Physiological and Genetic Adaptations to Diving in Sea Nomads.

Understanding the physiology and genetics of human hypoxia tolerance has important medical implications, but this phenomenon has thus far only been investigated in high-altitude human populations. Another system, yet to be explored, is humans who engage in breath-hold diving. The indigenous Bajau people ("Sea Nomads") of Southeast Asia live a subsistence lifestyle based on breath-hold diving and are renowned for their extraordinary breath-holding abilities. However, it is unknown whether this has a genetic basis. Using a comparative genomic study, we show that natural selection on genetic variants in the PDE10A gene have increased spleen size in the Bajau, providing them with a larger reservoir of oxygenated red blood cells. We also find evidence of strong selection specific to the Bajau on BDKRB2, a gene affecting the human diving reflex. Thus, the Bajau, and possibly other diving populations, provide a new opportunity to study human adaptation to hypoxia tolerance. VIDEO ABSTRACT.

Responses of intraspecific metabolic scaling to temperature and activity differ between water- and air-breathing ectothermic vertebrates.

Metabolism underpins all life-sustaining processes and varies profoundly with body size, temperature and locomotor activity. A current theory explains some of the size-dependence of metabolic rate (its mass exponent, b) through changes in metabolic level (L). We propose two predictive advances that: (a) combine the above theory with the evolved avoidance of oxygen limitation in water-breathers experiencing warming, and (b) quantify the overall magnitude of combined temperatures and degrees of locomotion on metabolic scaling across air- and water-breathers. We use intraspecific metabolic scaling responses to temperature (523 regressions) and activity (281 regressions) in diverse ectothermic vertebrates (fish, reptiles and amphibians) to show that b decreases with temperature-increased L in water-breathers, supporting surface area-related avoidance of oxygen limitation, whereas b increases with activity-increased L in air-breathers, following volume-related influences. This new theoretical integration quantitatively incorporates different influences (warming, locomotion) and respiration modes (aquatic, terrestrial) on animal energetics.

Mechanisms of cardiac collapse at high temperature in a marine teleost (Girella nigrians).

Heat-induced mortality in ectotherms may be attributed to impaired cardiac performance, specifically a collapse in maximum heart rate (fHmax), although the physiological mechanisms driving this phenomenon are still unknown. Here, we tested two proposed factors which may restrict cardiac upper thermal limits: noxious venous blood conditions and oxygen limitation. We hypothesized elevated blood [K+] (hyperkalemia) and low oxygen (hypoxia) would reduce cardiac upper thermal limits in a marine teleost (Girella nigricans), while high oxygen (hyperoxia) would increase thermal limits. We also hypothesized higher acclimation temperatures would exacerbate the harmful effects of an oxygen limitation. Using the Arrhenius breakpoint temperature test, we measured fHmax in acutely warmed fish under control (saline injected) and hyperkalemic conditions (elevated plasma [K+]) while exposed to hyperoxia (200% air saturation), normoxia (100% air saturation), or hypoxia (20% air saturation). We also measured ventricle lactate content and venous blood oxygen partial pressure (PO2) to determine if there were universal thresholds in either metric driving cardiac collapse. Elevated [K+] was not significantly correlated with any cardiac thermal tolerance metric. Hypoxia significantly reduced cardiac upper thermal limits (Arrhenius breakpoint temperature [TAB], peak fHmax, temperature of peak heart rate [TPeak], and temperature at arrhythmia [TARR]). Hyperoxia did not alter cardiac thermal limits compared to normoxia. There was no evidence of a species-wide threshold in ventricular [lactate] or venous PO2. Here, we demonstrate that oxygen limits cardiac thermal tolerance only in instances of hypoxia, but that other physiological processes are responsible for causing temperature-induced heart failure when oxygen is not limited.

A change of heart: Mechanisms of cardiac adaptation to acute and chronic hypoxia.

