Genomic insights into the formation of human populations in East Asia.

The deep population history of East Asia remains poorly understood owing to a lack of ancient DNA data and sparse sampling of present-day people1,2. Here we report genome-wide data from 166 East Asian individuals dating to between 6000 BC and AD 1000 and 46 present-day groups. Hunter-gatherers from Japan, the Amur River Basin, and people of Neolithic and Iron Age Taiwan and the Tibetan Plateau are linked by a deeply splitting lineage that probably reflects a coastal migration during the Late Pleistocene epoch. We also follow expansions during the subsequent Holocene epoch from four regions. First, hunter-gatherers from Mongolia and the Amur River Basin have ancestry shared by individuals who speak Mongolic and Tungusic languages, but do not carry ancestry characteristic of farmers from the West Liao River region (around 3000 BC), which contradicts theories that the expansion of these farmers spread the Mongolic and Tungusic proto-languages. Second, farmers from the Yellow River Basin (around 3000 BC) probably spread Sino-Tibetan languages, as their ancestry dispersed both to Tibet-where it forms approximately 84% of the gene pool in some groups-and to the Central Plain, where it has contributed around 59-84% to modern Han Chinese groups. Third, people from Taiwan from around 1300 BC to AD 800 derived approximately 75% of their ancestry from a lineage that is widespread in modern individuals who speak Austronesian, Tai-Kadai and Austroasiatic languages, and that we hypothesize derives from farmers of the Yangtze River Valley. Ancient people from Taiwan also derived about 25% of their ancestry from a northern lineage that is related to, but different from, farmers of the Yellow River Basin, which suggests an additional north-to-south expansion. Fourth, ancestry from Yamnaya Steppe pastoralists arrived in western Mongolia after around 3000 BC but was displaced by previously established lineages even while it persisted in western China, as would be expected if this ancestry was associated with the spread of proto-Tocharian Indo-European languages. Two later gene flows affected western Mongolia: migrants after around 2000 BC with Yamnaya and European farmer ancestry, and episodic influences of later groups with ancestry from Turan.

Genetic substructure and admixture of Mongolians and Kazakhs inferred from genome-wide array genotyping.

BACKGROUND: Mongolian populations are widely distributed geographically, showing abundant ethnic diversity with geographic and tribal differences. AIM: To infer the genetic substructure, admixture and ancient genetic sources of Mongolians together with Kazakhs. SUBJECTS AND METHODS: We genotyped more than 690,000 genome-wide SNPs from 33 Mongolian and Chinese Kazakh individuals and compared these with both ancient and present-day Eurasian populations using Principal Component Analysis (PCA), ADMIXTURE, Refine-IBD, f statistics, qpWave and qpAdm. RESULTS: We found genetic substructures within Mongolians corresponding to Ölöd, Chahar, and Inner Mongolian clusters, which was consistent with tribe classifications. Mongolian and Kazakh groups derived about 6-40% of West Eurasian related ancestry, most likely from Bronze Age Steppe populations. The East Asian related ancestry in Mongolian and Kazakh groups was well represented by the Neolithic DevilsCave related nomadic lineage, comprising 42-64% of studied groups. We also detected 10-51% of Han Chinese related ancestry in Mongolian and Kazakh groups, especially in Inner Mongolians. The average admixture times for Inner Mongolian, Mongolian_Chahar, Mongolian_Ölöd and Chinese Kazakh were about 1381, 626, 635 and 632 years ago, respectively, with Han and French as the sources. CONCLUSION: The DevilsCave related ancestry was once widespread westwards covering a wide geographical range from Far East Russia to the Mongolia Plateau. The formation of present-day Mongolic and Turkic-speaking populations has also received genetic influence from agricultural expansion.

The genetic admixture in Tibetan-Yi Corridor.

OBJECTIVES: The Tibetan-Yi Corridor located on the eastern edge of Tibetan Plateau is suggested to be the key region for the origin and diversification of Tibeto-Burman speaking populations and the main route of the peopling of the Plateau. However, the genetic history of the populations in the Corridor is far from clear due to limited sampling in the northern part of the Corridor. MATERIALS AND METHODS: We collected blood samples from 10 Tibetan and 10 Han Chinese individuals from Gansu province and genotyped about 600,000 genome-wide single nucleotide polymorphisms (SNPs). RESULTS: Our data revealed that the populations in the Corridor are all admixed on a genetic cline of deriving ancestry from Tibetans on the Plateau and surrounding lowland East Asians. The Tibetan and Han Chinese groups in the north of the Plateau show significant evidence of low-level West Eurasian admixture that could be probably traced back to 600∼900 years ago. DISCUSSION: We conclude that there have been huge population migrations from surrounding lowland onto the Tibetan Plateau via the Tibetan-Yi Corridor since the initial formation of Tibetans probably in Neolithic Time, which leads to the current genetic structure of Tibeto-Burman speaking populations.

