left ventricle concentric remodelling and grade I diastolic dysfunction. These changes in heart dimension and function tend to be more severe in highlanders with CMS. Polygraphy evaluations revealed a large reduction in nocturnal pulse oxygen saturation (median SpO2 = 79%), which is even more severe in CMS patients who also tended to show a higher oxygen desaturation index. The population of La Rinconada offers a unique opportunity to investigate the human responses to chronic severe hypoxia, at an altitude that is probably close to the maximum altitude human beings can permanently tolerate without presenting major health issues. [ABSTRACT FROM AUTHOR]

Acute respiratory distress syndrome (ARDS) is characterized by bilateral chest infiltration and acute hypoxic respiratory failure. ARDS carries significant morbidity and mortality despite advancements in medical management, calling for the development of novel therapeutic targets. Hypoxia‐inducible factor (HIF) is a heterodimeric protein involved in various essential pathways, including metabolic reprogramming, immune modulation, angiogenesis and cell cycle regulation. HIF is routinely degraded in homeostasis conditions via the prolyl hydroxylase domain/von Hippel–Lindau protein pathway. However, HIF is stabilized in ARDS via various mechanisms (oxygen‐dependent and independent) as an endogenous protective pathway and plays multifaceted roles in different cell populations. This review focuses on the functional role of HIF and its target genes during ARDS, as well as how HIF has evolved as a therapeutic target in current medical management. [ABSTRACT FROM AUTHOR]

Premature birth impairs cardiac and ventilatory responses to both hypoxia and hypercapnia, but little is known about cerebrovascular responses. Both at sea level and after 2 days at high altitude (3375 m), 16 young preterm‐born (gestational age, 29 ± 1 weeks) and 15 age‐matched term‐born (40 ± 0 weeks) adults were exposed to two consecutive 4 min bouts of hyperoxic hypercapnic conditions (3% CO2–97% O2; 6% CO2–94% O2), followed by two periods of voluntary hyperventilation‐induced hypocapnia. We measured middle cerebral artery blood velocity, end‐tidal CO2, pulmonary ventilation, beat‐by‐beat mean arterial pressure and arterialized capillary blood gases. Baseline middle cerebral artery blood velocity increased at high altitude compared with sea level in term‐born (+24 ± 39%, P = 0.036), but not in preterm‐born (−4 ± 27%, P = 0.278) adults. The end‐tidal CO2, pulmonary ventilation and mean arterial pressure were similar between groups at sea level and high altitude. Hypocapnic cerebrovascular reactivity was higher at high altitude compared with sea level in term‐born adults (+173 ± 326%, P = 0.026) but not in preterm‐born adults (−21 ± 107%, P = 0.572). Hypercapnic reactivity was altered at altitude only in preterm‐born adults (+125 ± 144%, P < 0.001). Collectively, at high altitude, term‐born participants showed higher hypocapnic (P = 0.012) and lower hypercapnic (P = 0.020) CO2 reactivity compared with their preterm‐born peers. In conclusion, exposure to high altitude revealed different cerebrovascular responses in preterm‐ compared with term‐born adults, despite similar ventilatory responses. These findings suggest a blunted cerebrovascular response at high altitude in preterm‐born adults, which might predispose these individuals to an increased risk of high‐altitude illnesses. Key points: Cerebral haemodynamics and cerebrovascular reactivity in normoxia are known to be similar between term‐born and prematurely born adults.In contrast, acute exposure to high altitude unveiled different cerebrovascular responses to hypoxia, hypercapnia and hypocapnia. In particular, cerebral vasodilatation was impaired in prematurely born adults, leading to an exaggerated cerebral vasoconstriction.Cardiovascular and ventilatory responses to both hypo‐ and hypercapnia at sea level and at high altitude were similar between control subjects and prematurely born adults. Other mechanisms might therefore underlie the observed blunted cerebral vasodilatory responses in preterm‐born adults at high altitude. [ABSTRACT FROM AUTHOR]

