A partition-ligation-combination-subdivision EM algorithm for haplotype inference with multiallelic markers: update of the SHEsis (http://analysis.bio-x.cn)

Haplotypic information in diploid organisms provides valuable information on human evolutionary history and plays an important role in identifying a candidate gene in the etiology of complex genetic diseases. However, haplotypes of diploid individuals cannot be acquired easily. Molecular haplotyping methods are very costly and have low throughput, and current genotyping and sequenc- ing methods do not provide information on the linkage phase in diploid organisms. The application of statistical methods to infer the haplotype phase in samples of diploid sequences is a very cost-effective approach.

SHEsis,a powerful software platform for analyses of linkage disequilibrium,haplotype construction,and genetic association at polymorphism loci

In multiloci-based genetic association studies of complex diseases, a powerful and high efficient tool for analyses oflinkage disequilibrium (LD) between markers, haplotype distributions and many chi-square/p values with a large numberof samples has been sought for long. In order to achieve the goal of obtaining meaningful results directly from raw data,we developed a robust and user-friendly software platform with a series of tools for analysis in association study withhigh efficiency. The platform has been well evaluated by several sets of real data.

维持性血液透析患者血管钙化和血清骨硬化蛋白的相关因素

目的探讨维持性血液透析(MHD)患者血清骨硬化蛋白与慢性肾脏病矿物质和骨异常(CKD-MBD)相关指标尤其是血管钙化的关系。方法筛选暨南大学附属第一医院MHD患者72例,收集一般资料,检测血钙、磷、甲状旁腺激素(IPTH)等矿物质代谢指标,透析前后肌酐、尿素,计算Kt/V。用酶联免疫吸附法检测血清骨硬化蛋白水平。行腰椎侧位片进行腹主动脉钙化评分(Kauppila半定量法)。按血清骨硬化蛋白水平(≤125 pg/mL和> 125 pg/mL)分为2组,比较分析CKD-MBD相关指标与骨硬化蛋白的关系,并对其进行多因素Logistic回归分析。结果低血清骨硬化蛋白组和高血清骨硬化蛋白组比较发现,MHD患者IPTH差异统计学意义(P <0.05)。将CKD-MBD等相关指标引入Logistic回归模型发现,透析龄、男性和无尿是MHD患者血清骨硬化蛋白的独立危险因素,IPTH和Kt/V是其保护因素。结论透析龄、男性和无尿是MHD患者血清骨硬化蛋白的独立危险因素,IPTH和Kt/V是其保护因素。腹主动脉钙化与血清骨硬化蛋白无关。

羊膜腔穿刺对母婴HBV垂直传播的meta分析

目的母婴乙肝病毒垂直传播已成为我国乙肝病毒感染的主要途径,本研究分析乙肝病毒感染的孕妇进行羊膜腔穿刺是否增加母婴垂直传播的风险。方法搜索1990年1月1日~2016年3月15日之间在Pubmed、Embase、谷歌学术和万方数据库等数据库中所有关于乙肝孕妇行羊膜腔穿刺对母婴垂直传播影响的相关英文或中文文章,根据纳入剔除标准对文章进行筛选,然后对文章治疗评分,最后有4篇文章纳入,共有3997孕妇,其中实验组167名、对照组3830名,使用Review Manager Version 5.0进行数据分析。结果荟萃分析结果显示,进行羊膜腔穿刺术与不行羊膜腔穿刺术两组婴儿HBsAg阳性率无明显差异(R^2=1.37,95%CI:0.70~2.69,P=0.36)。当孕妇是HBV-DNA≥10~7 copies/mL、HBeAg阳性时,进行羊膜腔穿刺术后胎儿宫内感染风险增加(R^2=9.54,95%CI:3.52~25.85,P<0.0004;R^2=3.41,95%CI:1.05~11.13,P=0.04)。结论孕妇HBV-DNA≥107 copy/mL和(或)HBeAg阳性时将增加母婴垂直传播的风险。

ATF4 regulates lipid metabolism and thermogenesis

Activating transcription factor 4 （ATF4） has been shown to play key roles in many physiological processes. There are no reports, however, demonstrating a direct link between ATF4 and lipid metabolism. We noticed that Atf4- deficient mice are lean, suggesting a possible role for ATF4 in regulating lipid metabolism. The goal of our current study is to investigate the involvement of ATF4 in lipid metabolism and elucidate the underlying mechanisms. Studies using Atf4-deficient mice revealed increased energy expenditure, as measured by oxygen consumption. These mice also showed increases in lipolysis, expression of uncoupling protein 2 （UCP2） and p-oxidation genes and decreases in expression of lipogenic genes in white adipose tissue （WAT）, suggesting increased utilization and decreased synthesis of fatty acids, respectively. Expression of UCP1, 2 and 3 was also increased in brown adipose tissue （BAT）, suggesting increased thermogenesis. The effect of ATF4 deletion on expression of UCPs in BAT suggests that increased thermogenesis may underlie increased energy expenditure. Thus, our study identifies a possible new function for ATF4 in regulating lipid metabolism and thermogenesis.

