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One of the most striking geological features of the Pamir is the south‐dipping lithospheric slab beneath the orogen characterized by an intracontinental Wadati‐Benioff zone. A widely accepted hypothesis over the past 40 years interprets the slab to represent southward subducted cratonic Asian continental lithosphere, which predicts significant cratonic Asia‐sourced crustal materials (e.g., Tarim Basin) beneath the Pamir. Alternatively, recent studies have interpreted the slab to be lithosphere delaminated from the base of the Pamir. To test these hypotheses, depth–tectonic affinity relations of crustal xenoliths carried by Miocene volcanic rocks in the eastern Pamir, interpreted to be sourced from the Pamir deep lithosphere, are used to determine whether they represented Asian affinity cratonic crust. Thermodynamic calculations, zircon U–Pb geochronology combined with rare earth element analysis, and whole‐rock major‐trace element and Sr–Nd isotopic analyses document that (1) eclogite and pyroxenite xenoliths (~31–43 kbar/~960–1170°C) are the deepest sourced portions of the lithosphere from ~100 to 140 km depth, the protoliths of which represent the mid‐lower crustal rocks of the Cretaceous Pamir magmatic arc, rather than material from cratonic Asia, and (2) granulite xenoliths (~20 kbar/~900°C) represent the Cenozoic lower crustal rocks of Pamir terranes from ~70 km depth. These results indicate the south‐dipping slab represents delaminated Pamir lower crust and mantle lithosphere, rather than intracontinental subduction of Asian lithosphere, and further support the hypothesis of minimal Cenozoic northward translation of the Pamir. [ABSTRACT FROM AUTHOR]

Background: This research aimed to explore the association between the RIG-I-like receptor (RIG-I and MDA5 encoded by DDX58 and IFIH1, respectively) pathways and the risk or severity of hand, foot, and mouth disease caused by enterovirus 71 (EV71-HFMD). In this context, we explored the influence of gene methylation and polymorphism on EV71-HFMD. Methodology/Principal findings: 60 healthy controls and 120 EV71-HFMD patients, including 60 mild EV71-HFMD and 60 severe EV71-HFMD patients, were enrolled. First, MiSeq was performed to explore the methylation of CpG islands in the DDX58 and IFIH1 promoter regions. Then, DDX58 and IFIH1 expression were detected in PBMCs using RT-qPCR. Finally, imLDR was used to detect DDX58 and IFIH1 single-nucleotide polymorphism (SNP) genotypes. Severe EV71-HFMD patients exhibited higher DDX58 promoter methylation levels than healthy controls and mild EV71-HFMD patients. DDX58 promoter methylation was significantly associated with severe HFMD, sex, vomiting, high fever, neutrophil abundance, and lymphocyte abundance. DDX58 expression levels were significantly lower in mild patients than in healthy controls and lower in severe patients than in mild patients. Binary logistic regression analysis revealed statistically significant differences in the genotype frequencies of DDX58 rs3739674 between the mild and severe groups. GeneMANIA revealed that 19 proteins displayed correlations with DDX58, including DHX58, HERC5, MAVS, RAI14, WRNIP1 and ISG15, and 19 proteins displayed correlations with IFIH1, including TKFC, IDE, MAVS, DHX58, NLRC5, TSPAN6, USP3 and DDX58. Conclusions/Significance: DDX58 expression and promoter methylation were associated with EV71 infection progression, especially in severe EV71-HFMD patients. The effect of DDX58 in EV71-HFMD is worth further attention. Author summary: EV71-HFMD is now prevalent in many Asia countries, including China, which caused a lot of death over the last few years. Therefore, it's important to distinguish patients with a severe tendency. In this research, we investigated the association between the epigenetic mechanisms of RIG-I-like pattern recognition receptors (DDX58 and IFIH1) and EV71-HFMD. It showed that children with higher level of DDX58 promoter methylation were related to severe EV71-HFMD and other clinical indicators. The DDX58 mRNA expression level was significantly lower in severe patients. Besides, DDX58 polymorphisms played an important role in the severity of EV71-HFMD. Therefore, various epigenetic biomarkers of DDX58 may be used as indicators to help clinicians identify EV71-HFMD patients with a tendency towards severity. [ABSTRACT FROM AUTHOR]

