An enzymatic approach to configurationally rare trans-androsteronyl-α-glucoside and Its potential anticancer application.

Enzymatic glycosylation of sterols/steroids with glycosyltransferase HP0421 shows protein plasticity on generation of configurationally rare steryl-α-glucosides. Investigation of trans-androsteronyl-α-glucoside on tamoxifen-treated MCF-7 breast cancer cells shows dose-dependent depression of cell viability and enhanced drug effectiveness, illustrating a new avenue for the production of novel steryl-α-glucosides with useful biological activities.

p6gag domain confers cis HIV-1 Gag-Pol assembly and release capability.

During virus assembly, HIV-1 Gag-Pol is packaged into virions via interaction with Pr55gag. Studies suggest that Gag-Pol by itself is incapable of virus particle assembly or cell release, perhaps due to the lack of a budding domain in the form of p6gag, which is truncated within Gag-Pol because of a ribosomal frameshift during Gag translation. Additionally (or alternatively), large molecular size may not support Gag-Pol assembly into virus-like particles (VLPs) or release from cells. To test these hypotheses, we constructed Gag-Pol expression vectors retaining and lacking p6gag, and then reduced Gag-Pol molecular size by removing various lengths of the Pol sequence. Results indicate that Gag-Pol constructs retaining p6gag were capable of forming VLPs with a WT HIV-1 particle density. Gag-Pol molecular size reduction via partial removal of the Pol sequence mitigated the Gag-Pol assembly defect to a moderate degree. Our results suggest that the Gag-Pol assembly and budding defects are largely due to a lack of p6gag, but also in part due to size limitation.

Further evidence for the association of genetic variants of ZNF804A with schizophrenia and a meta-analysis for genome-wide significance variant rs1344706.

Recent accumulating evidence has indicated that ZNF804A (zinc finger protein 804A) may be one of the most robustly implicated genes in schizophrenia. In this report, we examined ZNF804A single nucleotide polymorphisms (SNPs) encompassing exon 4 by performing an association study that used a Han Chinese sample comprised of 492 schizophrenia patients and 516 healthy control subjects. A meta-analysis based on previous studies was also performed. For markers rs4667000 and rs1366842, significant differences in allele frequencies were found between cases and controls (Mantel-Haenszel corrected P=0.014 and P=0.025, respectively). Analysis of haplotype rs61739290-rs1366842 showed significant association with schizophrenia (global P=0.0018). Moreover, several other two-, three-, and four-SNP tests of haplotype association were also significant. A meta-analysis comprised of studies that utilized sample sets of either European and/or Han Chinese origin revealed statistically significant associations for two SNPs (rs1366842, P=0.002; and rs3731834, P=0.03) and schizophrenia. In addition, we observed a significant association between marker rsl344706 and schizophrenia (P<1.0×10(-5)) in combined populations. When we separately analyzed the studies by population, consistent and significant differences were found between cases and controls both in the European samples (P<1.0×10(-4)) and in the Chinese samples (P=0.03). In summary, we have added new evidence supporting the association between ZNF804A and schizophrenia in our Han Chinese sample. Further functional exploration of ZNF804A will greatly help us to elucidate the pathogenesis of schizophrenia and find promising new approaches for the treatment of this disorder.

Is the EFNB2 locus associated with schizophrenia? Single nucleotide polymorphisms and haplotypes analysis.

Recently, evidence of linkage of schizophrenia to chromosome 13q22-q34 has been demonstrated in multiple studies. Based on structure and function, EFNB2 may be considered as a compelling candidate gene for schizophrenia on chromosome 13q33. We genotyped three single-nucleotide polymorphisms (SNPs: rs9520087, rs11069646, and rs8000078) in this region in 846 Han Chinese subjects (477 cases and 369 controls). Significant association between an allele of marker rs9520087 and schizophrenia was found. Furthermore, since no LD was observed in the three SNPs linkage disequilibrium estimation, all three SNPs were used in multiple SNPs haplotype analysis, and a strongly significant difference was found for the common haplotype TTC. Overall our findings indicate that EFNB2 gene may be a candidate susceptibility gene for schizophrenia in the Han Chinese population, and also provide further support for the potential importance of the NMDA receptor pathway in the etiology of schizophrenia.

Evidence for transmission disequilibrium at the DAOA gene locus in a schizophrenia family sample.

Recently, the DAOA gene locus on chromosome 13q32-q34 has been implicated in the etiology of schizophrenia. We genotyped three single-nucleotide polymorphisms (SNPs: rs778294, rs779293 and rs3918342) in this region in 126 Chinese family trios. In this study, we have identified statistically significant transmission disequilibrium in two markers rs778293 (P=0.01) and rs3918342 (P=0.02), and a highly significant under-transmission between haplotype CAT (P=0.0005) and schizophrenia. The results provide further evidence to support that DAOA gene locus is involved in conferring susceptibility to schizophrenia.