C/EBPα regulates SIRT1 expression during adipogenesis

SIRT1 plays an important role in adipogenesis, but how SIRT1 is regulated in adipogenesis is largely unknown. In this study, we show that both SIRT1 protein and mRNA levels were increased along with CCAAT/enhancer-binding protein a （C/EBPa） during adipocyte differentiation. C/EBPa, but not C/EBPap30, activated SIRT1 promoter in both HeLa cells and 3T3-L1 preadipocytes. Furthermore, C/EBPa upregulated SIRT1 mRNA and protein levels in HeLa cells and increased SIRT1 expression in a p53-independent manner in Soas2 cells. In preadipocytes, ectopic expression of C/EBPa upregulated SIRT1 protein level and knockdown of C/EBPa led to the decrease of SIRTI pro- tein level. Moreover, by promoter deletion analysis, gel shift assay and chromatin immunoprecipitation, we found that C/EBPa bound to the SIRT1 promoter at a consensus C/EBPα binding site. These data demonstrate that C/ EBPα regulates SIRT1 expression during adipogenesis by directly binding to the SIRT1 promoter.

Recent progress in the study of Hedgehog signaling

The Hedgehog （Hh） family of secreted signaling proteins plays a critical role in regulating the development of several tissues and organ systems. The ability of Hh proteins to exert their biological effects is regulated by a series of post-translational processes. These processes include an intramolecular cleavage, covalent addition of cholesterol and/or palmitate, and conversion into a multimeric freely diffusible form. The processing of Hh proteins affects their trafficking, potency, and ability to signal over several cell diameters. Here we review the current understanding of the Hh signaling mechanisms that govern the establishment of the Hh gradient and the transduction of the Hh signal in the light of recent data.

SHEsisEpi, a GPU-enhanced genome-wide SNP-SNP interaction scanning algorithm, efficiently reveals the risk genetic epistasis in bipolar disorder

Dear Editor, We developed a GPU-based analytical method, named as SHEsisEpi, which purely focuses on risk epistasis in a genome-wide association study （GWAS） of complex traits, excluding the contamination of marginal effects caused by single-locus association. We analyzed the Wellcome Trust Case Control Consortium＇s （WTCCC） GWAS data of bipolar disorder （BPD） with 500K SNPs.

Endocytosis of adiponectin receptor I through a clathrin- and Rab5-dependent pathway

In eukaryotic cells, receptor endocytosis is a key event regulating signaling transduction. Adiponectin receptors belong to a new receptor family that is distinct from G-protein-coupled receptors and has critical roles in the pathogenesis of diabetes and metabolic syndrome. Here, we analyzed the endocytosis of adiponectin and adiponectin receptor 1 （AdipoR1） and found that they are both internalized into transferrin-positive compartments that follow similar traffic routes. Blocking clathrin-mediated endocytosis by expressing Eps15 mutants or depleting K^＋ trapped AdipoR1 at the plasma membrane, and K^＋ depletion abolished adiponectin internalization, indicating that the endocytosis of AdipoR1 and adiponectin is clathrin-dependent. Depletion of K^＋ and overexpression of Eps15 mutants enhance adiponectin- stimulated AMP-activated protein kinase phosphorylation, suggesting that the endocytosis of AdipoR1 might down-regulate adiponectin signaling. In addition, AdipoR1 colocalizes with the small GTPase Rab5, and a dominant negative Rab5 abrogates AdipoR1 endocytosis. These data indicate that AdipoR1 is internalized through a clathrin- and Rab5- dependent pathway and that endocytosis may play a role in the regulation of adiponectin signaling.

Anti-fatigue effects of salidroside in mice

Objective： To study the anti-fatigue effects of salidroside in mice. Methods： Totally 120 normal male Kunming mice were randomized into 5 groups （4 salidroside intervention groups and the control group） based on body weight. The control group was given distilled water and the 4 intervention groups were given various doses of salidroside （60, 180, 360, 720 mg/kg） for 15 consecutive days, respectively. The levels of lactate, serum urea nitrogen, muscle and liver glycogen, the longest swimming time and hemoglobin were determined before and after swimming test. Results： Different doses of salidroside significantly lengthened the swimming time and increased the contents of hemoglobin and muscle and liver glycogen, while reducing that of lactate in blood significantly compared with control group, especially in the 180 mg/kg salidroside group. Conclusion： Salidroside has noticeable anti-fatigue effect on mice. These effects were dose-dependent, and the strongest effect on most biomarkers was seen with an intermediate dose.