Accurate and Real-Time Detection Method for the Exothermic Behavior of Enzymatic Nano-Microregions Using Temperature-Sensitive Amino-AgInS2 Quantum Dots.

The thermal behavior of enzymes in nanoscale is of great significance to life phenomena. This nonequilibrium state real-time thermal behavior of enzymes at nanoscale cannot be accurately detected by existing methods. Herein, a novel method is developed for the detection of this thermal behavior. The enzyme-quantum dot (QD) conjugates can be obtained by chemically grafting temperature-sensitive amino-AgInS2 QDs to the enzyme, where the QDs act as nanothermometers with a sensitivity of -2.82% °C-1 . Detecting the photoluminescence intensity changes of the enzyme-QD conjugates, the real-time thermal behavior of enzymes can be obtained. The enzyme-QD conjugates show a temperature difference as high as 6 °C above ambient temperature in nano-microregions with good reproducibility (maximum error of 4%) during catalysis, while solution temperature hardly changed. This method has a temperature resolution of ≈0.5 °C with a detection limit of 0.02 mg mL-1 of enzyme, and spatially ensured that the amino-AgInS2 QDs are quantitatively bound to the enzyme; thus, it can accurately detect the exothermic behavior of the enzyme and can be extended to other organisms' detection. This method has high sensitivity, good stability, and reliability, indicating its great potential application in investigating the thermal behavior of organisms in nanoscale and related life phenomena.

Prognostic value of EGFR and KRAS in resected non-small cell lung cancer: a systematic review and meta-analysis.

BACKGROUND: The prognostic value of EGFR and KRAS mutations in resected non-small cell lung cancer (NSCLC) has been reported. However, conflicting results were reported in these studies. The effect of mutations in these two genes in resected NSCLC remains controversial. METHODS: We searched Internet databases for studies reporting disease-free survival (DFS) and overall survival (OS) in resected NSCLC patients with EGFR or KRAS mutations. A meta-analysis calculating the pooled hazard ratio (HR) for DFS and OS was used to measure the association of EGFR or KRAS mutations with the prognosis of patients after surgery. RESULTS: A total of 9,635 patients from 32 studies were included in this analysis. The combined HR for EGFR mutations on DFS was 0.77 (95% CI 0.66-0.90, p=0.001) and on OS was 0.72 (95% CI 0.66-0.80, p<0.00001). In addition, the combined HR for KRAS mutations on DFS was 1.5 (95% CI 1.15-1.96, p=0.002) and on OS was 1.49 (95% CI 1.28-1.73, p<0.00001). Sensitivity analysis, subgroup analysis, and bias analysis proved the stability of the results. CONCLUSION: The analysis showed that EGFR mutations were significantly associated with DFS and OS. These findings indicated that surgically treated NSCLC patients with EGFR mutations were inclined to exhibit a prolonged DFS and OS. In addition, the results indicated that KRAS mutations predicted worse DFS and OS in patients with resected NSCLC.

Driver genes in non-small cell lung cancer: Characteristics, detection methods, and targeted therapies.

Lung cancer is one of the most common causes of cancer-related death in the world. The large number of lung cancer cases is non-small cell lung cancer (NSCLC), which approximately accounting for 75% of lung cancer. Over the past years, our comprehensive knowledge about the molecular biology of NSCLC has been rapidly enriching, which has promoted the discovery of driver genes in NSCLC and directed FDA-approved targeted therapies. Of course, the targeted therapies based on driver genes provide a more exact option for advanced non-small cell lung cancer, improving the survival rate of patients. Now, we will review the landscape of driver genes in NSCLC including the characteristics, detection methods, the application of target therapy and challenges.

Melatonin prevents sleep deprivation-associated anxiety-like behavior in rats: role of oxidative stress and balance between GABAergic and glutamatergic transmission.

