• 【CRB1杂合子与区域性视网膜功能障碍:对leber先天性黑病的基因检测的意义。】 复制标题 收藏 收藏
    DOI:10.1167/iovs.05-1637 复制DOI
    作者列表:Yzer S,Fishman GA,Racine J,Al-Zuhaibi S,Chakor H,Dorfman A,Szlyk J,Lachapelle P,van den Born LI,Allikmets R,Lopez I,Cremers FP,Koenekoop RK
    BACKGROUND & AIMS: PURPOSE:To test human CRB1 heterozygotes for possible clinical or functional retinal changes and to evaluate whether a patient with Leber congenital amaurosis (LCA) with CRB1 mutations not consistent with previously described CRB1 phenotypes carried a modifier allele in another LCA gene. METHODS:Seven unrelated heterozygous carriers of CRB1 mutations underwent phenotyping by full eye examinations (indirect ophthalmoscopy and slit lamp biomicroscopy) and functional testing (standard full-field electroretinography [ERG] and multifocal ERG). For genotyping of the LCA patients and their parents, denaturing high-performance liquid chromatography (dHPLC) analyses were performed, followed by sequence analysis of CRB1, followed by sequence analysis of the AIPL1 and CRX genes to identify a putative modifier effect in a patient with an atypical CRB1 phenotype. RESULTS:Reduced full-field ERG b-wave amplitudes were observed with scotopic -2 dB flash (140 microV; P < 0.05), normal full-field cone ERGs, and significant regional retinal dysfunction on mfERG in five of seven carriers of CRB1 mutations. A known AIPL1 mutation (p. R302L) was identified as a potential modifier allele in a patient with LCA carrying two CRB1 mutations and with a prominent maculopathy. CONCLUSIONS:In human heterozygotes of CRB1 mutations (parents of offspring with LCA), distinctive regional retinal dysfunctions were found by multifocal ERG measurements that were consistent with the focal histologic abnormalities reported for the two CRB1 knockout mice models. This phenotypic finding may identify CRB1 carriers and point to the causal gene defect in affected LCA offspring, significantly facilitating the molecular diagnostic process. Evidence suggests a modifier allele in AIPL1 in a patient with LCA with prominent atrophic macular lesions and homozygous defects in CRB1.
    背景与目标: 目的:测试人CRB1杂合子可能的临床或功能性视网膜变化,并评估患有CRB1突变的Leber先天性黑蒙病(LCA)患者是否与先前描述的CRB1表型不一致,是否在另一个LCA基因中携带修饰等位基因。
    方法:通过全眼检查(间接检眼镜和裂隙灯生物显微镜)和功能测试(标准全视野视网膜电图[ERG]和多焦点ERG)对7个无关的CRB1突变杂合子进行表型分析。为了对LCA患者及其父母进行基因分型,先进行变性高效液相色谱(dHPLC)分析,然后对CRB1进行序列分析,然后对AIPL1和CRX基因进行序列分析,以鉴定在患有LCA患者中的假定修饰子作用非典型CRB1表型。
    结果:在七个CRB1突变携带者中的五个携带者中,暗视-2 dB闪光(140 microV; P <0.05),正常的全视场ERGs和mfERG上的显着区域性视网膜功能障碍,观察到全视场ERG b波振幅降低。 。在患有携带两个CRB1突变且患有明显的黄斑病的LCA患者中,已知的AIPL1突变(p。R302L)被确定为潜在的修饰等位基因。
    结论:在人的CRB1突变杂合子(LCA后代的父母)中,通过多焦点ERG测量发现了独特的区域性视网膜功能障碍,这与两个CRB1基因敲除小鼠模型报道的局部组织学异常一致。此表型发现可能会识别出CRB1携带者,并指出受影响的LCA后代中的因果基因缺陷,从而大大促进了分子诊断过程。有证据表明,患有明显萎缩性黄斑病变和CRB1纯合缺陷的LCA患者中AIPL1的修饰等位基因。
  • 【MHC I类区域对巨细胞动脉炎遗传易感性的贡献。】 复制标题 收藏 收藏
    DOI:10.1093/rheumatology/kel324 复制DOI
    作者列表:Gonzalez-Gay MA,Rueda B,Vilchez JR,Lopez-Nevot MA,Robledo G,Ruiz MP,Fernández O,Garcia-Porrua C,Gonzalez-Escribano MF,Martín J
    BACKGROUND & AIMS: OBJECTIVE:The aim of this study was to assess the potential contribution of HLA-class I MICA and HLA-B gene polymorphisms towards the pathogenesis of giant cell arteritis (GCA). METHODS:Ninety-eight biopsy-proven GCA patients and 225 ethnically matched controls from Lugo, Northwest Spain, were genotyped for the MICA-TM microsatellite polymorphism using a polymerase chain reaction (PCR)-based method. Genotyping of HLA-B was performed using PCR and detection with a reverse sequence-specific oligonucleotide (SSO) probes system. RESULTS:A significant difference in the distribution of the alleles of MICA between patient and control groups (P = 0.005) was found. This was due to an increased frequency of the MICA A5 allele in GCA patients compared with controls (26 vs 13.6%; P = 0.0001; P(C) = 0.0005; OR 2.2, 95% CI 1.4-3.4). In addition, the HLA-B*15 allele showed a higher frequency in GCA patients compared with controls (P = 0.004; P(C) = 0.04; OR 2.7, 95% CI 1.3-5.7). Interestingly, the association observed with the MICA A5 allele seems to be independent of linkage disequilibrium with HLA-B, as well as independent of that previously described with HLA-DRB1*04. Remarkably, simultaneous presence of MICA A5 and HLA-B*15 or HLA-DRB1*04 genetic markers leads to an increase in the OR obtained for each individual genetic marker (MICA A5 + B*15 OR 3.2; MICA A5 + DRB1*04 OR 5.8). CONCLUSIONS:Our results provide the first evidence that the MICA and HLA-B genes are independently associated with the genetic susceptibility to GCA, and suggest that several genes within the MHC might have independent effects in the susceptibility to this systemic vasculitis.
