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In contrast to Andean natives, high-altitude Tibetans present with a lower hemoglobin concentration that correlates with reproductive success and exercise capacity. Decades of physiological and genomic research have assumed that the lower hemoglobin concentration in Himalayan natives results from a blunted erythropoietic response to hypoxia (i.e., no increase in total hemoglobin mass). In contrast, herein we test the hypothesis that the lower hemoglobin concentration is the result of greater plasma volume, rather than an absence of increased hemoglobin production. We assessed hemoglobin mass, plasma volume and blood volume in lowlanders at sea level, lowlanders acclimatized to high altitude, Himalayan Sherpa, and Andean Quechua, and explored the functional relevance of volumetric hematological measures to exercise capacity. Hemoglobin mass was highest in Andeans, but also was elevated in Sherpa compared with lowlanders. Sherpa demonstrated a larger plasma volume than Andeans, resulting in a comparable total blood volume at a lower hemoglobin concentration. Hemoglobin mass was positively related to exercise capacity in lowlanders at sea level and in Sherpa at high altitude, but not in Andean natives. Collectively, our findings demonstrate a unique adaptation in Sherpa that reorientates attention away from hemoglobin concentration and toward a paradigm where hemoglobin mass and plasma volume may represent phenotypes with adaptive significance at high altitude.

Monge’s disease (chronic mountain sickness (CMS)) is a maladaptive condition caused by chronic (years) exposure to high-altitude hypoxia. One of the defining features of CMS is excessive erythrocytosis with extremely high hematocrit levels. In the Andean population, CMS prevalence is vastly different between males and females, being rare in females. Furthermore, there is a sharp increase in CMS incidence in females after menopause. In this study, we assessed the role of sex hormones (testosterone, progesterone, and estrogen) in CMS and non-CMS cells using a well-characterized in vitro erythroid platform. While we found that there was a mild (nonsignificant) increase in RBC production with testosterone, we observed that estrogen, in physiologic concentrations, reduced sharply CD235a + cells (glycophorin A; a marker of RBC), from 56% in the untreated CMS cells to 10% in the treated CMS cells, in a stage-specific and dose-responsive manner. At the molecular level, we determined that estrogen has a direct effect on GATA1, remarkably decreasing the messenger RNA (mRNA) and protein levels of GATA1 ( p  < 0.01) and its target genes ( Alas2 , BclxL , and Epor , p  < 0.001). These changes result in a significant increase in apoptosis of erythroid cells. We also demonstrate that estrogen regulates erythropoiesis in CMS patients through estrogen beta signaling and that its inhibition can diminish the effects of estrogen by significantly increasing HIF1, VEGF, and GATA1 mRNA levels. Taken altogether, our results indicate that estrogen has a major impact on the regulation of erythropoiesis, particularly under chronic hypoxic conditions, and has the potential to treat blood diseases, such as high altitude severe erythrocytosis. Chronic mountain sickness: Female hormone provides protection The hormone estrogen protects against chronic mountain sickness (CMS) in pre-menopausal women and may prove valuable in treating the condition. People who live for years in high altitude mountain regions are susceptible to CMS because of prolonged oxygen deprivation. One factor in CMS is an over-production of red blood cells, thickening the blood and increasing the risk of strokes and cardiovascular diseases. Men are more likely to suffer CMS than women, although cases spike in females after menopause. Gabriel Haddad at the University of California in San Diego, USA, and co-workers used a cell culture model of CMS to demonstrate that estrogen provides protection against the disease. Estrogen significantly alters the expression and activity of red blood cell-related genes to regulate red blood cell levels by controlling cell death mechanisms.

