Genetic adaptation of skin pigmentation in highland Tibetans.

Strong ultraviolet (UV) radiation at high altitude imposes a serious selective pressure, which may induce skin pigmentation adaptation of indigenous populations. We conducted skin pigmentation phenotyping and genome-wide analysis of Tibetans in order to understand the underlying mechanism of adaptation to UV radiation. We observe that Tibetans have darker baseline skin color compared with lowland Han Chinese, as well as an improved tanning ability, suggesting a two-level adaptation to boost their melanin production. A genome-wide search for the responsible genes identifies GNPAT showing strong signals of positive selection in Tibetans. An enhancer mutation (rs75356281) located in GNPAT intron 2 is enriched in Tibetans (58%) but rare in other world populations (0 to 18%). The adaptive allele of rs75356281 is associated with darker skin in Tibetans and, under UVB treatment, it displays higher enhancer activities compared with the wild-type allele in in vitro luciferase assays. Transcriptome analyses of gene-edited cells clearly show that with UVB treatment, the adaptive variant of GNPAT promotes melanin synthesis, likely through the interactions of CAT and ACAA1 in peroxisomes with other pigmentation genes, and they act synergistically, leading to an improved tanning ability in Tibetans for UV protection.

Role of metabolic risk factors in the relationship between ambient fine particulate matter and depressive symptoms: Evidence from a longitudinal population study.

BACKGROUND: There is growing evidence indicating a connection between fine particulate matter (PM2.5) and depressive symptoms. Metabolic risk factors are critical determinants of depressive symptoms. However, the mediating role of these factors on the association between PM2.5 and depressive symptoms remains elusive. We aimed to investigate whether and to what extent metabolic risk factors mediated the link between long-term PM2.5 exposure and depressive symptoms. METHODS: This study comprised 7794 individuals aged between 30 and 79 years who participated in two waves of the on-site surveys in the China Multi-Ethnic Cohort. Ambient PM2.5 concentrations were assessed utilizing a random forest method based on satellite data. We employed the Patient Health Questionnaire-9 to assess depressive symptoms at wave 2, and the overall as well as three sub-domain symptom scores (emotional, neurovegetative, and neurocognitive symptoms) were calculated. Three metabolic risk factors, including hypertension, diabetes, and dyslipidemia, were considered. Mediation analyses were conducted to assess the indirect effects of PM2.5 on depressive symptoms through metabolic risk factors. RESULTS: We found a positive association between chronic exposure to ambient PM2.5 and overall depressive symptoms as well as the three sub-domains. In mediation analyses, metabolic risk factors partially mediated the associations of PM2.5 on depressive symptoms. The natural indirect effects (RR, 95% CI) of PM2.5 on overall, emotional, neurovegetative, and neurocognitive symptoms mediated through metabolic risk factors were 1.004(1.001, 1.007), 1.004 (1.001, 1.008), 1.004 (1.001, 1.007), and 1.003(0.999, 1.007), respectively. Larger indirect effects were found in elderly participants (mediated proportion, 29.3%), females (13.3%), and people who did not consume alcohol (19.6%). CONCLUSIONS: Metabolic risk factors may act as mediators in the relationship between chronic PM2.5 exposure and depression. Treatment of metabolic risk factors may be an opportunity to reduce the burden of depression caused by long-term exposure to PM2.5.

Diverse associations between adiposity and blood pressure among 80,000 multi-ethnic Chinese adults.