    背景与目标: 目的:本研究旨在评估HLA I类MICA和HLA-B基因多态性对巨细胞性动脉炎(GCA)发病的潜在作用。
    方法:采用聚合酶链反应(PCR)方法,对来自西班牙西北部卢戈市的98例经活检证实的GCA患者和225名种族匹配的对照进行了MICA-TM微卫星多态性的基因分型。使用PCR进行HLA-B的基因分型,并使用反向序列特异性寡核苷酸(SSO)探针系统进行检测。
    结果:在患者和对照组之间,MICA等位基因的分布存在显着差异(P = 0.005)。这是由于与对照相比,GCA患者中MICA A5等位基因的频率增加(26比13.6%; P = 0.0001; P(C)= 0.0005; OR 2.2,95%CI 1.4-3.4)。此外,与对照相比,GCA患者的HLA-B * 15等位基因频率更高(P = 0.004; P(C)= 0.04; OR 2.7,95%CI 1.3-5.7)。有趣的是,与MICA A5等位基因所观察到的关联似乎独立于与HLA-B的连锁不平衡,也独立于先前对HLA-DRB1 * 04的描述。值得注意的是,同时存在MICA A5和HLA-B * 15或HLA-DRB1 * 04遗传标记会导致每个单独的遗传标记获得的OR升高(MICA A5 B * 15或3.2; MICA A5 DRB1 * 04 OR 5.8 )。
    结论:我们的结果提供了第一个证据,表明MICA和HLA-B基因与对GCA的遗传易感性独立相关,并暗示MHC中的多个基因可能对该系统性血管炎的易感性具有独立影响。
  • 【全脑原发性和单发性下垂病的连续基因综合征:与18p11.3缺失相关。】 复制标题 收藏 收藏
    DOI:10.1002/ajmg.a.31386 复制DOI
    作者列表:Kantaputra PN,Limwongse C,Tochareontanaphol C,Mutirangura A,Mevatee U,Praphanphoj V
    BACKGROUND & AIMS: :We report a patient with a unique combination of features, including microcephaly; mental retardation; poorly developed frontal lobes; hypoplastic pituitary gland; hypothyroidism; alopecia universalis; single maxillary central incisor; taurodontism; median palatal ridge; longitudinally grooved nails; and scoliosis. His unbalanced karyotype was found to be 45,XY,der(15;18)(q10;q10). The constellation of anomalies appears to represent a contiguous gene syndrome caused, at least in part, by deletion of TGIF and the gene responsible for hereditary hypotrichosis simplex. The phenotype of our patient differs other reported patients with del(18p). Possible explanations include (1) the effects of a different deleted region, (2) a positional effect caused by a gene close by, or (3) by interruption of a different gene resulting from chromosomal translocation.
    背景与目标: :我们报告的患者具有独特的功能组合,包括小头畸形;智力低下;额叶发育不良;垂体发育不全甲状腺功能减退;普遍性脱发;单上颌中切牙;牛头牙症pa中纵向开槽的指甲;和脊柱侧弯。发现他的不平衡核型为45,XY,der(15; 18)(q10; q10)。异常群似乎代表着一种连续的基因综合征,这种综合征至少部分地是由于TGIF的缺失和负责遗传性单纯性遗传不足的基因引起的。我们患者的表型与其他报道的del(18p)患者不同。可能的解释包括(1)不同缺失区域的作用,(2)由附近基因引起的位置作用,或(3)由染色体易位引起的不同基因的中断。
  • 【谷胱甘肽缺乏症遗传模型中小脑颗粒神经元中多摩酸的神经毒性。】 复制标题 收藏 收藏
    DOI:10.1124/mol.106.027748 复制DOI
    作者列表:Giordano G,White CC,McConnachie LA,Fernandez C,Kavanagh TJ,Costa LG
    BACKGROUND & AIMS: :This study investigated the role of cellular antioxidant defense mechanisms in modulating the neurotoxicity of domoic acid (DomA), by using cerebellar granule neurons (CGNs) from mice lacking the modifier subunit of glutamate-cysteine ligase (Gclm). Glutamate-cysteine ligase (Glc) catalyzes the first and rate-limiting step in glutathione (GSH) biosynthesis. CGNs from Gclm (-/-) mice have very low levels of GSH and are 10-fold more sensitive to DomA-induced toxicity than CGNs from Gclm (+/+) mice. GSH ethyl ester decreased, whereas the Gcl inhibitor buthionine sulfoximine increased DomA toxicity. Antagonists of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate receptors and of N-methyl-D-aspartate (NMDA) receptors blocked DomA toxicity, and NMDA receptors were activated by DomA-induced l-glutamate release. The differential susceptibility of CGNs to DomA toxicity was not due to a differential expression of ionotropic glutamate receptors, as evidenced by similar calcium responses and L-glutamate release in the two genotypes. A calcium chelator and several antioxidants antagonized DomA-induced toxicity. DomA caused a rapid decrease in cellular GSH, which preceded toxicity, and the decrease was primarily due to DomA-induced GSH efflux. DomA also caused an increase in oxidative stress as indicated by increases in reactive oxygen species and lipid peroxidation, which was subsequent to GSH efflux. Astrocytes from both genotypes were resistant to DomA toxicity and presented a diminished calcium response to DomA and a lack of DomA-induced L-glutamate release. Because polymorphisms in the GCLM gene in humans are associated with low GSH levels, such individuals, as well as others with genetic conditions or environmental exposures that lead to GSH deficiency, may be more susceptible to DomA-induced neurotoxicity.