Precipitation, a basic component of the water cycle, is significantly important for meteorological, climatological and hydrological research. However, accurate estimation on the precipitation remains considerably challenging because of the sparsity of gauge networks and the large spatial variability of precipitation over mountainous regions. Moreover, meteorological stations in mountainous areas are often dispersed and have difficulty in accurately reflecting the intensity and evolution of precipitation events. In this study, we proposed a novel method to produce high-quality, high-resolution precipitation estimates in the Tianshan Mountains, China, based on area-to-point kriging (ATPK) downscaling and a two-step correction, i.e., probability density function matching-optimum interpolation (PDF-OI). We obtained 1-km hourly precipitation data in the Tianshan Mountains by merging estimates from the Integrated Multi-satellite Retrievals for Global Precipitation Measurement (IMERG) product with observations from 1065 meteorological stations in the warm season (May to September) during 2016–2018. The spatial resolution and accuracy of the merged precipitation data greatly increased compared to IMERG. According to a cross-validation with gauged observations, the correlation coefficient (CC), probability of detection (POD) and critical success index (CSI) increased from 0.30, 0.50 and 0.24 for IMERG to 0.63, 0.65 and 0.38, respectively, for the merged estimates, and the root mean squared error (RMSE), mean error (ME) and false alarm ratio (FAR) decreased from 0.46 to 0.38 mm/h, 0.06 to 0.05 mm/h and 0.69 to 0.52, respectively. The proposed method will be useful for developing high-resolution precipitation estimates in mountainous areas such as central Asia and the Belt and Road Initiative regions. [ABSTRACT FROM AUTHOR]

Background and Aims: Women with severe intrahepatic cholestasis of pregnancy (ICP) are at higher risks of fetal complications and without effective treatments. Changes in gut microbiota in pregnancy were found to be related to the altered intestinal bile acid composition, so we aimed to explore the alterations of microbiota in the gut of ICP patients. Methods: A total of 90 women were recruited, including 45 ICP patients and 45 healthy controls. The gut microbiota communities of ICP group were compared to control group through 16S ribosomal RNA gene sequencing. The results were then confirmed by real-time polymerase chain reaction (PCR) and generalized linear model (GLM). Furthermore, we analyzed the relationships between microbiota and the severity of ICP. Results: A total of seven genera and nine taxa with differential abundances between the ICP patients and the controls were identified. All of the seven genera were verified through real-time PCR, and three key genera Parabacteroides , Flavonifractor , and Megamonas were confirmed by using the GLM model. Further analysis found that the genera Escherichia_Shigella , Olsenella , and Turicibacter were enriched in the severe ICP group, the microbial gene function related to biosynthesis of unsaturated fatty acids and propanoate metabolism were also increased in them. Conclusions: Overall, our study was the first in Asia to demonstrate an association between gut microbiota and ICP. Our findings would contribute to a better understanding of the occurrence of ICP. [ABSTRACT FROM AUTHOR]

Bacillus thuringiensis (Bt) transgenic cotton (Gossypium hirsutum L.) has been widely planted in Asia. However, efficacy of the Bt protein to kill pests has been inconsistent. Effects of gibberellic acid (GA3) and dimethylpiperidinium chloride (DPC) on boll Bt protein content were investigated on 'Sikang1' and 'Siza3.' Treatment of DPC increased the Bt protein contents in carpel wall and cotton seed at 10 d after flowering (DAF) and 30 DAF in 2014 and 2015. However, Bt protein contents of the GA3 treatment only at 30 DAF were higher for both cultivars in comparison to the control. To further investigate the mechanism, we found the ability of protein synthesis (indicated by enzyme activities of nitrate reductase [NR], glutamic-pyruvic transaminase [GPT], and glutamic oxaloacetate transaminase [GOT], as well as contents of total nitrogen, free amino acid, and soluble protein) in bolls increased markedly with the application of DPC for both cultivars. Further analysis showed that there were positive linear correlations between Bt protein content and NR, GPT, and GOT activities and total nitrogen and soluble protein contents (r = 0.925**, r = 0.691**, r = 0.703**, r = 0.682*, r = 0.693**, respectively) in carpel wall of bolls. Thus, DPC is potentially an effective chemical application to increase boll Bt protein content. [ABSTRACT FROM AUTHOR]

