Genetic history of esophageal cancer group in southwestern China revealed by Y-chromosome STRs and genomic evolutionary connection analysis.

Genetic and environmental factors play crucial roles in the development of esophageal cancer (EC) and contribute uniquely or cooperatively to human cancer susceptibility. Sichuan is located in the interior of southwestern China, and the northern part of Sichuan is one of the regions with a high occurrence of EC. However, the factors influencing the high incidence rate of EC in the Sichuan Han Chinese population and its corresponding genetic background and origins are still poorly understood. Here, we utilized genome-wide single nucleotide polymorphisms (SNPs) and Y-chromosome short tandem repeats (Y-STRs) to characterize the genetic structure, connection, and origin of cancer groups and general populations. We generated Y-STR-based haplotype data from 214 Sichuan individuals, including the Han Chinese EC population and a control group of Han Chinese individuals. Our results, obtained from Y-STR-based population statistical methods (analysis of molecular variance (AMOVA), principal component analysis (PCA), and phylogenetic analysis), demonstrated that there was a genetic substructure difference between the EC population in the high-incidence area of northern Sichuan Province and the control population. Additionally, there was a strong genetic relationship between the EC population in the northern Sichuan high-incidence area and those at high risk in both the Fujian and Chaoshan areas. In addition, we obtained high-density SNP data from saliva samples of 60 healthy Han Chinese individuals from three high-prevalence areas of EC in China: Sichuan Nanchong, Fujian Quanzhou, and Henan Xinxiang. As inferred from the allele frequency of SNPs and sharing patterns of haplotype segments, the evolutionary history and admixture events suggested that the Han population from Nanchong in northern Sichuan Province shared a close genetic relationship with the Han populations from Xinxiang in Henan Province and Quanzhou in Fujian Province, both of which are regions with a high prevalence of EC. Our study illuminated the genetic profile and connection of the Northern Sichuan Han population and enriched the genomic resources and features of the Han Chinese populations in China, especially for the Y-STR genetic data of the Han Chinese EC population. Populations living in different regions with high incidences of EC may share similar genetic backgrounds, which offers new insights for further exploring the genetic mechanisms underlying EC.

Malaria resistance-related biological adaptation and complex evolutionary footprints inferred from one integrative Tai-Kadai-related genomic resource.

Pathogen‒host adaptative interactions and complex population demographical processes, including admixture, drift, and Darwen selection, have considerably shaped the Neolithic-to-Modern Western Eurasian population structure and genetic susceptibility to modern human diseases. However, the genetic footprints of evolutionary events in East Asia remain unknown due to the underrepresentation of genomic diversity and the design of large-scale population studies. We reported one aggregated database of genome-wide SNP variations from 796 Tai-Kadai (TK) genomes, including that of Bouyei first reported here, to explore the genetic history, population structure, and biological adaptative features of TK people from southern China and Southeast Asia. We found geography-related population substructure among TK people using the state-of-the-art population genetic structure reconstruction techniques based on the allele frequency spectrum and haplotype-resolved phased fragments. We found that the northern TK people from Guizhou harbored one TK-dominant ancestry maximized in the Bouyei people, and the southern TK people from Thailand were more influenced by Southeast Asians and indigenous people. We reconstructed fitted admixture models and demographic graphs, which showed that TK people received gene flow from ancient southern rice farmer-related lineages related to the Hmong-Mien and Austroasiatic people and from northern millet farmers associated with the Sino-Tibetan people. Biological adaptation focused on our identified unique TK lineages related to Bouyei, which showed many adaptive signatures conferring Malaria resistance and low-rate lipid metabolism. Further gene enrichment, the allele frequency distribution of derived alleles, and their correlation with the incidence of Malaria further confirmed that CR1 played an essential role in the resistance of Malaria in the ancient "Baiyue" tribes.

Differentiated adaptative genetic architecture and language-related demographical history in South China inferred from 619 genomes from 56 populations.