    背景与目标: :这项研究利用缺乏谷氨酸-半胱氨酸连接酶(Gclm)修饰子亚基的小鼠的小脑颗粒神经元(CGNs),研究了细胞抗氧化剂防御机制在调节多摩酸(DomA)的神经毒性中的作用。谷氨酸-半胱氨酸连接酶(Glc)催化谷胱甘肽(GSH)生物合成中的第一步和限速步骤。来自Gclm(/)小鼠的CGNs的GSH水平非常低,对DomA诱导的毒性的敏感性比来自Gclm(/)小鼠的CGNs高10倍。 GSH乙酯减少,而Gcl抑制剂丁硫氨酸亚砜亚胺增加DomA毒性。 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸/海藻酸酯受体和N-甲基-D-天冬氨酸(NMDA)受体的拮抗剂可阻断DomA毒性,并且NMDA受体被DomA诱导的L-谷氨酸激活。释放。 CGN对DomA毒性的敏感性差异不归因于离子型谷氨酸受体的差异表达,这由两种基因型的相似钙反应和L-谷氨酸释放所证明。钙螯合剂和几种抗氧化剂拮抗DomA诱导的毒性。 DomA导致细胞GSH迅速下降,而毒性先于毒性下降,而下降主要归因于DomA诱导的GSH外排。 DomA还引起氧化应激的增加,如活性氧和脂质过氧化作用的增加所表明的,这是GSH流出后的结果。两种基因型的星形胶质细胞都对DomA毒性有抵抗力,并且对DomA的钙反应减弱,并且缺乏DomA诱导的L-谷氨酸释放。由于人类GCLM基因的多态性与低GSH水平相关,因此此类个体以及遗传条件或环境暴露导致GSH缺乏的其他个体可能更容易受到DomA诱导的神经毒性。
  • 【躁狂抑郁症与来自GABRbeta-1基因的高度多态性标记之间的遗传关联研究。】 复制标题 收藏 收藏
    DOI:10.1002/(sici)1096-8628(19970531)74:3<342::aid-ajm 复制DOI
    作者列表:Puertollano R,Visedo G,Zapata C,Fernández-Piqueras J
    BACKGROUND & AIMS: We report on an association study between a tetranucleotide repeat polymorphism in the GABR beta1 gene and manic-depressive illness in a Spanish population. This gene may be an important candidate for bipolar affective disorders since severe GABergic alterations have been described in patients. Although our results do not reveal a clear evidence for association between manic-depressive illness and GABR beta1, we have found significant differences between patients and controls in the female subpopulation.

    背景与目标: 我们报告了GABR beta1基因中的四核苷酸重复多态性与西班牙人群的躁狂抑郁症之间的关联研究。该基因可能是双相情感障碍的重要候选者,因为已在患者中描述了严重的GAB能改变。尽管我们的结果并未显示出躁狂抑郁症与GABR beta1之间存在关联的明确证据,但我们发现女性亚人群中的患者与对照组之间存在显着差异。

  • 【在日本对泥蟹(Scylla paramamosain)进行连续遗传标记采样后,同时估计混合速率和遗传漂移。】 复制标题 收藏 收藏
    DOI:10.1534/genetics.106.056424 复制DOI
    作者列表:Kitakado T,Kitada S,Obata Y,Kishino H
    BACKGROUND & AIMS: :In stock enhancement programs, it is important to assess mixing rates of released individuals in stocks. For this purpose, genetic stock identification has been applied. The allele frequencies in a composite population are expressed as a mixture of the allele frequencies in the natural and released populations. The estimation of mixing rates is possible, under successive sampling from the composite population, on the basis of temporal changes in allele frequencies. The allele frequencies in the natural population may be estimated from those of the composite population in the preceding year. However, it should be noted that these frequencies can vary between generations due to genetic drift. In this article, we develop a new method for simultaneous estimation of mixing rates and genetic drift in a stock enhancement program. Numerical simulation shows that our procedure estimates the mixing rate with little bias. Although the genetic drift is underestimated when the amount of information is small, reduction of the bias is possible by analyzing multiple unlinked loci. The method was applied to real data on mud crab stocking, and the result showed a yearly variation in the mixing rate.
