Homozygous A polymorphism of the complement C1qA 276 correlates with prolonged overall survival in patients with diffuse large B cell lymphoma treated with R-CHOP

ABSTRACT: BACKGROUND: The precise mechanism of action for rituximab (R) is not fully elucidated. Besides antibodydependent cellular cytotoxicity (ADCC), complements may also play an important role in the clinical response to rituximab-based therapy in diffuse large B cell lymphoma (DLBCL). The purpose of this study was to explore the relationship between C1qA[276] polymorphism and the clinical response to standard frontline treatment with R-CHOP in DLBCL patients. METHODS: Genotyping for C1qA[276A/G] was done in 164 patients with DLBCL. 129 patients treated with R-CHOP as frontline therapy (R [greater than or equal to] 4 cycles) were assessable for the efficacy. RESULTS: Patients with homozygous A were found to have a higher overall response rate than those with heterozygous or homozygous G alleles (97.3% vs. 83.7%,P = 0.068). The complete response rate in patients with homozygous A was statistically higher than that in AG and GG allele carriers (89.2% vs. 51.1%,P = 0.0001). The overall survival of patients with homozygous A was longer than that of the G allele carriers (676 days vs. 497 days, P = 0.023). Multivariate Cox regression analysis showed that C1qA A/A allele was an independent favorable prognostic factor for DLBCL patients treated with R-CHOP as firstline therapy. CONCLUSION: These results suggest that C1qA polymorphism may be a biomarker to predict response to RCHOP as frontline therapy for DLBCL patients.     

Characterization of C1q in Teleosts: INSIGHT INTO THE MOLECULAR AND FUNCTIONAL EVOLUTION OF C1q FAMILY AND CLASSICAL PATHWAY*

C1qs are key components of the classical complement pathway. They have been well documented in human and mammals, but little is known about their molecular and functional characteristics in fish. In the present study, full-length cDNAs of c1qA, c1qB, and c1qC from zebrafish (Danio rerio) were cloned, revealing the conservation of their chromosomal synteny and organization between zebrafish and other species. For functional analysis, the globular heads of C1qA (ghA), C1qB (ghB), and C1qC (ghC) were expressed in Escherichia coli as soluble proteins. Hemolytic inhibitory assays showed that hemolytic activity in carp serum can be inhibited significantly by anti-C1qA, -C1qB, and -C1qC of zebrafish, respectively, indicating that C1qA, C1qB, and C1qC are involved in the classical pathway and are conserved functionally from fish to human. Zebrafish C1qs also could specifically bind to heat-aggregated zebrafish IgM, human IgG, and IgM. The involvement of globular head modules in the C1q-dependent classical pathway demonstrates the structural and functional conservation of these molecules in the classical pathway and their IgM or IgG binding sites during evolution. Phylogenetic analysis revealed that c1qA, c1qB, and c1qC may be formed by duplications of a single copy of c1qB and that the C1q family is, evolutionarily, closely related to the Emu family. This study improves current understanding of the evolutionary history of the C1q family and C1q-mediated immunity.     

HIF-1α 1772 C/T and 1790 G/A Polymorphisms Are Significantly Associated with Higher Cancer Risk: An Updated Meta-Analysis from 34 Case-Control Studies

Background

HIF-1 activates various genes in cancer progression and metastasis. HIF-1α 1772 C/T and 1790 G/A polymorphisms are reportedly associated with cancer risk; however, the results are inconclusive.

