Drinking tea-type endemic fluorosis is a type of fluorosis caused by the long-term consumption of tea with excessive fluoride content. Due to Xizang’s unique natural environment and special socio-cultural background， this disease is particularly prevalent in the region. Patients with drinking tea-type endemic fluorosis typically exhibit varying degrees of dental fluorosis and skeletal fluorosis， with the severity of the disease influenced by factors such as age， region， and the amount of brick tea consumed by residents. This paper systematically reviews relevant literature， summarizing the prevalence of drinking tea-type endemic fluorosis in Xizang from 1983 to 2020 and disease prevention strategies from 2015 to 2025. It explores the discovery process， geographical distribution characteristics， comparative analysis of different types of fluorosis， differences compared to fluorosis in other regions， and factors influencing the prevalence rate in Xizang. The aim is to provide a scientific basis and reference for further research and control of drinking tea-type endemic fluorosis in Xizang.

The global prevalence of non-alcoholic fatty liver disease (NAFLD) exceeds 32

High altitude-associated pathophysiological processes may potentially accelerate aging trajectory, while evidence remains limited. We present immune landscape characterization in human populations residing at 3656-meter (Lhasa) and 5070-meter (Tuiwacun) elevations on the Qinghai-Tibet Plateau, complemented by multiorgan single-cell RNA sequencing and spatially enhanced resolution omics sequencing (Stereo-seq) of mice under simulated 5000-meter hypoxic conditions. Comparative analysis revealed significantly elevated neutrophil proportions in high-altitude population (HAP) cohorts relative to low-altitude population cohorts. Notably, aging-associated immune cells (AICs) including exhausted T cells, age-associated B cells, and high-aging-score immune cells showed marked enrichment in HAP cohorts, a pattern conserved in mouse models. Stereo-seq analyses further identified coordinated niche interactions between AICs and aging-related intestinal epithelial cells, suggesting accelerated gut aging trajectories. Our work establishes the multiomics framework for high-altitude immune remodeling while providing mechanistic insights into high altitude-associated pathophysiological processes.

To identify genomic regions subject to positive selection that might contain genes involved in high-altitude adaptation (HAA), we performed a genome-wide scan by whole-genome sequencing of Tibetan highlanders and Han lowlanders. We revealed a collection of candidate genes located in 30 genomic loci under positive selection. Among them, MCUR1 at 6p23 was a novel pronounced candidate. By single-cell RNA sequencing and comprehensive functional studies, we demonstrated that MCUR1 depletion leads to impairment of erythropoiesis under hypoxia and normoxia. Mechanistically, MCUR1 knockdown reduced mitochondrial Ca2+ uptake and then concomitantly increased cytosolic Ca2+ levels, which thereby reduced erythropoiesis via the CAMKK2-AMPK-mTOR axis. Further, we revealed rs61644582 at 6p23 as an expression quantitative trait locus for MCUR1 and a functional variant that confers an allele-specific transcriptional regulation of MCUR1. Overall, MCUR1-mediated mitochondrial Ca2+ homeostasis is highlighted as a novel regulator of erythropoiesis, deepening our understanding of the genetic mechanism of HAA.

To identify novel susceptibility genes for hepatocellular carcinoma (HCC), we performed a rare-variant association study in Chinese populations consisting of 2,750 cases and 4,153 controls. We identified four HCC-associated genes, including NRDE2, RANBP17, RTEL1, and STEAP3. Using NRDE2 (index rs199890497 [p.N377I], p = 1.19 × 10-9) as an exemplary candidate, we demonstrated that it promotes homologous recombination (HR) repair and suppresses HCC. Mechanistically, NRDE2 binds to the subunits of casein kinase 2 (CK2) and facilitates the assembly and activity of the CK2 holoenzyme. This NRDE2-mediated enhancement of CK2 activity increases the phosphorylation of MDC1 and then facilitates the HR repair. These functions are eliminated almost completely by the NRDE2-p.N377I variant, which sensitizes the HCC cells to poly(ADP-ribose) polymerase (PARP) inhibitors, especially when combined with chemotherapy. Collectively, our findings highlight the relevance of the rare variants to genetic susceptibility to HCC, which would be helpful for the precise treatment of this malignancy.