BACKGROUND: The underrepresentation of human genomic resources from Southern Chinese populations limited their health equality in the precision medicine era and complete understanding of their genetic formation, admixture, and adaptive features. Besides, linguistical and genetic evidence supported the controversial hypothesis of their origin processes. One hotspot case was from the Chinese Guangxi Pinghua Han people (GPH), whose language was significantly similar to Southern Chinese dialects but whose uniparental gene pool was phylogenetically associated with the indigenous Tai-Kadai (TK) people. Here, we analyzed genome-wide SNP data in 619 people from four language families and 56 geographically different populations, in which 261 people from 21 geographically distinct populations were first reported here. RESULTS: We identified significant population stratification among ethnolinguistically diverse Guangxi populations, suggesting their differentiated genetic origin and admixture processes. GPH shared more alleles related to Zhuang than Southern Han Chinese but received more northern ancestry relative to Zhuang. Admixture models and estimates of genetic distances showed that GPH had a close genetic relationship with geographically close TK compared to Northern Han Chinese, supporting their admixture origin hypothesis. Further admixture time and demographic history reconstruction supported GPH was formed via admixture between Northern Han Chinese and Southern TK people. We identified robust signatures associated with lipid metabolisms, such as fatty acid desaturases (FADS) and medically relevant loci associated with Mendelian disorder (GJB2) and complex diseases. We also explored the shared and unique selection signatures of ethnically different but linguistically related Guangxi lineages and found some shared signals related to immune and malaria resistance. CONCLUSIONS: Our genetic analysis illuminated the language-related fine-scale genetic structure and provided robust genetic evidence to support the admixture hypothesis that can explain the pattern of observed genetic diversity and formation of GPH. This work presented one comprehensive analysis focused on the population history and demographical adaptative process, which provided genetic evidence for personal health management and disease risk prediction models from Guangxi people. Further large-scale whole-genome sequencing projects would provide the entire landscape of southern Chinese genomic diversity and their contributions to human health and disease traits.

Differentiated genomic footprints suggest isolation and long-distance migration of Hmong-Mien populations.

BACKGROUND: The underrepresentation of Hmong-Mien (HM) people in Asian genomic studies has hindered our comprehensive understanding of the full landscape of their evolutionary history and complex trait architecture. South China is a multi-ethnic region and indigenously settled by ethnolinguistically diverse HM, Austroasiatic (AA), Tai-Kadai (TK), Austronesian (AN), and Sino-Tibetan (ST) people, which is regarded as East Asia's initial cradle of biodiversity. However, previous fragmented genetic studies have only presented a fraction of the landscape of genetic diversity in this region, especially the lack of haplotype-based genomic resources. The deep characterization of demographic history and natural-selection-relevant genetic architecture of HM people was necessary. RESULTS: We reported one HM-specific genomic resource and comprehensively explored the fine-scale genetic structure and adaptative features inferred from the genome-wide SNP data of 440 HM individuals from 33 ethnolinguistic populations, including previously unreported She. We identified solid genetic differentiation between HM people and Han Chinese at 7.64‒15.86 years ago (kya) and split events between southern Chinese inland (Miao/Yao) and coastal (She) HM people in the middle Bronze Age period and the latter obtained more gene flow from Ancient Northern East Asians. Multiple admixture models further confirmed that extensive gene flow from surrounding ST, TK, and AN people entangled in forming the gene pool of Chinese coastal HM people. Genetic findings of isolated shared unique ancestral components based on the sharing alleles and haplotypes deconstructed that HM people from the Yungui Plateau carried the breadth of previously unknown genomic diversity. We identified a direct and recent genetic connection between Chinese inland and Southeast Asian HM people as they shared the most extended identity-by-descent fragments, supporting the long-distance migration hypothesis. Uniparental phylogenetic topology and network-based phylogenetic relationship reconstruction found ancient uniparental founding lineages in southwestern HM people. Finally, the population-specific biological adaptation study identified the shared and differentiated natural selection signatures among inland and coastal HM people associated with physical features and immune functions. The allele frequency spectrum of cancer susceptibility alleles and pharmacogenomic genes showed significant differences between HM and northern Chinese people. CONCLUSIONS: Our extensive genetic evidence combined with the historical documents supported the view that ancient HM people originated from the Yungui regions associated with ancient "Three-Miao tribes" descended from the ancient Daxi-Qujialing-Shijiahe people. Then, some have recently migrated rapidly to Southeast Asia, and some have migrated eastward and mixed respectively with Southeast Asian indigenes, Liangzhu-related coastal ancient populations, and incoming southward ST people. Generally, complex population migration, admixture, and adaptation history contributed to the complicated patterns of population structure of geographically diverse HM people.