BACKGROUND: Adiposity is widely recognized as one of the risk factors for high blood pressure (BP) and increasing adiposity is associated with elevated BP. However, which measures of adiposity could be most strongly associated with BP in multi-ethnic population remains uncertain, giving rise to implications that population-based adiposity measures could be necessary. METHODS: 80,000 multi-ethnic adults recruited from 5 provinces across Southwest China during 2018 ~ 2019 were studied. Multiple linear regression was applied to investigate the associations of systolic blood pressure (SBP) with: (1) two measures of general adiposity, body mass index (BMI) and height-adjusted weight; and (2) three measures of central adiposity, waist circumference (WC), hip circumference (HC) and waist hip ratio (WHR). RESULTS: Two distinct population-specific patterns were identified, as "BMI to SBP" and "WC to SBP". 90% of the participants fall into "BMI to SBP" pattern, in which the associations of SBP with BMI were independent of WC, and SBP-WC associations were considerably decreased by adjustment for BMI. And in this pattern, 10 kg/m2 greater BMI was associated with 11.9 mm Hg higher SBP on average. As for the rest population (Han males in Yunnan and Tibetans in Lhasa), they are suited for "WC to SBP" pattern, 10 cm wider WC was associated with 3.4 mm Hg higher SBP. CONCLUSION: Our results indicated that when selecting proper predictors for BP, population-specific adiposity measures are needed, considering ethnicity, sex and residing regions. A better understanding of adiposity and BP may better contribute to the potential clinical practices and developing precision application strategies.

Associations of long-term exposure to particulate matter with gallstone risks in Chinese adults: A large cross-sectional study.

BACKGROUND: Epidemiological evidence regarding the relation of exposure to ambient particulate matter (PM) with gallstone disease (GSD) risk remains lacking. We tested the hypothesis that long-term exposure to PM is related to the development of GSD and that dyslipidemia can mediate the effect of PM-associated GSD formation. METHODS: We extracted related information on the basis of the baseline survey of the China Multi-Ethnic Cohort Study. The exposure levels of PM (PM1, PM2.5, and PM10) were assessed by validated spatiotemporal models. The relation of exposure to ambient PM with GSD risks was analyzed by non-conditional logistic regression models. Additionally, mediation analysis was conducted to assess whether dyslipidemia was related to the relation of PM exposure with GSD risks. RESULTS: A total of 72,893 participants were included. Increased ambient PM exposure was positively associated with a higher GSD risk, with ORs (and 95% CI) of 1.17 (1.06, 1.28), 1.10 (1.05, 1.15), and 1.07 (1.04, 1.10) for every 10 µg/m3 increment in PM1, PM2.5, and PM10, separately. The association was more remarkable in males, drinkers, and central obesity participants. Dyslipidemia significantly mediated the association between PM and GSD, with mediating proportions of 5.37%, 9.13%, and 7.66% in PM1, PM2.5, and PM10, respectively. CONCLUSION: Exposure to PM may relate to the increased risk of GSD in Chinese adults, especially among males, drinkers, and central obesity participants. Dyslipidemia may partially mediate the effect of PM-associated GSD development. Our results might provide epidemiological evidence for the progression of GSD related to PM and give new insights into GSD prevention and screening priorities.

Ambient PM2.5 and its components associated with 10-year atherosclerotic cardiovascular disease risk in Chinese adults.

