Season of conception in rural gambia affects DNA methylation at putative human metastable epialleles

Throughout most of the mammalian genome, genetically regulated developmental programming establishes diverse yet predictable epigenetic states across differentiated cells and tissues. At metastable epialleles (MEs), conversely, epigenotype is established stochastically in the early embryo then maintained in differentiated lineages, resulting in dramatic and systemic interindividual variation in epigenetic regulation. In the mouse, maternal nutrition affects this process, with permanent phenotypic consequences for the offspring. MEs have not previously been identified in humans. Here, using an innovative 2-tissue parallel epigenomic screen, we identified putative MEs in the human genome. In autopsy samples, we showed that DNA methylation at these loci is highly correlated across tissues representing all 3 embryonic germ layer lineages. Monozygotic twin pairs exhibited substantial discordance in DNA methylation at these loci, suggesting that their epigenetic state is established stochastically. We then tested for persistent epigenetic effects of periconceptional nutrition in rural Gambians, who experience dramatic seasonal fluctuations in nutritional status. DNA methylation at MEs was elevated in individuals conceived during the nutritionally challenged rainy season, providing the first evidence of a permanent, systemic effect of periconceptional environment on human epigenotype. At MEs, epigenetic regulation in internal organs and tissues varies among individuals and can be deduced from peripheral blood DNA. MEs should therefore facilitate an improved understanding of the role of interindividual epigenetic variation in human disease.     

Rapamycin inhibits AR signaling pathway in prostate cancer by interacting with the FK1 domain of FKBP51

Reactivation of the androgen receptor signaling pathway in the emasculated environment is the main reason for the occurrence of castration-resistant prostate cancer (CRPC). The immunophilin FKBP51, as a co-chaperone protein, together with Hsp90 help the correct folding of AR. Rapamycin is a known small-molecule inhibitor of FKBP51, but its effect on the FKBP51/AR signaling pathway is not clear. In this study, the interaction mechanism between FKBP51 and rapamycin was investigated using steady-state fluorescence quenching, X-ray crystallization, MTT assay, and qRT-PCR. Steady-state fluorescence quenching assay showed that rapamycin could interact with FKBP51. The crystal of the rapamycin-FKBP51 complex indicated that rapamycin occupies the hydrophobic binding pocket of FK1 domain which is vital for AR activity. The residues involving rapamycin binding are mainly hydrophobic and may overlap with the AR interaction site. Further assays showed that rapamycin could inhibit the androgen-dependent growth of human prostate cancer cells by down-regulating the expression levels of AR activated downstream genes. Taken together, our study demonstrates that rapamycin suppresses AR signaling pathway by interfering with the interaction between AR and FKBP51. The results of this study not only can provide useful information about the interaction mechanism between rapamycin and FKBP51, but also can provide new clues for the treatment of prostate cancer and castration-resistant prostate cancer.     

DNA methylation profiles of primary colorectal carcinoma and matched liver metastasis

Background

The contribution of DNA methylation to the metastatic process in colorectal cancers (CRCs) is unclear.

Methods

We evaluated the methylation status of 13 genes (MINT1, MINT2, MINT31, MLH1, p16, p14, TIMP3, CDH1, CDH13, THBS1, MGMT, HPP1 and ERα) by bisulfite-pyrosequencing in 79 CRCs comprising 36 CRCs without liver metastasis and 43 CRCs with liver metastasis, including 16 paired primary CRCs and liver metastasis. We also performed methylated CpG island amplification microarrays (MCAM) in three paired primary and metastatic cancers.

Results

Methylation of p14, TIMP3 and HPP1 in primary CRCs progressively decreased from absence to presence of liver metastasis (13.1% vs. 4.3%; 14.8% vs. 3.7%; 43.9% vs. 35.8%, respectively) (P<.05). When paired primary and metastatic tumors were compared, only MGMT methylation was significantly higher in metastatic cancers (27.4% vs. 13.4%, P = .013), and this difference was due to an increase in methylation density rather than frequency in the majority of cases. MCAM showed an average 7.4% increase in DNA methylated genes in the metastatic samples. The numbers of differentially hypermethylated genes in the liver metastases increased with increasing time between resection of the primary and resection of the liver metastasis. Bisulfite-pyrosequencing validation in 12 paired samples showed that most of these increases were not conserved, and could be explained by differences in methylation density rather than frequency.