Patterning mechanisms controlling digit development

Vertebrate digits are essential structures for movement, feeding and communication. Specialized regions of the developing limb bud including the zone of polarizing activity （ZPA）, the apical ectodermal ridge （AER）, and the non-ridge ectoderm regulate the patterning of digits. Although a series of signaling molecules have been characterized as patterning signals from the organizing centers, the delicate cellular and molecular mechanisms that interpret how these patterning signals control the detailed digit anatomy remain unclear, Recent studies from model organisms and human hand malformations provide new insights into the mechanisms regulating this process. Here, we review the current understanding of the genetic networks governing digit morphogenesis

Different Patterns of Cyclin D1/CDK4-E2F-1/4 Pathways in Human Embryo Lung Fibroblasts Treated by Benzo[a]pyrene at Different Doses

Objective To investigate the roles of the cyclin D1/CDK4 and E2F-1/4 pathways and compare their work patterns in cell cycle changes induced by different doses of B[a]E Methods Human embryo lung fibroblasts （HELFs） were treated with 2 μmol/L or 100 μmol/L B[a]P which were provided with some characteristics of transformed cells （T-HELFs）. Cyclin D l, CDK4 and E2F-1/4 expressions were determined by Western blotting. Flow cytometry was used to detect the distribution of cell cycle. Results After B[a]P treatment, the proportion of the first gap （G 1） phase cells decreased. CDK4 and E2F-4 expression did not change significantly. In 2 μmol/L treated cells, a marked overexpression of cyclin D1 and E2F-1 was observed. However, in T-HELFs overexpression was limited to cyclin D1 only, and no overexpression of E2F-1 was observed. The decreases of G1 phase in response to B[a]P treatment were blocked in antisense cyclin D1 and antisense CDK4 transfected HELFs （A-D1 and A-K4） and T-HELFs （T-A-D1 and T-A-K4）. After 2 μmol/L B[a]P treatment, overexpression of E2F-1 was attenuated in A-D1, and E2F-4 expression was decreased significantly in A-K4. In T-A-D1 and T-A-K4, E2F-4 expression was increased significantly, compared with T-HELFs. The E2F-1 expression remained unchanged in T-A-D1 and T-A-K4. Condusions Cyclin DI/CDK4-E2F-1/4 pathways work in different patterns in response to low dose and high dose B[a]P treatment. In HELFs treated with 2 μmol/L B[a]P, cyclin D1 positively regulates the E2F-1 expression while CDK4 negatively regulates the E2F-4 expression; however, in HELFs treated with 100 μmol/L B[a]P, both cyclin D1 and CDK4 negatively regulate the E2F-4 expression.

Induction of CD4＋CD25＋Foxp3＋ regulatory T cell response by glatiramer acetate in type 1 diabetes

Glatiramer acetate （GA） is an immunomodulatory peptide drug used to treat multiple sclerosis. Its treatment effect has been expanded to other autoimmune conditions such as uveoretinitis, inflammatory bowel disease, graft re- jection and hepatic fibrosis. Here, we report that GA was effective in altering the clinical course of diabetes in cyclo- phosphamide （CY）-potentiated non-obese diabetic （CY-NOD） mice. Treatment with GA significantly reduced the dia- betic rate in the mice and ameliorated insulitis, which coincided with increased CD4＋CD25＋Foxp3＋ T cell response in treated mice. GA treatment led to increased expression of transcription factor Foxp3 and elevated production of interleukin-4 （IL-4） both in vivo and in vitro. It was evident that the effect of GA on up-regulation of Foxp3 was me- diated partially through IL-4. IL-4 was found to maintain Foxp3 expression and regulatory function of CD4＋CD25＋ regulatory T cells （Tregs）. This study provides new evidence that GA has treatment potential for type 1 diabetes through the induction of Tregs and that increased IL-4 production is partially responsible for the enhanced Treg＇s function in GA treatment.

