Analysis of the mechanism of high incidence of thanatophoric dysplasia type I

致死性侏儒症（thanatophoric dysplasia,TD）是重型短肢畸形病中相对常见的致死性遗传性骨病,分为TD-I和TD-II 2型,它们都是由于FGFR3基因发生致死突变所致。TD-I型存在多种致病性突变,其中以c.742C〉T/p.R248C突变最为常见。本病为常染色体显性遗传（autosomal dominant,AD）,杂合突变即可致死,但为何表型、基因型正常的父母会生出带有p.R248C突变的患胎并且是纯合突变的死胎？如果是新生突变,又为何会接连数胎生出同样的患胎？p.R248C高发突变的机制是什么？本文重点围绕这些问题,从＂FGFR3（Fibroblast growth factor receptor 3）基因和FGFR3受体（Fibroblast growth factor receptor 3）的结构和功能,TD-I型p.R248C高发突变的发生机制,正常父母生出纯合致死突变的可能机制＂几方面进行剖析,指出：（1）FGFR3基因及其受体蛋白结构和功能的特殊性是高发突变发生的物质基础;（2）位于IgⅡ和IgⅢ结构域连接区的氨基酸是极性很强的亲水氨基酸,很容易与带电离子结合而影响α螺旋结构,故易受外来理化因素的攻击、诱变而发生改变;（3）正常父母生出纯合致死突变,推测有两种可能：一种是夫妇一方的生殖腺已带有该高发突变,当胎儿从亲代遗传了一次突变后,只需在另一位点上再发生一次新生突变即可产生;另一种是夫妇双方的生殖腺都是该突变的嵌合体,当两者结合在一起,就有可能产生纯合突变。此外,还对未来发展趋势进行了展望。本文旨在探讨c.742C〉T/p.R248C高发突变和纯合突变发生的机制,进而为其今后的诊断和防治工作提供理论依据。Thanatophoric dysplasia（TD）,divided into TD type I and TD type II,is a genetic bone disease caused by the fatal mutation of FGFR3 gene.It is relatively common lethal hereditary osteopathy among severe short limb malformations.TD-I type has many kinds of pathogenic mutations,of which c.742CT/p.R248 C mutation is the most common.This disease is an autosomal dominant（AD） genetic disease which means heterozygous mutations can be lethal.However,why some parents with normal genotypes and phenotypes can give birth to a stillbirth who carried the homozygous mutation p.R248C？ If it is a novel mutation,why the successive fetuses with the same mutation were born？ What is the high incidence mechanism of p.R248 C mutation？ This paper focus mainly around these problems,from＂The structure and function of FGFR3 gene and FGFR3 receptor;The pathogenetic mechanism of high incidence of p.R248 C in TD type I;The possible mechanisms of normal parents producing homozygous lethal mutation＂,several aspects are analyzed and pointed out：（1）FGFR3 gene and the structure and function of its receptor protein is the material base of high frequent mutation;（2） Some amino acids,located in the connected region of Ig Ⅱ and Ig Ⅲ domain,are strong polar hydrophilic amino acids,which tend to bind charged ions to influence the alpha helical structure,therefore,it is easy to be affected by external physical and chemical factors;（3） Normal parents give birth to fetus with homozygous lethal mutation,there are 2 possibilities：one is the reproductive gonad of one of the parents has carried the hot mutation,and the fetus inherited the hot mutation,under these circumstances,as long as a same mutation happen in its allele,which will lead to the generation of homozygous mutation;another is the reproductive glands of couples are the mutant chimeras,when the two are combined together,it is possible to generate homozygous mutation.In addition,the future development trend is prospected.The purpose of this paper is to explore th闽粤合作科研基金（71010025

Fast detection of thanatophoric dysplasia type I p.R248C mutation hot spots and rapid prenatal diagnosis of three TD type I high-risk fetuses