    背景与目标: :在库存增强计划中,评估库存中已释放人员的混合比率很重要。为此,已应用遗传种群鉴定。复合种群中的等位基因频率表示为自然种群和释放种群中等位基因频率的混合。在等位基因频率的时间变化的基础上,在连续采样下从复合种群中估计混合速率是可能的。天然种群中的等位基因频率可以根据前一年的复合种群的等位基因频率进行估算。但是,应注意的是,由于遗传漂移,这些频率在世代之间可能会有所不同。在本文中,我们开发了一种新的方法,可以同时估算种群增强程序中的混合速率和遗传漂移。数值模拟表明,我们的方法估计的混合速率几乎没有偏差。尽管当信息量小时,遗传漂移会被低估,但通过分析多个未连锁的基因座可以降低偏倚。该方法应用于泥蟹放养的真实数据,结果表明混合速率逐年变化。
  • 【雌二醇调节反应的遗传控制的证据。对正常和病理性激素依赖性表型变异的影响。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Griffith JS,Jensen SM,Lunceford JK,Kahn MW,Zheng Y,Falase EA,Lyttle CR,Teuscher C
    BACKGROUND & AIMS: :The ovarian steroid hormone estrogen (E2) elicits a multiplicity of both systemic and uterotropic responses in vivo. For example, the administration of E2 to ovariectomized (Ovx) and sexually immature rodents leads to uterine-specific inflammatory infiltrates. In this study, we quantitated the number of eosinophils and BM8+, Ia+, and CD4+ cells in uteri obtained from adult Ovx control and E2-treated C57BL/6J, C3H/HeJ, and (C57BL/6J x C3H/HeJ) (B6C3) F1 hybrid mice. All three strains exhibited a significant increase in the number of uterine eosinophils and BM8+ macrophages after E2 treatment. However, C57BL/6J and B6C3 F1 hybrid mice responded with a greater number of infiltrating eosinophils and macrophages as compared with C3H/HeJ. A similar analysis of Ia+ and CD4+ cells showed that E2 treatment either down-regulates or does not affect the number of such cells in all three strains. Genome exclusion mapping using a (C57BL/6J x C3H/HeJ) x C3H/HeJ backcross population localized Est1, the major locus controlling the number of eosinophils infiltrating the uterus after E2 treatment, to chromosome 4. In addition, suggestive linkage to marker loci on chromosomes 10 and 16 was detected and evidence for locus interaction is presented. Our results conclusively demonstrate that E2-regulated/ dependent responses can be genetically controlled, indicating that the phenotypic variation observed in both the normal and pathological effects of E2 may, in part, be due to a genetic component.
    背景与目标: :卵巢类固醇激素雌激素(E2)在体内引起多种全身和子宫促反应。例如,将E2给予去卵巢(Ovx)和性不成熟的啮齿动物会导致子宫特异性炎症浸润。在这项研究中,我们量化了从成年Ovx对照和经E2处理的C57BL / 6J,C3H / HeJ和(C57BL / 6J x C3H / HeJ)(B6C3)获得的子宫中嗜酸性粒细胞和BM8,Ia和CD4细胞的数量F1杂种小鼠。在E2处理后,所有三个菌株均表现出子宫嗜酸性粒细胞和BM8巨噬细胞数量的显着增加。但是,与C3H / HeJ相比,C57BL / 6J和B6C3 F1杂种小鼠反应的浸润性嗜酸性粒细胞和巨噬细胞数量更多。对Ia和CD4细胞的类似分析显示,E2处理在所有三个菌株中均下调或不影响此类细胞的数量。使用(C57BL / 6J x C3H / HeJ)x C3H / HeJ回交群体定位的基因组排斥定位于Est1,Est1是控制E2处理后浸润子宫的嗜酸性粒细胞数量的主要基因座,并指向染色体4。检测到10号和16号染色体上的基因并提供了基因座相互作用的证据。我们的结果最终证明,E2调节/依赖性反应可以通过基因控制,这表明在E2的正常和病理效应中观察到的表型变异可能部分归因于遗传成分。
  • 【青春期妇女之间的关系质量,激素避孕选择和不使用避孕套的发展联系。】 复制标题 收藏 收藏
    DOI:10.1016/j.jadohealth.2005.12.027 复制DOI
    作者列表:Sayegh MA,Fortenberry JD,Shew M,Orr DP
    BACKGROUND & AIMS: PURPOSE:Consistent condom use is critical to efforts to prevent sexually transmitted infections among adolescents, but condom use may decline as relationships and contraceptive needs change. The purpose of this research is to assess changes in condom non-use longitudinally in the context of changes in relationship quality, coital frequency and hormonal contraceptive choice. METHODS:Participants were women (aged 14-17 years at enrollment) recruited from three urban adolescent medicine clinics. Data were collected at three-month intervals using a face-to-face structured interview. Participants were able to contribute up to 10 interviews, but on average contributed 4.2 interviews over the 27-month period. Independent variables assessed partner-specific relationship quality (five items; scale range 5-25; alpha = .92, e.g., this partner is a very important person to me); and, number of coital events with a specific partner. Additional items assessed experience with oral contraceptive pills (OCP) use and injected depo medroxy-progesterone acetate (DMPA). The outcome variable was number of coital events without condom use during the past three months. Analyses were conducted as a three-level hierarchical linear growth curve model using HLM 6. The Level 1 predictor was time, to test the hypothesis that condom non-use increases over time. Level 2 predictors assessed relationship quality and coital frequency across all partners to assess hypotheses that participants' condom non-use increases over time as a function of relationship quality and coital frequency. Level 3 predictors assessed the participant-level influence of OCP or DMPA experience on time-related changes in condom non-use. RESULTS:A total of 176 women reported 279 sex partners and contributed 478 visits. Both average coital frequency and average condom non-use linearly increased during the 27-month follow-up. At any given follow-up, about 35% reported recent OCP use, and 65% reported DMPA use. HLM analyses showed that condom non-use increased as a function of time (beta = .12; p = .03, Level 1 analysis). Increased condom non-use over time was primarily a function of increased coital frequency (beta = .01; p = .00), although higher levels of relationship quality were associated with increased condom non-use at enrollment (beta = .44; p = .00, Level 2 analysis). The temporal rise in condom non-use significantly increased among DMPA users (beta = .06; p = .00) but not OCP users (Level 3 analysis) (beta = -.04; p = .06). CONCLUSIONS:Developmentally, relationship characteristics and coital frequency appear to have increasing weight in decisions about condom use. Hormonal contraceptive methods are not equivalently associated with the overall temporal decline in condom use. Future research associated with dual contraceptive/condom use should address differential factors associated condom use in combination with different hormonal methods.