Pulmonary Arterial Hypertension(PAH)is a chronic progressive cardiopulmonary disease.The main pathological changes are vasoconstriction and pulmonary artery proliferative remodeling and right ventricular hypertrophy.Further exploration of the pathogenesis of PAH can reveal that its related pathways include vascular proliferation,vascular wall remodeling,oxidative stress,inflammatory response and gene regulation.Although great progress has been made in the treatment of PAH in recent years,the mortality rate is still high,current clinical treatments have not effectively improved the prognosis,and the disease has great impact on the physical,social,work and emotional aspects of patients.This article will review the latest research on the treatment of PAH,aiming to provide new clues for the clinical treatment of PAH.

Supplementary Figure 1. An overview of the study workflow; Supplementary Figure 2. The principal components analyses (PCA) of samples in the discovery stage and reference samples from the 1000 Genomes Project data. Supplementary Figure 3. Manhattan plots of the genome-wide P values from the association tests on HBV-related HCC. Supplementary Figure 4. Quantile-quantile plots of the observed P values from the association tests on HBV-related HCC. Supplementary Figure 5. Forest plots for rs10272859 across all studies. Supplementary Figure 6. Expression levels of CDK14 mRNA were significantly higher in HCC tissues compared with adjacent non-tumor liver tissues. Supplementary Figure 7. The at-risk G allele of rs10272859 was significantly associated with higher mRNA levels of CDK14 in liver tissues based on the TCGA data. Supplementary Figure 8. The SNPs at 7q21.13 interact physically with the promoter region of CDK14 in GM12878 cells. Supplementary Figure 9. Kaplan-Meier estimates of the overall survival time for the HCC patients stratified by CDK14 mRNA expression levels. Supplementary Figure 10. Kaplan-Meier estimates of disease-free survival time for patients with HBV-related HCC stratified by genotypes of rs10272859. Supplementary Table 1. Summary description of the populations used in this study. Supplementary Table 2. Summary of the quality controls in proband-parent trios. Supplementary Table 3. Summary of SNP imputation in the discovery stage. Supplementary Table 4. The amount of SNPs with various P values in TDT for the 189 trios in the discovery stage. Supplementary Table 5. Summary of the SNPs that have been reported significantly associated with HBV-related HCC in previous GWASs. Supplementary Table 6. Summary of SNPs that have been reported to be significantly associated with HBV-related phenotypes in previous GWASs. Supplementary Table 6. Summary of SNPs that have been reported to be significantly associated with HBV-related phenotypes in previous GWASs (Continued). Supplementary Table 7. Summary of the top 15 SNPs in the discovery stage. Supplementary Table 8. Primers and probes used in this study. Supplementary Table 9. Summary of the replication studies for the 14 SNPs newly identified in the discovery stage. Supplementary Table 10. Stratification analyses of rs10272859 by gender and age. Supplementary Table 11. The associations between genotypes of rs10272859 and mRNA levels of nearby genes. Supplementary Table 12. The predicted functional relevance of rs10272859 and the other 74 SNPs in strong linkage disequilibrium with rs10272859 at the ~110 Kb region of 7q21.13. Supplementary Table 13. Details for the genotypes of rs10272859 and the prognosis of patients with HBV-related HCC. Supplementary Table 14. Multivariate analyses of overall survival time and disease-free survival time of patients with HBV-related HCC. Supplementary Table 15. Genotype distribution of rs10272859 across TNM stages in patients with HBV-related HCC. Supplementary Table 16. Powers for various genetic effects and various minor allele frequencies. Supplementary Table 17. The allele and genotype frequencies of rs10272859 in different populations.

在过去三十年中,高血压的负担一直在增加[1].2019年中国心血管病报告显示:我国心血管疾病死亡率占居首位,且呈上升趋势,高血压是心血管疾病死亡的首要危险因素.高血压以体循环高动脉压为特征,影响人体许多系统的慢性疾病,引起不可逆的终末器官损害,是全球过早死亡的主要原因[2].