Lowlanders sojourning for more than 1 day at high altitude (HA) experience a reduction in plasma volume (PV) that increases haemoglobin concentration and thus restores arterial oxygen content. If the sojourn extends over weeks, an expansion of total red cell volume (RCV) occurs and contributes to the haemoconcentration. While the reduction in PV was classically attributed to an increased diuretic fluid loss, recent studies support fluid redistribution, rather than loss, as the underlying mechanism. The fluid redistribution is presumably driven by a disappearance of proteins from the circulation and the resulting reduction in oncotic pressure exerted by the plasma, although the fate of the disappearing proteins remains unclear. The RCV expansion is the result of an accelerated erythropoietic activity secondary to enhanced renal erythropoietin release, but a contribution of other mechanisms cannot be excluded. After return from HA, intravascular volumes return to normal values and the normalisation of RCV might involve selective destruction of newly formed erythrocytes, although this explanation has been strongly challenged by recent studies. In contrast to acclimatised lowlanders, native highlanders originating from the Tibetan and the Ethiopian plateaus present with a normal or only mildly elevated haemoglobin concentration. Genetic adaptations blunting the erythropoietic response to HA exposure have been proposed as an explanation for the absence of more pronounced haemoconcentration in these populations, but new evidence also supports a contribution of a larger than expected PV. The functional significance of the relatively low haemoglobin concentration in Tibetan and Ethiopian highlanders is incompletely understood and warrants further investigation. [ABSTRACT FROM AUTHOR]

Babies born with fetal growth restriction (FGR) are at higher risk of developing cardiometabolic diseases across the life course. The reduction in substrate supply to the developing fetus that causes FGR not only alters cardiac growth and structure but may have deleterious effects on metabolism and function. Using a sheep model of placental restriction to induce FGR, we investigated key cardiac metabolic and functional markers that may be altered in FGR. We also employed phase‐contrast magnetic resonance imaging MRI to assess left ventricular cardiac output (LVCO) as a measure of cardiac function. We hypothesized that signalling molecules involved in cardiac fatty acid utilisation and contractility would be impaired by FGR and that this would have a negative impact on LVCO in the late gestation fetus. Key glucose (GLUT4 protein) and fatty acid (FATP, CD36 gene expression) substrate transporters were significantly reduced in the hearts of FGR fetuses. We also found reduced mitochondrial numbers as well as abundance of electron transport chain complexes (complexes II and IV). These data suggest that FGR diminishes metabolic and mitochondrial capacity in the fetal heart; however, alterations were not correlated with fetal LVCO. Overall, these data show that FGR alters fetal cardiac metabolism in late gestation. If sustained ex utero, this altered metabolic profile may contribute to poor cardiac outcomes in FGR‐born individuals after birth. Key points: Around the time of birth, substrate utilisation in the fetal heart switches from carbohydrates to fatty acids. However, the effect of fetal growth restriction (FGR) on this switch, and thus the ability of the fetal heart to effectively metabolise fatty acids, is not fully understood.Using a sheep model of early onset FGR, we observed significant downregulation in mRNA expression of fatty acid receptors CD36 and FABP in the fetal heart. FGR fetuses also had significantly lower cardiac mitochondrial abundance than controls.There was a reduction in abundance of complexes II and IV within the electron transport chain of the FGR fetal heart, suggesting altered ATP production.This indicates reduced fatty acid metabolism and mitochondrial function in the heart of the FGR fetus, which may have detrimental long‐term implications and contribute to increased risk of cardiovascular disease later in life. [ABSTRACT FROM AUTHOR]

High altitude is a natural setting in which to study human acclimatization and adaptation. Here, I identify where and in whom high‐altitude physiology research has occurred. There has been a mismatch between countries with large high‐altitude populations vs. where high‐altitude research has been conducted. From 1970 to 2020, 83% of high‐altitude physiology research took place in just seven countries: Nepal, China, USA, Peru, India, Bolivia and Italy. Collectively, these countries account for only 35% of the global population living above 2500 m. Furthermore, high‐altitude physiology research has predominantly studied low‐altitude residents visiting high altitude and female participants are under‐represented. Accordingly, the included populations are not necessarily a proportional representation of high‐altitude residents. Here, I discuss how this influences our understanding of high‐altitude adaptation. Finally, I highlight past initiatives to increase diversity in high‐altitude research. By identifying the broad gaps in high‐altitude physiology research, I propose exciting, inclusive opportunities to study human high‐altitude physiology. [ABSTRACT FROM AUTHOR]