Distinguished biological adaptation architecture aggravated population differentiation of Tibeto-Burman-speaking people.

Tibeto-Burman (TB) people have endeavored to adapt to the hypoxic, cold, and high-UV high-altitude environments in the Tibetan Plateau and complex disease exposures in lowland rainforests since the late Paleolithic period. However, the full landscape of genetic history and biological adaptation of geographically diverse TB-speaking people, as well as their interaction mechanism, remain unknown. Here, we generate a whole-genome meta-database of 500 individuals from 39 TB-speaking populations and present a comprehensive landscape of genetic diversity, admixture history, and differentiated adaptative features of geographically different TB-speaking people. We identify genetic differentiation related to geography and language among TB-speaking people, consistent with their differentiated admixture process with incoming or indigenous ancestral source populations. A robust genetic connection between the Tibetan-Yi corridor and the ancient Yellow River people supports their Northern China origin hypothesis. We finally report substructure-related differentiated biological adaptative signatures between highland Tibetans and Loloish speakers. Adaptative signatures associated with the physical pigmentation (EDAR and SLC24A5) and metabolism (ALDH9A1) are identified in Loloish people, which differed from the high-altitude adaptative genetic architecture in Tibetan. TB-related genomic resources provide new insights into the genetic basis of biological adaptation and better reference for the anthropologically informed sampling design in biomedical and genomic cohort research.

DNA polymerase ζ suppresses the radiosensitivity of glioma cells by regulating the PI3K/AKT/mTOR pathway.

Glioblastoma is the most common glioma with high mortality and poor prognosis. Radiation resistance is one of the large challenges in the treatment of glioma. The study aimed to identify whether DNA polymerase ζ affects glioma cell radiosensitivity. The mRNA and protein levels of REV3L and REV7 were examined using quantitative real-time PCR and western blot. After REV3L and REV7 knockdown in a GBM cell line (A172), we assessed cell viability, colonies, apoptosis, and immune escape. The underlying mechanisms were evaluated using western blot and were confirmed using rescue experiments. The results showed that REV3L and REV7 levels were increased in glioma and related to poor survival. γ-ray treatment inhibited cell viability, survival fraction, and immune escape, and induced apoptosis of glioma cells from a GBM cell line, whereas knockdown of REV3L or REV7 enhanced these effects. Mechanically, silencing of REV3L or REV7 inactivated the PI3K/AKT/mTOR pathway. IGF-1 treatment abrogated the effects on cell viability, colonies, and apoptosis induced by REV3L or REV7 knocking down. Taken together, silencing of REV3L and REV7 inhibited radiation resistance via inactivating the PI3K/AKT/mTOR pathway, suggesting that targeting DNA polymerase ζ may be a new strategy to reduce the radiotherapy resistance of glioma.

Extensive genetic admixture between Tai-Kadai-speaking people and their neighbours in the northeastern region of the Yungui Plateau inferred from genome-wide variations.