    背景与目标: 目的:持续使用避孕套对于预防青少年性传播感染至关重要,但是随着人际关系和避孕需求的变化,避孕套的使用可能会减少。这项研究的目的是在关系质量,性交频率和激素避孕选择的变化的背景下,纵向评估未使用安全套的变化。
    方法:参与者是从三个城市青少年医学诊所招募的女性(入学年龄14-17岁)。使用面对面的结构化访谈,每三个月收集一次数据。参加者最多可以贡献10个访谈,但在27个月内平均贡献了4.2个访谈。自变量评估了特定于伴侣的关系质量(五个项目;等级范围5-25;α= 0.92,例如,这个伴侣对我来说是非常重要的人);以及与特定伴侣发生性行为的次数。其他项目评估了口服避孕药(OCP)的使用经验和注射醋酸去甲羟孕酮(DMPA)的经验。结果变量是在过去三个月中未使用安全套的性交事件的数量。使用HLM 6作为三级分层线性增长曲线模型进行了分析。1级预测因子是时间,以检验安全套不使用随时间增加的假设。 2级预测变量评估了所有伴侣之间的关系质量和性交频率,以评估以下假设:参与者不使用安全套会随着时间的推移而增加,这是关系质量和性交频率的函数。 3级预测变量评估了OCP或DMPA经验对安全套不使用时间相关变化的参与者水平影响。
    结果:总共176名妇女报告了279个性伴侣,并贡献了478次探视。在27个月的随访中,平均性交频率和平均不使用安全套均呈线性增加。在任何给定的随访中,约35%的患者报告了最近的OCP使用,而65%的患者报告了DMPA的使用。 HLM分析表明,不使用安全套随时间增加(β= .12; p = .03,1级分析)。随着时间的流逝,不使用安全套的增加主要是性交频率增加的函数(β= .01; p = .00),尽管较高的关系质量与入学时不使用安全套的增加相关(β= .44; p = .00,第2级分析)。在DMPA用户中,未使用安全套的时间增加显着增加(β= .06; p = .00),但在OCP用户中则没有(第三级分析)(β= -.04; p = .06)。
    结论:在发展上,关系特征和性交频率似乎在有关使用安全套的决策中具有越来越大的重要性。激素避孕方法与使用避孕套的总体时间下降没有同等的联系。与双重避孕/避孕套使用相关的未来研究应解决与不同激素方法结合使用避孕套相关的差异因素。
  • 【与人类神经胶质瘤细胞系SNB-19中获得性替莫唑胺抗性相关的遗传改变。】 复制标题 收藏 收藏
    DOI:10.1158/1535-7163.MCT-05-0428 复制DOI
    作者列表:Auger N,Thillet J,Wanherdrick K,Idbaih A,Legrier ME,Dutrillaux B,Sanson M,Poupon MF
    BACKGROUND & AIMS: :Gliomas are highly lethal neoplasms that cannot be cured by currently available therapies. Temozolomide is a recently introduced alkylating agent that has yielded a significant benefit in the treatment of high-grade gliomas. However, either de novo or acquired chemoresistance occurs frequently and has been attributed to increased levels of O6-methylguanine-DNA methyltransferase or to the loss of mismatch repair capacity. However, very few gliomas overexpress O6-methylguanine-DNA methyltransferase or are mismatch repair-deficient, suggesting that other mechanisms may be involved in the resistance to temozolomide. The purpose of the present study was to generate temozolomide-resistant variants from a human glioma cell line (SNB-19) and to use large-scale genomic and transcriptional analyses to study the molecular basis of acquired temozolomide resistance. Two independently obtained temozolomide-resistant variants exhibited no cross-resistance to other alkylating agents [1,3-bis(2-chloroethyl)-1-nitrosourea and carboplatin] and shared genetic alterations, such as loss of a 2p region and loss of amplification of chromosome 4 and 16q regions. The karyotypic alterations were compatible with clonal selection of preexistent resistant cells in the parental SNB-19 cell line. Microarray analysis showed that 78 out of 17,000 genes were differentially expressed between parental cells and both temozolomide-resistant variants. None are implicated in known resistance mechanisms, such as DNA repair, whereas interestingly, several genes involved in differentiation were down-regulated. The data suggest that the acquisition of resistance to temozolomide in this model resulted from the selection of less differentiated preexistent resistant cells in the parental tumor.
