Functional EPAS1/HIF2A missense variant is associated with hematocrit in Andean highlanders.

Hypoxia-inducible factor pathway genes are linked to adaptation in both human and nonhuman highland species. EPAS1, a notable target of hypoxia adaptation, is associated with relatively lower hemoglobin concentration in Tibetans. We provide evidence for an association between an adaptive EPAS1 variant (rs570553380) and the same phenotype of relatively low hematocrit in Andean highlanders. This Andean-specific missense variant is present at a modest frequency in Andeans and absent in other human populations and vertebrate species except the coelacanth. CRISPR-base-edited human cells with this variant exhibit shifts in hypoxia-regulated gene expression, while metabolomic analyses reveal both genotype and phenotype associations and validation in a lowland population. Although this genocopy of relatively lower hematocrit in Andean highlanders parallels well-replicated findings in Tibetans, it likely involves distinct pathway responses based on a protein-coding versus noncoding variants, respectively. These findings illuminate how unique variants at EPAS1 contribute to the same phenotype in Tibetans and a subset of Andean highlanders despite distinct evolutionary trajectories.

Time Domains of Hypoxia Responses and -Omics Insights.

The ability to respond rapidly to changes in oxygen tension is critical for many forms of life. Challenges to oxygen homeostasis, specifically in the contexts of evolutionary biology and biomedicine, provide important insights into mechanisms of hypoxia adaptation and tolerance. Here we synthesize findings across varying time domains of hypoxia in terms of oxygen delivery, ranging from early animal to modern human evolution and examine the potential impacts of environmental and clinical challenges through emerging multi-omics approaches. We discuss how diverse animal species have adapted to hypoxic environments, how humans vary in their responses to hypoxia (i.e., in the context of high-altitude exposure, cardiopulmonary disease, and sleep apnea), and how findings from each of these fields inform the other and lead to promising new directions in basic and clinical hypoxia research.

Cryo-EM structure of an activated GPCR-G protein complex in lipid nanodiscs.

G-protein-coupled receptors (GPCRs) are the largest superfamily of transmembrane proteins and the targets of over 30% of currently marketed pharmaceuticals. Although several structures have been solved for GPCR-G protein complexes, few are in a lipid membrane environment. Here, we report cryo-EM structures of complexes of neurotensin, neurotensin receptor 1 and Gαi1ß1γ1 in two conformational states, resolved to resolutions of 4.1 and 4.2 Å. The structures, determined in a lipid bilayer without any stabilizing antibodies or nanobodies, reveal an extended network of protein-protein interactions at the GPCR-G protein interface as compared to structures obtained in detergent micelles. The findings show that the lipid membrane modulates the structure and dynamics of complex formation and provide a molecular explanation for the stronger interaction between GPCRs and G proteins in lipid bilayers. We propose an allosteric mechanism for GDP release, providing new insights into the activation of G proteins for downstream signaling.

Antibacterial soap use impacts skin microbial communities in rural Madagascar.

The skin harbors diverse communities of microorganisms, and alterations to these communities can impact the effectiveness of the skin as a barrier to infectious organisms or injury. As the global availability and adoption of antibacterial products increases, it is important to understand how these products affect skin microbial communities of people living in rural areas of developing countries, where risks of infection and injury often differ from urban populations in developed countries. We investigated the effect of antibacterial soap on skin microbial communities in a rural Malagasy population that practices subsistence agriculture in the absence of electricity and running water. We quantified the amount of soap used by each participant and obtained skin swab samples at three time points: prior to soap use, immediately after one week of soap use, and two weeks after soap use was discontinued. Soap use did not significantly impact ecological measures of diversity and richness (alpha diversity). However, the amount of soap used was a predictor of community-level change (beta diversity), with changes persisting for at least two weeks after subjects stopped using soap. Our results indicate that the overall species richness of skin microbial communities may be resistant to short-term use of antibacterial soap in settings characterized by regular contact with the natural environment, yet these communities may undergo shifts in microbial composition. Lifestyle changes associated with the use of antibacterial soap may therefore cause rapid alterations in skin microbial communities, with the potential for effects on skin health.

Environmental influences on the skin microbiome of humans and cattle in rural Madagascar.

BACKGROUND AND OBJECTIVES: The skin harbors a dynamic community of microorganisms, where contact with humans, other animals and the environment can alter microbial communities. Most research on the human skin microbiome features Western populations living in hygienic conditions, yet these populations have vastly different patterns of environmental contact than the majority of people on Earth, including those living in developing countries. METHODOLOGY: We studied skin microbial communities of humans and cattle (zebu) in rural Madagascar to investigate how zebu ownership affects microbial composition of the human skin, and to characterize non-Western human and zebu skin communities more generally. A portion of the 16S rRNA gene was sequenced from samples of zebu backs and human ankles, forearms, hands and armpits. Analyses were conducted in QIIME, R and LEfSe. RESULTS: Human and zebu samples varied in microbial community composition, yet we did not find evidence for a shared microbial signature between an individual and his zebu. Microbial communities differed across human body sites, with ankles reflecting increased diversity and greater similarity to samples from zebu, likely due to extensive shared contact with soil by humans and zebu. CONCLUSIONS AND IMPLICATIONS: Cattle ownership had, at best, weak effects on the human skin microbiome. We suggest that components of human biology and lifestyles override the microbial signature of close contact with zebu, including genetic factors and human-human interaction, irrespective of zebu ownership. Understanding ecological drivers of microbial communities will help determine ways that microbial transfer and community composition change as populations adopt Western lifestyles, and could provide insights into zoonotic disease transmission.

Segmented sleep in a nonelectric, small-scale agricultural society in Madagascar.

OBJECTIVES: We studied sleep in a rural population in Madagascar to (i) characterize sleep in an equatorial small-scale agricultural population without electricity, (ii) assess whether sleep is linked to noise levels in a dense population, and (iii) examine the effects of experimentally introduced artificial light on sleep timing. METHODS: Using actigraphy, sleep-wake patterns were analyzed for both daytime napping and nighttime wakefulness in 21 participants for a sum total of 292 days. Functional linear modeling was used to characterize 24-h time-averaged circadian patterns and to investigate the effect of experimentally introduced mobile field lights on sleep timing. We also obtained the first polysomnography (PSG) recordings of sleep in a traditional population. RESULTS: In every measure of sleep duration and quality, the Malagasy population experienced shorter and lower quality sleep when compared to similarly measured postindustrial values. The population slept for a total of 6.5 h per night and napped during 89% of recorded days. We observed a peak in activity after midnight for both sexes on 49% of nights, consistent with segmented sleep. Access to mobile field lights had no statistical effect on nighttime sleep timing. From PSG, we documented relatively short rapid eye movement (14%), poor sleep efficiency (66%), and high wake after sleep onset (162 min). CONCLUSIONS: Sleep in this population is segmented, similar to the "first" sleep and "second" sleep reported in the historical record. Moreover, although average sleep duration and quality were lower than documented in Western populations, circadian rhythms were more stable across days.