Conclusions

Most DNA methylation differences between primary CRCs and matched liver metastasis are due to random variation and an increase in DNA methylation density rather than de-novo inactivation and silencing. Thus, DNA methylation changes occur for the most part before progression to liver metastasis.     

Factors influencing wild boar damage in Taohongling National Nature Reserve in China: a model approach

Conflicts between humans and wildlife, especially wild boar (Sus scrofa), have caused serious problems across the world in recent years. It is necessary to effectively control wild boar agricultural damage that may be influenced by many factors. In this study, we collected data on agricultural damage caused by wild boars from November 2009 to October 2010 using field surveys and social interviews in Taohongling National Nature Reserve of Jiangxi Province, China. We constructed models using binary logistic regression analysis to predict damage risks and to identify the factors influencing damage risks. About 8.1 % of croplands were damaged by wild boars, and the damage to rice, cotton, and other crops were not distributed based on their respective availability as shown by the result of a chi-square goodness-of-fit test. Five factors (Japanese silvergrass, soil conditions, terrain, distances to settlements, and water sources) were explained in a model based on damage area (area-based model) with the prediction accuracy being 72.1 %. In addition to these five factors, one additional factor (i.e. distance to forest edge) was retained in a model based on damage frequency (frequency-based model) with the prediction accuracy being 83.1 %. Caution is needed when we apply these two models to predict boar damage to crops, and it is recommended that both models be used in combination to predict the damage probabilities more accurately.     

马铃薯甲虫结节性硬化复合物基因LdTSC1和LdTSC2基因的克隆及功能分析

【目的】通过RNAi技术明确马铃薯甲虫TOR上游的关键信号集成节点及类胰岛素信号通道下游基因结节性硬化复合物TSC1和TSC2的功能。旨在为探明马铃薯甲虫类胰岛素信号转导提供更多理论支持。【方法】在NCBI(美国国家生物技术信息中心)获取马铃薯甲虫LdTSC1/2序列,分别利用多重序列比对和系统发育分析确定该基因的完整性和系统发育关系;采用喂食幼虫dsRNA的方法,观察该基因的调低对马铃薯甲虫幼虫生长发育、糖脂代谢的影响。【结果】克隆得到马铃薯甲虫TSC1编码蛋白的氨基酸序列与鞘翅目白蜡窄吉丁直系同源蛋白的氨基酸序列的自展一致度为100%,聚为一支;TSC2编码蛋白的氨基酸序列与鞘翅目白蜡窄吉丁和赤拟谷盗的同源蛋白氨基酸序列的自展一致度为100%,聚为一支。通过分别喂食2龄幼虫LdTSC1/2的dsRNA能有效降低靶标基因的表达量,幼虫出现体重减轻,化蛹率和羽化率显著下降,葡萄糖的吸收转化效率降低,海藻糖含量升高和甘油三酯均减少。【结论】下调2龄幼虫LdTSC1/2的表达量,导致试虫出现抑制了糖脂代谢、脂肪体减少、体重减轻以及发育延迟;结果表明LdTSC1/2调控了马铃薯甲虫幼虫的糖脂代谢过程,显著影响幼虫化蛹和蜕皮过程。     

Association between two genetic variants in miRNA and primary liver cancer risk in the Chinese population