Breathing mild bouts of low oxygen air (i.e. acute intermittent hypoxia, AIH) has been shown to improve locomotor function in humans after a spinal cord injury. How AIH‐induced gains in motor performance are achieved remains unclear. We examined the hypothesis that AIH augments motor learning and motor retention during a locomotor adaptation task. We further hypothesized that gains in motor learning and retention will be associated with reductions in net metabolic power, consistent with the acquisition of energetically favourable mechanics. Thirty healthy individuals were randomly allocated into either a control group or an AIH group. We utilized a split‐belt treadmill to characterize adaptations to an unexpected belt speed perturbation of equal magnitude during an initial exposure and a second exposure. Adaptation was characterized by changes in spatiotemporal step asymmetry, anterior–posterior force asymmetry, and net metabolic power. While both groups adapted by reducing spatial asymmetry, only the AIH group achieved significant reductions in double support time asymmetry and propulsive force asymmetry during both the initial and the second exposures to the belt speed perturbation. Net metabolic power was also significantly lower in the AIH group, with significant reductions from the initial perturbation exposure to the second. These results provide the first evidence that AIH mediates improvements in both motor learning and retention. Further, our results suggest that reductions in net metabolic power continue to be optimized upon subsequent learning and are driven by more energetically favourable temporal coordination strategies. Our observation that AIH facilitates motor learning and retention can be leveraged to design rehabilitation interventions that promote functional recovery. Key points: Brief exposures to low oxygen air, known as acute intermittent hypoxia (AIH), improves locomotor function in humans after a spinal cord injury, but it remains unclear how gains in motor performance are achieved.In this study, we tested the hypothesis that AIH induces enhancements in motor learning and retention by quantifying changes in interlimb coordination, anterior–posterior force symmetry and metabolic cost during a locomotor adaptation task.We show the first evidence that AIH improves both motor learning and savings of newly learned temporal interlimb coordination strategies and force asymmetry compared to untreated individuals.We further demonstrate that AIH elicits greater reductions in metabolic cost during motor learning that continues to be optimized upon subsequent learning.Our findings suggest that AIH‐induced gains in locomotor performance are facilitated by enhancements in motor learning and retention of more energetically favourable coordination strategies. [ABSTRACT FROM AUTHOR]

A key question in biology concerns the extent to which distributional range limits of species are determined by intrinsic limits of physiological tolerance. Here, we use common‐garden data for wild rodents to assess whether species with higher elevational range limits typically have higher thermogenic capacities in comparison to closely related lowland species. Among South American leaf‐eared mice (genus Phyllotis), mean thermogenic performance is higher in species with higher elevational range limits, but there is little among‐species variation in the magnitude of plasticity in this trait. In the North American rodent genus Peromyscus, highland deer mice (Peromyscus maniculatus) have greater thermogenic maximal oxygen uptake (V̇O2max${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$) than lowland white‐footed mice (Peromyscus leucopus) at a level of hypoxia that matches the upper elevational range limit of the former species. In highland deer mice, the enhanced thermogenic V̇O2max${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ in hypoxia is attributable to a combination of evolved and plastic changes in physiological pathways that govern the transport and utilization of O2 and metabolic substrates. Experiments with Peromyscus mice also demonstrate that exposure to hypoxia during different stages of development elicits plastic changes in cardiorespiratory traits that improve thermogenic V̇O2max${\dot V_{{{\mathrm{O}}_{\mathrm{2}}}{\mathrm{max}}}}$ via distinct physiological mechanisms. Evolved differences in thermogenic capacity provide clues about why some species are able to persist in higher‐elevation habitats that lie slightly beyond the tolerable limits of other species. Such differences in environmental tolerance also suggest why some species might be more vulnerable to climate change than others. [ABSTRACT FROM AUTHOR]