Sleep deprivation (SD) has been shown to induce anxiety-like behavior. Melatonin, an endogenous potent antioxidant, protects neurons from oxidative stress in many disease models. Here we investigated the effect of melatonin against SD-induced anxiety-like behavior and attempted to define the possible mechanisms involved. SD was induced in rats using modified multiple platform model. Melatonin (15 mg/kg) was administered to the rats via intraperitoneal injection. The elevated plus maze test, open field test and light-dark exploration were used to evaluate anxiety-like behavior. Serum corticosterone was measured to determine stress level. Malondialdehyde (MDA) level and superoxide dismutase (SOD) enzyme activity of amygdala and serum were performed to determine the level of oxidative stress. Levels of protein were detected by means of Western blot. The results showed that SD induces anxiety-like behavior, while melatonin treatment prevented these changes. Serum corticosterone also increased with SD but its levels were normalized by melatonin. In addition, melatonin reversed SD-induced changes in MDA and SOD in both of amygdala and serum. The results of Western blot showed that melatonin attenuated the up-regulation of NR2B-containing N-methyl-D-aspartate receptors, GluR1 subunit of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor as well as phosphorylation of GluR1 at Ser831, and Ca2+/calmodulin-dependent protein kinase II-alpha in SD rats. Meanwhile, melatonin blocked the down-regulation of γ-aminobutyric acid A-alpha-2 receptor. In conclusion, our results suggest that melatonin prevents anxiety-like behavior induced by SD. The possible mechanism may be attributed to its ability to reduce oxidative stress and maintain balance between GABAergic and glutamatergic transmission.

Investigation on maternal lineage of a Neolithic group from northern Shaanxi based on ancient DNA.

A magnetic bead purification method was successfully used to extract ancient DNA from the skeletal remains of 10 specimens excavated from Wuzhuangguoliang (Wzhgl) site, which was located in northern Shaanxi. The multidimensional scaling (MDS) and analysis of molecular variance approach (AMOVA) revealed that ancient Wzhgl people bored a very high similarity to southern Han Chinese. By constructing the MJ-network of various modern people including Han Chinese and Japanese, the phylogenetic analysis indicated that the Wzhgl population had close maternal distance with ancient Shandong and Xinjiang people. These findings indicated that Wzhgl contributed to the gene pool of Han Chinese and modern Japanese. In addition, population migration and interflow between Wzhgl people and ancient Shandong or Xinjiang probably occurred in Neolithic period.

Identifying key regulating miRNAs in hepatocellular carcinomas by an omics' method.

The miRNAs play important regulating roles in the pathogenesis of hepatocellular carcinoma (HCC). To uncover key regulating miRNAs in HCC that were neglected by traditional analyzing methods of transcriptomics data, we proposed a novel molecular-network-based omics' (MNBO) method. With this method, we predicted HCC-regulating miRNAs, and confirmed the role of a novel miR-590-3P/EED axis by a clinical study and in vitro, in vivo wet-experiments. The miR-590-3P is significantly down-regulated in HCC patients. And low level of miR-590-3P in HCC is associated with poor prognosis of patients. In HCC cell lines, the miR-590-3P suppressed cell proliferation by inhibiting the transformation G1 phase to S phases of the cell cycle. Moreover, the miR-590-3P inhibited migration and invasion of HCC cells. Further investigations indicated that miR-590-3P play its roles by inhibiting polycomb protein EED. The experiments in animal model implied miR-590-3P could be a potential therapeutic agent for HCC in the future. In conclusion, the discovery of miR-590-3P revealed the MNBO would be a useful strategy to uncover key regulating miRNAs in HCC.

Precision medicine for hepatocellular carcinoma: driver mutations and targeted therapy.

Hepatocellular carcinoma (HCC) is the third most frequent cause of tumor-related mortality and there are an estimated approximately 850,000 new cases annually. Most HCC patients are diagnosed at middle or advanced stage, losing the opportunity of surgery. The development of HCC is promoted by accumulated diverse genetic mutations, which confer selective growth advantages to tumor cells and are called "driver mutations". The discovery of driver mutations provides a novel precision medicine strategy for late stage HCC, called targeted therapy. In this review, we summarized currently discovered driver mutations and corresponding signaling pathways, made an overview of identification methods of driver mutations and genes, and classified targeted drugs for HCC. The knowledge of mutational landscape deepen our understanding of carcinogenesis and promise future precision medicine for HCC patients.

[Homologous amelogenin gene test of archaeological samples].