    背景与目标: :胶质瘤是高度致死性的肿瘤,目前尚无法治愈。替莫唑胺是最近引入的烷基化剂,已在治疗高级神经胶质瘤中产生了显着的益处。然而,从头或获得性化学抗性经常发生,并且归因于O6-甲基鸟嘌呤-DNA甲基转移酶水平的增加或失配修复能力的丧失。但是,极少的神经胶质瘤过表达O6-甲基鸟嘌呤-DNA甲基转移酶或错配修复缺陷,提示其他机制可能与对替莫唑胺的抗性有关。本研究的目的是从人类神经胶质瘤细胞系(SNB-19)产生抗替莫唑胺的变体,并使用大规模的基因组和转录分析来研究获得的替莫唑胺抗性的分子基础。两个独立获得的替莫唑胺抗性变体对其他烷基化剂[1,3-双(2-氯乙基)-1-亚硝基脲和卡铂]无交叉抗性,并且共有遗传变异,例如2p区域丢失和扩增丢失染色体4和16q区域。核型改变与亲本SNB-19细胞系中先前存在的抗性细胞的克隆选择相容。基因芯片分析显示,在17,000个基因中,有78个在亲代细胞和两种替莫唑胺耐药变体之间差异表达。没有人参与已知的抗性机制,例如DNA修复,而有趣的是,参与分化的几个基因被下调。数据表明,在该模型中获得对替莫唑胺的抗药性是由于在亲本肿瘤中选择了分化程度较低的抗药性细胞而引起的。
  • 【生长激素的遗传疾病-胰岛素样生长因子-I轴。】 复制标题 收藏 收藏
    DOI:10.1159/000095161 复制DOI
    作者列表:Walenkamp MJ,Wit JM
    BACKGROUND & AIMS: :In the last few years, our knowledge of genetically determined causes of short stature has greatly increased by reports of challenging patients, who offered the opportunity to study genes that play a role in growth. Since the first paper that showed the etiology of Laron syndrome [Godowski PJ, et al: Proc Natl Acad Sci USA 1989;86:8083-8087], many mutations in the growth hormone (GH) receptor have been identified. Recently, new mutations or deletions have been found in several components of the GH-insulin-like growth factor-I (IGF-I) axis: a homozygous mutation of the GH1 gene, resulting in a bio-inactive GH; mutations in the STAT5b gene, which plays a major role in the GH signal transduction; a homozygous missense mutation in the IGF-I gene; heterozygous mutations in the IGF-I receptor gene and a homozygous deletion of the acid-labile subunit gene. In this mini review, we describe the clinical and biochemical features of these genetic defects. Genetic analysis has become essential in the diagnostic workup of a patient with short stature. However, regarding the time consuming nature of molecular analysis, it is important to carefully select the patient for specific genetic evaluation. To help in this selection process, we developed flowcharts, based on the recently described patients, that can be used as guidelines in the diagnostic process of patients with severe short stature of unknown origin.
    背景与目标: :在过去的几年中,由于挑战性患者的报道,我们对遗传决定的矮小身高原因的了解大大增加了,这些患者为研究在生长中起作用的基因提供了机会。自从第一篇显示Laron综合征病因的论文以来[Godowski PJ等人:Proc Natl Acad Sci USA 1989; 86:8083-8087],已经确定了生长激素(GH)受体的许多突变。最近,在GH-胰岛素样生长因子-I(IGF-I)轴的几个组成部分中发现了新的突变或缺失:GH1基因的纯合突变,导致了生物失活的GH; STAT5b基因的突变,在GH信号转导中起主要作用; IGF-I基因的纯合错义突变; IGF-1受体基因中的杂合突变和对酸不稳定的亚基基因的纯合缺失。在这个小型综述中,我们描述了这些遗传缺陷的临床和生化特征。遗传分析已成为身材矮小的患者的诊断检查中必不可少的。但是,考虑到分子分析的耗时性质,重要的是要仔细选择患者进行特定的基因评估。为了帮助选择过程,我们根据最近描述的患者制定了流程图,可以将其用作诊断患有严重身材矮小,来源不明的患者的诊断过程中的指导原则。
  • 【肌营养不良症的遗传修饰因子:对治疗的意义。】 复制标题 收藏 收藏
    DOI:10.1016/j.bbadis.2006.06.013 复制DOI
    作者列表:Heydemann A,Doherty KR,McNally EM
    BACKGROUND & AIMS: :The genetic understanding of the muscular dystrophies has advanced considerably in the last two decades. Over 25 different individual genes are now known to produce muscular dystrophy, and many different "private" mutations have been described for each individual muscular dystrophy gene. For the more common forms of muscular dystrophy, phenotypic variability can be explained by precise mutations. However, for many genetic mutations, the presence of the identical mutation is associated with marked phenotypic range that affects muscle function as well as cardiac function. The explanation for phenotype variability in the muscular dystrophies is only now being explored. The availability of genetically engineered animal models has allowed the generation of single mutations on the background of highly inbred strain. Phenotypic variation that is altered by genetic background argues for the presence of genetic modifier loci that can ameliorate or enhance aspects of the dystrophic phenotype. A number of individual genes have been implicated as modifiers of muscular dystrophy by studies in genetically engineered mouse models of muscular dystrophy. The value of these genes and products is that the pathways identified through these experiments may be exploited for therapy.