Over the last 100 years, high-altitude researchers have amassed a comprehensive understanding of the global cardiac responses to acute, prolonged and lifelong hypoxia. When lowlanders are exposed to hypoxia, the drop in arterial oxygen content demands an increase in cardiac output, which is facilitated by an elevated heart rate at the same time as ventricular volumes are maintained. As exposure is prolonged, haemoconcentration restores arterial oxygen content, whereas left ventricular filling and stroke volume are lowered as a result of a combination of reduced blood volume and hypoxic pulmonary vasoconstriction. Populations native to high-altitude, such as the Sherpa in Asia, exhibit unique lifelong or generational adaptations to hypoxia. For example, they have smaller left ventricular volumes compared to lowlanders despite having larger total blood volume. More recent investigations have begun to explore the mechanisms underlying such adaptive responses by combining novel imaging techniques with interventions that manipulate cardiac preload, afterload, and/or contractility. This work has revealed the contributions and interactions of (i) plasma volume constriction; (ii) sympathoexcitation; and (iii) hypoxic pulmonary vasoconstriction with respect to altering cardiac loading, or otherwise preserving or enhancing biventricular systolic and diastolic function even amongst high altitude natives with excessive erythrocytosis. Despite these advances, various areas of investigation remain understudied, including potential sex-related differences in response to high altitude. Collectively, the available evidence supports the conclusion that the human heart successfully adapts to hypoxia over the short- and long-term, without signs of myocardial dysfunction in healthy humans, except in very rare cases of maladaptation.

Oxygen Pathway Limitations in Patients With Chronic Thromboembolic Pulmonary Hypertension.

BACKGROUND: Exertional intolerance is a limiting and often crippling symptom in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Traditionally the pathogenesis has been attributed to central factors, including ventilation/perfusion mismatch, increased pulmonary vascular resistance, and right heart dysfunction and uncoupling. Pulmonary endarterectomy and balloon pulmonary angioplasty provide substantial improvement of functional status and hemodynamics. However, despite normalization of pulmonary hemodynamics, exercise capacity often does not return to age-predicted levels. By systematically evaluating the oxygen pathway, we aimed to elucidate the causes of functional limitations in patients with CTEPH before and after pulmonary vascular intervention. METHODS: Using exercise cardiac magnetic resonance imaging with simultaneous invasive hemodynamic monitoring, we sought to quantify the steps of the O2 transport cascade from the mouth to the mitochondria in patients with CTEPH (n=20) as compared with healthy participants (n=10). Furthermore, we evaluated the effect of pulmonary vascular intervention (pulmonary endarterectomy or balloon angioplasty) on the individual components of the cascade (n=10). RESULTS: Peak Vo2 (oxygen uptake) was significantly reduced in patients with CTEPH relative to controls (56±17 versus 112±20% of predicted; P<0.0001). The difference was attributable to impairments in multiple steps of the O2 cascade, including O2 delivery (product of cardiac output and arterial O2 content), skeletal muscle diffusion capacity, and pulmonary diffusion. The total O2 extracted in the periphery (ie, ΔAVo2 [arteriovenous O2 content difference]) was not different. After pulmonary vascular intervention, peak Vo2 increased significantly (from 12.5±4.0 to 17.8±7.5 mL/[kg·min]; P=0.036) but remained below age-predicted levels (70±11%). The O2 delivery was improved owing to an increase in peak cardiac output and lung diffusion capacity. However, peak exercise ΔAVo2 was unchanged, as was skeletal muscle diffusion capacity. CONCLUSIONS: We demonstrated that patients with CTEPH have significant impairment of all steps in the O2 use cascade, resulting in markedly impaired exercise capacity. Pulmonary vascular intervention increased peak Vo2 by partly correcting O2 delivery but had no effect on abnormalities in peripheral O2 extraction. This suggests that current interventions only partially address patients' limitations and that additional therapies may improve functional capacity.

Discontinuous gas exchange in Madagascar hissing cockroaches is not a consequence of hysteresis around a fixed PCO2 threshold.

It has been hypothesised that insects display discontinuous gas-exchange cycles (DGCs) as a result of hysteresis in their ventilatory control, where CO2-sensitive respiratory chemoreceptors respond to changes in haemolymph PCO2 only after some delay. If correct, DGCs would be a manifestation of an unstable feedback loop between chemoreceptors and ventilation, causing PCO2 to oscillate around some fixed threshold value: PCO2 above this ventilatory threshold would stimulate excessive hyperventilation, driving PCO2 below the threshold and causing a subsequent apnoea. This hypothesis was tested by implanting micro-optodes into the haemocoel of Madagascar hissing cockroaches and measuring haemolymph PO2 and PCO2 simultaneously during continuous and discontinuous gas exchange. The mean haemolymph PCO2 of 1.9 kPa measured during continuous gas exchange was assumed to represent the threshold level stimulating ventilation, and this was compared with PCO2 levels recorded during DGCs elicited by decapitation. Cockroaches were also exposed to hypoxic (PO2 10 kPa) and hypercapnic (PCO2 2 kPa) gas mixtures to manipulate haemolymph PO2 and PCO2. Decapitated cockroaches maintained DGCs even when their haemolymph PCO2 was forced above or below the putative ∼2 kPa ventilation threshold, demonstrating that the characteristic oscillation between apnoea and gas exchange is not driven by a lag between changing haemolymph PCO2 and a PCO2 chemoreceptor with a fixed ventilatory threshold. However, it was observed that the gas exchange periods within the DGC were altered to enhance O2 uptake and CO2 release during hypoxia and hypercapnia exposure. This indicates that while respiratory chemoreceptors do modulate ventilatory activity in response to haemolymph gas levels, their role in initiating or terminating the gas exchange periods within the DGC remains unclear.