Effects of titanium dioxide nanoparticles on intestinal commensal bacteria

Nanomaterials and nanotechnology have great potential in the biological and biomedical field. Recent studies reveal that many nanomaterials possess antibacterial activities. While most of these studies focus on the ability of nanomaterials to inhibit the growth of pathogenic bacteria in vitro, few of them test the effects of nanomaterials on intestinal commensal bacteria. Here, we report that Ti O_2nanoparticles(10, 50 and 100 nm in size) can inhibit the growth of Drosophila intestinal commensal bacteria in vitro. This activity depends on the dosage or size, but is independent of the photocatalytic activity of Ti O_2 nanoparticles. Surprisingly, dietary Ti O_2 nanoparticles of the same dosage fail to display similar effects in Drosophila larvae or adults. These flies show a normal amount of intestinal commensal bacteria, as well as a normal developmental cycle, energy store, and locomotor activity. These results imply that the antibacterial effect of Ti O_2 nanoparticles differs in vitro and in vivo.

Genome engineering of stem cell organoids for disease modeling

Precision medicine emerges as a new approach that takes into account individual variability. Successful realization of precision medicine requires disease models that are able to incorporate personalized dis- ease information and recapitulate disease development processes at the molecular, cellular and organ levels. With recent development in stem cell field, a variety of tissue organoids can be derived from patient specific pluripotent stem cells and adult stem cells. In combi- nation with the state-of-the-art genome editing tools, organoids can be further engineered to mimic disease- relevant genetic and epigenetic status of a patient. This has therefore enabled a rapid expansion of sophisticated in vitro disease models, offering a unique system for fundamental and biomedical research as well as the development of personalized medicine. Here we summarize some of the latest advances and future perspectives in engineering stem cell organoids for human disease modeling.

Amygdala, an important regulator for food intake

Amygdala plays a critical role in the regulation of emotional behavior and food intake.Neuropeptides are short chains of amino acids secreted by neurons as intercellular messengers,which regulate different functions such as emotion,food intake,learning and memory.In this review,we summarize the recent progress on the regulation of food intake by amygadala,which is mediated by those neuropeptides known to be critical in the regulation of this process.

Role of Resistin in Inflammation and Inflammation-Related Diseases

Resistin is a newly identified adipocyte secreted hormone belonging to a cysteine-rich protein family. It is expressed in white adipose tissues in rodents and has also been found in several other tissues in human. Insulin, glucose, many cytokines and anti-diabetic thiazolidinediones are regulators of resistin gene expression. Resistin was firstly proposed to be involved in insulin resistance and type 2 diabetes. Recently, it was found to be relevant to inflammation and inflammation-related diseases like atherosclerosis and arthritis.

Analogic China map constructed by DNA

In this research,a nanoscale DNA structure of analogic China map is created. The nanostructure of roughly 150 nm in diameter with a spatial resolution of 6 nm is purely constructed by folding DNA. The picture observed by atomic force microscopy (AFM) is almost identical with the de-signed shape. The DNA origami technology invented by Rothemund in 2006 is employed in the construc-tion of this shape,which has proved the capability of constructing almost any complicated shape enabled by DNA origami,and provides new bottom-up method for constructing nanostructures.

Chemotherapy drugs induce pyroptosis through caspase-3-dependent cleavage of GSDME

Chemotherapy drugs can induce cancer cell death via a series of regulated cell death（RCD）pathways including apoptosis and regulated necrosis（Vanden Berghe et al.,2014）.Characterized by activation of the caspase family of cystine proteases,the occurrence of apoptosis leads to cell shrinkage and formation of apoptotic bodies.

Control of Leaf Senescence by an MeOH- Jasmonates Cascade that Is Epigenetically Regulated by OsSRT1 in Rice

Although considerable progress has been made in identifying the genes regulating accumulation of hormones that are involved in leaf senescence, only a few studies have focused on natural variations in jasmonates content and much less on the underlying genetic basis. Moreover, the epigenetic regulation of jasmonate-mediated leaf senescence remains largely unknown, in this study, we carried out metabolic profiling of a worldwide collection of rice accessions and demonstrated that there are substantial variations in jasmonate levels among these accessions. A subsequent metabolite-based genornewide association study identified candidates for two major quantitative genes （QTGs）, OsPME1 and OsTSD2, affecting the content of jasmonates. Further investigations using a series of relevant mutants and transgenic lines revealed the MeOH-jasmonata cascade plays an important role in regulating leaf senescence. Moreover, we showed that OsSRT1, one of the two Sir2 （silent information regugator 2） homologs in rice, negatively regulates leaf senescence by repressing expression of the biosynthetic genes of this metabolic cascade and at least particiaUy through histone H3K9 deacetylation of OsPME1. Taken together, our results indicate that the MeOH-jasmonates cascade and its epigenetic regulation are crucial for controlling leaf senescence process in rice.