Cortical and subcortical structural alteration has been extensively reported in schizophrenia, including the unusual expansion of gray matter volumes (GMVs) of basal ganglia (BG), especially putamen. Previous genome-wide association studies pinpointed kinectin 1 gene (KTN1) as the most significant gene regulating the GMV of putamen. In this study, the role of KTN1 variants in risk and pathogenesis of schizophrenia was explored. A dense set of SNPs (n = 849) covering entire KTN1 was analyzed in three independent European- or African-American samples (n = 6704) and one mixed European and Asian Psychiatric Genomics Consortium sample (n = 56,418 cases vs. 78,818 controls), to identify replicable SNP-schizophrenia associations. The regulatory effects of schizophrenia-associated variants on the KTN1 mRNA expression in 16 cortical or subcortical regions in two European cohorts (n = 138 and 210, respectively), the total intracranial volume (ICV) in 46 European cohorts (n = 18,713), the GMVs of seven subcortical structures in 50 European cohorts (n = 38,258), and the surface areas (SA) and thickness (TH) of whole cortex and 34 cortical regions in 50 European cohorts (n = 33,992) and eight non-European cohorts (n = 2944) were carefully explored. We found that across entire KTN1, only 26 SNPs within the same block (r2 > 0.85) were associated with schizophrenia across ≥ 2 independent samples (7.5 × 10–5 ≤ p ≤ 0.048). The schizophrenia-risk alleles, which increased significantly risk for schizophrenia in Europeans (q < 0.05), were all minor alleles (f < 0.5), consistently increased (1) the KTN1 mRNA expression in 12 brain regions significantly (5.9 × 10–12 ≤ p ≤ 0.050; q < 0.05), (2) the ICV significantly (6.1 × 10–4 ≤ p ≤ 0.008; q < 0.05), (3) the SA of whole (9.6 × 10–3 ≤ p ≤ 0.047) and two regional cortices potentially (2.5 × 10–3 ≤ p ≤ 0.042; q > 0.05), and (4) the TH of eight regional cortices potentially (0.006 ≤ p ≤ 0.050; q > 0.05), and consistently decreased (1) the BG GMVs significantly (1.8 × 10–19 ≤ p ≤ 0.050; q < 0.05), especially putamen GMV (1.8 × 10–19 ≤ p ≤ 1.0 × 10–4; q < 0.05, (2) the SA of four regional cortices potentially (0.010 ≤ p ≤ 0.048), and (3) the TH of four regional cortices potentially (0.015 ≤ p ≤ 0.049) in Europeans. We concluded that we identified a significant, functional, and robust risk variant block covering entire KTN1 that might play a critical role in the risk and pathogenesis of schizophrenia.

Background As a chronic mountain sickness(CMS) with the highest incidence and the greatest harm, the pathogenesis of high altitude polycythemia (HAPC) is still not fully understood. Methods 37 HAPC patients and 42 healthy subjects were selected from plateau, and peripheral venous blood samples were collected for transcriptome sequencing on Illumina NovaSeq platform. The sequenced data were analyzed by bioinformatics and phenotypic association analysis. Results The results showed significant differences in multiple clinical indicators including RBC and HGB et al. existed between HAPC and control. Based on the RNA-seq data, 550 genes with significant differential expression were identified in HAPC patients. GO and KEGG pathway enrichment analysis showed that the up-regulated genes were mainly enriched in processes such as erythrocyte differentiation and development and homeostasis of number of cells, while the down-regulated genes were mainly enriched in categories such as immunoglobulin production, classical pathway of complement activation and other biological processes. The coupling analysis of differential expression genes(DEGs) and pathological phenotypes revealed that 91 DEGs were in close correlation with in the phenotype of red blood cell volume distribution (width-CV and width-SD), and they were all up-regulated in HAPC and involved in the process of erythrocyte metabolism. Combined with the functional annotation of DEGs and literature survey, we found that the expression of several potential genes might be responsible for pathogenesis of HAPC. Besides, cell type deconvolution analysis result suggested that the changes in the number of some immune cell types was significantly lower in HAPC patients than control, implying the autoimmune level of HAPC patients was affected to a certain extent. Conclusion This study provides an important data source for understanding the pathogenesis and screening pathogenic genes of HAPC. We found for the first time that there was a significant correlation between HAPC and the pathological phenotype of width-CV and width-SD, wherein the enriched genes were all up-regulated expressed and involved in the process of erythrocyte metabolism. Although the role of these genes needs to be further studied, the candidate genes can provide a starting point for functionally pinning down the underlying mechanism of HAPC.

