Erythrocytes retain hypoxic adenosine response for faster acclimatization upon re-ascent

Faster acclimatization to high altitude upon re-ascent is seen in humans; however, the molecular basis for this enhanced adaptive response is unknown. We report that in healthy lowlanders, plasma adenosine levels are rapidly induced by initial ascent to high altitude and achieved even higher levels upon re-ascent, a feature that is positively associated with quicker acclimatization. Erythrocyte equilibrative nucleoside transporter 1 (eENT1) levels are reduced in humans at high altitude and in mice under hypoxia. eENT1 deletion allows rapid accumulation of plasma adenosine to counteract hypoxic tissue damage in mice. Adenosine signalling via erythrocyte ADORA2B induces PKA phosphorylation, ubiquitination and proteasomal degradation of eENT1. Reduced eENT1 resulting from initial hypoxia is maintained upon re-ascent in humans or re-exposure to hypoxia in mice and accounts for erythrocyte hypoxic memory and faster acclimatization. Our findings suggest that targeting identified purinergic-signalling network would enhance the hypoxia adenosine response to counteract hypoxia-induced maladaptation

Epithelial maturation and molecular biology of oral HPV

Human papillomavirus (HPV) is widespread and can cause latent infection in basal cells, with low HPV DNA copy-number insufficient for transmission of infection; can cause subclinical infection that is active but without clinical signs; or can cause clinical infection leading to benign, potentially malignant or malignant lesions. The HPV cycle is influenced by the stage of maturation of the infected keratinocytes, and the production of virions is restricted to the post-mitotic suprabasal epithelial cells where all the virus genes are expressed

AltitudeOmics: The Integrative Physiology of Human Acclimatization to Hypobaric Hypoxia and Its Retention upon Reascent

<div><p>An understanding of human responses to hypoxia is important for the health of millions of people worldwide who visit, live, or work in the hypoxic environment encountered at high altitudes. In spite of dozens of studies over the last 100 years, the basic mechanisms controlling acclimatization to hypoxia remain largely unknown. The AltitudeOmics project aimed to bridge this gap. Our goals were 1) to describe a phenotype for successful acclimatization and assess its retention and 2) use these findings as a foundation for companion mechanistic studies. Our approach was to characterize acclimatization by measuring changes in arterial oxygenation and hemoglobin concentration [Hb], acute mountain sickness (AMS), cognitive function, and exercise performance in 21 subjects as they acclimatized to 5260 m over 16 days. We then focused on the retention of acclimatization by having subjects reascend to 5260 m after either 7 (n = 14) or 21 (n = 7) days at 1525 m. At 16 days at 5260 m we observed: 1) increases in arterial oxygenation and [Hb] (compared to acute hypoxia: PaO₂ rose 9±4 mmHg to 45±4 while PaCO₂ dropped a further 6±3 mmHg to 21±3, and [Hb] rose 1.8±0.7 g/dL to 16±2 g/dL; 2) no AMS; 3) improved cognitive function; and 4) improved exercise performance by 8±8% (all changes p<0.01). Upon reascent, we observed retention of arterial oxygenation but not [Hb], protection from AMS, retention of exercise performance, less retention of cognitive function; and noted that some of these effects lasted for 21 days. Taken together, these findings reveal new information about retention of acclimatization, and can be used as a physiological foundation to explore the molecular mechanisms of acclimatization and its retention.</p></div

Neurocognitive Function During Acclimatization and Upon Reascent.

<p>Five tests of cognitive function revealed marked decrements in performance from SL to ALT1, and improvement back to sea level values by ALT16. Code Substitution—Simultaneous and Match to Sample retained levels found at ALT16 on POST7, while Simple Reaction Time-1, Simple Reaction Time-2, and Procedural Reaction Time essentially reflected a loss of during acclimatization upon reascent at POST7. None of the cognitive function tests showed any retention of acclimatization at POST21. (tp  =  throughput  =  mean number of correct responses made within one min). *Significantly different than SL (p<0.01); ^†significantly different vs. ALT1 (p<0.01); ^‡significantly different vs. ALT16 (p<0.01).</p

Timeline for AltitudeOmics Studies.

<p>Each subject completed this study timeline, with n = 14 staying at low altitude for POST7 and n = 7 staying at low altitude for POST21. Subjects flew from the USA to Bolivia aboard commercial aircraft with no recording of barometric pressure during the flight; the profile for travel in the figure is therefore approximate.</p

General Subject Characteristics.

<p>Height (HT); Weight (WT); Body Mass Index (BMI).</p

Arterial Blood Gases and [Hb] During Acclimatization and Upon Reascent.

<p>Resting indices of ventilatory and hematological acclimatization at SL, ALT1, ALT16, and POST7/21 demonstrating acclimatization after 16 days at a constant altitude and the degree of retention in these variables. *Significantly different vs. SL (p<0.01); ^† significantly different than ALT1 (p<0.01); ^‡significantly different than ALT16 (p<0.01).</p