BACKGROUND: Exposure to particulate matter with aerodynamic diameters less than 2.5 µm (PM2.5) may increase the risk of 10-year atherosclerotic cardiovascular disease (ASCVD) risk. While PM2.5 is comprised of various components, the evidence on the correlation of its components with 10-year ASCVD risk and which component contributes most remains limited. METHODS: Data were derived from the baseline assessments of China Multi-Ethnic Cohort (CMEC). In total, 69,722 individuals aged 35-74 years were included into this study. The annual average concentration of PM2.5 and its components (black carbon, ammonium, nitrate, sulfate, organic matter, soil particles, and sea salt) were estimated by satellite remote sensing and chemical transport models. The ASCVD risk of individuals was calculated by the equations from the China-PAR Project (prediction for ASCVD risk in China). The relationship between single exposure to PM2.5 and its components and predicted 10-year ASCVD risk was assessed using the logistic regression model. The effect of joint exposure was estimated, and the most significant contributor was identified using the weighted quantile sum approach. RESULTS: Totally 69,722 participants were included, of which 95.8 % and 4.2 % had low and high 10-year ASCVD risk, respectively. Per standard deviation increases in the 3-year average concentration of PM2.5 mass (odds ratio [OR] 1.23, 95 % confidence interval [CI]: 1.12-1.35), black carbon (1.21, 1.11-1.33), ammonium (1.21, 1.10-1.32), nitrate (1.25, 1.14-1.38), organic matter (1.29, 1.18-1.42), sulfate (1.17, 1.07-1.28), and soil particles (1.15, 1.04-1.26) were related to high 10-year ASCVD risk. The overall effect (1.19, 1.11-1.28) of the PM2.5 components was positively associated with 10-year ASCVD risk, and organic matter had the most contribution to this relationship. Female participants were more significantly impacted by PM2.5, black carbon, ammonium, nitrate, organic matter, sulfate, and soil particles compared to others. CONCLUSION: Long-term exposure to PM2.5 mass, black carbon, ammonium, nitrate, organic matter, sulfate, and soil particles were positively associated with high 10-year ASCVD risk, while sea salt exhibited a protective effect. Moreover, the organic matter might take primary responsibility for the relationship between PM2.5 and 10-year ASCVD risk. Females were more susceptible to the adverse effect.

Kaempferitrin alleviates LPS-induced septic acute lung injury in mice through downregulating NF-κB pathway.

BACKGROUND: Acute lung injury (ALI) causes severe and uncontrolled pulmonary inflammation and has high morbidity in dying patients. OBJECTIVE: This study aimed to evaluate the potential function of Kaempferitrin (Kae) and uncover its mechanisms in ALI. MATERIAL AND METHODS: We evaluated the role of Kae in ALI through the lipopolysaccharide (LPS)-induced histopathological changes, lung wet/dry (W/D) ratio, total bronchoalveolar lavage fluid (BALF) cells count, pulmonary inflammation, and the levels of interleukin (IL)-6, tumor necrosis factor-α (TNF-α), and IL-1ß. The effect of Kae on NF-κB signaling pathway was discovered through the protein expression levels of transcription factors p65, p-p65, IκBα, and p-IκBα by Western blot analysis. RESULTS: The results showed that Kae could improve lung injury by reducing apoptosis, histopathological changes, and lung W/D ratio; more importantly, Kae enhanced the survival of ALI mice. Moreover, Kae relieved inflammation, as it reduced total BALF cells count, and deceased the levels of TNF-α, IL-6, and IL-1ß in serum. In addition, Western blot analysis data suggested that Kae could decrease the protein expression levels of transcription factors p65, p-p65, IκB-α, and p-IκB-α, which were promoted by LPS. CONCLUSION: The results of this study suggested that Kae could relieve LPS-induced ALI in mice and reduce inflammation and apoptosis through NF-κB pathway.

[Myrislignan Induces Apoptosis in Gastric Cancer Cell Line Through PI3K/AKT Signaling Pathway].