Hypoxic pulmonary vasoconstriction as a regulator of alveolar-capillary oxygen flux: A computational model of ventilation-perfusion matching.

The relationship between regional variabilities in airflow (ventilation) and blood flow (perfusion) is a critical determinant of gas exchange efficiency in the lungs. Hypoxic pulmonary vasoconstriction is understood to be the primary active regulator of ventilation-perfusion matching, where upstream arterioles constrict to direct blood flow away from areas that have low oxygen supply. However, it is not understood how the integrated action of hypoxic pulmonary vasoconstriction affects oxygen transport at the system level. In this study we develop, and make functional predictions with a multi-scale multi-physics model of ventilation-perfusion matching governed by the mechanism of hypoxic pulmonary vasoconstriction. Our model consists of (a) morphometrically realistic 2D pulmonary vascular networks to the level of large arterioles and venules; (b) a tileable lumped-parameter model of vascular fluid and wall mechanics that accounts for the influence of alveolar pressure; (c) oxygen transport accounting for oxygen bound to hemoglobin and dissolved in plasma; and (d) a novel empirical model of hypoxic pulmonary vasoconstriction. Our model simulations predict that under the artificial test condition of a uniform ventilation distribution (1) hypoxic pulmonary vasoconstriction matches perfusion to ventilation; (2) hypoxic pulmonary vasoconstriction homogenizes regional alveolar-capillary oxygen flux; and (3) hypoxic pulmonary vasoconstriction increases whole-lobe oxygen uptake by improving ventilation-perfusion matching.

Comparison of apnoeic oxygen techniques in term pregnant subjects: a computational modelling study.

BACKGROUND: Hypoxaemia during general anaesthesia can cause harm. Apnoeic oxygenation extends safe apnoea time, reducing risk during airway management. We hypothesised that low-flow nasal oxygenation (LFNO) would extend safe apnoea time similarly to high-flow nasal oxygenation (HFNO), whilst allowing face-mask preoxygenation and rescue. METHODS: A high-fidelity, computational, physiological model was used to examine the progression of hypoxaemia during apnoea in virtual models of pregnant women in and out of labour, with BMI of 24-50 kg m-2. Subjects were preoxygenated with oxygen 100% to reach end-tidal oxygen fraction (FE'O2) of 60%, 70%, 80%, or 90%. When apnoea started, HFNO or LFNO was commenced. To simulate varying degrees of effectiveness of LFNO, periglottic oxygen fraction (FgO2) of 21%, 60%, or 100% was configured. HFNO provided FgO2 100% and oscillating positive pharyngeal pressure. RESULTS: Application of LFNO (FgO2 100%) after optimal preoxygenation (FE'O2 90%) resulted in similar or longer safe apnoea times than HFNO FE'O2 80% in all subjects in labour. For BMI of 24, the time to reach SaO2 90% with LFNO was 25.4 min (FE'O2 90%/FgO2 100%) vs 25.4 min with HFNO (FE'O2 80%). For BMI of 50, the time was 9.9 min with LFNO (FE'O2 90%/FgO2 100%) vs 4.3 min with HFNO (FE'O2 80%). A similar finding was seen in subjects with BMI ≥40 kg m-2 not in labour. CONCLUSIONS: There is likely to be clinical benefit to using LFNO, given that LFNO and HFNO extend safe apnoea time similarly, particularly when BMI ≥40 kg m-2. Additional benefits to LFNO include the facilitation of rescue face-mask ventilation and ability to monitor FE'O2 during preoxygenation.

Blood Flow and Respiratory Gas Exchange in the Human Placenta at Term: A Data Update.

