长效重组人超氧化物歧化酶的研制及其辐射防护作用

选用无毒、无免疫原性的高分子化合物聚乙二醇(PEG)为修饰剂,以活性酯法制备出PEG- 重组人超氧化物歧化酶(PEG-rh SOD)共价结合物.修饰酶的生物半衰期为15h,比修饰前延长了90倍,对酸、碱、热的耐受力明显高于修饰前.用照射小鼠的活存率评价了PEG-rhSOD的辐射防护作用.小鼠受8.5Gy γ射线照射前1h腹腔注射30万U/kg PEG-rh SOD,可提高活存率42%,与未修饰的rhSOD相比,活存率提高14%.实验仍在进行中.     

Extensive allelic sequence variation in the J region of the human immunoglobulin heavy chain gene locus

During the initial stages of B lymphocyte differentiation heavy chain variable (VH), diversity (DH) and joining (JH) gene segments recombine to form a functional heavy chain variable region (VDJ) gene. Evidence for genetic polymorphism of the human JH gene segments has been obtained from mature rearranged VDJ sequences. We conducted an analysis of the published rearranged JH gene sequences and found that the JH alleles present in the two published germ-line JH region sequences were rare (approx. 2%) in the rearranged sequences. As an attempt to explain this discrepancy a 2.5-kb strech of DNA containing all the six heavy chain JH region genes and the most 3' DH gene segment, DHQ52, was amplified by the polymerase chain reaction from 39 individuals and analyzed for restriction fragment length polymorphism. Five new JH region haplotypes were found and sequenced. These new haplotypes contained the coding segment alleles that were frequent in antibody genes. Surprisingly, a high number of interallelic differencies in the non-coding sequence was found between the new and the two previously published haplotypes implying that the haplotypes had been separated early in evolution. In this respect the JH locus resembles HLA loci.     

GREB1L基因突变致后天性单侧肾萎缩一例报道并文献复习

肾发育不良和肾发育不全（RAH）是先天性肾脏与尿路畸形（CAKUT）的主要表现之一,是导致儿童慢性肾脏病的重要原因。遗传因素与发病密切相关,随着全基因检测技术的发展,越来越多与RAH相关的基因突变被报道,GREB1L基因突变已被证实可导致RAH。本研究报道了1例后天性单侧肾萎缩GREB1L基因c.4688A>G杂合突变患儿,并复习相关文献。该患儿基因突变源自母亲,该变异为罕见变异,并且具有不完全外显特性,多种蛋白质危害预测软件预测该突变为有害变异。本文发现了新的GREB1L基因突变位点,可能拓展了与RAH相关的基因突变谱和临床谱。     

基于两样本孟德尔随机化方法探讨睡眠与痛风的关联

[目的] 通过两样本孟德尔随机化设计,探讨睡眠与痛风之间的关联。[方法] 从一项包含763 813名参与者的全基因组关联研究(genome-wide association study,GWAS)中获取痛风遗传关联数据。以与打鼾、睡眠时间、睡眠类型、失眠及白日困倦程度等睡眠表型相关的单核苷酸多态性(single nucleotide polymorphism,SNP)作为工具变量,采用逆方差加权(inverse variance weighted,IVW)评估遗传学预测的不同睡眠表型与痛风发生风险的关系。采用MR-Egger回归和孟德尔随机多态性残差和离群值(MR pleiotropy residual sum and outlier,MR-PRESSO)检验进行敏感性分析,以评估工具变量的多效性。进一步采用加权中位数法、简单中位数法、最大似然比法等分析方法检验结果的稳健性与可靠性。[结果] IVW结果显示,遗传学预测的打鼾[优势比(odds ratio,OR)=3.12,95%置信区间(confidence interval,CI)(1.21～8.05),PFDR=0.045]和失眠[OR=1.09,95%CI(1.04～1.15),PFDR=0.005]与痛风发生风险呈正相关,而睡眠时间、睡眠类型及白日困倦程度与痛风发生之间不存在统计学关联。MR-Egger回归提示上述因果关联未受到水平多效性影响,加权中位数法、简单中位数法、最大似然比法得出与IVW相似的结果。[结论] 打鼾、失眠与痛风发生风险呈正相关,纠正打鼾和失眠可能对痛风有一定的预防作用。     