Background: The treatment outcomes of multidrug-resistant tuberculosis (MDR-TB) patients in the 1990s in Taiwan was not satisfactory. To strengthen programmatic management of drug-resistant tuberculosis (PMDT), Taiwan MDR-TB Consortium (TMTC) was established in 2007. We assess the performance and epidemiologic impact of TMTC. Methodology/Principle findings: We analyzed the trends of proportion of TB cases with drug susceptibility testing, enrollment of MDR-TB patients into TMTC and outcomes of treatment of all MDR-TB patients in Taiwan from 2007–2016. We computed the trends of both incidence and prevalence of MDR-TB from 2007–2016. We assessed the trends of MDR-TB among both new and recurrent TB cases. The proportion of TB cases with drug susceptibility testing results increased from 24.2% in 2007 to 97.9% in 2016. Of the 1,452 MDR-TB patients who were eligible for TMTC care, 1,197 (82.4%) were enrolled in TMTC, in whom 82.9% had treatment success. MDR-TB incidence was 9.0 cases per million in 2007, which declined to 4.6 cases per million in 2016 (p<0.0001). MDR-TB prevalence decreased from 19.4 cases per million in 2007 to 8.4 cases per million in 2016 (p<0.0001). The proportion of MDR-TB among new TB cases decreased from 1.4% in 2010 to 1.0% in 2016 (p = 0.039); and that among recurrent TB cases from 9.0% in 2010 to 1.8% in 2016 (p<0.0001). Conclusions: We concluded that effective PMDT have had a significant impact on the epidemic of drug-resistant TB in Taiwan. [ABSTRACT FROM AUTHOR]

The role of insulin resistance (IR) and hepatic steatosis in fibrogenesis in chronic hepatitis C infection (CHC) has yielded conflicting data and few studies have been performed in Asian-region populations. We retrospectively investigated the relationship between host metabolic variables, including IR and hepatic steatosis, to hepatic fibrosis in Asian-region CHC genotype 2/3 patients. A total of 303 treatment-naïve Asian-region patients with CHC genotype 2/3 were enrolled in a multicenter phase 3 study of albinterferon alfa-2b plus ribavirin for 24 weeks. IR was defined as Homeostasis Model for Assessment of IR (HOMA-IR) > 2. Baseline liver biopsy was evaluated by a single expert histopathologist. Post hoc subgroup logistic regression modeling selected for independent variables associated with significant fibrosis (METAVIR stage F2-F4). Insulin resistance was available in 263 non-diabetic Asian-region patients (hepatitis C virus-2 [HCV-2] = 171, HCV-3 = 92), and 433 non-Asian region patients (407 'Caucasian'); METAVIR fibrosis prevalence F0-F1 (minimal fibrosis) = 201 (77%) and F2-F4 (significant fibrosis) = 59 (23%), and steatosis prevalence of grade 0 = 169 (65%), grade 1 = 64 (25%), grade 2/3 = 27 (10%). Median HOMA-IR was 1.8 (interquartile range: 1.2-2.7); 100 (38%) patients had HOMA-IR > 2. Factors independently associated with significant fibrosis included HOMA-IR (odds ratio [OR] = 8.42), necro-inflammatory grade (OR = 3.17), age (OR = 1.07) and serum total cholesterol levels (OR = 0.008). This was similar to non-Asian region patients, but steatosis was not associated with significant fibrosis in either cohort. In this subgroup study of Asian-region HCV genotype 2 or 3 patients, insulin resistance, along with age, cholesterol levels and necro-inflammation, but not steatosis may be associated with significant hepatic fibrosis. [ABSTRACT FROM AUTHOR]