Reliable measurements using modern techniques and consensus in experimental design have enabled the assessment of novel data sets for normal maternal and foetal respiratory physiology at term. These data sets include (a) principal factors affecting placental gas transfer, e.g., maternal blood flow through the intervillous space (IVS) (500 mL/min) and foeto-placental blood flow (480 mL/min), and (b) O2, CO2 and pH levels in the materno-placental and foeto-placental circulation. According to these data, the foetus is adapted to hypoxaemic hypoxia. Despite flat oxygen partial pressure (pO2) gradients between the blood of the IVS and the umbilical arteries of the foetus, adequate O2 delivery to the foetus is maintained by the higher O2 affinity of the foetal blood, high foetal haemoglobin (HbF) concentrations, the Bohr effect, the double-Bohr effect, and high foeto-placental (=umbilical) blood flow. Again, despite flat gradients, adequate CO2 removal from the foetus is maintained by a high diffusion capacity, high foeto-placental blood flow, the Haldane effect, and the double-Haldane effect. Placental respiratory gas exchange is perfusion-limited, rather than diffusion-limited, i.e., O2 uptake depends on O2 delivery.

Enhanced oxygen unloading in two marine percomorph teleosts.

Teleost fishes are diverse and successful, comprising almost half of all extant vertebrate species. It has been suggested that their success as a group is related, in part, to their unique O2 transport system, which includes pH-sensitive hemoglobin, a red blood cell ß-adrenergic Na+/H+ exchanger (RBC ß-NHE) that protects red blood cell pH, and plasma accessible carbonic anhydrase which is absent at the gills but present in some tissues, that short-circuits the ß-NHE to enhance O2 unloading during periods of stress. However, direct support for this has only been examined in a few species of salmonids. Here, we expand the knowledge of this system to two warm-water, highly active marine percomorph fish, cobia (Rachycentron canadum) and mahi-mahi (Coryphaena hippurus). We show evidence for RBC ß-NHE activity in both species, and characterize the Hb-O2 transport system in one of those species, cobia. We found significant RBC swelling following ß-adrenergic stimulation in both species, providing evidence for the presence of a rapid, active RBC ß-NHE in both cobia and mahi-mahi, with a time-course similar to that of salmonids. We generated oxygen equilibrium curves (OECs) for cobia blood and determined the P50, Hill, and Bohr coefficients, and used these data to model the potential for enhanced O2 unloading. We determined that there was potential for up to a 61% increase in O2 unloading associated with RBC ß-NHE short-circuiting, assuming a - 0.2 ∆pHa-v in the blood. Thus, despite phylogenetic and life history differences between cobia and the salmonids, we found few differences between their Hb-O2 transport systems, suggesting conservation of this physiological trait across diverse teleost taxa.

Physoxia Influences Global and Gene-Specific Methylation in Pluripotent Stem Cells.

Pluripotent stem cells (PSC) possess unlimited proliferation, self-renewal, and a differentiation capacity spanning all germ layers. Appropriate culture conditions are important for the maintenance of self-renewal, pluripotency, proliferation, differentiation, and epigenetic states. Oxygen concentrations vary across different human tissues depending on precise cell location and proximity to vascularisation. The bulk of PSC culture-based research is performed in a physiologically hyperoxic, air oxygen (21% O2) environment, with numerous reports now detailing the impact of a physiologic normoxia (physoxia), low oxygen culture in the maintenance of stemness, survival, morphology, proliferation, differentiation potential, and epigenetic profiles. Epigenetic mechanisms affect multiple cellular characteristics including gene expression during development and cell-fate determination in differentiated cells. We hypothesized that epigenetic marks are responsive to a reduced oxygen microenvironment in PSCs and their differentiation progeny. Here, we evaluated the role of physoxia in PSC culture, the regulation of DNA methylation (5mC (5-methylcytosine) and 5hmC (5-hydroxymethylcytosine)), and the expression of regulatory enzyme DNMTs and TETs. Physoxia enhanced the functional profile of PSC including proliferation, metabolic activity, and stemness attributes. PSCs cultured in physoxia revealed the significant downregulation of DNMT3B, DNMT3L, TET1, and TET3 vs. air oxygen, accompanied by significantly reduced 5mC and 5hmC levels. The downregulation of DNMT3B was associated with an increase in its promoter methylation. Coupled with the above, we also noted decreased HIF1A but increased HIF2A expression in physoxia-cultured PSCs versus air oxygen. In conclusion, PSCs display oxygen-sensitive methylation patterns that correlate with the transcriptional and translational regulation of the de novo methylase DNMT3B.