Excessive erythrocytosis (EE) is a major hallmark of patients suffering from chronic mountain sickness (CMS, also known as Monge's disease) and is responsible for major morbidity and even mortality in early adulthood. We took advantage of unique populations, one living at high altitude (Peru) showing EE, with another population, at the same altitude and region, showing no evidence of EE (non-CMS). Through RNA-Seq, we identified and validated the function of a group of long noncoding RNAs (lncRNAs) that regulate erythropoiesis in Monge's disease, but not in the non-CMS population. Among these lncRNAs is hypoxia induced kinase-mediated erythropoietic regulator (HIKER)/LINC02228, which we showed plays a critical role in erythropoiesis in CMS cells. Under hypoxia, HIKER modulated CSNK2B (the regulatory subunit of casein kinase 2). A downregulation of HIKER downregulated CSNK2B, remarkably reducing erythropoiesis; furthermore, an upregulation of CSNK2B on the background of HIKER downregulation rescued erythropoiesis defects. Pharmacologic inhibition of CSNK2B drastically reduced erythroid colonies, and knockdown of CSNK2B in zebrafish led to a defect in hemoglobinization. We conclude that HIKER regulates erythropoiesis in Monge's disease and acts through at least one specific target, CSNK2B, a casein kinase.

Despite aerobic activity requiring up to tenfold increases in air intake, human populations in high-altitude hypoxic environments can sustain high levels of endurance physical activity. While these populations generally have relatively larger chest and lung volumes, how thoracic motions actively increase ventilation is unknown. Here we show that rib movements, in conjunction with chest shape, contribute to ventilation by assessing how adulthood acclimatization, developmental adaptation, and population-level adaptation to high-altitude affect sustained aerobic activity. We measured tidal volume, heart rate, and rib-motion during walking and running in lowland individuals from Boston (~ 35 m) and in Quechua populations born and living at sea-level (~ 150 m) and at high altitude (> 4000 m) in Peru. We found that Quechua participants, regardless of birth or testing altitudes, increase thoracic volume 2.0–2.2 times more than lowland participants (p < 0.05). Further, Quechua individuals from hypoxic environments have deeper chests resulting in 1.3 times greater increases in thoracic ventilation compared to age-matched, sea-level Quechua (p < 0.05). Thus, increased thoracic ventilation derives from a combination of acclimatization, developmental adaptation, and population-level adaptation to aerobic demand in different oxygen environments, demonstrating that ventilatory demand due to environment and activity has helped shape the form and function of the human thorax.

At high altitude Andean region, hypoxia-induced excessive erythrocytosis (EE) is the defining feature of Monge’s disease or chronic mountain sickness (CMS). At the same altitude, resides a population that has developed adaptive mechanism(s) to constrain this hypoxic response (non-CMS). In this study, we utilized an in vitro induced pluripotent stem cell model system to study both populations using genomic and molecular approaches. Our whole genome analysis of the two groups identified differential SNPs between the CMS and non-CMS subjects in the ARID1B region. Under hypoxia, the expression levels of ARID1B significantly increased in the non-CMS cells but decreased in the CMS cells. At the molecular level, ARID1B knockdown (KD) in non-CMS cells increased the levels of the transcriptional regulator GATA1 by 3-fold and RBC levels by 100-fold under hypoxia. ARID1B KD in non-CMS cells led to increased proliferation and EPO sensitivity by lowering p53 levels and decreasing apoptosis through GATA1 mediation. Interestingly, under hypoxia ARID1B showed an epigenetic role, altering the chromatin states of erythroid genes. Indeed, combined Real-time PCR and ATAC-Seq results showed that ARID1B modulates the expression of GATA1 and p53 and chromatin accessibility at GATA1 / p53 target genes. We conclude that ARID1B is a novel erythroid regulator under hypoxia that controls various aspects of erythropoiesis in high-altitude dwellers. Red blood cell: Regulating production under low oxygen conditions Insights into a disorder associated with excess red blood cell production in high-altitude dwellers could have broader relevance to certain cancers and blood diseases. Some people living in the Andes will eventually develop Monge’s disease, in which excessive red cell proliferation induced by low oxygen conditions leads to thickening of the blood and increased risk of heart attack or stroke. Researchers led by Gabriel Haddad of the University of California, San Diego, USA, have shown that a protein called ARID1B normally manages red blood cell levels under low oxygen conditions by regulating other genes that govern cell proliferation and survival. These same ARID1B-modulated gene networks may also contribute to various blood disorders as well as the uncontrolled growth seen in some tumor types in which cells must thrive in very oxygen-poor environments.