中国江苏地区汉族人群肿瘤坏死因子β遗传多态性研究

目的　探讨中国江苏地区汉族人群肿瘤坏死因子 β遗传多态性分布。方法　收集江苏地区 16 8名无血缘关系健康个体的静脉血提取DNA ,应用聚合酶链反应限制性片段长度多态性 (PCR -RFLP) ,对TNFβ基因多态性进行分析。结果　TNFβ检测到三个等位基因 ,其基因型频率分别为TNFβ 1/ 1=2 1 4 % ,TNFβ 1/ 2 =4 7% ,TNFβ 2 / 2 =31 5 % ,基因型分布符合Hardy-Weinberg定律。统计分析显示 :江苏地区汉族人群TNFβ等位基因频率分布与欧美白种人均有显著性差异(P <0 0 5 )。结论　TNFβ等位基因频率分布具有种族差异     

Influence of neonatal sympathectomy on proximal renal resistance artery function in spontaneously hypertensive rats

Renal transplantation experiments have shown that the kidney contributes to chronic sympathectomy-induced arterial pressure reduction in spontaneously hypertensive rats (SHR). The underlying mechanisms are currently unclear but may include alterations in the function of small renal arteries. Neonatal SHR were sympathectomized by intraperitoneal guanethidine injections and removal of adrenal medullary tissue. Controls were sham- or hydralazine-treated. At 12 weeks of age, distal interlobar artery segments were investigated using small-vessel wire myography. Vessels from sympathectomized animals showed increased sensitivity to noradrenaline (NE). Vasopressin- and endothelin-1-induced vasoconstriction was similar in all groups (as reflected by the pD₂, i.e. –logEC₅₀, where EC₅₀ is the molar concentration of agonist eliciting a half-maximal response). Maximum vasopressin-induced tension was similar in all groups while endothelin-1-induced maximum tension was significantly higher in sympathectomized than in sham-treated SHR. The sensitivity of NE-induced vasoconstriction to extracellular Ca²⁺ did not differ between groups while sensitivity to L-type Ca²⁺ channel activation was significantly higher in both sympathectomized and hydralazine-treated animals than in sham-treated animals. Endothelium-dependent and independent vasodilation were similar in all groups. Sequential blockade of NO-synthase and cyclooxygenase had similar effects in all groups. In conclusion, neonatal sympathectomy does not induce any changes in the function of isolated proximal renal resistance arteries from SHR that could explain the blood pressure lowering effect of a kidney graft from sympathectomized SHR.     

Animal models in the investigation of anorexia

Anorexia nervosa (AN) is an eating disorder of unknown origin that most commonly occurs in women and usually has its onset in adolescence. Patients with AN invariably have a disturbed body image and an intense fear of weight gain. There is currently no definitive treatment for this disease, which carries a 20% mortality over 20 years. Development of an appropriate animal model of AN has been difficult, as the etiology of this eating disorder likely involves a complex interaction between genetic, environmental, social, and cultural factors. In this review, we focus on several possible rodent models of AN. In our laboratory, we have developed and studied three different mouse models of AN based on clinical profiles of the disease; separation stress, activity, and diet restriction (DR). In addition, we discuss the spontaneous mouse mutation anx/anx and several mouse gene knockout models, which have resulted in an anorexic phenotype. We highlight what has been learned from each of these models and possibilities for future models. It is hoped that a combination of the study of such models, together with genetic and clinical studies in patients, will lead to more rational and successful prevention/treatment of this tragic, and often fatal, disease.     