Effects of hypoxia and reoxygenation on gill remodeling, apoptosis, and oxidative stress in hypoxia-tolerant new variety blunt snout bream (Megalobrama amblycephala).

Blunt snout bream plays an important role in freshwater aquaculture in China, but the development of its culture industry has been restricted by increasing hypoxia problem. Through the breeding of wild blunt snout bream populations (F0), a hypoxia-tolerant new variety (F6) was obtained. In this study, the new variety was stressed under low oxygen concentration (2.0 mg·L-1) for 4 and 7 days, the morphological structure of the gill tissue showed a striking change, the interlamellar cell mass (ILCM) volume reduced significantly (P < 0.05), and the lamellar respiratory surface area enlarged significantly (P < 0.05), compared to normoxic controls. After 7 days of oxygen recovery, gill remodeling was completely reversed. Additionally, the TUNEL-positive apoptotic fluorescence signals increased in the gills exposed to hypoxia up to 4 and 7 days; the apoptosis rate also increased significantly (P < 0.05). Under 4 and 7 days of hypoxia stress, the expression of anti-apoptotic gene Bcl-2 in the gills downregulated significantly (P < 0.05), with the significantly (P < 0.05) upregulated expression of pro-apoptotic gene Bad. Furthermore, under hypoxia stress, the activity or content of oxidative stress-related enzymes (superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), and glutathione (GSH)) in gill tissue increased to varying degrees compared to normoxic controls. These results offer a new perspective into the cellular and molecular mechanism of hypoxia-induced gill remodeling in blunt snout bream and a theoretical basis for its hypoxia adaptation mechanism.

Do reactive oxygen species or does oxygen itself confer obligate anaerobiosis? The case of Bacteroides thetaiotaomicron.

Bacteroides thetaiotaomicron was examined to determine whether its obligate anaerobiosis is imposed by endogenous reactive oxygen species or by molecular oxygen itself. Previous analyses established that aerated B. thetaiotaomicron loses some enzyme activities due to a high rate of endogenous superoxide formation. However, the present study establishes that another key step in central metabolism is poisoned by molecular oxygen itself. Pyruvate dissimilation was shown to depend upon two enzymes, pyruvate:formate lyase (PFL) and pyruvate:ferredoxin oxidoreductase (PFOR), that lose activity upon aeration. PFL is a glycyl-radical enzyme whose vulnerability to oxygen is already understood. The rate of PFOR damage was unaffected by the level of superoxide or peroxide, showing that molecular oxygen itself is the culprit. The cell cannot repair PFOR, which amplifies the impact of damage. The rates of PFOR and fumarase inactivation are similar, suggesting that superoxide dismutase is calibrated so the oxygen- and superoxide-sensitive enzymes are equally sensitive to aeration. The physiological purpose of PFL and PFOR is to degrade pyruvate without disrupting the redox balance, and they do so using catalytic mechanisms that are intrinsically vulnerable to oxygen. In this way, the anaerobic excellence and oxygen sensitivity of B. thetaiotaomicron are two sides of the same coin.

Oxygenated versus standard cold perfusion preservation in kidney transplantation (COMPARE): a randomised, double-blind, paired, phase 3 trial.