Background Alterations in the gut microbiota have been observed in patients with pulmonary hypertension (PH), though whether the roles of the gut microbiota in PH at different altitudes are the same is unknown. This study aims to evaluate the associations of the gut microbiome with PH in highlanders and lowlanders. Methods PH patients and controls were recruited from those who permanently live on the Tibetan plateau (highlanders) or the plains (lowlanders), and underwent transthoracic echocardiography close to their altitude of residence (at 5070 m for highlanders versus 6 m for lowlanders). The gut microbiome was profiled using metagenomic shotgun sequencing. Results In total, 13 PH patients (46% highlanders) and 88 controls (70% highlanders) were included. The overall microbial composition was different in PH patients compared to controls (p = 0.003). Notably, among lowlanders, a composite microbial score of pro-atherosclerotic trimethylamine-producing species was increased in PH patients compared with that in controls (p = 0.028), while among highlanders no such difference was observed (p = 0.087). Another composite gut microbial score including eight species of Lactobacillus , which has shown beneficial effects on cardiovascular functions, was higher in highlanders than lowlanders (p<0.01). Furthermore, this score tended to be lower in PH patients than controls among highlanders (p=0.056) but not among lowlanders (p=0.840). In addition, the gut microbiome showed a good performance in distinguishing PH patients from controls in both lowlanders and highlanders. Conclusions Our study reported differently altered gut microbiome profiles between highland and lowland PH patients, highlighting the distinct microbial mechanism in PH in highlanders compared with lowlanders.

Objectives Numerous genome-wide association studies have identified CACNA1C as one of the top risk genes for schizophrenia. As a necessary post-genome-wide association study (GWAS) follow-up, here, we focused on this risk gene, carefully investigated its novel risk variants for schizophrenia, and explored their potential functions. Methods We analyzed four independent samples (including three European and one African-American) comprising 5648 cases and 6936 healthy subjects to identify replicable single nucleotide polymorphism-schizophrenia associations. The potential regulatory effects of schizophrenia-risk alleles on CACNA1C mRNA expression in 16 brain regions (n = 348), gray matter volumes (GMVs) of five subcortical structures (n = 34 431), and surface areas and thickness of 34 cortical regions (n = 36 936) were also examined. Results A novel 17-variant block across introns 36-45 of CACNA1C was significantly associated with schizophrenia in the same effect direction across at least two independent samples (1.8 x 10(-4) <= P <= 0.049). Most risk variants within this block showed significant associations with CACNA1C mRNA expression (1.6 x 10(-3) <= P <= 0.050), GMVs of subcortical structures (0.016 <= P <= 0.048), cortical surface areas (0.010 <= P <= 0.050), and thickness (0.004 <= P <= 0.050) in multiple brain regions. Conclusion We have identified a novel and functional risk variant block at CACNA1C for schizophrenia, providing further evidence for the important role of this gene in the pathogenesis of schizophrenia. Psychiatr Genet 33: 182-190 Copyright (c) 2023 Wolters Kluwer Health, Inc. All rights reserved.