Association of AKT1 gene polymorphisms with risk of schizophrenia and with response to antipsychotics in the Chinese population.

BACKGROUND: A number of studies have pointed to the involvement of AKT signaling pathways in the etiology of schizophrenia. The purpose of this study was to determine whether the AKT1 gene is involved in the etiology of schizophrenia and whether it affects therapeutic outcomes in the Chinese population. METHOD: Five single nucleotide polymorphisms (SNPs) were genotyped among 384 schizophrenic patients (DSM-IV criteria) and 384 healthy controls from the Chinese population. We systematically analyzed the association of the AKT1 gene with schizophrenia on the basis of sex, age at onset, therapeutic response to typical antipsychotics and atypical antipsychotics, and presence or absence of extrapyramidal syndrome. The study was conducted from May 2004 to June 2006. RESULTS: We found a positive association of the G allele of the SNP marker rs3803300 with schizophrenia (p = .003), both in early-onset and late-onset subjects, and that a haplotype A-G-C-G-A constructed by the 5 SNPs showed significant association (p = .00004886). However, we found no relationship between any of the 5 SNP markers and therapeutic response to typical and atypical antipsychotics and chlorpromazine-induced extrapyramidal syndrome. CONCLUSIONS: Our study suggests that AKT1 is a susceptibility gene for schizophrenia in the Chinese population and that the AKT1 gene may play no major role in the therapeutic response to antipsychotics or in chlorpromazine-induced extrapyramidal syndrome.

Association study of the A2M and LRP1 Genes with Alzheimer disease in the Han Chinese.

BACKGROUND: Low-density lipoprotein receptor-related protein 1 (LRP1) and alpha-2-macroglobulin (A2M) are two plausible candidate genes for Alzheimer disease (AD) based on their important biological function and positional information. To date, numerous studies have investigated their possible association with AD but the results are controversial. METHODS: To investigate the potential genetic contribution of the two genes in the Han Chinese population, we performed a case-control association study using 10 polymorphisms (4 in LRP1 and 6 in A2M) that span approximately the whole corresponding gene. RESULTS: Comparison of allele, genotype, and haplotype frequencies for polymorphisms in A2M revealed no significant differences between patients and control subjects. For the LRP1 gene, however, we found an overrepresentation of the CTCG haplotype in the control group (p = .002). The difference was still of statistical significance in the apolipoprotein E (APOE) epsilon 4 negative subjects (p(CTCG) = .003). Multiple logistic regression analysis did not show any evidence of synergism between A2M, LRP1, and APOE. CONCLUSIONS: Our results indicate that the CTCG haplotype of LRP1 may reduce the risk of late-onset AD, but A2M is not associated with this disease in the Han Chinese population.

Polymorphisms in the TSHR (thyrotropin receptor) gene on chromosome 14q31 are not associated with mental retardation in the iodine-deficient areas of China.

Mental retardation (MR) is one of the most frequent handicaps among children. Fetal iodine deficiency disorder (FIDD) is the commonest cause of preventable MR. However, not everyone in the iodine-deficient areas is affected and familial aggregation is common. This suggests that genetic factors may play an important role. Thyroid hormone (TH) plays an important role in fetal and early postnatal brain development. The thyroid-stimulating hormone (TSH, or thyrotropin) receptor (TSHR) is located on the surface of thyroid cells and binds TSH. It results in the production of thyroid hormones via the activation of adenylate cyclase and phospatidylinositol-dependent signaling pathways. Some researchers formulated the hypothesis that TSH receptor expression in the brain may be involved in local thyroid homeostasis through TSH stimulating the DIO2 activity. In the previous study, we have proposed that DIO2 may protect against FIDD in the iodine-deficient areas of China. The TSHR gene, which located on chromosome 14q31 is a potential candidate gene for susceptibility to FIDD. To investigate the potential genetic contribution of TSHR gene, we performed a case-control association study in Chinese Han population from the Qin-Ba mountain regions using four common SNPs in the gene (rs2284716, rs917986, rs2075173 and rs2075179). Pairwise linkage disequilibrium (LD) analysis showed that LD was observed between rs2284716 and rs917986 and between rs2075173 and rs2075179. Single-locus analysis found that all four SNPs in TSHR gene showed no association after correction for multiple testing. Haplotype analysis showed no significant differences in frequency for three sets of haplotypes based on the pariwise LD results. In conclusion, our association results suggest that TSHR gene is not a susceptibility gene for FIDD in the iodine-deficient areas of China.