Analysis of the HLA-A,-B allele polymorphism in 5844 umbilical cord blood samples taken from Han population of Shandong province

To investigate the HLA-A, -B allele polymorphism in Han population of Shandong province and to explore the possibility to find out the HLA-A, -B-matched cord blood donors for stem cell transplantation to be used in other area in China, 5844 umbilical cord blood samples were taken from Han population donors of Shandong province, and assayed with PCR-sequence-oligonucleotide (PCR-SSO) assay. In Shandong Han donors, 20 alleles at HLA-A locus and 46 alleles at HLA-B locus could be detected as revealed in the present study. Among the 20 alleles at HLA-A locus, the most prevalent five alleles included A * 02(0.3041), A * 11(0.1443), A * 24(0.1434), A * 30(0.0975) and A * 33(0.0859), while, the alleles with lower gene frequencies included A * 34(0.0006), A * 25 (0.0005), A*66(0.0005), A* 74(0.0004) and A* (0.0001). Of the 46 HLA-B alleles detected, the most prevalent five alleles were B * 13(0.1348), B * 51(0.0713), B * 62(0.0712), B * 61 (0.0676) and B * 60(0.0642); while alleles with lower gene frequencies included B * 77(0.0001), B * 76(0.0002), B * 47(0.0003), B * 42(0.0003) and B * 72(0.0004). In comparison with those of the other Han population in China, the HLA-A, -B gene frequencies in the umbilical cord blood of Shandong province possess unique distribution features among the investigated populations from various regions of the same race origin, and the differences in various regions of the same race were less than those among the different race. It is evident that the HLA-A,-B alleles of the umbilical cord blood taken in Shangdong province show high degree of polymorphism, and it might be part of those of Northern Han population in China. So, it is reasonable for patients of Northern Chinese to receive HLA class I -match transplant of cord blood stem cells for tissue and organ transplantation from Shangdong umbilical cord blood bank.     

An Extension of the Regression of Offspring on Mid-Parent to Test for Association and Estimate Locus-Specific Heritability: The Revised ROMP Method

The Regression of Offspring on Mid-Parent (ROMP) method is a test of association between a quantitative trait and a candidate locus. ROMP estimates the trait heritability and the heritability attributable to a locus and requires genotyping the offspring only. In this study, the theory underlying ROMP was revised (ROMP_rev) and extended. Computer simulations were used to determine the type I error and power of the test of association, and the accuracy of the locus-specific heritability estimate. The ROMP_rev test had good power at the 5% significance level with properly controlled type I error. Locus-specific heritability estimates were, on average, close to simulated values. For non-zero locus-specific heritability, the proposed standard error was downwardly biased, yielding reduced coverage of 95% confidence intervals. A bootstrap approach with proper coverage is suggested as a second step for loci of interest.
ROMP_rev was applied to a study of cardiovascular-related traits to illustrate its use. An association between polymorphisms within the fibrinogen gene cluster and plasma fibrinogen was detected (p < 0.005) that accounted for 29% of the estimated fibrinogen heritability. The ROMP_rev method provides a computationally fast and simple way of testing for association and obtaining accurate estimates of locus-specific heritability while minimizing the genotyping required.     

中国人群DXS102座位多态性鉴定及其应用

目的探讨中国人群中ＤＸＳ１０２座位的多态分布。方法应用ＰＣＲ扩增片段长度多态性（Ａｍｐ－ＦＬＰ）研究了无亲缘关系的２３４条Ｘ染色体。结果ＤＸＳ１０２座位等位片段有８个，核心单元ＡＣ二核苷酸重复数为１３～２１，频率分布在０．０１３～０．１５６之间，杂合度观察值和无偏估测值分别为０．８７和０．８０，多态信息含量（ＰＩＣ）０．８０，女性基因型数为２２个，男性基因型数为８个，该座位多态分布符合Ｈａｒｄｙ－Ｗｅｉｎｂｅｒｇ平衡定律。ＤＸＳ１０２座位在中国人群和欧洲人群的分布有明显的种族差异，在中国人群中发现了两个新的等位片段。应用ＤＸＳ１０２座位的短串联重复序列多态性对一接受基因治疗的血友病Ｂ家系进行分析和携带者筛查。结论ＤＸＳ１０２座位连锁分析有望成为一种有效的血友病Ｂ基因诊断的方法。