Objective: To investigate the effect of myrislignan (MYR) on the apoptosis of gastric cancer cell line and its relationship with phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. Methods: The gastric cells (SGC-7901) were treated with MYR at different concentrations, i.e., 0, 25, 50, 100, and 200 µmol/L, for 48 h and 72 h and the effect of MYR on the proliferation of SGC-7901 cells was measured by CCK-8 assay. Then, SGC-7901 cells were treated with different concentrations of MYR at 50, 100, and 200 µmol/L for 48 h. Meanwhile, a normal control group and a dimethyl sulfoxide (DMSO) solvent control group (0.1% DMSO) were established. Flow cytometry was used to determine the apoptosis rate of SGC-7901 cells. The protein expression levels of PI3K, AKT, Bcl-2-associated X protein (BAX), cysteine-dependent aspartate-specifc protease-3 (Caspase-3), and Caspase-9 were determined by Western blot. Then, PI3K activator (20 µmol/mL) was used to treat SGC-7901 cells for 48 h in 4 groups, the control group, 0.1% DMSO group, MYR group, and MYR+PI3K activator group, and the effect on MYR's induction of apoptosis and regulation of the protein expression levels of PI3K, AKT, BAX, Caspase-3, and Caspase-9 in SGC-7901 cells. Results: Compared with the control group, MYR at 50, 100 and 200 µmol/L inhibited the proliferation of gastric cancer cells, increased the apoptosis rate, down-regulated the protein expression levels of PI3K and AKT, and up-regulated the protein expression levels of BAX, Caspase-3, and Caspase-9 in a dose-dependent manner ( P<0.05). However, PI3K activator attenuated MYR-induced apoptosis in gastric cancer cells and MYR's regulation of PI3K, AKT, BAX, Caspase-3, and Caspase-9 protein expression ( P<0.05). Conclusion: MYR induces the expression of BAX, Caspase-3, and Caspase-9 proteins by inhibiting the PI3K/AKT signaling pathway, thereby promoting the apoptosis of gastric cancer cells.

Joint exposure to air pollution, ambient temperature and residential greenness and their association with metabolic syndrome (MetS): A large population-based study among Chinese adults.

Previous studies assessing adverse health have traditionally focused on a single environmental exposure, failing to reflect the reality of various exposures present simultaneously. Air pollution, ambient temperature and greenness have been proposed as critical environmental factors associated with metabolic syndrome (MetS). However, evidence exploring their joint relationships with MetS is needed for identifying interactive factors and developing more targeted public health interventions. The baseline data was obtained from China Multi-Ethnic Cohort (CMEC). Environmental data of air pollutants (PM2.5, O3) and NDVI for greenness was calculated from satellites data. Ambient temperature data were obtained from European Center for Medium-Range Weather Forecasts (ECMWF). MetS was classified based on National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) using anthropometric measures and biomarkers. Logistic regression models were utilized to examine the combined relationship of MetS with three-year exposure to air pollutants, temperature and NDVI. Relative excess risk due to interaction (RERI) was calculated to evaluate interaction on an additive scale. We found associations between prevalent MetS and interquartile range (IQR) increases in PM2.5 (OR: 1.38; 95% confidence interval [95% CI]: 1.23, 1.55) and O3 (OR: 1.15; 95% CI: 1.09, 1.22). Additive and multiplicative interactions were observed between air pollutants and temperature exposure. Compared to low-temperature level, the relationship between PM2.5 and MetS attenuated (RERI: 0.22, 95% CI: 0.44, -0.04) at high-temperature level, while the relationship between O3 and MetS enhanced (RERI: 0.05, 95% CI: 0.02, 0.11). At low NDVI 250 m, the association between PM2.5 and MetS was stronger (RERI: 0.13, 95% CI: 0.05, 0.19) with high NDVI 250 m as the reference group. Our findings showed that ambient temperature and residential greenness could affect the relationship between air pollutants and MetS.

The joint effects of physical activity and air pollution on type 2 diabetes in older adults.