MicroRNAs (miRNAs) play an important role in the growth and development of human beings. Single nucleotide polymorphisms (SNPs) within miRNA could change their production or affinity with target genes, thus leading to malignant diseases. This case-control study conducted in Western China aimed to explore the relationship between polymorphisms in miR-146a (rs2910164 G>C) and miR-499 (rs3746444 T>C) and primary liver cancers in the Chinese population. 186 primary liver cancer cases and 483 healthy controls were genotyped using polymerase chain reaction-restriction fragment length polymorphism. No significant differences were observed between distributions of the two SNPs and susceptibility of primary liver cancer or diverse clinicopathologic features. However, we found that patients with genotype CG of the SNP in miR-146a tended to have earlier onset and better liver function than patients with genotype CC (average age: 49.9 vs. 54.9, p=0.038; average Child-Pugh grade: 5.55 vs. 6.15, p=0.021), and further analysis showed that patients who had at least one G allele were diagnosed at an earlier age (average age: 49.6 vs. 54.9, p=0.022) and had better liver function (average Child-Pugh grade:5.60 vs. 6.15, p=0.026). Our data suggested lack of association between the two SNPs and primary liver cancer risk, though, interestingly, the miR-146a SNP may influence the age of onset and Child-Pugh grade.     

基于mtDNA D-loop分析高原鳅群体遗传多样性和系统发育

本研究以高原鳅属6个群体共82尾个体的线粒体DNA D-loop高变区为标记,采用分子生物信息学方法分析其遗传多样性及系统发育关系.结果表明,在570 bp的mtDNA D-loop中共检测到149个多态位点,由此界定了 39个单倍型.在6个群体中,单倍型多样度(Hd)由高到低依次为细尾高原鳅(T.stenura)(0...     

Hollow CuS Nanoboxes as Li‐Free Cathode for High‐Rate and Long‐Life Lithium Metal Batteries

Transition metal sulfides hold promising potentials as Li‐free conversion‐type cathode materials for high energy density lithium metal batteries. However, the practical deployment of these materials is hampered by their poor rate capability and short cycling life. In this work, the authors take the advantage of hollow structure of CuS nanoboxes to accommodate the volume expansion and facilitate the ion diffusion during discharge–charge processes. As a result, the hollow CuS nanoboxes achieve excellent rate performance (≈371 mAh g^?1 at 20 C) and ultra‐long cycle life (>1000 cycles). The structure and valence evolution of the CuS nanobox cathode are identified by scanning electron microscopy, transmission electron microscopy, and X‐ray photoelectron spectroscopy. Furthermore, the lithium storage mechanism is revealed by galvanostatic intermittent titration technique and operando Raman spectroscopy for the initial charge–discharge process and the following reversible processes. These results suggest that the hollow CuS nanobox material is a promising candidate as a low‐cost Li‐free cathode material for high‐rate and long‐life lithium metal batteries.     

五种假单胞菌的分离鉴定及其生物活性

【目的】从湖南长沙市采集到的土样中分离假单胞菌并进行归类,研究各菌株抑菌和抗肿瘤生物活性,以丰富假单胞菌菌种资源并为微生物次级代谢物的挖掘奠定基础。【方法】采用大蜡螟诱集法诱集分离假单胞菌,结合形态观察、生理生化特征和16S rRNA基因序列同源性分析,鉴定并归类各细菌,通过平板扩散法、对峙培养法和肿瘤细胞毒性试验分别研究各菌株抑制细菌、拮抗真菌和抗肿瘤细胞等生物活性。【结果】从湖南长沙市郊区菜地、林地中分离得到5株假单胞菌,归类并命名为Pseudomonas protegens CY01、绿针假单胞菌CY02(Pseudomonas chlororaphis CY02)、栖稻假单胞菌CY04(Pseudomonas oryzihabitans CY04)、Pseudomonas sp.CY05和恶臭假单胞菌CY06(Pseudomonas putida CY06)。P.protegens CY01和P.chlororaphis CY02对枯草芽胞杆菌(Bacillus subtillis)和金黄色葡萄球菌(Staphylococcus aureus)具有较好的抑菌效果,P.chlororaphis CY02对水稻稻瘟病菌(Pyricularia oryzae)具有良好的拮抗作用,对小鼠黑色素瘤细胞B16具有较强的细胞毒性。【结论】分离得到的P.chlororaphis CY02,在抑制病原细菌、拮抗水稻稻瘟病菌和抗肿瘤细胞等方面具有显著效果。