Methodology/Principal Findings

A meta-analysis of 34 studies that involved 7522 cases and 9847 controls for 1772 C/T and 24 studies that involved 4884 cases and 8154 controls for 1790 G/A was conducted to identify the association of C/T and G/A polymorphisms with cancer risk. Odds ratio (OR) and 95% confidence intervals (95% CI) were used to assess the strength of association.HIF-1α 1772 C/T and 1790 G/A polymorphisms were associated with higher cancer risk in homozygote comparison (1772C/T: TT vs. CC: OR = 2.45, 95% CI: 1.52, 3.96; P _{heterogeneity} = 0.028; 1790G/A: AA vs. GG: OR=4.74, 95% CI: 1.78, 12.6; P _{heterogeneity} < 0.01), dominant model (1772C/T: TT/CT vs. CC: OR = 1.27, 95% CI: 1.04, 1.55; P _{heterogeneity} < 0.01, 1790G/A: AA/GA vs. GG: OR = 1.65, 95% CI: 1.05, 2.60; P _{heterogeneity} < 0.01), T allele versus C allele (T vs. C: OR = 1.42, 95% CI: 1.18, 1.70; P _{heterogeneity} < 0.01), and A allele versus G allele (A vs. G: OR = 1.83, 95% CI: 1.13, 2.96; P _{heterogeneity} < 0.01). On a subgroup analysis, the 1772 C/T polymorphism was significantly linked to higher risks for breast cancer, lung cancer, prostate cancer, and cervical cancer, whereas the 1790 G/A polymorphism was significantly linked to higher risks for lung cancer and prostate cancer. A significantly increased cancer risk was found in both Asians and Caucasians for 1772C/T polymorphism, whereas a significantly increased cancer risk was found in Caucasians in the heterozygote comparison and recessive model for 1790G/A polymorphism.

Conclusions

HIF-1α 1772 C/T and 1790 G/A polymorphisms are significantly associated with higher cancer risk.     

A meta-analysis of the association of glutathione S-transferase P1 gene polymorphism with the susceptibility of breast cancer

Glutathione S-transferase P1 (GSTP1) is one of the important mutant sites for the cancer risk at present. The conclusions of the published reports on the relationship between GSTP1 A/G gene polymorphism and the risk of breast cancer are still debated. This meta-analysis was performed to evaluate the association between GSTP1 and the risk of breast cancer. The association reports were identified from PubMed and Cochrane Library, and eligible studies were included and synthesized using meta-analysis method. 35 investigations were included into this meta-analysis for the association of GSTP1 A/G gene polymorphism and breast cancer susceptibility, consisting of 40,347 subjects (18,665 patients with breast cancer and 21,682 controls). The association between GSTP1 A/G gene polymorphism and breast cancer risk was not found for overall population, Caucasians and Africans. Interestingly, the GSTP1 A/G gene polymorphism was associated with the susceptibility of breast cancer in Asians (G allele: OR = 1.10, 95 % CI: 1.04–1.17, P = 0.001; GG genotype: OR = 1.36, 95 % CI: 1.14–1.62, P = 0.0008; AA genotype: OR = 0.92, 95 % CI: 0.85–0.98, P = 0.02). Furthermore, the GSTP1 A/G gene polymorphism was associated with the susceptibility of breast cancer for the analysis of the controls from hospital. In conclusion, GSTP1 A/G gene polymorphism is associated with the breast cancer susceptibility in Asians. However, more studies on the relationship between GSTP1 A/G gene polymorphism and the risk of breast cancer should be performed in further.     

Molecular screening of interleukin-6 gene promoter and influence of −174G/C polymorphism on breast cancer

Interleukin-6 (IL-6) is a cytokine involved in different physiologic and pathophysiologic processes including carcinogenesis. In 2003, a single nucleotide polymorphism (−174G/C) of the IL-6 gene promoter has been linked to breast cancer prognosis in node-positive (N+) breast cancer patients. Since, different studies have led to conflicting conclusions about its role as a prognostic and/or diagnostic marker. The primary aim of our study was to investigate the link between −174G/C polymorphism and breast cancer risk on the one hand, and −174G/C polymorphism and prognosis in different groups of patients: sporadic N+ breast cancers (n = 138), sporadic N− breast cancers (n = 95) and familial breast cancer (n = 60) on the other hand. The variables of interest were disease-free survival and overall survival. The secondary aim of the study was to screen IL-6 gene promoter using direct sequencing to identify new polymorphisms in our French Caucasian breast cancer population. No association or trend of association between −174G/C polymorphism of IL-6 gene promoter gene and breast cancer diagnosis or prognosis was shown, even in meta-analyses. Furthermore, we have identified four novel polymorphic sites in the IL-6 gene promoter region: −764G → A, −757C → T, −233T → A, 15C → A.     