BACKGROUND: Older adults with type 2 diabetes are at higher risk of developing common geriatric syndromes and have a lower quality of life. To prevent type 2 diabetes in older adults, it's unclear whether the health benefits of physical activity (PA) will be influenced by the harms caused by increased exposure to air pollution during PA, especially in developing countries with severe air pollution problem. We aimed to investigate the joint effects of PA and long-term exposure to air pollution on the type 2 diabetes in older adults from China. METHODS: This cross-sectional study was based on the China Multi-Ethnic cohort (CMEC) study. The metabolic equivalent of PA was calculated according to the PA scale during the CMEC baseline survey. High resolution air pollution datasets (PM10, PM2.5 and PM1) were collected from open products. The joint effects were assessed by the marginal structural mean model with generalized propensity score. RESULTS: A total of 36,562 participants aged 50 to 79 years were included in the study. The prevalence of type 2 diabetes was 10.88%. The mean (SD) level of PA was 24.93 (18.60) MET-h/d, and the mean (SD) level of PM10, PM2.5, and PM1 were 70.00 (23.32) µg/m3, 40.45 (15.66) µg/m3 and 27.62 (6.51) µg/m3, respectively. With PM10 < 92 µg/m3, PM2.5 < 61 µg/m3, and PM1 < 36 µg/m3, the benefit effects of PA on type 2 diabetes was significantly greater than the harms due to PMs when PA levels were roughly below 80 MET-h/d. With PM10 ≥ 92 µg/m3, PM2.5 ≥ 61 µg/m3, and PM1 ≥ 36 µg/m3, the odds ratio (OR) first decreased and then rose rapidly with confidence intervals progressively greater than 1 and break-even points close to or even below 40 MET-h/d. CONCLUSIONS: Our findings implied that for the prevention of type 2 diabetes in older adults, the PA health benefits outweighed the harms of air pollution except in extreme air pollution situations, and suggested that when the air quality of residence is severe, the PA levels should ideally not exceed 40 MET-h/d.

Associations between long-term exposure to ambient air pollution and renal function in Southwest China: The China Multi-Ethnic Cohort (CMEC) study.

BACKGROUND: Limited studies have examined associations between air pollutants exposure and renal function, especially in China, with the most extensive chronic kidney disease (CKD) disease burden worldwide. OBJECTIVES: This study examines associations between long-term exposure to ambient PM2.5, NO2, CO, O3, SO2 and renal function. METHODS: We included 80,225 participants aged 30-79 years from the baseline data of the China Multi-Ethnic Cohort (CMEC) study. Three-year average concentrations of PM2.5, NO2, CO, O3, and SO2 were estimated using satellite-based spatiotemporal models. Renal function is determined by the estimated glomerular filtration rate (eGFR) using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. After adjusting for covariates, generalized propensity scores (GPS) weighting regression was used to estimate associations between ambient air pollutants and renal function. RESULTS: An increase of 0.1 mg/m3 CO (OR [odds ratio] =1.20 95% CI [confidence interval], 1.05-1.37) was positively associated with CKD. An increase of 1 µg/m3 in SO2 (1.07, 1.00-1.14) concentration was positively associated with CKD. An increase of 10 µg/m3 in PM2.5 (1.17, 0.99-1.38), NO2 (1.12, 0.83-1.51) and O3 (1.10, 0.81-1.50) concentration was not associated with CKD. These effects are stronger in those younger than 65, smoking and with low BMI. CONCLUSIONS: In this study, we found that long-term exposure to ambient CO and SO2 were positively associated with CKD. Gaseous pollutants should also arouse the concern of relevant departments.

Association of long-term exposure to ambient air pollutants with blood lipids in Chinese adults: The China Multi-Ethnic Cohort study.

BACKGROUND: Dyslipidemia is a crucial risk factor for cardiovascular diseases. Previous studies have suggested that air pollution is associated with blood lipids. However, little evidence exists in low- and middle-income regions. We aimed to investigate the association between air pollution and blood lipids in southwestern China. METHODS: We included 67,305 participants aged 30-79 years from the baseline data of the China Multi-Ethnic Cohort (CMEC) study. Three-year average concentrations of particles with diameters ≤1 µm (PM1), particles with diameters ≤ 2.5 µm (PM2.5), particles with diameters ≤ 10 µm (PM10), nitrogen dioxide (NO2), and ozone (O3) were estimated using satellite-based spatiotemporal models. Individual serum lipids, including cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C), were measured. Linear, logistic, and quantile regression models were used to evaluate the association between ambient air pollution and blood lipids. RESULTS: All five air pollutants in our study were associated with lipid levels. Increased air pollution exposure was associated with a high risk of dyslipidemia. Each 10 µg/m3 increase in PM2.5 was associated with 0.92% (95% confidence interval (CI): 0.64%, 1.20%), 2.23% (95% CI: 1.44%, 3.02%), and 3.04% (95% CI: 2.61%, 3.47%) increases in TC, TG, and LDL-C levels, respectively, and a 2.03% (95% CI: 1.69%, 2.37%) decrease in HDL-C levels, and high risks of dyslipidemia (OR = 1.14, 95% CI: 1.10, 1.18). Stronger associations of air pollution with blood lipids were found in participants with high lipid levels than in those with low lipid levels. CONCLUSION: Long-term exposure to air pollutants was associated with blood lipid levels and the risk of dyslipidemia. People with high lipid levels were more susceptible to air pollution. Therefore, air pollution prevention and control may help reduce the incidence of dyslipidemia and the burden of CVDs.

