The hypoxic environment imposes severe selective pressure on species living at high altitude. To understand the genetic bases of adaptation to high altitude in dogs, we performed whole-genome sequencing of 60 dogs including five breeds living at continuous altitudes along the Tibetan Plateau from 800 to 5100 m as well as one European breed. More than 1503 sequencing coverage for each breed provides us with a comprehensive assessment of the genetic polymorphisms of the dogs, including Tibetan Mastiffs. Comparison of the breeds from different altitudes reveals strong signals of population differentiation at the locus of hypoxia-related genes including endothelial Per-Arnt-Sim (PAS) domain protein 1 (EPAS1) and beta hemoglobin cluster. Notably, four novel nonsynonymous mutations specific to high-altitude dogs are identified at EPAS1, one of which occurred at a quite conserved site in the PAS domain. The association testing between EPAS1 genotypes and blood-related phenotypes on additional high-altitude dogs reveals that the homozygous mutation is associated with decreased blood flow resistance, which may help to improve hemorheologic fitness. Interestingly, EPAS1 was also identified as a selective target in Tibetan highlanders, though no amino acid changes were found. Thus, our results not only indicate parallel evolution of humans and dogs in adaptation to high-altitude hypoxia, but also provide a new opportunity to study the role of EPAS1 in the adaptive processes.

Abundant and diverse domestic mammals living on the Tibetan Plateau provide useful materials for investigating adaptive evolution and genetic convergence. Here, we used 327 genomes from horses, sheep, goats, cattle, pigs and dogs living at both high and low altitudes, including 73 genomes generated for this study, to disentangle the genetic mechanisms underlying local adaptation of domestic mammals. Although molecular convergence is comparatively rare at the DNA sequence level, we found convergent signature of positive selection at the gene level, particularly the EPAS1 gene in these Tibetan domestic mammals. We also reported a potential function in response to hypoxia for the gene C10orf67, which underwent positive selection in three of the domestic mammals. Our data provide an insight into adaptive evolution of high-altitude domestic mammals, and should facilitate the search for additional novel genes involved in the hypoxia response pathway.

BackgroundHealth-related quality of life (HRQoL) has been brought up for decades in haemophilia patients. However, no data to date are available about HRQoL in children with haemophilia using long-term follow up data. This nearly 4-year follow-up study aimed to assess the long-term HRQoL of haemophilia children.MethodsA prospective cohort study among 42 children with haemophilia and their parents was conducted in August 2014 in a children’s hospital; follow-up was completed in January 2018. Primary endpoint was the change in patient HRQoL evaluated by Canadian Haemophilia Outcomes–Kids’ Life Assessment Tool (CHO-KLAT) from baseline to year 4; secondary endpoint was the impact of bleeding rates, physical activity restriction, financial burden and treatment (prophylaxis vs on-demand treatment) on HRQoL, as well as the impact of treatment on event-free survival.ResultsTotally 42 patients (mean age, 5.48[SD, 4.63] years) and 42 parents were included. 38 families completed 4-year follow up. Patients reported a small increase in HRQoL from baseline to year 4. The mean scores of child self-report and parent proxy report of CHO-KLAT at baseline were 60.69 (SD = 20.28) and 61.01 (SD = 12.14), respectively. Scores at follow-up were 64.69 (SD = 13.71) and 65.33 (SD = 15.78), respectively. Haemophilia patients without physical activity restriction, living in urban areas, and receiving prophylactic treatment and home injection, had higher average values for HRQoL scores than the others. Bleeding rates were proportionally negatively correlated with HRQoL. Patients who had received prophylactic treatment had better event-free survival.ConclusionsHaemophilia decreased HRQoL of patients, but this effect weakened after 4 years. HRQoL of children is influenced by severity of haemophilia, bleeding rates, physical activity restriction, financial burden and treatment. Prophylactic treatment is a key factor contributing to event-free survivor prognosis and the optimal form of therapy for childhood haemophilia.

Tibetan pigs have survived at high altitude for millennia and they have a suite of adaptive features to tolerate the hypoxic environment. However, the molecular mechanisms underlying the regulation of hypoxia-adaptive phenotypes have not been completely elucidated. In this study, we analyzed differentially expressed genes (DEGs), biological pathways and constructed co-expression regulation networks using whole-transcriptome microarrays from lung tissues of Tibetan and Duroc pigs both at high and low altitude. A total of 3,066 DEGs were identified and this list was over-represented for the ontology terms including metabolic process, catalytic activity, and KEGG pathway including metabolic pathway and PI3K-Akt signaling pathway. The regulatory (RIF) and phenotypic (PIF) impact factor analysis identified several known and several potentially novel regulators of hypoxia adaption, including: IKBKG, KLF6 and RBPJ (RIF1), SF3B1, EFEMP1, HOXB6 and ATF6 (RIF2). These findings provide new details of the regulatory architecture of hypoxia-adaptive genes and also insight into which genes may undergo epigenetic modification for further study in the high-altitude adaptation.

A rapid, selective and sensitive sensor based on the Fe(III) modulated nitrogen-doped graphene quantum dots (N-GQDs) was developed and applied as fluorescence sensor for ascorbic acid (AA) detection. The N-GQDs was one-step synthesized in an easy and green way using citric acid as the carbon source and urea as nitrogen source. The sensor was based on the different quenching effects of Fe(III) and Fe(II) on the fluorescence intensity of N-GQDs. The fluorescence of N-GQDs was quenched by Fe(III) via the strong selective coordination interaction between them. In the presence of AA, Fe(III) can be transformed to Fe(II) ascribed to the oxidation-reduction reaction, leading to the recovery of fluorescence. On the basis of this principle, a fluorescence sensor for AA detection was constructed. Under optimal conditions, the method showed a response to AA within a concentration range of 1.0-90 μmol L(-1) with a good linear relationship and the detection limit for AA was 18 nmol L(-1). The developed sensor was successfully applied for the determination of AA in beverage samples with quantitative recoveries from 95.3 % to 104.3 %.