Protein Tyrosine Phosphatase 1B Variant Associated with Fat Distribution and Insulin Metabolism

Protein tyrosine phosphatase 1B (PTPN1) affects the regulation of insulin signaling and energy metabolism. We studied whether polymorphisms in the PTPN1 gene impact body fat distribution in the HERITAGE Family Study cohort in 502 white and 276 black subjects. Insulin sensitivity index, glucose disappearance index, acute insulin response to glucose (AIR_glucose), and the disposition index (DI) were obtained from the frequently sampled intravenous glucose tolerance test. White subjects with the G82G at the PTPN1 IVS6+G82A polymorphism had higher body fat levels (p = 0.031) and sum of eight skinfolds (p = 0.003) and highest subcutaneous fat on the limbs (p = 0.002). G82A subjects had the lowest AIR_glucose (p = 0.005) and disposition index (p = 0.040). Interaction effects between PTPN1 and leptin receptor gene variants influenced insulin sensitivity index and AIR_glucose (p from 0.006 to 0.010). The variant PTPN1 Pro387Leu was associated with lower fasting insulin level (p = 0.035) and glucose disappearance index (p = 0.038). In summary, PTPN1 IVS6+G82G homozygotes showed higher levels of all measures of adiposity. G82 allele heterozygotes are potentially at higher risk for type 2 diabetes. Gene‐gene interactions between the PTPN1 and leptin receptor genes contributed to the phenotypic variability of insulin sensitivity. The PTPN1 Pro387Leu variant was associated with lower glucose tolerance.     

BRCA1 mutations in African Americans

The breast cancer predisposing gene, BRCA1, was analyzed for germline mutations in 45 African American families at high-risk for hereditary breast cancer. Patients were considered high-risk if they had a family history of the disease, early onset breast cancer, bilateral breast cancer, or breast and ovarian cancer. The entire BRCA1 coding and flanking intron regions have been examined by single stranded conformation polymorphism analysis followed by sequencing of variant bands. Eleven different BRCA1 germline mutations/variations were identified in 7 patients from the 45 high-risk families. Two pathogenic, protein-truncating mutations were detected in exon 11. A ten base pair tandem duplication, 943ins10, was present in a woman with breast and ovarian cancer whose first-degree relatives had prostate cancer. A four base pair deletion, 3450del4, was detected in a breast cancer patient with five cases of breast cancer in the family; two of the proband's sisters with breast cancer also carried the same mutation. Four amino acid substitutions (Lys1183Arg, Leu1564Pro, Gln1785His, and Glu1794Asp) and four nucleotide substitutions in intron 22 (IVS22+78 C/A, IVS22+67 T/C, IVS22+8 T/A and IVS22+7 T/C) were observed in patients and not in control subjects. One early onset breast cancer patient carried five distinct BRCA1 variations, two amino acid substitutions and three substitutions in intron 22. An amino acid substitution in exon 11, Ser1140Gly, was identified in 3 different unrelated patients and in 6 of 92 control samples. The latter probably represents a benign polymorphism. Electronic Publication     

The contribution of SIPA1 and RRP1B germline polymorphisms to breast cancer phenotype,lymph node status and survival in a group of Lithuanian young breast cancer patients

The germline polymorphisms in signal-inducing proliferation-associated protein 1 (SIPA1) and ribosomal RNR processing 1B (RRP1B) might be involved in breast cancer metastasis. The aim of this study was to analyze how SIPA1 and RRP1B polymorphisms contribute to breast cancer phenotype, lymph node status and survival. A group of 100 young, I–II stage breast cancer patients were analyzed for SIPA1 and RRP1B polymorphisms with PCR-RFLP assay. SIPA1 c.2760G?>?A, c.545C?>?T and RRP1B c.436T?>?C polymorphisms were associated with lymph node status, survival and tumor grade, respectively. Our results suggest that SIPA1 and RRP1B germline polymorphisms are important for breast cancer prognosis.     