目的针对致死性侏儒症I型（thanatophoric dysplasia typeⅠ,TD-Ⅰ）FGFR3基因的突变热点＂p.R248C＂,建立快速特异的酶切鉴定法（restriction endonuelease testing,RE）和扩增受阻突变系统（amplification refractory mutation system,ARMS）/RE法,并应用于后续3例疑似TD-I高危胎儿的快速产前诊断,以及时防止患胎出生,同时为今后的胚胎植入前遗传学诊断（preimplantation genetic diagnosis,PGD）打下良好基础。方法首先,针对突变热点p.R248C突变前后的序列特点,选择合适的内切酶＂Afe I＂,建立酶切鉴定法。其次,设计双错配碱基特异引物结合Apa LI酶切,建立ARMS/RE双重特异鉴定法。对阴性和阳性结果均再用普通引物扩、测的结果进行验证。结果用Afe I酶切FGFR3基因exons（6-7）普通引物的PCR产物（535 bp）,正常对照及非p.R248C突变的TD病例均能被切成255 bp和280 bp 2个片段,而胎1~胎3均切出255 bp、280 bp和535 bp 3个片段。用特异引物E7（p.R248C）扩增,正常对照和非p.R248C突变的TD病例均扩增阴性,无法进一步做酶切鉴定;而p.R248C突变均扩增阳性,当再用Apa LI酶切PCR产物（365 bp）时,胎1~胎3均切出22 bp和343 bp 2个片段。通过引物扩、测结果显示：胎1~胎3均是p.R248C杂合突变。结论该法快速特异、准确可靠,可用于p.R248C突变热点的快速检测及含该突变高危胎儿的快速产前诊断。该法还可用于含p.R248C突变TD-I型家系的PGD。胎1~胎3都是TD-I患胎,建议尽早终止妊娠。Objective To build up the specific rapid methods of RE and ARMS/RE for mutation hotspot＂p.R248C＂in the FGFR3 gene of thanatophoric dysplasia type I（TD-I）,then use the method for rapid prenatal diagnosis of 3 follow-up high-risk fetuses of TD-I to stop the birth of suffering fetuses,at the same time,lay a good foundation of preimplantation genetic diagnosis（PGD） for the future.Methods First,according to the characteristics of the sequence of the mutation hot spot p.248 C before and after mutation,the appropriate enzyme＂Afe I＂was selected to establish the identification method of enzyme digestion.After that,specific primers of double mismatch bases were devised,combining the method of digestion of Apa LI（ARMS/RE） to achieve the double identification.In the end,the sequences obtained by common primers were used to verify the negative and positive results through DNA sequencing.Results For the normal control and the patient without p.R248 C mutation of TD-I,PCR products（535 bp） of exons（6-7） of FGFR3 gene,amplified by common primers,could be digested into 2 fragments（255 bp and 280 bp） by Afe I.However,for fetuses 1~3,the PCR products could be digested into 3 fragments（255 bp,280 bp and 535 bp）.The normal control and the patient without p.R248 C mutation of TD-I were negative using the specific primers E7（p.R248C）,which could not be further identified by enzyme digestion.For the fetuses with p.R248 C mutation of TD-I,PCR products（365 bp） of exon 7 of FGFR3 gene,amplified by specific primers,could be digested by Apa LI and all the digested products were 22 bp and 343 bp.Sequencing results of common primers＇ products indicated：fetuses 1~3 were p.R248 C heterozygous mutation.Conclusions The method is fast,accurate and reliable,which can be available for the fast detection of mutation hot spot p.R248 C and the rapid prenatal diagnosis of high-risk fetus with p.R248 C mutation.This method can also be applied to PGD of high-risk fetus of TD-I with the mutation＂p.R248C＂.Fo闽粤合作科研基金（71010025

Product BOM difference analyzing and synchronous updating method

本发明涉及一种产品BOM差异分析与同步更新方法，包括以下步骤：将不同数据源的BOM数据按照数据结构及层次关系生成相应的XML格式的BOM数据文件，并根据BOM数据文件生成哈希值树；对不同数据源的哈希值树的相对应结点进行比较，得出不同数据源BOM数据的差异点；根据BOM数据差异点类型及内容生成BOM数据的同步脚本，在需进行同步的数据源中通过执行同步脚本实现BOM数据的同步。本发明将企业信息系统中的产品BOM数据信息以XML文件形式进行处理，方便制定标准化的文件格式，便于体现产品BOM数据层次关系，而且XML文件易于应用系统解析与查询，可以直观的显示BOM数据间的差异