BACKGROUND: Deceased donor kidneys are preserved in cold hypoxic conditions. Providing oxygen during preservation might improve post-transplant outcomes, particularly for kidneys subjected to greater degrees of preservation injury. This study aimed to investigate whether supplemental oxygen during hypothermic machine perfusion (HMP) could improve the outcome of kidneys donated after circulatory death. METHODS: This randomised, double-blind, paired, phase 3 trial was done in 19 European transplant centres. Kidney pairs from donors aged 50 years or older, donated after circulatory death, were eligible if both kidneys were transplanted into two different recipients. One kidney from each donor was randomly assigned using permuted blocks to oxygenated hypothermic machine perfusion (HMPO2), the other to HMP without oxygenation. Perfusion was maintained from organ retrieval to implantation. The primary outcome was 12-month estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration equation in pairs of donated kidneys in which both transplanted kidneys were functioning at the end of follow-up. Safety outcomes were reported for all transplanted kidneys. Intention-to-treat analyses were done. This trial is registered with the ISRCTN Registry, ISRCTN32967929, and is now closed. FINDINGS: Between March 15, 2015, and April 11, 2017, 197 kidney pairs were randomised with 106 pairs transplanted into eligible recipients. 23 kidney pairs were excluded from the primary analysis because of kidney failure or patient death. Mean eGFR at 12 months was 50·5 mL/min per 1·73 m2 (SD 19·3) in the HMPO2 group versus 46·7 mL/min per 1·73m2 (17·1) in HMP (mean difference 3·7 mL/min per 1·73m2, 95% CI -1·0 to 8·4; p=0·12). Fewer severe complications (Clavien-Dindo grade IIIb or more) were reported in the HMPO2 group (46 of 417, 11%, 95% CI 8% to 14%) than in the HMP group (76 of 474, 16%, 13% to 20%; p=0·032). Graft failure was lower with HMPO2 (three [3%] of 106) compared with HMP (11 [10%] of 106; hazard ratio 0·27, 95% CI 0·07 to 0·95; p=0·028). INTERPRETATION: HMPO2 of kidneys donated after circulatory death is safe and reduces post-transplant complications (grade IIIb or more). The 12-month difference in eGFR between the HMPO2 and HMP groups was not significant when both kidneys from the same donor were still functioning 1-year post-transplant, but potential beneficial effects of HMPO2 were suggested by analysis of secondary outcomes. FUNDING: European Commission 7th Framework Programme.

HYPOXIA AND REPRODUCTIVE HEALTH: Hypoxic regulation of preimplantation embryos: lessons from human embryonic stem cells.

Development of the preimplantation embryo is reliant on nutrients present in the milieu of the reproductive tract. While carbohydrates, amino acids, lipids, and micronutrients are often considered when discussing preimplantation embryo nutrition, environmental oxygen is frequently overlooked. Although oxygen is not classically considered a nutrient, it is an important component of the in vitro culture environment and a critical regulator of cellular physiology. Oxygen is required to sustain an oxidative metabolism but when oxygen becomes limited, cells mount a physiological response driven by a family of transcription factors termed 'hypoxia inducible factors' which promote expression of a multitude of oxygen sensitive genes. It is this hypoxic response that is responsible not only for the switch to a glycolytic metabolism but also for a plethora of other cellular responses. There has been much debate in recent years over which environmental oxygen tension is preferential for the culture of preimplantation embryos. The review will evaluate this question and highlights how research using human embryonic stem cells can inform our understanding of why culturing under physiological oxygen tensions may be beneficial for the development of embryos generated through clinical in vitro fertilisation.

HYPOXIA AND REPRODUCTIVE HEALTH: Hypoxia and ovarian function: follicle development, ovulation, oocyte maturation.

The ovarian follicle provides the oocyte with the ideal environment for growth and development in preparation for ovulation and fertilisation. The follicle undergoes many structural changes as it grows, including changes in vasculature, cell proliferation and differentiation and the formation of a fluid-filled antrum. These changes collectively create a low oxygen environment within the follicle. Thus, the oocyte itself develops in a potentially hypoxic environment. The survival of hypoxic tissues is controlled by hypoxia-inducible factors (HIFs) that are activated in a low oxygen state. The understanding of HIF pathways is growing across all fields of biology, and its role in ovarian development is steadily gaining clarity. One of the genes upregulated by HIF is a vascular endothelial growth factor, the main inducer of angiogenesis which is required for follicle development and corpus formation. Ovulation is also intrinsically linked to HIF activity through the ovulatory luteinising hormone surge increasing HIF expression. The role for HIF in oocyte maturation is less understood, as efforts to replicate the low oxygen environment of the in vivo follicle are not achievable by culturing in low oxygen alone. There is potential for other factors present in vivo, but lost in vitro, to be involved in oxygen regulation. One factor of interest is haemoglobin, the oxygen-binding protein, which brings the exciting possibility of sensitive oxygen regulation, consequently affecting HIF-regulated gene expression. A thorough understanding of oxygen regulation within the follicle would provide vital applications for the field of assisted reproductive technologies, in particular in vitro oocyte maturation.

HYPOXIA AND REPRODUCTIVE HEALTH: Oxygen and development of the human placenta.