牛源金黄色葡萄球菌FnBPA-A分子不同遗传多态性重组质粒的免疫生物学特性的比较

【目的】为了解Fn BPA-A分子遗传多态性对新疆部分地区牛源金黄色葡萄球菌免疫生物学特性的影响。【方法】对采自新疆不同地区的牛源金黄色葡萄球菌Fn BPA-A氨基酸序列进行分析,构建了Fn BPA-A 8个不同遗传多态性的真核重组质粒,分别免疫C57BL/6小鼠,收集免疫后的抗血清。对不同重组质粒免疫小鼠后免疫保护力进行比较分析。【结果】进化树显示GS801、GS819、GS856属于同一分支,GW10-1、GW20-2、GY288、GY309为同一分支,GY278为一分支。免疫小鼠并进行攻击保护检测,GW20-2、GS801、GS819、GS856与GY288免疫组对小鼠的免疫保护率较高,GY278免疫组免疫保护率最低。【结论】Fn BPA-A分子的遗传多态性可以影响免疫小鼠的免疫水平和攻毒保护力。     

Apolipoprotein A1 −75 G/A and +83 C/T polymorphisms: susceptibility and prognostic implications in breast cancer

Apolipoprotein A1 (ApoA1) is the major apoprotein constituent of high-density lipoprotein that can play important roles in tumor invasion and metastasis. In the current report, we evaluated the role of the functional ApoA1 polymorphisms (−75 G/A and +83 C/T) as genetic markers for breast cancer susceptibility and prognosis. We used the polymerase chain reaction and restriction enzyme digestion (RFLP-PCR) to characterize the variations of the ApoA1 gene in 295 unrelated Tunisian patients with breast carcinoma and 197 healthy control subjects. No association was found between the +83 C/T genetic variation in ApoA1 gene and the risk of breast cancer occurrence. The presence of the (+83) T allele appeared however to be associated with an increased risk of lymph node metastasis occurrence (OR = 2.94; P = 0.01). Furthermore, a positive association was found between ApoA1 −75 A allele carriers and breast cancer risk (OR = 1.57; P = 0.02). Regarding prognostic indicators, a significant association was found between ApoA1 (−75) A allele carriers and the premenopausal status of breast cancer patients (OR = 1.73; P = 0.03). Additionally, the presence of the −75 A allele was correlated with the oestrogen receptor status among premenopausal women (OR = 2.45; P = 0.02). This is the first report on the studies of ApoA1 single nucleotide polymorphisms (SNPs) in breast carcinomas. Our data suggest that these genetic variations of ApoA1 may represent a marker for the increased risk of breast cancer.     

Association between DNA damage, DNA repair genes variability and clinical characteristics in breast cancer patients

The cell's susceptibility to DNA damage and its ability to repair this damage are important for cancer induction, promotion and progression. In the present work we determined the level of basal (total endogenous) and endogenous oxidative DNA damage as well as polymorphism of the DNA repair genes: RAD51 (135 G/C), XRCC3 (Thr241Met), OGG1 (Ser326Cys) and XPD (Lys751Gln) in peripheral blood lymphocytes of 41 breast cancer patients and 48 healthy individuals. DNA damage was evaluated by alkaline comet assay with DNA repair enzymes: Endo III and Fpg, preferentially recognizing oxidized DNA bases. The genotypes of the polymorphisms were determined by restriction fragment length polymorphism PCR. We observed a strong association between breast cancer occurrence and the genotypes C/C of the RAD51-135G/C polymorphism, Ser/Ser of the OGG1-Ser326Cys and Lys/Gln of the XPD-Lys751Gln, whereas the genotypes G/C of the RAD51-135G/C and Lys/Lys of the XPD-Lys751Gln exerted a protective effect against breast cancer. We also found that individuals with the G/C genotype of the RAD51-135G/C polymorphism and with the Lys/Lys genotype of the XPD-Lys751Gln polymorphism displayed a lower extent of basal and oxidative DNA damage. A strong association between higher level of oxidative DNA damage and the Lys/Gln genotype of the latter polymorphism was found. We also correlated genotypes with clinical characteristics of breast cancer patients. We observed a strong association between the G/C genotype of the RAD51-135 G/C polymorphism and the expression of the progesterone receptor and between both alleles of the OGG1-Ser326Cys polymorphism and lymph node metastasis. Our results suggest that the polymorphism of the RAD51, OGG1 and XPD genes may be linked with breast cancer by the modulation of the cellular response to oxidative stress and these polymorphisms may be considered as markers in breast cancer along with the genetic or/and environmental indicators of oxidative stress.     