Hypoxic ischaemic brain injury after resuscitation from cardiac arrest is associated with dismal clinical outcomes. To date, most clinical interventions have been geared towards the restoration of cerebral oxygen delivery after resuscitation; however, outcomes in clinical trials are disappointing. Therefore, alternative disease mechanism(s) are likely to be at play, of which the response of the innate immune system to sterile injured tissue in vivo after reperfusion has garnered significant interest. The innate immune system is composed of three pillars: (i) cytokines and signalling molecules; (ii) leucocyte migration and activation; and (iii) the complement cascade. In animal models of hypoxic ischaemic brain injury, pro‐inflammatory cytokines are central to propagation of the response of the innate immune system to cerebral ischaemia–reperfusion. In particular, interleukin‐1 beta and downstream signalling can result in direct neural injury that culminates in cell death, termed pyroptosis. Leucocyte chemotaxis and activation are central to the in vivo response to cerebral ischaemia–reperfusion. Both parenchymal microglial activation and possible infiltration of peripherally circulating monocytes might account for exacerbation of an immunopathological response in humans. Finally, activation of the complement cascade intersects with multiple aspects of the innate immune response by facilitating leucocyte activation, further cytokine release and endothelial activation. To date, large studies of immunomodulatory therapies have not been conducted; however, lessons learned from historical studies using therapeutic hypothermia in humans suggest that quelling an immunopathological response might be efficacious. Future work should delineate the precise pathways involved in vivo in humans to target specific signalling molecules. [ABSTRACT FROM AUTHOR]

Fetal growth restriction (FGR) is associated with cardiovascular and respiratory complications after birth and beyond. Despite research showing a range of neurological changes following FGR, little is known about how FGR affects the brainstem cardiorespiratory control centres. The primary neurons that release serotonin reside in the brainstem cardiorespiratory control centres and may be affected by FGR. At two time points in the last trimester of sheep brain development, 110 and 127 days of gestation (0.74 and 0.86 of gestation), we assessed histopathological alterations in the brainstem cardiorespiratory control centres of the pons and medulla in early‐onset FGR versus control fetal sheep. The FGR cohort were hypoxaemic and asymmetrically growth restricted. Compared to the controls, the brainstem of FGR fetuses exhibited signs of neuropathology, including elevated cell death and reduced cell proliferation, grey and white matter deficits, and evidence of oxidative stress and neuroinflammation. FGR brainstem pathology was predominantly observed in the medullary raphé nuclei, hypoglossal nucleus, nucleus ambiguous, solitary tract and nucleus of the solitary tract. The FGR groups showed imbalanced brainstem serotonin and serotonin 1A receptor abundance in the medullary raphé nuclei, despite evidence of increased serotonin staining within vascular regions of placentomes collected from FGR fetuses. Our findings demonstrate both early and adaptive brainstem neuropathology in response to placental insufficiency. Key points: Early‐onset fetal growth restriction (FGR) was induced in fetal sheep, resulting in chronic fetal hypoxaemia.Growth‐restricted fetuses exhibit persistent neuropathology in brainstem nuclei, characterised by disrupted cell proliferation and reduced neuronal cell number within critical centres responsible for the regulation of cardiovascular and respiratory functions. Elevated brainstem inflammation and oxidative stress suggest potential mechanisms contributing to the observed neuropathological changes.Both placental and brainstem levels of 5‐HT were found to be impaired following FGR. [ABSTRACT FROM AUTHOR]