BACKGROUND: Yungui Plateau in Southwest China is characterized by multi-language and multi-ethnic communities and is one of the regions with the wealthiest ethnolinguistic, cultural and genetic diversity in East Asia. There are numerous Tai-Kadai (TK)-speaking populations, but their detailed evolutionary history and biological adaptations are still unclear. RESULTS: Here, we genotyped genome-wide SNP data of 77 unrelated TK-speaking Zhuang and Dong individuals from the Yungui Plateau and explored their detailed admixture history and adaptive features using clustering patterns, allele frequency differentiation and sharing haplotype patterns. TK-speaking Zhuang and Dong people in Guizhou are closely related to geographically close TK and Hmong-Mien (HM)-speaking populations. Besides, we identified that Guizhou TK-speaking people have a close genetic relationship with Austronesian (AN)-speaking Atayal and Paiwan people, which is supported by the common origin of the ancient Baiyue tribe. We additionally found subtle genetic differences among the newly studied TK people and previously reported Dais via the fine-scale genetic substructure analysis based on the shared haplotype chunks. Finally, we identified specific selection candidate signatures associated with several essential human immune systems and neurological disorders, which could provide evolutionary evidence for the allele frequency distribution pattern of genetic risk loci. CONCLUSIONS: Our comprehensive genetic characterization of TK people suggested the strong genetic affinity within TK groups and extensive gene flow with geographically close HM and Han people. We also provided genetic evidence that supported the common origin hypothesis of TK and AN people. The best-fitted admixture models further suggested that ancestral sources from northern millet farmers and southern inland and coastal people contributed to the formation of the gene pool of the Zhuang and Dong people.

Numerical Simulation Study of Multi-Field Coupling for Laser Cladding of Shaft Parts.

Since shaft parts operate under harsh environments for a long time, many critical parts suffer from corrosion, wear and other problems, leading to part failure and inability to continue in service. It is imperative to repair failed parts and increase their service life. An orthogonal experimental scheme is designed to numerically simulate the process of laser cladding of Inconel 718 alloy powder on 4140 alloy structural steel based on the ANSYS simulation platform, derive the relationship equation of cladding layer thickness according to the heat balance principle, establish a finite element model, couple three modules of temperature field, stress field and fluid field, and analyze different modules to realize the monitoring of different processes of laser cladding. The optimal cladding parameters were laser power 1000 W, scanning speed 15 rad/s, spot radius 1.5 mm, thermal stress maximum value of 696 Mpa, residual stress minimum value of 281 Mpa, and the degree of influence of three factors on thermal stress maximum value: laser power > spot radius > scanning speed. The pool in the melting process appears to melt the "sharp corner" phenomenon, the internal shows a double vortex effect, with a maximum flow rate of 0.02 m/s. The solidification process shows a different shape at each stage due to the different driving forces. In this paper, multi-field-coupled numerical simulations of the laser cladding process were performed to obtain optimal cladding parameters with low residual stresses in the clad layer. The melt pool grows and expands gradually during melting, but the laser loading time is limited, and the size and shape of the melt pool are eventually fixed, and there is a vortex flowing from the center to both sides of the cross-section inside the melt pool, forming a double vortex effect. The solidification is divided into four stages to complete the transformation of the liquid phase of the melt pool to the solid phase, and the cladding layer is formed. The multi-field-coupled numerical simulation technique is used to analyze the temperature, stress and fluid fields to provide a theoretical basis for the residual stress and surface quality of the clad layer for subsequent laser cladding experiments.

Genome-wide allele and haplotype-sharing patterns suggested one unique Hmong-Mein-related lineage and biological adaptation history in Southwest China.