Nucleotide Polymorphism at the rp49 region of Drosophila subobscura: Lack of geographic subdivision within chromosomal arrangements in Europe

Restriction-site polymorphism at the rp49 gene region has been studied in 234 lines of Drosophila subobscura representing different gene arrangements for the O chromosome. The population surveyed (El Pedroso, Spain) was sampled four times in each of two consecutive years. The data indicate that the two chromosomal classes studied, O_[ST] and O_{[3 + 4]}, are genetically differentiated in El Pedroso. Comparison of the present results with those previously obtained for two other populations further supports that, for a given chromosomal class, European populations are not genetically differentiated. This lack of differentiation at the rp49 region within O_[ST] and within O_{[3 + 4]} stands in contrast to the clear latitudinal clines found in Europe for these arrangements.     

C2ORF40 suppresses breast cancer cell proliferation and invasion through modulating expression of M phase cell cycle genes

Recently, it has been suggested that C2ORF40 is a candidate tumor suppressor gene in breast cancer. However, the mechanism for reduced expression of C2ORF40 and its functional role in breast cancers remain unclear. Here we show that C2ORF40 is frequently silenced in human primary breast cancers and cell lines through promoter hypermethylation. C2ORF40 mRNA level is significantly associated with patient disease-free survival and distant cancer metastasis. Overexpression of C2ORF40 inhibits breast cancer cell proliferation, migration and invasion. By contrast, silencing C2ORF40 expression promotes these biological phenotypes. Bioinformatics and FACS analysis reveal C2ORF40 functions at G2/M phase by downregulation of mitotic genes expression, including UBE2C. Our results suggest that C2ORF40 acts as a tumor suppressor gene in breast cancer pathogenesis and progression and is a candidate prognostic marker for this disease.     

Polymorphisms of CYP1B1 and COMT in Breast and Endometrial Cancer

CYP1B1 and COMT code for the key enzymes of catecholestrogen biosynthesis and metabolism, and their polymorphisms determine the variation of enzyme activities. RFLP analysis was used to study the allele and genotype frequency distributions of CYP1B1 polymorphisms Arg48Gly, Ala119Ser, and Val432Leu, and COMT polymorphism Val158Met among 210 breast cancer patients, 138 endometrial cancer patients, and 152 healthy women. The COMT polymorphism showed no significant association with breast or endometrial cancer. For the first time, such association was observed for the CYP1B1 polymorphisms. CYP1B1 allele C (Arg48), which codes for the enzyme more active in estradiol 4-hydroxylation, was associated with higher risk of breast (OR = 3.22, CI 2.34–4.43, P = 0.000) and endometrial (OR = 2.43, CI 1.72–3.44, P = 0.000) cancer. Similar data were obtained for CYP1B1 allele G (Ala119): OR = 2.18, CI 1.58–3.01, P = 0.000 in breast cancer and OR = 2.52, CI 1.78–3.56, P = 0.000 in endometrial cancer. Risk of endometrial but not breast cancer was significantly higher in carriers of CYP1B1 genotype Val432/Val. This was explained by stronger estrogen dependence and, consequently, higher estrogen responsiveness of the endometrium as compared with the mammary gland.     

Genetic predisposition of six well‐defined polymorphisms in HMGB1/RAGE pathway to breast cancer in a large Han Chinese population