OBJECTIVE: Based on the sequence differences of Amelogenin homologous gene in the X and Y chromosomes, a pair of specific primers was designed to identify the sex of archaeological samples. METHODS: Ancient DNA fragments were extracted from the bones and teeth of sacrificial slaves with an improved method that combines phenol-chloroform extraction, silicon dioxide adsorption with ultrafiltration concentration. The polyacrylamide gel electrophoresis (PAGE) was used to detect PCR products. RESULTS: Seven in sixteen samples from eight graves showed positive results and the targeted segments were visible: a male with two bands of 106bp (Amel-X) and 112 bp (Amel-Y), while a female with only one band of 106 bp (Amel-X). Ancient DNA analyzing results from tooth samples are more marked than that from bones. CONCLUSION: The improved extraction method is more effective for ancient DNA extraction, which reduced the PCR inhibitors and lowered experimental costs. The sex determination technology based on Amelogenin homologous gene is an important and feasible method in the molecular archaeological research.

CTNNA3 is a tumor suppressor in hepatocellular carcinomas and is inhibited by miR-425.

Hepatocellular carcinoma (HCC) is a common and leading cause of death worldwide. Here, we identified that a cell-cell adhesion gene, CTNNA3, is a tumor suppressor in HCC. CTNNA3 inhibited the proliferation, migration and invasion of HCC cell lines. In these cells, CTNNA3 inhibited Akt signal, and in turn decreased the proliferating cell nuclear antigen (PCNA) and the matrix metallopeptidase MMP-9, and increased the cell cycle inhibitor p21(Cip1/Waf1). Meanwhile, CTNNA3 is inhibited by miR-425 in HCC. The miR-425 directly bound to the 3'UTR of CTNNA3 and inhibited its expression. The tumor suppressor function of CTNNA3 and the oncogenic function of miR-425 were further confirmed in HCC cell xenograft in nude mice. The miR-425/CTNNA3 axis may provide insights into the mechanisms underlying HCC, and contribute to potential therapeutic strategy of HCC.

Melatonin ameliorates cognitive impairment induced by sleep deprivation in rats: role of oxidative stress, BDNF and CaMKII.

Sleep deprivation (SD) has been shown to induce oxidative stress which causes cognitive impairment. Melatonin, an endogenous potent antioxidant, protects neurons from oxidative stress in many disease models. The present study investigated the effect of melatonin against SD-induced cognitive impairment and attempted to define the possible mechanisms involved. SD was induced in rats using modified multiple platform model. Melatonin (15 mg/kg) was administered to the rats via intraperitoneal injection. The open field test and Morris water maze were used to evaluate cognitive ability. The cerebral cortex (CC) and hippocampus were dissected and homogenized. Nitric oxide (NO) and malondialdehyde (MDA) levels and the superoxide dismutase (SOD) enzyme activity of hippocampal and cortical tissues (10% wet weight per volume) were performed to determine the level of oxidative stress. The expression of brain-derived neurotrophic factor (BDNF) and calcium-calmodulin dependent kinase II (CaMKII) proteins in CC and hippocampus was assayed by means of immunohistochemistry. The results revealed that SD impairs cognitive ability, while melatonin treatment prevented these changes. In addition, melatonin reversed SD-induced changes in NO, MDA and SOD in both of the CC and hippocampus. The results of immunoreactivity showed that SD decreased gray values of BDNF and CaMKII in CC and hippocamal CA1, CA3 and dentate gyrus regions, whereas melatonin improved the gray values. In conclusion, our results suggest that melatonin prevents cognitive impairment induced by SD. The possible mechanism may be attributed to its ability to reduce oxidative stress and increase the levels of CaMKII and BDNF in CC and hippocampus.

Prevalence of dental caries and tooth wear in a Neolithic population (6700-5600 years BP) from northern China.

OBJECTIVES: The purpose of this study was to assess the prevalence, distribution and intensity of dental caries as well as tooth wear in Neolithic population of northern China to increase our knowledge about the type of food, dietary habit and social stratification in this Neolithic population. MATERIALS AND METHODS: The samples analysed were dental remains of 1007 permanent teeth from 79 adult individuals, who were excavated from three Yangshao archaeological sites in the Xi'an district and adjacent Counties (northern China). The sex and the age-at-death of the samples were estimated. RESULTS: The frequency of antemortem tooth loss in the samples was 1.6%. The proportion of individuals with at least one carious tooth reached 41.8%, and the frequency of carious lesion was 5.7%. The most frequent carious lesions were occlusal lesions (4.4%), followed by interproximal (1.4%) and buccal/lingual lesions (0.4%). All 79 individuals were affected by attrition (100%) with various degrees of dental wear observed. The anterior teeth were much more worn than the posterior ones. The frequency of caries in men (3.9%) was significantly lower than that in women (8.1%), but the prevalence of tooth wear in men (99.0%) was significantly higher than that in women (95.2%). CONCLUSIONS: These findings indicate that both caries and tooth wear may be related to the subsistence and diet of this Neolithic population.