BACKGROUND: Fine-scale genetic structure of ethnolinguistically diverse Chinese populations can fill the gap in the missing diversity and evolutionary landscape of East Asians, particularly for anthropologically informed Chinese minorities. Hmong-Mien (HM) people were one of the most significant indigenous populations in South China and Southeast Asia, which were suggested to be the descendants of the ancient Yangtze rice farmers based on linguistic and archeological evidence. However, their deep population history and biological adaptative features remained to be fully characterized. OBJECTIVES: To explore the evolutionary and adaptive characteristics of the Miao people, we genotyped genome-wide SNP data in Guizhou HM-speaking populations and merged it with modern and ancient reference populations via a comprehensive population genetic analysis and evolutionary admixture modeling. RESULTS: The overall genetic admixture landscape of Guizhou Miao showed genetic differentiation between them and other linguistically diverse Guizhou populations. Admixture models further confirmed that Miao people derived their primary ancestry from geographically close Guangxi Gaohuahua people. The estimated identity by descent and effective population size confirmed a plausible population bottleneck, contributing to their unique genetic diversity and population structure patterns. We finally identified several natural selection candidate genes associated with several biological pathways. CONCLUSIONS: Guizhou Miao possessed a specific genetic structure and harbored a close genetic relationship with geographically close southern Chinese indigenous populations and Guangxi historical people. Miao people derived their major ancestry from geographically close Guangxi Gaohuahua people and experienced a plausible population bottleneck which contributed to the unique pattern of their genetic diversity and structure. Future ancient DNA from Shijiahe and Qujialing will provide new insights into the origin of the Miao people.

Design and Simulation of a Magnetization Drive Coil Based on the Helmholtz Principle and an Experimental Study.

In order to realize the magnetization of hydrogel mixed with NdFeB powder, a magnetization drive coil based on a Helmholtz coil is designed in this paper. The 3D model of the magnetic field system is drawn by the Maxwell software 3D module, and the influence of different factors on the magnetic induction intensity is analyzed to obtain the optimized structure of the magnetization drive coil; then, the central magnetic induction intensity and magnetic induction line distribution density of the magnetization drive coil and Helmholtz coil are compared to verify the reliability of the structure optimization. The results show that the central magnetic induction intensity is the highest when the distance between the auxiliary coils is 70 mm, the central magnetic induction intensity of the magnetized drive coil is significantly higher than that of the Helmholtz coil when the number of turns is the same, and the central magnetic induction intensity of the optimized magnetized drive coil can reach 1.37 T with a more uniform and dense magnetic induction line distribution. After building the magnetization drive coil, the magnetic induction intensity of the center of the magnetization drive coil can reach 1.34 T by a handheld digital Gauss meter test, and the error is no more than 2% with the simulation result. This design approach provides a reference for the structural design and operating characteristics analysis of magnetized drive coils and shortens the design cost and development cycle of magnetized drive coils.

Identification of enhancer RNA AC005515.1 as a novel biomarker for prognosis in esophageal cancer and predictors of immunotherapy response.

Background: The enhancer RNA (eRNA) signature shows excellent promise in the prognostic role of many malignancies, but its value has not been fully explored in esophageal cancer (ESCA). Methods: We comprehensively analyzed 33 oncogene expression matrices and clinical data from The Cancer Genome Atlas (TCGA) and identified ESCA prognostic-related key eRNAs by Kaplan-Meier and co-expression analysis. We also investigated the prognostic role of the key eRNA using a series of bioinformatics approaches, including immune infiltration, immune function, immune subtypes, and the tumor microenvironment. Finally, the tumor immune dysfunction and exclusion (TIDE) score was used to predict the immune response to immune checkpoint blockade (ICB) therapy. Results: We identified eRNA AC005515.1, AC012368.1, AP003469.2, Clorf61, and WDFY3-AS2 were associated with the prognosis of ESCA. AC005515.1 is a critical prognostic-related eRNA in ESCA and was significantly co-expressed with immune checkpoint genes (CTLA4, CD274, etc.). In the pan-cancer analysis, AC005515.1 was also associated with the prognosis of seven cancers, including kidney renal papillary cell carcinoma and low-grade brain glioma. It was also found to be co-expressed with immune checkpoint genes in these tumors. Moreover, high expression of AC005515.1 was associated with CD8+ T cells and M1 macrophages infiltration, and the AC005515.1 high-expression group had a higher TIDE score in ESCA. Conclusions: Overall, eRNA AC005515.1 is associated with the local immune environment of ESCA and may become a new biomarker of ESCA prognosis and immunotherapy response.

Comparison of external stents and DJ stents techniques for pediatric pyeloplasty: A systematic review and meta-analysis.