Down-Regulation of EPAS1 Transcription and Genetic Adaptation of Tibetans to High-Altitude Hypoxia.

Tibetans are well adapted to the hypoxic environments at high altitude, yet the molecular mechanism of this adaptation remains elusive. We reported comprehensive genetic and functional analyses of EPAS1, a gene encoding hypoxia inducible factor 2α (HIF-2α) with the strongest signal of selection in previous genome-wide scans of Tibetans. We showed that the Tibetan-enriched EPAS1 variants down-regulate expression in human umbilical endothelial cells and placentas. Heterozygous EPAS1 knockout mice display blunted physiological responses to chronic hypoxia, mirroring the situation in Tibetans. Furthermore, we found that the Tibetan version of EPAS1 is not only associated with the relatively low hemoglobin level as a polycythemia protectant, but also is associated with a low pulmonary vasoconstriction response in Tibetans. We propose that the down-regulation of EPAS1 contributes to the molecular basis of Tibetans' adaption to high-altitude hypoxia.

HMOX2 Functions as a Modifier Gene for High-Altitude Adaptation in Tibetans.

Tibetans are well adapted to high-altitude environments. Among the adaptive traits in Tibetans, the relatively low hemoglobin level is considered a blunted erythropoietic response to hypoxic challenge. Previously, EPAS1 and EGLN1, the major upstream regulators in the hypoxic pathway, were reportedly involved in the hemoglobin regulation in Tibetans. In this study, we report a downstream gene (HMOX2) involved in heme catabolism, which harbors potentially adaptive variants in Tibetans. We first resequenced the entire genomic region (45.6 kb) of HMOX2 in Tibetans, which confirmed the previously suspected signal of positive selection on HMOX2 in Tibetans. Subsequent association analyses of hemoglobin levels in two independent Tibetan populations (a total of 1,250 individuals) showed a male-specific association between the HMOX2 variants and hemoglobin levels. Tibetan males with the derived C allele at rs4786504:T>C displayed lower hemoglobin level as compared with the T allele carriers. Furthermore, our in vitro experiments indicated that the C allele of rs4786504 could increase the expression of HMOX2, presumably leading to a more efficient breakdown of heme that may help maintain a relatively low hemoglobin level at high altitude. Collectively, we propose that HMOX2 contributes to high-altitude adaptation in Tibetans by functioning as a modifier in the regulation of hemoglobin metabolism.

Two a posteriori dietary patterns are associated with risks of hyperuricemia among adults in less-developed multiethnic regions in Southwest China.

