Indigenous Tibetan people have lived on the Tibetan Plateau for millennia. There is a long-standing question about the genetic basis of high-altitude adaptation in Tibetans. We conduct a genome-wide study of 7.3 million genotyped and imputed SNPs of 3,008 Tibetans and 7,287 non-Tibetan individuals of Eastern Asian ancestry. Using this large dataset, we detect signals of high-altitude adaptation at nine genomic loci, of which seven are unique. The alleles under natural selection at two of these loci [methylenetetrahydrofolate reductase (MTHFR) and EPAS1] are strongly associated with blood-related phenotypes, such as hemoglobin, homocysteine, and folate in Tibetans. The folate-increasing allele of rs1801133 at the MTHFR locus has an increased frequency in Tibetans more than expected under a drift model, which is probably a consequence of adaptation to high UV radiation. These findings provide important insights into understanding the genomic consequences of high-altitude adaptation in Tibetans.high-altitude adaptation | Tibetans | genome-wide association study | mixed linear model | polygenic selection G enetic adaptation to a novel environment is a fundamental process for the survival and adaptation of a species. In humans, one of the most recent examples is adaptation to high altitude, such as the Tibetan highlands. The Tibetan Plateau (TP; also known as the Qinghai-Tibet Plateau in China) has an average elevation of ∼4,000 m above sea level, where the oxygen concentration is ∼40% lower (1) and UV radiation is ∼30% stronger (2) than at sea level. The indigenous Tibetan people have developed a distinctive set of physiological characteristics to adapt to the extreme environmental conditions in the highlands (1). Previous population-based genetic studies have reported evidence that genetic variants at the EPAS1 and EGLN1 loci have been under positive natural selection (3-7). These genetic variants are associated with phenotypic variation of hemoglobin concentration (HGB) in Tibetans (3-5). The EPAS1 gene, which encodes the hypoxia inducible factor-2α (HIF-2α) subunit of HIF complex, is a transcription factor involved in body response to hypoxia (8, 9). EGLN1 encodes PHD2, which is a major oxygen-dependent negative regulator of HIFs (10, 11). Apart from these two known genes that have biological relevance to hypoxia adaptation (3-7, 12), several other candidate gene loci (e.g., PPARA and HBB) have been highlighted in recent studies (3,4,(13)(14)(15). Genetic adaptation to high altitude, however, is likely to be a complex process, with a large number of genes involved in response to not only hypoxia but also, other extreme environmental conditions, such as low temperature, high UV radiation, and insufficient food supply. If the strength of natural selection at these gene loci has been small to moderate, these loci would not be detected in previous studies (3-7) of small sample size (typically n < 150). In this study, we perform a largescale genome-wide study to detect genetic signals of high-altitude adaptation in 3...
The global tuberculosis crisis urgently demands new, efficacious, orally available drugs with the potential to shorten and simplify the long and complex treatments for drug-sensitive and drug-resistant disease. Clofazimine, a riminophenazine used for many years to treat leprosy, demonstrates efficacy in animal models of tuberculosis via a novel mode of action. However, clofazimine's physicochemical and pharmacokinetic properties contribute to side effects that limit its use; in particular, an extremely long half-life and propensity for tissue accumulation together with clofazimine's dye properties leads to unwelcome skin discoloration. We recently conducted a systematic structure-activity study of more than 500 riminophenazine analogs for antiMycobacterium tuberculosis activity. We describe here the characteristics of 12 prioritized compounds in more detail. The new riminophenazine analogs demonstrated enhanced in vitro activity compared to clofazimine against replicating M. tuberculosis H37Rv, as well as panels of drug-sensitive and drug-resistant clinical isolates. The new compounds demonstrate at least equivalent activity compared to clofazimine against intracellular M. tuberculosis and, in addition, most of them were active against nonreplicating M. tuberculosis. Eleven of these more water-soluble riminophenazine analogs possess shorter half-lives than clofazimine when dosed orally to mice, suggesting that they may accumulate less. Most importantly, the nine compounds that progressed to efficacy testing demonstrated inhibition of bacterial growth in the lungs that is superior to the activity of an equivalent dose of clofazimine when administered orally for 20 days in a murine model of acute tuberculosis. The efficacy of these compounds, along with their decreased potential for accumulation and therefore perhaps also for tissue discoloration, warrants further study. Despite global efforts, tuberculosis (TB) remains responsible for the second greatest number of deaths due to an infectious disease with 1.7 million deaths reported due to TB in 2009 (45). Of particular concern, the increasing prevalence of TB caused by multidrug-resistant (MDR) and extensively drugresistant (XDR) strains of Mycobacterium tuberculosis puts at risk hard-won gains to public health. MDR-TB treatment regimens, where available, comprise multiple expensive drugs with limited efficacy and significant toxicity that must be administered by both oral and parenteral routes for up to 24 months (30). Treatment of drug-sensitive TB is also long and complex, requiring at least 6 months of a four-drug regimen to achieve a stable cure. The first-line TB drugs are poorly tolerated, reducing compliance and increasing the risk of resistance development. New TB drugs that are safe, orally available, have novel modes of action and efficacy sufficient to simplify and shorten the regimen required to cure TB would impact both patients and TB control by providing improved treatment for drug-resistant TB and by providing a faster, more tolerable cure for dr...
Clofazimine (CFZ), a member of the riminophenazine class, has been studied in clinical trials for the treatment of multidrug-resistant tuberculosis (MDR-TB). CFZ has several side effects which can be attributed to its extremely high lipophilicity. A series of novel riminophenazine analogues bearing a C-2 pyridyl substituent was designed and synthesized with the goal of maintaining potent activity against Mycobacterium tuberculosis (M. tuberculosis) while improving upon its safety profile by lowering the lipophilicity. All compounds were evaluated for their in vitro activity and cytotoxicity. The results demonstrated that many new compounds had potent activity against M. tuberculosis with MICs of less than 0.03 μg/mL and low cytotoxicity with IC(50) values greater than 64 μg/mL. Some compounds were tested for in vivo efficacy against MDR-TB in an experimental mouse infection model. Two compounds demonstrated equivalent or better efficacy than CFZ in this model with significantly reduced skin discoloration potential.
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