ATM与BRCA1的双杂合性通过影响若干通路增加肿瘤发生风险

<正>目的:流行病学统计数据表明杂合性与肿瘤发生相关。ATM和BRCA1都是DNA损伤修复通路中的多功能基因,其单杂合性对于肿瘤易感性的影响已见报道,但双杂合

ATM蛋白表达与四种肿瘤细胞的辐射敏感性的关系

<正>毛细管扩张共济失调症(AT)由ATM基因引起,其特点是对放射线非常敏感。ATM基因是电离辐射所致的DNA损伤信号转导途径中必不可少的一部分,因此,ATM的表

Radiosensitivity to high energy iron ions is influenced by heterozygosity for Atm, Rad9 and Brca1

Loss of function of DNA repair genes has been implicated in the development of many types of cancer. In the last several years, heterozygosity leading to haploinsufficiency for proteins involved in DNA repair was shown to play a role in genomic instability and carcinogenesis after DNA damage is induced, for example by ionizing radiation. Since the effect of heterozygosity for one gene is relatively small, we hypothesize that predisposition to cancer could be a result of the additive effect of heterozygosity for two or more genes critical to pathways that control DNA damage signaling, repair or apoptosis. We investigated the role of heterozygosity for Aim, Rad9 and Brad on cell oncogenic transformation and cell survival induced by 1 GeV/n Fe-56 ions. Our results show that cells heterozygous for both Aim and Rad9 or A tin and Brca1 have high survival rates and are more sensitive to transformation by high energy iron ions when compared with wild-type controls or cells haploinsufficient for only one of these proteins. Since mutations or polymorphisms for similar genes exist in a small percentage of the human population, we have identified a radiosensitive sub-population. This finding has several implications. First, the existence of a radiosensitive sub-population may distort the shape of the dose response relationship. Second, it would not be ethical to put exceptionally radiosensitive individuals into a setting where they may potentially be exposed to substantial doses of radiation. (C) 2010 COSPAR. Published by Elsevier Ltd. All rights reserved.

Hemizygosity for Atm and Brca1 influence the balance between cell transformation and apoptosis

Background: In recent years data from both mouse models and human tumors suggest that loss of one allele of genes involved in DNA repair pathways may play a central role in genomic instability and carcinogenesis. Additionally several examples in mouse models confirmed that loss of one allele of two functionally related genes may have an additive effect on tumor development. To understand some of the mechanisms involved, we examined the role of monoallelic loss or Atm and Brca1 on cell transformation and apoptosis induced by radiation. Methods: Cell transformation and apoptosis were measured in mouse embryo fibroblasts (MEF) and thymocytes respectively. Combinations of wild type and hemizygous genotypes for ATM and BRCA1 were tested in various comparisons. Results: Haploinsufficiency of either ATM or BRCA1 resulted in an increase in the incidence of radiation-induced transformation of MEF and a corresponding decrease in the proportion of thymocytes dying an apoptotic death, compared with cells from wild-type animals. Combined haploinsufficiency for both genes resulted in an even larger effect on apoptosis. Conclusions: Under stress, the efficiency and capacity for DNA repair mediated by the ATM/BRCA1 cell signalling network depends on the expression levels of both proteins.

愿区区十七万元成为社会进步的推动费——许霆无罪以及许霆案正确判决的深远意义

《羊城借记卡章程》第4条规定,密码相符的交易"视为持卡人的合法交易"。本文证明这一交易规则是在广州市商业银行充分考虑银行自动柜员机(ATM)取款时有出现异常的可能性后慎重制定的,因此,根据本交易规则,ATM 出现异常情况时取款的合法性是银行的意愿和许诺。许霆在明知 ATM 有问题的情况下,连续多次提取银行款项,这并不违反银行和 ATM 公司的本意,根本不是什么秘密窃取,因此不符合盗窃罪的客观要件。批驳了关于许霆有盗窃罪的几种典型的论据。宣判许霆无罪,是对作为现代社会根本特征的契约的严肃性的一次伸张,这将大大地引起全社会的反思,起到促进公民社会进步的作用。

Modelling Study On The Plasma Flow and Heat Transfer In A Laminar Arc Plasma Torch Operating At Atmospheric and Reduced Pressure

A modelling study is performed to investigate the characteristics of both plasma flow and heat transfer of a laminar non-transferred arc argon plasma torch operated at atmospheric and reduced pressure. It is found that the calculated flow fields and temperature distributions are quite similar for both cases at a chamber pressure of 1.0 atm and 0.1 atm. A fully developed flow regime could be achieved in the arc constrictor-tube between the cathode and the anode of the plasma torch at 1.0 atm for all the flow rates covered in this study. However the flow field could not reach the fully developed regime at 0.1 atm with a higher flow rate. The arc-root is always attached to the torch anode surface near the upstream end of the anode, i.e. the abruptly expanded part of the torch channel, which is in consistence with experimental observation. The surrounding gas would be entrained from the torch exit into the torch interior due to a comparatively large inner diameter of the anode channel compared to that of the arc constrictor-tube.