The cerebral vasculature manages oxygen delivery by adjusting arterial blood in‐flow in the face of reductions in oxygen availability. Hypoxic cerebral vasodilatation, and the associated hypoxic cerebral blood flow reactivity, involve many vascular, erythrocytic and cerebral tissue mechanisms that mediate elevations in cerebral blood flow via micro‐ and macrovascular dilatation. This contemporary review focuses on in vivo human work – with reference to seminal preclinical work where necessary – on hypoxic cerebrovascular reactivity, particularly where recent advancements have been made. We provide updates with the following information: in humans, hypoxic cerebral vasodilatation is partially mediated via a – likely non‐obligatory – combination of: (1) nitric oxide synthases, (2) deoxygenation‐coupled S‐nitrosothiols, (3) potassium channel‐related vascular smooth muscle hyperpolarization, and (4) prostaglandin mechanisms with some contribution from an interrelationship with reactive oxygen species. And finally, we discuss the fact that, due to the engagement of deoxyhaemoglobin‐related mechanisms, reductions in O2 content via haemoglobin per se seem to account for ∼50% of that seen with hypoxic cerebral vasodilatation during hypoxaemia. We further highlight the issue that methodological impediments challenge the complete elucidation of hypoxic cerebral reactivity mechanisms in vivo in healthy humans. Future research is needed to confirm recent advancements and to reconcile human and animal findings. Further investigations are also required to extend these findings to address questions of sex‐, heredity‐, age‐, and disease‐related differences. The final step is to then ultimately translate understanding of these mechanisms into actionable, targetable pathways for the prevention and treatment of cerebral vascular dysfunction and cerebral hypoxic brain injury. [ABSTRACT FROM AUTHOR]

Summary: Numerous investigations have studied relationships between satiation, satiety, or food intake and single factors like food composition and resting metabolic rate. However, a comprehensive framework connecting food, physiological, and psychological factors together has not previously been reported. As an exploratory study with a trained panel consisting of nine participants, the contributions of twenty‐eight variables (seven food, seven psychological, and fourteen physiological factors) to satiation, satiety, and food intake of a mid‐morning snack were investigated. Both human factors and foods had contributions to perceived satiation and satiety, but with large differences in loadings, especially for metabolic factors. Food factors, including nutrient and energy contents, were major determinants of food intake, with only small contributions from human factors. Investigating diverse factors together provides a comprehensive approach linking appetite to both food and human factors. This study suggests the potential to guide manipulation of satiation, satiety, and food intake depending on individual psychological and physiological profiles. [ABSTRACT FROM AUTHOR]

Hypoxia at high altitude facilitates changes in ventilatory control that can lead to nocturnal periodic breathing (nPB). Here, we introduce a placebo‐controlled approach to prevent nPB by increasing inspiratory CO2 and used it to assess whether nPB contributes to the adverse effects of hypoxia on sleep architecture. In a randomized, single‐blinded, crossover design, 12 men underwent two sojourns (three days/nights each, separated by 4 weeks) in hypobaric hypoxia corresponding to 4000 m altitude, with polysomnography during the first and third night of each sojourn. During all nights, subjects' heads were encompassed by a canopy retaining exhaled CO2, and CO2 concentration in the canopy (i.e. inspiratory CO2 concentration) was controlled by adjustment of fresh air inflow. Throughout the placebo sojourn inspiratory CO2 was ≤0.2%, whereas throughout the other sojourn it was increased to 1.76% (IQR, 1.07%–2.44%). During the placebo sojourn, total sleep time (TST) with nPB was 54.3% (37.4%–80.8%) and 45.0% (24.5%–56.5%) during the first and the third night, respectively (P = 0.042). Increased inspiratory CO2 reduced TST with nPB by an absolute 38.1% (28.1%–48.1%), the apnoea–hypopnoea index by 58.1/h (40.1–76.1/h), and oxygen desaturation index ≥3% by 56.0/h (38.9.1–73.2/h) (all P < 0.001), whereas it increased the mean arterial oxygen saturation in TST by 2.0% (0.4%–3.5%, P = 0.035). Increased inspiratory CO2 slightly increased the percentage of N3 sleep during the third night (P = 0.045), without other effects on sleep architecture. Increasing inspiratory CO2 effectively prevented hypoxia‐induced nPB without affecting sleep macro‐architecture, indicating that nPB does not explain the sleep deterioration commonly observed at high altitudes. Key points: Periodic breathing is common during sleep at high altitude, and it is unclear how this affects sleep architecture.We developed a placebo‐controlled approach to prevent nocturnal periodic breathing (nPB) with inspiratory CO2 administration and used it to assess the effects of nPB on sleep in hypobaric hypoxia.Nocturnal periodic breathing was effectively mitigated by an increased inspiratory CO2 fraction in a blinded manner.Prevention of nPB did not lead to relevant changes in sleep architecture in hypobaric hypoxia.We conclude that nPB does not explain the deterioration in sleep architecture commonly observed at high altitude. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective Methods Results Conclusions Exposure to environmental contaminants is globally universal. However, communities vary in the specific combination of contaminants to which they are exposed, potentially contributing to variation in human health and creating “locally situated biologies.” We investigated how environmental exposures differ across environments by comparing exposure profiles between two contexts that differ markedly across political, economic, and sociocultural factors—Namqom, Formosa, Argentina, and New Haven, Connecticut, United States.We collected infant urine, maternal urine, and human milk samples from mother–infant dyads in Formosa (n = 13) and New Haven (n = 21). We used untargeted liquid chromatography with high‐resolution mass spectrometry (LC‐HRMS) to annotate environmental contaminants and endogenous metabolites in these samples, and we analyzed the data using exposome‐wide association studies (EWAS) followed by pathway enrichment.We found statistically significant differences between the chemical exposure profiles of the Argentinian and US mothers, mostly involving pesticides; however, we observed similarities in the infant urine and human milk environmental contaminant profiles, suggesting that the maternal body may buffer infant exposure through human milk. We also found that infants and mothers were exposed to contaminants that were associated with alterations in amino acid and carbohydrate metabolism. Infants additionally showed alterations in vitamin metabolism, including vitamins B1, B3, and B6.Differences in chemical exposure profiles may be related to structural factors. Despite variation in the composition of exposure profiles between the two study sites, environmental contaminant exposure was associated with similar patterns in human physiology when we considered contaminants comprehensively rather than individually, with implications for metabolic and cardiovascular disease risk as well as infant cognitive development. [ABSTRACT FROM AUTHOR]