Millions of people visit high-altitude regions annually and more than 80 million live permanently above 2,500 m. Acute high-altitude exposure can trigger high-altitude illnesses (HAIs), including acute mountain sickness (AMS), high-altitude cerebral oedema (HACE) and high-altitude pulmonary oedema (HAPE). Chronic mountain sickness (CMS) can affect high-altitude resident populations worldwide. The prevalence of acute HAIs varies according to acclimatization status, rate of ascent and individual susceptibility. AMS, characterized by headache, nausea, dizziness and fatigue, is usually benign and self-limiting, and has been linked to hypoxia-induced cerebral blood volume increases, inflammation and related trigeminovascular system activation. Disruption of the blood–brain barrier leads to HACE, characterized by altered mental status and ataxia, and increased pulmonary capillary pressure, and related stress failure induces HAPE, characterized by dyspnoea, cough and exercise intolerance. Both conditions are progressive and life-threatening, requiring immediate medical intervention. Treatment includes supplemental oxygen and descent with appropriate pharmacological therapy. Preventive measures include slow ascent, pre-acclimatization and, in some instances, medications. CMS is characterized by excessive erythrocytosis and related clinical symptoms. In severe CMS, temporary or permanent relocation to low altitude is recommended. Future research should focus on more objective diagnostic tools to enable prompt treatment, improved identification of individual susceptibilities and effective acclimatization and prevention options. Acute or chronic exposure to elevations above 2,500 m can lead to altitude illnesses, including acute mountain sickness, high-altitude cerebral or pulmonary oedema, and chronic mountain sickness. In this Primer, Gatterer et al. summarize the epidemiology and pathophysiology of these disorders, discuss diagnosis, prevention and treatment, and highlight areas for future research.

Monge's disease, or Chronic Mountain Sickness (CMS), is a chronic high-altitude disorder characterized by hypoxia-induced excessive erythrocytosis (EE), elevating the risk of stroke and myocardial infarction. Using RNA-seq and ATAC-seq, we profiled iPSC-derived erythroid cells from CMS and non-CMS subjects under normoxia and hypoxia to identify statistically significant, disease-associated transcriptional and chromatin accessibility changes. RNA-seq revealed induction of inflammatory, stress, and erythropoiesis programs in CMS even under normoxia, including robust activation of JAK/STAT signaling, upregulation of heme metabolism and VEGF, and accelerated erythrocyte lineage commitment alongside repression of Notch and WNT/β-catenin. Hypoxia amplified this dysregulated state, and critically, activated NFκB-driven inflammatory signaling together with canonical HIF targets. ATAC-seq revealed pronounced hypoxia-induced changes, with increased accessibility within inflammatory and erythrocyte lineage genes occurring concomitantly with decreased accessibility within pluripotency and ectodermal lineage genes. Pharmacological NFκB inhibition in CMS cells significantly reduced EE ( -value <0.0001), whereas NFκB activation in non-CMS cells was sufficient to drive EE ( -value <0.01), confirming the causal role inferred by our multiomics analyses. Collectively, our multiomics and functional experiments substantiate a coordinated chromatin-transcription paradigm favoring an inflammatory axis that, through hypoxia-driven NFκB activation, accelerates stress-induced erythroid commitment and underlies EE in CMS.