Diet is a major determinant of hyperuricemia, but little is known about the association between diet and hyperuricemia in less-developed multiethnic regions (LMERs). This study aimed to assess the hypothesis that dietary patterns (including 2 a-priori and 3 a posteriori dietary patterns) are associated with hyperuricemia in LMERs. The 2 a priori dietary patterns were the Dietary Approaches to Stop Hypertension (DASH) and the alternative Mediterranean diet (aMED). We derived 3 a posteriori dietary patterns from the China Multi-Ethnic Cohort study by principal component factor analysis. Given that those dietary patterns had high geographic discrimination, they were named the Sichuan Basin (economically developed industrial region), Yunnan-Guizhou Plateau (agricultural region), and Qinghai-Tibet Plateau (nomadic region) dietary pattern, respectively. We performed a logistic regression model to investigate associations between dietary patterns and hyperuricemia with potential confounders identified by the directed acyclic graph. Comparing the highest with the lowest quintiles, the Sichuan Basin dietary pattern was positively associated with hyperuricemia, whereas the Yunnan-Guizhou Plateau dietary pattern showed an inverse association with hyperuricemia. For the Qinghai-Tibet Plateau dietary pattern, DASH, or aMED, our results did not show a significant association with hyperuricemia. The results were robust among stratified analyses and different analyzing strategies. The dietary patterns showed great diversity in Southwest China. Both DASH and aMED, which many studies widely recommended, did not show expected beneficial effects on preventing hyperuricemia. However, the plant-based protein dietary pattern in the Yunnan-Guizhou Plateau showed a beneficial association with the risk of hyperuricemia, which can provide insights for dietary guidance in LMERs.

Long-term exposure to ambient PM2.5 and its constituents is associated with MAFLD.

Background & Aims: Existing evidence suggests that long-term exposure to ambient fine particulate pollution (PM2.5) may increase metabolic dysfunction-associated fatty liver disease (MAFLD) risk. However, there is still limited evidence on the association of PM2.5 constituents with MAFLD. Therefore, this study explores the associations between the five main chemical constituents of PM2.5 and MAFLD to provide more explicit information on the liver exposome. Methods: A total of 76,727 participants derived from the China Multi-Ethnic Cohort, a large-scale epidemic survey in southwest China, were included in this study. Multiple linear regression models were used to estimate the pollutant-specific association with MAFLD. Weighted quantile sum regression was used to evaluate the joint effect of the pollutant-mixture on MAFLD and identify which constituents contribute most to it. Results: Three-year exposure to PM2.5 constituents was associated with a higher MAFLD risk and more severe liver fibrosis. Odds ratios for MAFLD were 1.480, 1.426, 1.294, 1.561, 1.618, and 1.368 per standard deviation increase in PM2.5, black carbon, organic matter, ammonium, sulfate, and nitrate, respectively. Joint exposure to the five major chemical constituents was also positively associated with MAFLD (odds ratio 1.490, 95% CI 1.360-1.632). Nitrate contributed most to the joint effect of the pollutant-mixture. Further stratified analyses indicate that males, current smokers, and individuals with a high-fat diet might be more susceptible to ambient PM2.5 exposure than others. Conclusions: Long-term exposure to PM2.5 and its five major chemical constituents may increase the risk of MAFLD. Nitrate might contribute most to MAFLD, which may provide new clues for liver health. Males, current smokers, and participants with high-fat diets were more susceptible to these associations. Impact and implications: This large-scale epidemiologic study explored the associations between constituents of fine particulate pollution (PM2.5) and metabolic dysfunction-associated fatty liver disease (MAFLD), and further revealed which constituents play a more important role in increasing the risk of MAFLD. In contrast to previous studies that examined the effects of PM2.5 as a whole substance, this study carefully explored the health effects of the individual constituents of PM2.5. These findings could (1) help researchers to identify the specific particles responsible for hepatotoxicity, and (2) indicate possible directions for policymakers to efficiently control ambient air pollution, such as targeting the sources of nitrate pollution.

Phylogenetic analysis of clinical strains of Helicobacter pylori isolated from patients with gastric diseases in Tibet.