Automobile Assembly Management and Control Integrative System

针对汽车装配过程特点与管控要点，构建了基于Prism/MVVM（model-view-view model）架构的汽车装配过程管控一体化系统。然后，对系统实现的关键技术进行研究，基于企业服务总线（enterprise service bus，ESB）技术以松散耦合方式实现异构管理系统间集成，依据不同作业环境采取自动采集与移动式作业采集感知汽车装配过程，设计可配置图形模型的车辆自动识别（automatic vehicle identification，AVI）跟踪模式以满足不同类别和不同层级监管人员需求，基于采集器、触发器、调度器与控制器实现汽车装配过程中自动路由控制（route control，RC）调度。设计系统集成灵活、模块可插拔、界面与业务可分离设计开发、具有良好的扩展性与维护性。最后，企业案例验证了系统有效性

西安地区2008年降雨129I 水平与特征分析

降雨是大气中碘向陆地沉降的最主要方式。通过分析降雨中的浓度和~(129)I/127I比值,既可获得研究区域放射性碘的基础数据,也可为认识碘的来源提供基础数据。本工作分析了在西安收集的近1年(2008年4&mdash;10月)的降雨的~(129)I的浓度和水平,由于雨水样品中有机碘份额较高,采用NaOH热分解有机碘的方法对其进行了分解,萃取过程的化学回收率达63.3%-74.8%。127I浓度为0.45-14.10 &mu;g&middot;L~(-1), ~(129)I浓度为(1.18&mdash;48.91) &times;10~7 atoms.~(129)I和~(127)I浓度的变化趋势相似,具有随季节变化的特点,春季降雨~(129)I的浓度为(2.49-4.89) &times;10~8 atoms&middot;L~(-1), ~(l29)I/~(127)I比值为(7.3-9.8) &times;10~(-9),夏、秋季降雨 ~(129)I的浓度为(1.18&mdash;7.32) &times;10~7 atoms&middot;L~(-1),~(129)I/~(127)I比值为(1.2-12.0) &times;10~(-9),春季(4&mdash;5月)~(129)I、~(127)I浓度出现一个峰值,可能是由于春季降雨量少,大气中的~(127)I、~(129)I能够积累较长时间,之后通过湿沉降从大气中被去除。西安地区2008年降雨~(129)I的浓度及水平,与国际上已报道的不同地区雨水的~(129)I浓度和水平比较,处于较低水平,主要原因是我国及周边没有正在运行的大型核燃料后处理厂。西安降雨~(129)I/~(127)I比值总体上高于我国沿海海水和以海水中碘为主要来源的海藻,这一特征比值提示了西安降雨中的碘与我国沿海海水中的碘的来源存在差异。</p

丙型肝炎病毒自发清除者的血清代谢组学研究

目的探索HCV自发清除者、慢性丙型肝炎(丙肝)及健康人血清代谢组学的差异。方法纳入HCV自发清除者、慢性丙肝患者和健康对照各30例,采用快速液相色谱-串联质谱联用(LC-MS/MS)技术,应用主成分分析(PCA)、正交偏最小二乘法-判别分析(OPLS-DA)进行模式识别,然后通过变量重要性因子(VIP)、非参数检验,结合数据库检索筛选鉴定有差异的代谢物。结果25个变量被确认为存在显著差异的代谢物,其中7个变量被鉴定为花生四烯酸、棕榈油酸、葵酰基肉碱、溶血磷脂酰胆碱(20:5,16:0)、溶血磷脂酰乙醇胺(16:0,18:0),涉及脂肪酸、磷脂等代谢。其中花生四烯酸以及未鉴定出明确结构的m/z 179. 0719, m/z 382. 1360, m/z 548. 3475, m/z680. 4281,m/z 303. 2323等物质与自发清除组的相关性较好,受试者工作特征曲线下面积为0.887~0.977,具有较好的特异度和敏感度。结论HCV自发清除者、慢性丙肝感染者、健康人在血清代谢水平上存在明显差异,这些差异的意义有待进一步探索