Genome sequences from diverse human groups are needed to understand the structure of genetic variation in our species and the history of, and relationships between, different populations. We present 929 high-coverage genome sequences from 54 diverse human populations, 26 of which are physically phased using linked-read sequencing. Analyses of these genomes reveal an excess of previously undocumented common genetic variation private to southern Africa, central Africa, Oceania, and the Americas, but an absence of such variants fixed between major geographical regions. We also find deep and gradual population separations within Africa, contrasting population size histories between hunter-gatherer and agriculturalist groups in the past 10,000 years, and a contrast between single Neanderthal but multiple Denisovan source populations contributing to present-day human populations., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: Chemotherapy for patients with advanced oesophageal squamous cell carcinoma offers poor long-term survival prospects. We report the final analysis from our study of the immune checkpoint PD-1 inhibitor nivolumab versus chemotherapy in patients with previously treated advanced oesophageal squamous cell carcinoma., Methods: We did a multicentre, randomised, open-label, phase 3 trial (ATTRACTION-3) at 90 hospitals and cancer centres in Denmark, Germany, Italy, Japan, South Korea, Taiwan, the UK, and the USA. We enrolled patients aged 20 years and older with unresectable advanced or recurrent oesophageal squamous cell carcinoma (regardless of PD-L1 expression), at least one measurable or non-measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, a baseline Eastern Cooperative Oncology Group performance status of 0-1, and who were refractory or intolerant to one previous fluoropyrimidine-based and platinum-based chemotherapy and had a life expectancy of at least 3 months. Patients were randomly assigned (1:1) to either nivolumab (240 mg for 30 min every 2 weeks) or investigator's choice of chemotherapy (paclitaxel 100 mg/m 2 for at least 60 min once per week for 6 weeks then 1 week off; or docetaxel 75 mg/m 2 for at least 60 min every 3 weeks), all given intravenously. Treatment continued until disease progression assessed by the investigator per RECIST version 1.1 or unacceptable toxicity. Randomisation was done using an interactive web response system with a block size of four and stratified according to geographical region (Japan vs rest of the world), number of organs with metastases, and PD-L1 expression. Patients and investigators were not masked to treatment allocation. The primary endpoint was overall survival, defined as the time from randomisation until death from any cause, in the intention-to-treat population that included all randomly assigned patients. Safety was assessed in all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT02569242, and follow-up for long-term outcomes is ongoing., Findings: Between Jan 7, 2016, and May 25, 2017, we assigned 419 patients to treatment: 210 to nivolumab and 209 to chemotherapy. At the time of data cutoff on Nov 12, 2018, median follow-up for overall survival was 10·5 months (IQR 4·5-19·0) in the nivolumab group and 8·0 months (4·6-15·2) in the chemotherapy group. At a minimum follow-up time (ie, time from random assignment of the last patient to data cutoff) of 17·6 months, overall survival was significantly improved in the nivolumab group compared with the chemotherapy group (median 10·9 months, 95% CI 9·2-13·3 vs 8·4 months, 7·2-9·9; hazard ratio for death 0·77, 95% CI 0·62-0·96; p=0·019). 38 (18%) of 209 patients in the nivolumab group had grade 3 or 4 treatment-related adverse events compared with 131 (63%) of 208 patients in the chemotherapy group. The most frequent grade 3 or 4 treatment-related adverse events were anaemia (four [2%]) in the nivolumab group and decreased neutrophil count (59 [28%]) in the chemotherapy group. Five deaths were deemed treatment-related: two in the nivolumab group (one each of interstitial lung disease and pneumonitis) and three in the chemotherapy group (one each of pneumonia, spinal cord abscess, and interstitial lung disease)., Interpretation: Nivolumab was associated with a significant improvement in overall survivaland a favourable safety profile compared with chemotherapy in previously treated patients with advanced oesophageal squamous cell carcinoma, and might represent a new standard second-line treatment option for these patients., Funding: ONO Pharmaceutical Company and Bristol-Myers Squibb., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Sixty genetic loci associated with abdominal obesity, measured by waist circumference (WC) and waist-hip ratio (WHR), have been previously identified, primarily from studies conducted in European-ancestry populations. We conducted a meta-analysis of associations of abdominal obesity with approximately 2.5 million single nucleotide polymorphisms (SNPs) among 53,052 (for WC) and 48,312 (for WHR) individuals of Asian descent, and replicated 33 selected SNPs among 3,762 to 17,110 additional individuals. We identified four novel loci near the EFEMP1, ADAMTSL3 , CNPY2, and GNAS genes that were associated with WC after adjustment for body mass index (BMI); two loci near the NID2 and HLA-DRB5 genes associated with WHR after adjustment for BMI, and three loci near the CEP120, TSC22D2, and SLC22A2 genes associated with WC without adjustment for BMI. Functional enrichment analyses revealed enrichment of corticotropin-releasing hormone signaling, GNRH signaling, and/or CDK5 signaling pathways for those newly-identified loci. Our study provides additional insight on genetic contribution to abdominal obesity.

Asia harbors substantial cultural and linguistic diversity, but the geographic structure of genetic variation across the continent remains enigmatic. Here we report a large-scale survey of autosomal variation from a broad geographic sample of Asian human populations. Our results show that genetic ancestry is strongly correlated with linguistic affiliations as well as geography. Most populations show relatedness within ethnic/linguistic groups, despite prevalent gene flow among populations. More than 90% of East Asian (EA) haplotypes could be found in either Southeast Asian (SEA) or Central-South Asian (CSA) populations and show clinal structure with haplotype diversity decreasing from south to north. Furthermore, 50% of EA haplotypes were found in SEA only and 5% were found in CSA only, indicating that SEA was a major geographic source of EA populations.