Breast cancer constitutes an enormous burden in China. A strong familial clustering of breast cancer suggests a genetic component in its carcinogenesis. To examine the genetic predisposition of high mobility group box‐1/receptor for advanced glycation end products (HMGB1/RAGE) pathway to breast cancer, we genotyped six well‐defined polymorphisms in this pathway among 524 breast cancer patients and 518 cancer‐free controls from Heilongjiang province, China. There were no deviations from Hardy–Weinberg equilibrium for all polymorphisms. In single‐locus analysis, the frequency of rs1800624 polymorphism mutant A allele in RAGE gene was significantly higher in patients than in controls (24.52% versus 19.50%, P = 0.006), with the carriers of rs1800624‐A allele being 1.51 times more likely to develop breast cancer relative to those with rs1800624‐GG genotype after adjustment (95% confidence interval or CI: 1.17–1.94, P = 0.001). In HMGB1 gene, haplotype analysis did not reveal any significance, while in RAGE gene, haplotypes C‐T‐A and C‐A‐G (alleles in order of rs1800625, rs18006024, rs2070600) were significantly associated with an increased risk of breast cancer (adjusted OR = 2.72 and 10.35; 95% CI: 1.20–6.18 and 1.58–67.80; P = 0.017 and 0.015 respectively). In further genetic score analysis, per unit and quartile increments of unfavourable alleles were significantly associated with an increased risk of breast cancer after adjustment (odds ratio or OR = 1.20 and 1.26; 95% CI: 1.09–1.32 and 1.12–1.42; P < 0.001 and <0.001 respectively). Our findings altogether demonstrate a significant association between RAGE gene rs1800624 polymorphism and breast cancer risk, and more importantly a cumulative impact of multiple risk associated polymorphisms in HMGB1/RAGE pathway on breast carcinogenesis.     

Associations of polymorphisms of folate cycle enzymes and risk of breast cancer in a Brazilian population are age dependent

Polymorphisms in genes involved in folate metabolism have been shown to be implicated in breast cancer risk but with contradictory results. In this case–control study, we investigated the association between MTHFR C677T and A1298C, TYMS 5′-UTR, MTR A2756G and cSHMT C1420T and also the folate carrier (RFC1 G80A) and breast cancer risk in a northeastern Brazilian population. The study included 183 women diagnosed with breast cancer and 183 controls volunteers without any history of cancer. Also a significant number of healthy individuals were included for allelic frequency in the population studied. Risk of breast cancer was estimated by conditional logistic regression. An association with risk was found for women carrying the MTR A2756G polymorphic allele (AG, P = 0.0036; AG/GG, P = 0.0040), and a protective effect in carriers of the RFC1 G80A polymorphic allele (GA, P = 0.0015; AA, P = 0.0042). Stratifying the data by age (cutoff point of 50 years old), different distributions were observed for breast cancer risk. For women ≤50 years, the risk observed in the presence of the polymorphic allele MTR 2756 (AG/GG) in the general analysis was, restricted to this age group (P = 0.0118). Conversely, for women over 50, the risk of breast cancer development was statistically associated with the MTHFR 677CT genotype, but especially significant was risk associated with the presence of the polymorphic allele of cSHMT C1420T (P = 0.0120) and the protective effect associated with the RFC1 G80A polymorphism allele (P = 0.0021), was restrict to this age group. These data indicate that the cutoff age used (50 years old) was appropriate, since it was able to discriminate risk in each age group in the population studied and also to point to the importance of age in the analyses of cancer-associated polymorphisms.     

喙尾琵琶甲肠道来源链霉菌(Streptomyces sp.)BPA71次级代谢产物的分离鉴定及其生物活性评价

【背景】昆虫是世界上种类最多、肠道菌群资源最丰富且多样的动物类群之一。昆虫肠道微生物具有产生活性次级代谢产物的能力,是活性天然产物的重要来源。【目的】研究药用昆虫喙尾琵琶甲(Blaps rynchopetera)成虫肠道来源链霉菌(Streptomyces sp.) BPA71的次级代谢产物及其生物活性。【方法】利用正相硅胶柱色谱、葡聚糖凝胶Sephadex LH-20柱色谱等方法分离纯化该菌株的发酵粗提物,采用牛津杯法进行抗菌活性追踪,确定抗菌活性部位,通过ESI-MS、NMR等波谱数据分析对化合物结构进行鉴定,采用微量肉汤稀释法测定最低抑菌浓度(minimal inhibitory concentration, MIC),采用MTS法测定抗肿瘤活性。【结果】从Streptomyces sp. BPA71的固体发酵提取物中共分离得到4个已知化合物,通过对比核磁数据确定为糠酸甲酯(1)、吡咯甲酰胺A (2)、吡咯甲酰胺B (3)和吲哚-3-乙酸甲酯(4)。抗菌活性结果显示化合物2具有广谱抗菌活性。此外,化合物2对宫颈癌细胞HeLa、肺癌细胞A549、肝癌细胞SMMC-7721、乳腺癌细胞MDA-MB-231和结肠癌细胞SW480这5株肿瘤细胞均有明显的抑制活性。【结论】喙尾琵琶甲肠道来源Streptomyces sp. BPA71可产生丰富的生物活性物质,该研究结果为进一步挖掘喙尾琵琶甲肠道链霉菌的活性天然产物奠定了基础,同时丰富了人们对喙尾琵琶甲肠道微生物的认识。     