    背景与目标: 在过去的二十年中,人们对肌肉营养不良的遗传学认识有了很大的提高。现在已知产生肌营养不良症的超过25个不同的个体基因,并且对于每个个体肌营养不良症基因已经描述了许多不同的“私人”突变。对于更常见的肌肉营养不良形式,表型变异性可以通过精确的突变来解释。然而,对于许多遗传突变,相同突变的存在与影响肌肉功能以及心脏功能的显着表型范围有关。肌肉营养不良症的表型变异性的解释目前才被探索。基因工程动物模型的可用性允许在高度近交系的背景下产生单个突变。由遗传背景改变的表型变异主张存在可以改善或增强营养不良表型方面的遗传修饰基因座。通过对肌营养不良症的基因工程小鼠模型的研究,许多个体基因被认为是肌营养不良症的修饰因子。这些基因和产物的价值在于通过这些实验确定的途径可用于治疗。
  • 【通量的遗传调控:大肠杆菌的铁稳态。】 复制标题 收藏 收藏
    DOI:10.1093/nar/gkl627 复制DOI
    作者列表:Semsey S,Andersson AM,Krishna S,Jensen MH,Massé E,Sneppen K
    BACKGROUND & AIMS: :Iron is an essential trace-element for most organisms. However, because high concentration of free intracellular iron is cytotoxic, cells have developed complex regulatory networks that keep free intracellular iron concentration at optimal range, allowing the incorporation of the metal into iron-using enzymes and minimizing damage to the cell. We built a mathematical model of the network that controls iron uptake and usage in the bacterium Escherichia coli to explore the dynamics of iron flow. We simulate the effect of sudden decrease or increase in the extracellular iron level on intracellular iron distribution. Based on the results of simulations we discuss the possible roles of the small RNA RyhB and the Fe-S cluster assembly systems in the optimal redistribution of iron flows. We suggest that Fe-S cluster assembly is crucial to prevent the accumulation of toxic levels of free intracellular iron when the environment suddenly becomes iron rich.
    背景与目标: 铁是大多数生物必不可少的微量元素。但是,由于高浓度的游离细胞内铁具有细胞毒性,因此细胞已开发出复杂的调节网络,可将游离细胞内铁的浓度保持在最佳范围,从而将金属掺入使用铁的酶中,并将对细胞的损害降至最低。我们建立了控制该细菌大肠杆菌中铁的吸收和使用的网络数学模型,以探索铁流量的动态变化。我们模拟了细胞外铁水平突然降低或增加对细胞内铁分布的影响。基于模拟的结果,我们讨论了小RNA RyhB和Fe-S簇组装系统在铁流的最佳重新分配中的可能作用。我们建议,当环境突然变得富含铁时,Fe-S簇组装对于防止游离细胞内铁的毒性水平的积累至关重要。
  • 【正常年轻妇女和老年妇女的肠道维生素D受体,钙吸收与血清1,25二羟基维生素D之间的关联。】 复制标题 收藏 收藏
    DOI:10.1359/jbmr.1997.12.6.922 复制DOI
    作者列表:Kinyamu HK,Gallagher JC,Prahl JM,DeLuca HF,Petranick KM,Lanspa SJ
    BACKGROUND & AIMS: The exact mechanism for the decrease in intestinal calcium absorption with age is not yet understood. A decrease with age in serum 1,25-dihydroxyvitamin D (1,25(OH)2D) or a decrease in the intestinal vitamin D receptor (VDR) protein concentration are possible causes. The objective of this study was to examine the effect of age on these factors. Fifty-nine young women age 25-35 years were compared with 41 elderly women age 65-83 years who underwent measurements of VDR, calcium absorption using a 20 mg and 100 mg calcium carrier, and calciotropic hormones. Calcium absorption by both tests was lower in the elderly women compared with the young women (p < 0.05). Serum 1,25(OH)2D and duodenal VDR protein concentration were not significantly different between the two age groups. Serum 1,25(OH)2D correlated with the 20 mg calcium absorption test in both young (r = 0.35, p < 0.007) and elderly women (r = 0.58, p < 0.0001) and with the 100 mg calcium absorption in the elderly (r = 0.32; p < 0.05). VDR did not correlate with calcium absorption in young women or elderly women, nor did VDR correlate with serum 1,25(OH)2D and serum 25-hydroxyvitamin D. In summary, the decrease in calcium absorption cannot be explained by a decrease in intestinal VDR. The correlation between serum 1,25(OH)2D and both calcium absorption tests only accounts for 12-30% of the variance in the age-related change in the calcium absorption tests. Other factors, not yet understood, are responsible for the decline in calcium absorption with age.