高血压(HT)以体循环高动脉压为特征,累及心脏、肾脏、大脑等器官,是全球过早死亡的主要原因.高血压发病机制由肾素-血管紧张素-醛固酮系统(RAAS)、交感神经系统、氧化应激、遗传、生活环境等多种因素共同作用;其中氧化应激和内皮功能障碍是这些过程的重要催化剂.我国是砷暴露超标的国家之一,研究显示砷暴露与高血压、心律失常和其他心血管疾病的关联,但具体作用机制不明.目前有报道砷暴露通过氧化应激、血管内皮损伤引起外周血管阻力升高,引起高血压的发生.基于我国高血压患病率高,砷在环境中的广泛分布,且与高血压患病率相关.

碘是甲状腺激素合成的必需物,它还可作为抗氧化剂、抗增殖和促进凋亡因子.缺碘是一个持续存在的问题.近年来,食盐加碘的实施显著降低了全球缺碘的影响,目前缺碘为轻度至中度.孕妇、哺乳期妇女和儿童尤其受到缺碘的影响,会导致甲状腺疾病,代谢和发育障碍以及癌症.然而,过量的碘摄入导致甲状腺疾病的发展.纠正碘缺乏症可能会降低患恶性肿瘤的机会,需要进一步的研究来更好地了解碘对癌变的影响以及碘缺乏补偿对癌症患者预后的临床结果.即将到来的公共卫生挑战似乎是减少盐的摄入量,这可能导致碘摄入量降低.因此,如果不增加盐碘水平以补偿,则可以考虑除盐以外的碘富集载体,并且应更频繁地监测尿碘水平.

Abstract The Tibetan Plateau is populated by diverse ethnic groups, but most of them are underrepresented in genomics studies compared with the Tibetans (TIB). Here, to gain further insight into the genetic diversity and evolutionary history of the people living in the Tibetan Plateau, we sequenced 54 whole genomes of the Deng people with high coverage (30–60×) and analyzed the data together with that of TIB and Sherpas, as well as 968 ancient Asian genomes and available archaic and modern human data. We identified 17.74 million novel single-nucleotide variants from the newly sequenced genomes, although the Deng people showed reduced genomic diversity and a relatively small effective population size. Compared with the other Tibetan highlander groups which are highly admixed, the Deng people are dominated by a sole ancestry that could be traced to some ancient northern East Asian populations. The divergence between Deng and Tibetan people (∼4,700–7,200 years) was more recent than that between highlanders and the Han Chinese (Deng-HAN, ∼9,000–14,000 years; TIB-HAN, 7,200–10,000 years). Adaptive genetic variants (AGVs) identified in the Deng are only partially shared with those previously reported in the TIB like HLA-DQB1, whereas others like KLHL12 were not reported in TIB. In contrast, the top candidate genes harboring AGVs as previously identified in TIB, like EPAS1 and EGLN1, do not show strong positive selection signals in Deng. Interestingly, Deng also showed a different archaic introgression scenario from that observed in the TIB. Our results suggest that convergent adaptation might be prevalent on the Tibetan Plateau.

Environmental stresses,such as temperature,disease and altitude could induce systematic changes of biological systems which manifests as concerted responses across multiple systems within a certain period of time[1].High altitude acclimatization （HAA） refers to a series of adaptive physiological responses to hypoxic stress.During these processes,

Exercise plays an important role in delaying aging, preventing diseases and enhancing immunity. However, some people believe that for residents living in and commuting to the plateau area, exercise training will not help them to adapt to the plateau environment, but increase the burden on the body. It not only causes inadaptability to the plateau environment, but induce seriously high diseases. High altitude heart disease is one of the most serious altitude diseases. Research shows that the external environment not only cause changes in the body, but may even be passed on to generations in an epigenetic way. This article reviews the two points above, namely epigenetic inheritance and high altitude heart disease and exercise intervention.