以用户为中心的场景设计方法研究

图形用户界面(GUI)的可用性在于给用户的任务提供了有用的图形表示和操作,以使用户无须分心于那些不必要的交互和领域特征.然而,当前的GUI设计通常反映了系统的状态和操作,迫使人们学习和适应预定义的系统任务.以用户为中心的GUI设计旨在提高系统可用性,但是众多的以用户为中心的设计研究只给出一些设计准则和经验性的方法,缺乏对实际软件设计的可操作指导.基于场景的设计是GUI设计的有效方法,然而,场景本身并没给出好的实现以用户为中心设计的方法.该文在研究以用户为中心的设计和基于场景的设计的基础上,提出一种以用户为中心的场景设计方法,力图给出一种提高GUI可用性的更有效的方法.该方法的核心是:用场景描述方式来体现用户为中心的设计思想,并将其贯穿到系统开发的各个阶段,真正实现从用户的角度设计系统.最后以ATM机的界面设计为例说明使用该方法进行设计的有效性.

糠醇和糠醇与三－（2－羟乙基）－异氰尿酸酯缩聚和磺化反应及结构性能表征

本工作对糠醇（FA）和FA与三－（2－羟乙基）异氰尿酸酯（THEIC）的缩聚和磺化反应以及产物的结构和抗氧，抗氯稳定性进行了系统的研究。对FA与THEIC表面聚合制备反渗透复合膜具有十分重要的指导意义。由热分析方法研究发现，FA和FA与THEIC共缩聚反应过程在DSC谱图上有四个放热反应峰。I、II峰（50～80 ℃）为FA头－尾及头－头醚化脱水线性缩聚反应。III峰（110～130 ℃）为FA缩聚物的端羟甲基与亚甲基脱水反应。IN峰（150～190 ℃）为高温下呋喃甲醚链脱出甲醛，甲醛与亚甲基发生交联反应。催化剂用量的增加有利于羟甲基间脱水醚化反应。FA与THEIC共缩聚反应在150 ℃左右有突变，THEIC参加反应的活性增加。体系中大量硫酸存在对THEIC参加反应不利，同时引起FA缩聚物裂解反应。THEIC的加入可改善FA缩聚物的耐热氧化裂解性能。空气下使起始热失重温度提高了60 ℃；氮气下，起始热失重温度提高80 ℃。FA缩聚物的磺化反应在低温下就开始进行，140 ℃时磺化程度最高。磺化度为0.067个SO_3H／重复单元，离子交换容量（电荷密度）为0.84 meg/g酸型。FA和甲基呋喃齐聚物和其磺化后的~(13)C-NMR分析表明，磺化反应容易发生在端呋喃环与H相连的α位，β位，中间呋喃环β位也可发生磺化反应。磺化反应速度较慢，磺化程度不高。H_2SO_4与FA重量之比大于四分之一时，磺化程度基本不变，H_2SO_4量过高时对产物有裂解作用，因此选择此比例比较适宜。由液体和固体~(13)C-NMR观察到FA缩聚反应过程中，羟甲基于100 ℃基本消失，而呋喃甲醚链生成。产生交联的主要原因是甲醛与亚甲基反应进行的。甲醛也可同呋喃环端αH位和β位发生反应生成羟甲基，羟甲基可继续参加反应使缩聚物产生交联。缩聚物中有明显的端甲基酮、醛和羧酸基的生成。产生的原因如下：FA缩聚物中呋喃环间在较高温度下可发生Diels-Alder反应，裂解色谱－质谱分析检出裂解产物中有CH_3和CH_3等芳香族化合物，证实发生了Diels-Alder反应。FA和甲基呋喃齐聚物在大量硫酸作用下，室温磺化交联产物的固体~(13)C-NMR表明有呋喃环上双键打开的反应。可能为Diels-Alder反应，也可能是环双键打开交联的反应。但形成的温度和反应速度还不十分清楚。FA和FA与THEIC缩聚物经过氧化氢氧化裂解产物裂解失重较大，主链发生了断裂反应红外光谱和固体~(13)C-NMR分析表明产生了大量的酮，醛和羧酸。反应过程可能如下：FA缩聚物经游离氯作用后，有少量缩聚物被裂解掉，共缩聚物中脂肪醚被裂解，生成醇，THEIC部分被裂解掉。于是可初步确定FA缩聚物和FA与TEHIC共缩聚物链中的亚甲基和脂肪醚键是易受氧化攻击的弱点。利用表面内反射红外光谱，电子能谱和电子显微镜等对PEC－1000复合膜和试剂复合膜进行了结构与组成剖析，发现PEC－1000膜分离功能层中含有较多伯醇化合物。膜表面含有较多的O, S, N等原子，因此制复合膜的溶液中，THEIC的含量较高，膜的流动电位随压力变化的速率为-4.67mV/atm，膜功能层中含有较多的极性SO_3~-基团。