Objective: To evaluate and compare the efficacy and safety between an external stent and a Double J stent for pediatric Pyeloplasty. Methods: Through a systematical search of multiple scientific databases in July 2022, we performed a systematic review and meta-analysis of the primary outcomes of interest according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), whose protocol was registered with PROSPERO(CRD42021274087). Results: Eleven studies involving 1,758 patients were included. No significant differences were observed in operative time (MD: 2.26; 95% CI -9.62 to 14.14; P = 0.79), operative success rate (OR: 1.10; 95% CI 0.57 to 2.10; P = 0.780), length of hospital stay (MD: 0.65; 95% CI -0.04 to 1.34; P = 0.063), or complications (OR: 0.87; 95%CI 0.48 to 1.56; P = 0.630) between external stents and DJ stents in pediatric pyeloplasty. According to the subgroup analysis, we found the external stent group had a shorter operative time than the DJ stent group in terms of robot-assisted laparoscopic pyeloplasty (MD: -17.13; 95% CI -32.8 to -1.45; P = 0.032). Conclusions: There were no significant differences in operative time, operative success rate, length of hospital stay, or complications between external stents and DJ stents in pediatric pyeloplasty. The external stented procedure seemed to have less operative time when using robot-assisted laparoscopic pyeloplasty. However, due to the limitations of our analysis, more studies are still required to support our conclusion. Systematic review registration: This systematic review has been registered on PROSPERO, the registration ID is CRD42021274087.

Calponin 3 Acts as a Potential Diagnostic and Prognostic Marker and Promotes Glioma Cell Proliferation, Migration, and Invasion.

BACKGROUND: Calponin 3 (CNN3) is involved in the proliferation and invasion of cervical cancer and osteosarcoma cells. However, the role of CNN3 in glioma tumorigenesis remains to be elucidated. METHODS: CNN3 mRNA expression in normal brain tissue and gliomas, including glioblastoma multiforme and lower-grade glioma, was analyzed using GEPIA 2 and Oncomine. CNN3 levels in glioma tissues were identified using immunohistochemical data provided by the Human Protein Atlas website. The relationship between CNN3 mRNA expression and clinical characteristics of patients with glioma was analyzed using the Oncomine database and The Cancer Genome Atlas. The diagnostic value of CNN3 expression in glioma was analyzed using receiver operating characteristic analysis according to The Cancer Genome Atlas and Genotype-Tissue Expression data. The relationship between CNN3 and prognosis was analyzed using GEPIA 2. The function of CNN3 knockdown in glioma cell lines was analyzed using cell proliferation, Transwell, and Western blot assays. RESULTS: Both mRNA and protein levels of CNN3 were distinctly higher in lower-grade glioma and glioblastoma multiforme tissues than those in normal brain tissues, particularly glioblastoma. A higher CNN3 mRNA level had significant relationship with higher World Health Organization grade, isocitrate dehydrogenase wild-type status, and 1p/19q noncodeletion. CNN3 mRNA expression is a highly accurate marker for the diagnosis of glioma. Patients with glioma in the high-CNN3 group had significantly lower disease-free survival and survival rates. In addition, CNN3 silencing significantly inhibited cell proliferation, migration, invasion, and the phosphorylation of P65 NF-κB. CONCLUSIONS: CNN3 expression is increased in glioma, particularly glioblastoma. Silencing CNN3 expression inhibited the proliferation, migration, and invasion of glioma cell lines.

Modeling manufacturing resources based on manufacturability features.

Manufacturability evaluation is an effective way to shorten the development period, optimize manufacturing processes, and reduce product costs. The manufacturability of a product depends on the processing ability of specific manufacturing resources. The development of a manufacturing resources model serves as the foundation for manufacturability evaluation. To better utilize the information on manufacturing resources, this study adopted a hybrid approach by integrating the fuzzy c-means clustering algorithm and the genetic algorithm to group manufacturing resources based on manufacturing and geometric features. The information model of manufacturing resources was built by using the object-oriented method. Subsequently, the framework to evaluate manufacturing capability based on manufacturing resources was defined. Further, an application sample was exploited and its results were analyzed. The results of the subgroup showed that the hybrid algorithm was reliable and valid and helped improve the overall performance of the company chosen for this study. The proposed approach enhanced feasibility in decision-making and facilitated the management to make more informed decisions.