ABSTRACT Invasive biological samples collected during clinical care represent a valuable yet underutilized source of information about human biology. However, the challenges of working with clinical personnel and the invasive nature of sample collection in biomedical studies can hinder the acquisition of sufficiently large sample sizes for robust statistical analyses. In addition, the incorporation of demographic data from participants is crucial for ensuring the inclusiveness of representative populations, identifying at‐risk groups, and addressing healthcare disparities. Drawing on both research experiences and the existing literature, this article provides recommendations for researchers aiming to undertake efficient and impactful projects involving invasive human samples. The suggested strategies include: (1) establishing productive collaborations with clinicians; (2) optimizing sample quality through meticulous collection and handling procedures; and (3) strategically implementing a retrospective model to capitalize on existing invasive sample repositories. When established, cooperative work between clinical health care workers and biological anthropologists can yield insights into human biology that have the potential to improve human health and wellbeing. [ABSTRACT FROM AUTHOR]

Background: Endometriosis is a complex disorder with genetic, immune, inflammatory, and multifactorial etiologies. Zinc, an essential trace element, plays a crucial role in various physiological processes. Dysregulation or deficiency of zinc can lead to aberrations in human physiology. However, the association between dietary zinc and endometriosis remains ambiguous. This study aimed to investigate the link between dietary zinc intake and endometriosis. Methods: Utilizing cross-sectional data from the National Health and Nutrition Examination Survey, we analyzed information from American women aged 20–54 years between 1999 and 2006. After adjusting for relevant covariates, multivariable logistic regression analysis was employed to assess correlations. Results: A total of 4315 women were included in the study. The multivariable logistic regression model revealed a positive correlation between dietary zinc intake and the risk of endometriosis, even after controlling for confounding variables. Relative to individuals with lower zinc consumption (≤ 8 mg/day), the adjusted odds ratio (OR) values for dietary zinc intake and endometriosis in the 8–14 mg/day and > 14 mg/day groups were 1.19 (95% CI: 0.92–1.54, p = 0.189) and 1.60 (95% CI: 1.12–2.27, p = 0.009), respectively. Conclusions: Our findings suggest a positive correlation between dietary zinc intake and the prevalence of endometriosis. However, further investigations are necessary to better understand this association and explore the potential role of dietary zinc in endometriosis. [ABSTRACT FROM AUTHOR]