BACKGROUND: Helicobacter pylori (H. pylori) is a Gram-negative pathogenic bacterium that causes chronic gastritis and other gastric diseases in humans. In Tibet, China, the infection of H. pylori is an important risk factor that caused gastric cancer. METHODS: To understand the characteristics of this pathogen in Tibet, five strains of H. pylori were isolated from three patients' oral cavity or stomach who had either a gastric ulcer or gastritis. We performed genome sequences of these five clinical strains on Illumina Hiseq, and 55,016-63666 SNVs/InDels were identified by comparing to the reference strain of H. pylori 26995. RESULTS: The phylogenetic analysis with multi-locus sequence typing (MLST) showed that five Tibetan strains were defined as hpEurope population and their proteins encoded by the cagA gene also presented a western type. Also, the strains that were isolated from the same patients' oral cavity and stomach exhibited homology in molecular evolution. CONCLUSIONS: This is the first study to investigate the phylogenetic population structure of the epidemic strains of H. pylori in Tibet, which may improve cognition of Tibetan strains and confirm the homology of the strains from oral cavity and stomach.

Correlation between circulating tumor cells and D-D and platelet in patients with pulmonary malignancies.

The aim of the present study was to investigate the correlation between circulating tumor cells (CTC) and D-dimer (D-D) and platelet (PLT) in patients with pulmonary malignancies. A total of 98 patients with lung cancer admitted to West China Hospital, Sichuan University, from June 2016 to February 2017 were enrolled in the present study. D-D and PLT levels were measured in the fasting elbow vein of the patients. The expression of CTC in peripheral blood was detected by negative separation using immunomagnetic beads and immunocytochemical staining. The correlation between CTC and D-D and PLT in patients with lung cancer was analyzed. The mean level of D-D in the peripheral blood of 98 patients was 1.80±1.63 µg/l, and the level of D-D was correlated with distant metastasis (P<0.05). The mean level of PLT in peripheral blood was 305.53±141.22×109/l in 98 patients, and the level of PLT was correlated with patient age, clinical stage and distant metastasis (P<0.05). The levels of D-D, PLT and distant metastasis were significantly higher in CTC-positive than in CTC-negative patients (P<0.05). Therefore, CTC can predict the distant metastasis of lung cancer, and the incidence of distant metastasis is high in patients with hypercoagulable state.

GCH1 plays a role in the high-altitude adaptation of Tibetans.

Tibetans are well adapted to high-altitude hypoxia. Previous genome-wide scans have reported many candidate genes for this adaptation, but only a few have been studied. Here we report on a hypoxia gene ( GCH1, GTP-cyclohydrolase I), involved in maintaining nitric oxide synthetase (NOS) function and normal blood pressure, that harbors many potentially adaptive variants in Tibetans. We resequenced an 80.8 kb fragment covering the entire gene region of GCH1 in 50 unrelated Tibetans. Combined with previously published data, we demonstrated many GCH1 variants showing deep divergence between highlander Tibetans and lowlander Han Chinese. Neutrality tests confirmed a signal of positive Darwinian selection on GCH1 in Tibetans. Moreover, association analysis indicated that the Tibetan version of GCH1 was significantly associated with multiple physiological traits in Tibetans, including blood nitric oxide concentration, blood oxygen saturation, and hemoglobin concentration. Taken together, we propose that GCH1 plays a role in the genetic adaptation of Tibetans to high altitude hypoxia.

EP300 contributes to high-altitude adaptation in Tibetans by regulating nitric oxide production.

The genetic adaptation of Tibetans to high altitude hypoxia likely involves a group of genes in the hypoxic pathway, as suggested by earlier studies. To test the adaptive role of the previously reported candidate gene EP300 (histone acetyltransferase p300), we conducted resequencing of a 108.9 kb gene region of EP300 in 80 unrelated Tibetans. The allele-frequency and haplotype-based neutrality tests detected signals of positive Darwinian selection on EP300 in Tibetans, with a group of variants showing allelic divergence between Tibetans and lowland reference populations, including Han Chinese, Europeans, and Africans. Functional prediction suggested the involvement of multiple EP300 variants in gene expression regulation. More importantly, genetic association tests in 226 Tibetans indicated significant correlation of the adaptive EP300 variants with blood nitric oxide (NO) concentration. Collectively, we propose that EP300 harbors adaptive variants in Tibetans, which might contribute to high-altitude adaptation through regulating NO production.