Comparison of enucleation between thulium laser and holmium laser for benign prostatic hyperplasia: A systematic review and meta-analysis.

To compare the clinical efficacy and safety of Thulium laser enucleation of prostate (ThuLEP) and Holmium laser enucleation of prostate (HoLEP). We systematically searched PubMed, Embase, and Cochrane Library databases within a period from the date of database establishment to October 2020. RevMan 5.4. was used for calculation and statistical analyses. 8 studies of 2125 patients were included. ThuLEP provided less hemoglobin decrease (MD: -0.37, 95%CI -0.61 to -0.14, P = 0.002) and shorter length of hospital stay (MD: -0.41, 95%CI -0.72 to -0.10, P = 0.01). During the postoperative follow-ups, statistically significant differences only were found in IPSS (MD: -0.96; 95%CI -1.27 to -0.65; P < 0.00001) at the 3rd month. In conclusion, our study demonstrates that ThuLEP, compared with HoLEP, has better security, faster improvement of symptoms. However, our conclusions still require a larger sample size, multi-center, and longer follow-up randomized controlled trials to verify.

Significant East Asian Affinity of the Sichuan Hui Genomic Structure Suggests the Predominance of the Cultural Diffusion Model in the Genetic Formation Process.

The ancestral origin and genomic history of Chinese Hui people remain to be explored due to the paucity of genome-wide data. Some evidence argues that an eastward migration of Central Asians gave rise to modern Hui people, which is referred to as the demic diffusion hypothesis; other evidence favors the cultural diffusion hypothesis, which posits that East Asians adopted Muslim culture to form the modern culturally distinct populations. However, the extent to which the observed genetic structure of the Huis was mediated by the movement of people or the assimilation of Muslim culture also remains highly contentious. Analyses of over 700 K SNPs in 109 western Chinese individuals (49 Sichuan Huis and 60 geographically close Nanchong Hans) together with the available ancient and modern Eurasian sequences allowed us to fully explore the genomic makeup and origin of Hui and neighboring Han populations. The results from PCA, ADMIXTURE, and allele-sharing-based f-statistics revealed a strong genomic affinity between Sichuan Huis and Neolithic-to-modern Northern East Asians, which suggested a massive gene influx from East Asians into the Sichuan Hui people. Three-way admixture models in the qpWave/qpAdm analyses further revealed a small stream of gene influx from western Eurasians into the Sichuan Hui people, which was further directly confirmed via the admixture event from the temporally distinct Western sources to Sichuan Hui people in the qpGraph-based phylogenetic model, suggesting the key role of the cultural diffusion model in the genetic formation of the Sichuan Huis. ALDER-based admixture date estimation showed that this observed western Eurasian admixture signal was introduced into the Sichuan Huis during the historic periods, which was concordant with the extensive western-eastern communication along the Silk Road and historically documented Huis' migration history. In summary, although significant cultural differentiation exists between Hui people and their neighbors, our genomic analysis showed their strong genetic affinity with modern and ancient Northern East Asians. Our results support the hypothesis that the Sichuan Huis arose from a mixture of minor western Eurasian ancestry and predominant East Asian ancestry.

Knockdown of DNA polymerase ζ relieved the chemoresistance of glioma via inhibiting the PI3K/AKT signaling pathway.