Tibetan, one of the largest indigenous populations living in the high-altitude region of the Tibetan Plateau (TP), has developed a suite of physiological adaptation strategies to cope with the extreme highland environment in TP. Here, we reported genome-wide SNP data from 48 Kham-speaking Nagqu Tibetans and analyzed it with published data from 1,067 individuals in 167 modern and ancient populations to characterize the detailed Tibetan subgroup history and population substructure. Overall, the patterns of allele sharing and haplotype sharing suggested (1) the relatively genetic homogeny between the studied Nagqu Tibetans and ancient Nepalese as well as present-day core Tibetans from Lhasa, Nagqu, and Shigatse; and (2) the close relationship between our studied Kham-speaking Nagqu Tibetans and Kham-speaking Chamdo Tibetans. The fitted qpAdm models showed that the studied Nagqu Tibetans could be fitted as having the main ancestry from late Neolithic upper Yellow River millet farmers and deeply diverged lineages from Southern East Asians (represented by Upper Paleolithic Guangxi_Longlin and Laos_Hoabinhian), and a non-neglectable western Steppe herder-related ancestry (∼3%). We further scanned the candidate genomic regions of natural selection for our newly generated Nagqu Tibetans and the published core Tibetans via FST, iHS, and XP-EHH tests. The genes overlapping with these regions were associated with essential human biological functions such as immune response, enzyme activity, signal transduction, skin development, and energy metabolism. Together, our results shed light on the admixture and evolutionary history of Nagqu Tibetan populations.

Background Coronavirus disease 2019 (COVID-19) has had a devastating impact on public health services worldwide. Currently, there are no standard remedies or therapies for COVID-19. it is important to identify and diagnose COVID-19 to control the spread. But clinical symptoms of COVID-19 are very similar to those of other respiratory viruses. Results As a result, the diagnosis of COVID-19 relies heavily on detecting pathogens. We established a bunch of triplex new TaqMan real-time PCR assays. Three sets of primers and probes (targeting the ORF1ab, N, and E genes, respectively) are poorly consistent with other human coronaviruses and the human influenza virus. The sensitivity of established PCR assays notices as few as 100 copies per PCR of the ORF1ab, N, and E genes. Meanwhile, standard curves concluded from constant PCR reaction all showed glorious linear correlations between Ct values and the polymer loading copy variety (correlation coefficient (R-2) of ORF1ab, N, and E genes is 0.996, 0.991, and 0.998, respectively). Surveillance of RNA-based pseudovirus demonstrated that they were identified to be positive with respect to SARS-CoV-2 and that established PCR assays are achievable. Conclusion The assays established provide a smaller reaction volume for diagnosing COVID-19.

Background: The incidence of gallstones in the Tibetan population is increasing rapidly. Previous studies indicated that genetic variation located in the cholesterol metabolism pathway may be associated with the incidence of gallstones.Methods: By recruiting 132 Tibetan gallstone patients and 52 normal Tibetan controls, we performed next-generation sequencing for 508 genes in the cholesterol metabolism pathway. Additionally, by integrating the sequence data of 41 normal Tibetan subjects in the public database, we finally obtained 93 normal Tibetan controls. Single nucleotide polymorphisms (SNPs) calling were performed by using the GATK pipeline. The quality control criteria for SNPs were: missing rate <0.05; minor allele frequency (MAF) > 0.01; and p value >0.001 in the Hardy-Weinberg Equilibrium (HWE) test. To eliminate the influence of population heterogeneity, Principal Component Analysis (PCA) was carried out by using the smartpca software. Association analyses were performed by Plink software. Multiple tests were adjusted by the false discovery rate (FDR) method.Results: A total of 2,401 SNPs were obtained by analyzing 508 genes, and 2,011 SNPs left after quality control. After adjusting the eigen vectors, we found that 10 SNPs (SNV05997, rs80145081, rs80005560, rs79074685, rs748546375, rs201880593, rs142559357, rs750769471, rs869789 and rs4072341) were significantly associated with gallstone. Subsequently, by comparing the case group with our control group and the public database control group separately, we further found that the SNP rs869789 was consistently significantly associated with gallstone (p = 9.04 × 10–3 in cases vs. our controls and 5.73 × 10–3 in cases vs. public controls, respectively).Conclusion: By systematically analyzed SNPs in the cholesterol metabolism pathway, we identified one polymorphic locus rs869789 significantly associated with the pathogenesis of gallstone in the Tibetan population. This study will provide clue for further mechanism study of gallstone in the Tibetan population.