Currently, despite the vast amounts of time and money invested in cancer treatment, cancer remains one of the primary threats to human life. The primary factor contributing to the low treatment efficacy is cancer heterogeneity. The unclear molecular mechanisms underlying tumorigenesis, coupled with the complexity of human physiology, and the inability of animal models to accurately replicate the human tumor microenvironment, pose significant hurdles in the development of novel cancer therapies. Tumor-microenvironment-on-chip (TMOC) represents a research platform that integrates three-dimensional cell culture with microfluidic systems, simulating the essential components and physiological traits of the in vivo tumor microenvironment. It offers a dynamic setting within the chip system to study tumor progression, potentially heralding a breakthrough in cancer research. In this review, we will summarize the current advancements in this platform, encompassing various types of TMOCs and their applications in different types of cancer. From our perspective, the TMOC platform necessitates enhanced integration with tissue engineering techniques and microphysiological environments before it can evolve into a more refined preclinical model for cancer research. [ABSTRACT FROM AUTHOR]

Soluble CD163 (sCD163) is a circulating inflammatory mediator, indicative of acute and chronic, systemic and non-systemic inflammatory conditions. It is the cleavage outcome, consisting of almost the entire extracellular domain, of the CD163, a receptor expressed in monocytic lineages. Its expression is proportional to the abundance of CD163+ macrophages. Various mechanisms trigger the shedding of the CD163 receptor or the accumulation of CD163-expressing macrophages, inducing the sCD163 concentration in the circulation and bodily fluids. The activities of sCD163 range from hemoglobin (Hb) scavenging, macrophage marker, decoy receptor for cytokines, participation in immune defense mechanisms, and paracrine effects in various tissues, including the endothelium. It is an established marker of macrophage activation and thus participates in many diseases, including chronic inflammatory conditions, such as atherosclerosis, asthma, and rheumatoid arthritis; acute inflammatory conditions, such as sepsis, hepatitis, and malaria; insulin resistance; diabetes; and tumors. The sCD163 levels have been correlated with the severity, stage of the disease, and clinical outcome for many of these conditions. This review article summarizes the expression and role of sCD163 and its precursor protein, CD163, outlines the sCD163 generation mechanisms, the biological activities, and the known underlying molecular mechanisms, with an emphasis on its impact on the endothelium and its contribution in the pathophysiology of human diseases. [ABSTRACT FROM AUTHOR]

Excitatory glutamatergic NMDA receptors (NMDARs) are key regulators of spinal pain processing, and yet the biophysical properties of NMDARs in dorsal horn nociceptive neurons remain poorly understood. Despite the clinical implications, it is unknown whether the molecular and functional properties of synaptic NMDAR responses are conserved between males and females or translate from rodents to humans. To address these translational gaps, we systematically compared individual and averaged excitatory synaptic responses from lamina I pain‐processing neurons of adult Sprague–Dawley rats and human organ donors, including both sexes. By combining patch‐clamp recordings of outward miniature excitatory postsynaptic currents with non‐biased data analyses, we uncovered a wide range of decay constants of excitatory synaptic events within individual lamina I neurons. Decay constants of synaptic responses were distributed in a continuum from 1–20 ms to greater than 1000 ms, suggesting that individual lamina I neurons contain AMPA receptor (AMPAR)‐only as well as GluN2A‐, GluN2B‐ and GluN2D‐NMDAR‐dominated synaptic events. This intraneuronal heterogeneity in AMPAR‐ and NMDAR‐mediated decay kinetics was observed across sex and species. However, we discovered an increased relative contribution of GluN2A‐dominated NMDAR responses at human lamina I synapses compared with rodent synapses, suggesting a species difference relevant to NMDAR subunit‐targeting therapeutic approaches. The conserved heterogeneity in decay rates of excitatory synaptic events within individual lamina I pain‐processing neurons may enable synapse‐specific forms of plasticity and sensory integration within dorsal horn nociceptive networks. Key points: Synaptic NMDA receptors (NMDARs) in spinal dorsal horn nociceptive neurons are key regulators of pain processing, but it is unknown whether their functional properties are conserved between males and females or translate from rodents to humans.In this study, we compared individual excitatory synaptic responses from lamina I pain‐processing neurons of male and female adult Sprague–Dawley rats and human organ donors.Individual lamina I neurons from male and female rats and humans contain AMPA receptor‐only as well as GluN2A, GluN2B‐ and GluN2D‐NMDAR‐dominated synaptic events. This may enable synapse‐specific forms of plasticity and sensory integration within dorsal horn nociceptive networks.Human lamina I synapses have an increased relative contribution of GluN2A‐dominated NMDAR responses compared with rodent synapses.These results uncover a species difference relevant to NMDAR subunit‐targeting therapeutic approaches. [ABSTRACT FROM AUTHOR]