Development of the human placenta takes place in contrasting oxygen concentrations at different stages of gestation, from ~20 mmHg during the first trimester rising to ~60 mmHg at the start of the second trimester before gradually declining to ~40 mmHg at term. In view of these changes, the early placenta has been described as 'hypoxic'. However, placental metabolism is heavily glycolytic, supported by the rich supply of glucose from the endometrial glands, and there is no evidence of energy compromise. On the contrary, the trophoblast is highly proliferative, with the physiological low-oxygen environment promoting maintenance of stemness in progenitor populations. These conditions favour the formation of the cytotrophoblastic shell that encapsulates the conceptus and interfaces with the endometrium. Extravillous trophoblast cells on the outer surface of the shell undergo an epithelial-mesenchymal transition and acquire invasive potential. Experimental evidence suggests that these changes may be mediated by the higher oxygen concentration present within the placental bed. Interpreting in vitro data is often difficult, however, due to the use of non-physiological oxygen concentrations and trophoblast-like cell lines or explant models. Trophoblast is more vulnerable to hyperoxia or fluctuating levels of oxygen than to hypoxia, and some degree of placental oxidative stress likely occurs in all pregnancies towards term. In complications of pregnancy, such as early-onset pre-eclampsia, malperfusion generates high levels of oxidative stress, causing release of factors that precipitate the maternal syndrome. Further experiments are required using genuine trophoblast progenitor cells and physiological concentrations to fully elucidate the pathways by which oxygen regulates placental development.

Protective effects of rapamycin on the retinal vascular bed during the vaso-obliteration phase in mouse oxygen-induced retinopathy model.

Retinopathy of prematurity (ROP) is a vision-threatening disorder characterized with retinal vaso-obliteration in phase 1 and pathological neovascularization (NV) in phase 2. However, there has been no effective and safe treatment for ROP. Current management is mainly focused on the reduction of abnormal NV in phase 2, and anti-vascular endothelial growth factor (VEGF) therapy is the first-line treatment, yet, with great risks of late recurrence and systemic side effects. It has been reported that the severity of vaso-obliteration in phase 1 largely influences subsequent NV, suggesting that it may be a promising target to develop novel treatments for ROP. Here, we investigated the therapeutic potential and safety of early rapamycin intervention in treating phase 1 ROP and possible underlying mechanisms using the mouse model of oxygen-induced retinopathy (OIR). We found that intravitreal injection of rapamycin at postnatal day 7 (P7) significantly reduced retinal avascular area, increased vascular density, and reversed the suppression of deep capillaries development in phase 1 of OIR mice. Rapamycin treatment not only reduced vascular apoptosis, but also promoted proliferation and tip cell functions. Additionally, rapamycin did not interfere with normal retinal vascular development. Further investigation showed that Ang1/Tie2 pathway might be involved in rapamycin's vascular protection in phase 1 OIR retinas. Moreover, early rapamycin treatment at P7 had long-term protective effects of reducing retinal NV and avascular area, as well as enhancing vascular maturity in phase 2 of OIR mice. Together, our data suggest that rapamycin may be a safe and promising strategy for early intervention of ROP.

Monitoring and modifying brain oxygenation in patients at risk of hypoxic ischaemic brain injury after cardiac arrest.

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2021. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2021 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from https://link.springer.com/bookseries/8901 .

Archaeorhynchus preserving significant soft tissue including probable fossilized lungs.

We describe a specimen of the basal ornithuromorph Archaeorhynchus spathula from the Lower Cretaceous Jiufotang Formation with extensive soft tissue preservation. Although it is the fifth specimen to be described, unlike the others it preserves significant traces of the plumage, revealing a pintail morphology previously unrecognized among Mesozoic birds, but common in extant neornithines. In addition, this specimen preserves the probable remnants of the paired lungs, an identification supported by topographical and macro- and microscopic anatomical observations. The preserved morphology reveals a lung very similar to that of living birds. It indicates that pulmonary specializations such as exceedingly subdivided parenchyma that allow birds to achieve the oxygen acquisition capacity necessary to support powered flight were present in ornithuromorph birds 120 Mya. Among extant air breathing vertebrates, birds have structurally the most complex and functionally the most efficient respiratory system, which facilitates their highly energetically demanding form of locomotion, even in extremely oxygen-poor environments. Archaeorhynchus is commonly resolved as the most basal known ornithuromorph bird, capturing a stage of avian evolution in which skeletal indicators of respiration remain primitive yet the lung microstructure appears modern. This adds to growing evidence that many physiological modifications of soft tissue systems (e.g., digestive system and respiratory system) that characterize living birds and are key to their current success may have preceded the evolution of obvious skeletal adaptations traditionally tracked through the fossil record.