Carbonic anhydrases (CAs) are fundamental and ubiquitous enzymes that catalyse the reversible hydration of CO2 to form HCO3- and H+ ions. Evidence derived from heterologous expression systems has led to the proposal of a novel role for CA in intracellular pH regulation, where its physical and functional coupling to membrane H+ -equivalent transport proteins appears to enhance their activity. It has yet to be established whether such a functional association occurs naturally in wild-type cells. Additional evidence on CA activity in-vitro, has also suggested that certain CA isoforms are regulated by physiological changes of pH, an effect that may then affect their ability to enhance H+ -equivalent transport. No information, however, exists on the pH sensitivity of CA in intact cells. Finally, pharmacological inhibition of CA activity has been reported previously for various compounds, in addition to those designed specifically as CA inhibitors. It is possible that some compounds, currently used to inhibit membrane H+ transport, may also target CA. The present work has examined functional aspects of CA activity in ventricular myocytes isolated enzymically from rat heart, focusing on the potential role of C A in controlling sarcolemmal Na+/H+ exchange (NHE) and sarcolemmal Na+-HCO3- cotransport (NEC). NHE and NEC activity were estimated from the rate of recovery of intracellular pH (pHi), following an intracellular acid load in myocytes loaded with carboxy-SNARF-1 (a pH-sensitive fluorescent dye, used to measure pHi)). In other experiments, in-vitro CA activity was assessed from the time-course of pH change after addition of CO2-saturated water to a buffered solution containing either CA II or a cardiac homogenate. In further experiments, intracellular CA activity was assessed from the rate of CO2-induced fall of pHi. Three major results emerged, (i) In intact myocytes, CA activity doubles acid extrusion on sarcolemmal NBC, but has no effect on NHE activity. Facilitation of NBC activity by CA is likely to be mediated by an intracellular CA isoform. (ii) In-vitro and intracellular CA activity displays strong pH-dependence within the physiological pH range, activity declining with a fall of pH. (iii) The NHE inhibitor, cariporide, the bicarbonate transport inhibitors DIDS (4,4'- diisothiocyanatostilbene-2,2'-disulphonic acid) and S0859 (an experimental compound from Sanofi-Aventis), and the aquaporin blocker, pCMBS (p-chloromercuribenzene sulphonate), all showed strong inhibitory activity towards CA in-vitro, but had no effect on intracellular CA activity. Overall, the work provides the first clear demonstration of a functional role of CA activity in H+-equivalent transport in a wild-type cell. CA thus represents an important regulatory mechanism of H+ -equivalent transport. The pH sensitivity displayed by in-vitro and intracellular CA activity may also have significant functional consequences for pHi regulation. CA inhibition by various membrane transport inhibitors highlights the need for careful drug and experimental design, to avoid secondary inhibition of CA activity and its side-effects. The present work thus provides insight into the functional roles of CA, plus important new information on the enzyme's pharmacological properties.

Damage caused by wildlife foraging can lead to significant agricultural losses and the problem can be further complicated if the damage-inducing animal is a valuable resource in its own right. Provision of alternative food sources such as cover crops might be a means of reducing the damage which appears to be linked to scarcity of alternative foods in intensively-managed agroecosystems. Cover crops may provide other benefits to agroecosystems, i.e. preventing soil erosion but can potentially have some undesired consequences, i.e. water competition with the cash crop. In our study, we tested the effectiveness of cover crops in reducing the damage caused by foraging European rabbit Oryctolagus cuniculus to vineyards in a semi-arid agroecosystem in southern Spain. Experimental treatments consisted of a combination of the presence/absence of sown cover crops (70% oat Avena sativa and 30% garden vetch Vicia sativa) with/without rabbit exclusion. In the 2009 growing season, we assessed rabbit-induced damage using a browsing index on vine shoots, rabbit use of plots was estimated based on faecal pellet counts and grapevine yield was measured at harvest. Rabbits ate the cover crops, and rabbit use was highest in the plots sown with the oat and vetch cover crop. However, the effect of the presence of the cover crop on the amount of damage caused by rabbits was limited and, moreover, the presence of the cover crop had a negative effect on grapevine yield. Exclosure fences effectively reduced rabbit damage by keeping rabbit densities close to zero, but even a low rabbit number (∼ 1 rabbit/ha) can cause significant damage. Although cover crops provided rabbits with an alternative food source, they acted as attractants for rabbits and were not effective in reducing the damage caused to vineyards by higher rabbit numbers. Therefore, adding cover crops might not be an effective measure in controlling rabbit-induced damage in semi-arid wine-growing regions.