Crystal structure of zebrafish complement 1qA globular domain

C1q contains three globular domains (C1qgD) that are the key functional component of the classical complement system. C1qgD can interact with important immune molecules, including IgG and C‐reactive protein (CRP) to form defense systems to protect animals. Here, the first non‐mammalian structure, zebrafish C1qA globular domain (Dare‐C1qAgD) was solved. Although the overall architecture of Dare‐C1qAgD is similar to human C1qA, residues involved in C1qBgD, C1qCgD, and CRP binding are somewhat different while residues involved in IgG binding are not present in zebrafish. The structure gives insight into how human and fish C1qA evolved from an ancestral protein.     

Left ventricular mass and +276 G/G single nucleotide polymorphism of the adiponectin gene in uncomplicated obesity

The single nucleotide polymorphism at position 276 in the adiponectin gene (APM1/ACDC +276 G>T) and left ventricular mass (LVM) have been associated with increased cardiovascular risk. We sought to evaluate whether +276 G>T variants in the adiponectin gene are correlated with LVM in uncomplicated obese subjects. APM1/ACDC +276 G>T single nucleotide polymorphism, echocardiographic indexed LVM (LVM/body surface area and LVM/height(2.7)), insulin sensitivity by euglycemic clamp, and plasma adiponectin levels were analyzed in 62 obese subjects without complications (51 women and 11 men; mean age, 34.2 +/- 10.2 years; BMI, 38.6 +/- 9.1 kg/m2). Forty lean subjects formed the control group for LVM evaluation. We found 23 (37%) uncomplicated obese subjects with the APM1/ACDC +276 G/G genotype, 25 (40%) with the G/T genotype, and 14 (23%) with the T/T genotype. G/G uncomplicated obese subjects showed significant higher LVM/body surface area and LVM/height(2.7) (within the normal range in the majority of them) than uncomplicated obese subjects carrying the G/T and T/T genotypes (p < 0.01 and p < 0.05, respectively). This study showed that LVM is significantly higher in uncomplicated obese subjects carrying the G/G genotype at position 276 of the human adiponectin gene.     

嗜热II型内含子Tel3c/4c-RT结构域活性位点分析

【背景】嗜热Ⅱ型内含子是一类由内含子RNA和内含子编码蛋白(intron encoded protein,IEP)组成且在高温条件下能够在染色体上高频移动的反转录转座子,目前已被开发为高效基因打靶工具Thermotargetron,阐明其活性催化位点,对深入研究其“归巢”机制及开发新型遗传工具具有重要意义。【目的】筛选嗜热Ⅱ型内含子Tel3c/4c-RT结构域关键活性位点,并获得失活反转录功能的内含子编码蛋白突变体。【方法】先利用生物信息学技术分析并筛选可能影响Tel3c/4c-RT反转录功能的关键氨基酸位点;然后对筛选到的关键氨基酸位点进行定点突变,并以Thermotargetron质粒为基础构建失活反转录功能的突变型嗜热Ⅱ型内含子打靶系统;最后以大肠杆菌lacZ基因为例,通过蓝白斑计数分析突变型Thermotargetron系统的打靶效率,体内验证Tel3c/4c-RT结构域关键活性位点突变对嗜热Ⅱ型内含子打靶效率的影响。【结果】共筛选到15个可能影响反转录活性的氨基酸位点,包括D194、I195、S196、G197、C198、F199、Q241、G242、R274、Y275、A2...