Background: Monkeys are an appropriate model for periodontal research owing to their similar dental anatomy and physiology unlike humans. Extensive literature exists on pathological periodontitis in monkeys and humans, although concerns regarding whether healthy middle-aged monkeys and humans display the same periodontal and oral microbial status remains unclear. Aims and objectives: The current study aimed to compare alveolar bone resorption, gingival inflammatory infiltrate, and salivary microbiota profile in periodontally healthy middle-aged humans and monkeys. Methods: CBCT examination and histological analysis were performed to compare the periodontal status in middle-aged healthy humans and monkeys. Oral saliva16S rRNA sequencing was performed to analyze the oral microbial profile. Results: The alveolar resorption was compared between humans and monkeys, to determine the periodontal health. The percentage attachment of attachment loss was more around the posteriors teeth in humans when compared to monkeys (p<0.05). The degree of gingival inflammation was analyzed in both the groups, the expression of CD 34,45was higher in humans. 16S rRNA analysis demonstrated less diversity of salivary microorganisms in humans than in monkeys. The relative abundance of Aggregatibacter, Haemophilus, Gemella, and Porphyromonas at the genus level was significantly less in humans than in monkeys (p(<0.05). Conclusion: The periodontally healthy middle-aged humans and monkeys display different alveolar bone resorption and gingival inflammatory infiltrate levels. Furthermore, the salivary microbiota profile showed distinctly different oral microbiomes in these two primates. Our results suggest that the difference in alveolar bone status and gingival inflammatory infiltrate in healthy humans and monkeys might be associated with the diversity of the oral microbiome. [ABSTRACT FROM AUTHOR]

The article emphasizes the importance of transparency in scientific research, specifically focusing on the benefits of preregistration and registered reporting to enhance credibility and reproducibility. It discusses the value of separating hypothesis-testing and hypothesis-generating analyses, as well as the role of interdisciplinary collaborations in study design. The study also addresses common misconceptions about registered reports, highlighting their applicability across various disciplines and their contribution to improving research quality and credibility, particularly in the biomedical field. [Extracted from the article]

The gut microbiota, recognised for its vital functions in host health, operates as an endocrine organ, exerting systemic effects beyond the gastrointestinal tract. This "virtual organ" produces hormones that influence distal organs, including the brain. With its diverse microbial composition, the gut microbiota surpasses the biochemical complexity of traditional endocrine organs, generating neurotransmitters like GABA, dopamine, and serotonin. Despite challenges in culturing gut bacteria, advances in research methodologies have elucidated their role in behaviour, metabolism, appetite, and insulin resistance. As microbial endocrinology continues to evolve, further exploration of the intricate connections between hormones and the microbiome are anticipated, highlighting hormones' pivotal role in the dynamic host–microbiota relationship. [ABSTRACT FROM AUTHOR]

The architectural construction process on planets is an architectural issue that develops day by day due to extreme environmental conditions and uncertainties. Architectural design needs structural systems to survive. Structural systems on planets encounter load factors that are different from the load factors on Earth. Choosing the optimum structural system is important for the structures planned to be built on planets to survive under the effects and loads of the environment and to adapt to human physiology. Some of the different types of structural systems used on Earth are featured in the literature for building a structure on planets. An evaluation system has been created to determine the correct system type for the first settlements on planets among the prominent structural system types and to narrow down the selection area of these system features. In line with this evaluation system in this study, a structural system model that stands up to harsh environmental conditions and protects human health is proposed for the first settlements on the planets. It is aimed that the evaluation system will be developed in the light of research emerging from developing technologies and can be used in future studies. [ABSTRACT FROM AUTHOR]