Previous reports suggest that DNA polymerase ζ is highly expressed in glioma tissues. The present study aimed to investigate the roles of the REV7 subunit of DNA polymerase ζ in glioma cell chemoresistance and its underlying mechanisms. The bioinformatics method was used to compare the expression of REV7 in glioma and normal tissues. The expression of REV7 in glioma tumor samples and the adjacent tissue was examined by reverse transcription polymerase chain reaction. Moreover, an in vitro analysis using glioma cells was used to test the effects of REV7 siRNA on the proliferation and apoptosis of glioma cell line U251 cells, and the effect of REV7 siRNA on the sensitivity of the U251 cells to cisplatin was also explored. The expression of REV7 in glioma tumors was significantly increased. Moreover, the knockdown of REV7 in glioma cells decreased the proliferation and increased the apoptosis of U251 cells; moreover, REV7 siRNA also increased the sensitivity of U251 cells to cisplatin. Finally, REV7 may regulate the proliferation, apoptosis, and chemosensitivity of U251 cells by affecting phosphoinositide 3-kinase signaling. Our data suggest that REV7 is involved in the chemosensitivity of glioma cells and provides a theoretical basis for targeting DNA polymerase ζ to improve the sensitivity of glioma cells to chemotherapy.

Ontogeny of different subsets of yellow fever virus-specific circulatory CXCR5+ CD4+ T cells after yellow fever vaccination.

Monitoring the frequency of circulatory CXCR5+ (cCXCR5+) CD4+ T cells in periphery blood provides a potential biomarker to draw inferences about T follicular helper (TFH) activity within germinal center. However, cCXCR5+ T cells are highly heterogeneous in their expression of ICOS, PD1 and CD38 and the relationship between different cCXCR5 subsets as delineated by these markers remains unclear. We applied class II tetramer reagents and mass cytometry to investigate the ontogeny of different subsets of cCXCR5+ T cell following yellow fever immunization. Through unsupervised analyses of mass cytometry data, we show yellow fever virus-specific cCXCR5 T cells elicited by vaccination were initially CD38+ICOS+PD1+, but then transitioned to become CD38+ICOS-PD1+ and CD38-ICOS-PD1+ before coming to rest as a CD38-ICOS-PD1- subset. These results imply that most antigen-specific cCXCR5+ T cells, including the CD38-ICOS-PD1- CXCR5+ T cells are derived from the CXCR5+CD38+ICOS+PD1+ subset, the subset that most resembles preTFH/TFH in the germinal center.

Increased islet antigen-specific regulatory and effector CD4+ T cells in healthy individuals with the type 1 diabetes-protective haplotype.

The DRB1*15:01-DQB1*06:02 (DR1501-DQ6) haplotype is linked to dominant protection from type 1 diabetes, but the cellular mechanism for this association is unclear. To address this question, we identified multiple DR1501- and DQ6-restricted glutamate decarboxylase 65 (GAD65) and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-specific T cell epitopes. Three of the DR1501/DQ6-restricted epitopes identified were previously reported to be restricted by DRB1*04:01/DRB1*03:01/DQB1*03:02. We also used specific class II tetramer reagents to assess T cell frequencies. Our results indicated that GAD65- and IGRP-specific effector and CD25+CD127-FOXP3+ regulatory CD4+ T cells were present at higher frequencies in individuals with the protective haplotype than those with susceptible or neutral haplotypes. We further confirmed higher frequencies of islet antigen-specific effector and regulatory CD4+ T cells in DR1501-DQ6 individuals through a CD154/CD137 up-regulation assay. DR1501-restricted effector T cells were capable of producing interferon-γ (IFN-γ) and interleukin-4 (IL-4) but were more likely to produce IL-10 compared with effectors from individuals with susceptible haplotypes. To evaluate their capacity for antigen-specific regulatory activity, we cloned GAD65 and IGRP epitope-specific regulatory T cells. We showed that these regulatory T cells suppressed DR1501-restricted GAD65- and IGRP-specific effectors and DQB1*03:02-restricted GAD65-specific effectors in an antigen-specific fashion. In total, these results suggest that the protective DR1501-DQ6 haplotype confers protection through increased frequencies of islet-specific IL-10-producing T effectors and CD25+CD127-FOXP3+ regulatory T cells.