    背景与目标: 随着年龄的增长,肠道钙吸收减少的确切机制尚不清楚。血清1,25-二羟基维生素D(1,25(OH)2D)随年龄的减少或肠道维生素D受体(VDR)蛋白质浓度的减少是可能的原因。这项研究的目的是研究年龄对这些因素的影响。比较了59名年龄在25-35岁之间的年轻女性与41位年龄在65-83岁之间的女性,这些女性进行了VDR测量,使用20 mg和100 mg钙载体的钙吸收量以及亲钙性激素。与年轻女性相比,老年女性的两种测试中的钙吸收均较低(p <0.05)。在两个年龄组之间,血清1,25(OH)2D和十二指肠VDR蛋白浓度无显着差异。血清1,25(OH)2D与年轻(r = 0.35,p <0.007)和老年妇女(r = 0.58,p <0.0001)的20 mg钙吸收测试以及老年人的100 mg钙吸收相关(r = 0.32; p <0.05)。 VDR与年轻妇女或老年妇女的钙吸收无关,也不与血清1,25(OH)2D和血清25-羟维生素D相关。 VDR。血清1,25(OH)2D与两种钙吸收试验之间的相关性仅占钙吸收试验中与年龄相关的变化方差的12%至30%。钙吸收随着年龄的增长而下降的其他原因尚不明确。

  • 【小儿多形性肉瘤的细胞遗传学和分子遗传学分析显示与成人恶性纤维组织细胞瘤相似。】 复制标题 收藏 收藏
    DOI:10.1016/s0165-4608(96)00243-9 复制DOI
    作者列表:Palmer JL,Masui S,Pritchard S,Kalousek DK,Sorensen PH
    BACKGROUND & AIMS: Cytogenetic and molecular genetic studies were performed on a pleomorphic sarcoma removed from the left atrium of a 15-year-old girl. Histologic analysis was consistent with a storiform-pleomorphic malignant fibrous histiocytoma (MFH). Although MFH is the most common soft-tissue sarcoma of late adulthood. It is extremely rare in childhood and its existence in the pediatric population remains controversial. Cytogenetic analysis revealed several alterations previously associated with adult MFH, including abnormalities of chromosomal bands 11p11 and 19p13. Moreover, the tumor demonstrated homogeneously staining regions (HSR) and double minute chromosomes (dmin) suggestive of gene amplification. We therefore screened the case for amplification of genes localized to chromosomal bands 12q13-14, including the putative protooncogenes MDM2, CDK4, SAS, CHOP, and CLI, which are frequently amplified and overexpressed in adult MFH. Southern and Northern blot analysis confirmed the coamplification of MDM2, CDK4, SAS, and CHOP. To our knowledge, such coamplification studies of the 12q13-14 amplicon have not been previously detected in pediatric MFH. Our results provide cytogenetic and molecular genetic evidence that pediatric and adult MFH are histogenetically related entities.

    背景与目标: 细胞遗传学和分子遗传学研究是从一个15岁女孩的左心房切除的多形性肉瘤。组织学分析与星形样多形性恶性纤维组织细胞瘤(MFH)一致。尽管MFH是成年后期最常见的软组织肉瘤。它在儿童时期极为罕见,其在儿科人群中的存在仍然引起争议。细胞遗传学分析揭示了以前与成人MFH相关的几种改变,包括染色体条带11p11和19p13的异常。此外,肿瘤表现出均一的染色区(HSR)和双分钟染色体(dmin),提示基因扩增。因此,我们筛选了扩增位于染色体12q13-14的基因的案例,包括推定的原癌基因MDM2,CDK4,SAS,CHOP和CLI,这些基因在成年MFH中经常被扩增和过表达。 Southern和Northern印迹分析证实了MDM2,CDK4,SAS和CHOP的共扩增。据我们所知,这种12q13-14扩增子的共扩增研究以前未在儿科MFH中检测到。我们的研究结果提供了细胞遗传学和分子遗传学证据,表明小儿和成人MFH是组织遗传学相关的实体。

  • 【来自“进化峡谷”的酿酒酵母自然种群中的分子遗传生物多样性:微卫星多态性,倍性和有争议的性状态。】 复制标题 收藏 收藏
    DOI:10.1534/genetics.106.062745 复制DOI
    作者列表:Ezov TK,Boger-Nadjar E,Frenkel Z,Katsperovski I,Kemeny S,Nevo E,Korol A,Kashi Y
    BACKGROUND & AIMS: :The yeast S. cerevisiae is a central model organism in eukaryotic cell studies and a major component in many food and biotechnological industrial processes. However, the wide knowledge regarding genetics and molecular biology of S. cerevisiae is based on an extremely narrow range of strains. Studies of natural populations of S. cerevisiae, not associated with human activities or industrial fermentation environments, are very few. We isolated a panel of S. cerevisiae strains from a natural microsite, "Evolution Canyon" at Mount Carmel, Israel, and studied their genomic biodiversity. Analysis of 19 microsatellite loci revealed high allelic diversity and variation in ploidy level across the panel, from diploids to tetraploids, confirmed by flow cytometry. No significant differences were found in the level of microsatellite variation between strains derived from the major localities or microniches, whereas strains of different ploidy showed low similarity in allele content. Maximum genetic diversity was observed among diploids and minimum among triploids. Phylogenetic analysis revealed clonal, rather than sexual, structure of the triploid and tetraploid subpopulations. Viability tests in tetrad analysis also suggest that clonal reproduction may predominate in the polyploid subpopulations.
    背景与目标: :酿酒酵母是真核细胞研究中的中心模型生物,在许多食品和生物技术工业过程中都是主要成分。但是,关于酿酒酵母的遗传学和分子生物学的广泛知识是基于非常狭窄的菌株。与人类活动或工业发酵环境无关的酿酒酵母自然种群研究很少。我们从以色列卡梅尔山的天然微型站点“进化峡谷”中分离出一组酿酒酵母菌株,并研究了它们的基因组生物多样性。对19个微卫星基因座的分析显示,从二倍体到四倍体,整个等位基因组中的高等位基因多样性和倍性水平存在差异,这已通过流式细胞仪进行了确认。在来自主要地区或微生态位的菌株之间,微卫星变异水平没有发现显着差异,而具有不同倍性的菌株在等位基因含量上的相似性很低。在二倍体中观察到最大的遗传多样性,而在三倍体中观察到了最小的遗传多样性。系统发育分析显示三倍体和四倍体亚群的克隆结构,而不是有性结构。四元分析中的生存力测试还表明,在多倍体亚群中克隆繁殖可能占主导地位。

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