盐和有机物对氨基酸热力学性质的影响-NaCl氨基酸-葡萄糖-水体系

在278.15-318.15范围内，本文测定了以下四个无液接电池的电动势：Pt,H_2(g, 1 atm)|HCl(m)、X Mass% Glucose-H_2O|Ag-AgCl (A) Pt,H_2 (g, 1 atm)|G(m_1), HGCl (m_2), X Mass% Glucose-H_2O|Ag-AgCl (B) Pt,H_2 (g, 1 atm) |HCl (m), NaCl (M-m), X Mass% Glucose-H_2O|Ag-AgCl (C) Pt,H_2 (g, 1 atm)|G(m_1), HGCl (m_2), NaCl (M-m), X Mass% Glucose-H_2O|Ag-AgCl (D) 其中G为中性甘氨酸，NH_3CH_2COO~-, HGClm为甘氨酸的盐酸盐，为相应电解质的质量摩尔浓度，X为葡萄糖在葡萄糖-水混合溶剂中的质量百分数，M为恒定的离子强度且M = 1.0mol/kg。并且测定了Glucose-H_2O的密度和介电常数。利用传统的D-H公式外推法和基于Pitzer理论的多项式逼近法分别确定了电池的标准电动势E°_3、E°_3，以及甘氨酸的一级热力学解离1.0mol/kg）-葡萄糖-水-HCl的HCl无限稀释溶液为参考态，并将两种方法得到的结果作了比较。甘氨酸的一级热力学解离常数符合Harned-Robinson方程：pK = A_1/T + A_2 + A+3 T 本文讨论了盐和有机物对pK_1的影响，并根据前人及我们的工作，指出在极性质子溶剂中和在极性非质子溶剂中的pK_1对1/D作图，分别得到直线和曲线。同时讨论了混合溶剂中甘氨酸的一级解离过程的各个热力学量ΔG°，ΔH°，ΔS°，ΔCp°，并讨论HCl的迁移性质和有机物葡萄糖、盐对它们的影响。最后将不同混合溶剂中甘氨酸解离过程的迁移能，迁移熵等作了比较。

Extinction of lean near-limit methane/air flames at elevated pressures under normal- and reduced-gravity

perimentally at evaluated pressures and under normal- and micro-gravity conditions utilizing the 3.5 s drop tower of the National Microgravity Laboratory of China. The results showed that under micro-gravity conditions the natural convection is minimized and the flames become more planar and symmetric compared to normal gravity. In both normal- and micro-gravity experiments and for a given strain rate and fuel concentration, the flame luminosity was found to enhance as the pressure increases. On the other hand, at a given pressure, the flame luminosity was determined to weaken as the strain rate decreases. At a given strain rate, the fuel concentration at extinction was found to vary non-monotonically with pressure, namely it first increases and subsequently decreases with pressure. The limit fuel concentration peaks around 3 and 4 atm under normal- and micro-gravity, respectively. The extinction limits measured at micro-gravity were in good agreement with predictions obtained through detailed numerical simulations but they are notably lower compared to the data obtained under normal gravity. The simulations confirmed the non-monotonic variation of flammability limits with pressure, in agreement with previous studies. Sensitivity analysis showed that for pressures between one and 5 atm, the near-limit flame response is dominated by the competition between the main branching, H + O2 ? OH + O, and the pressure sensitive termination, H+O2+M? HO2 + M, reaction. However, for pressures greater than 5 atm it was determined that the HO2 kinetics result in further chain branching in a way that is analogous to the third explosion limit of H2/O2 mixtures. 2010 The Combustion Institute. Published by Elsevier Inc. All rights reserved.

喷管长度对氨电弧加热发动机性能影响的模拟研究

本文对低功率氨电弧加热发动机内的传热与流动过程进行了数值模拟，研究了发动机喷管扩张 段长度变化对发动机工作性能的影响。模拟结果表明：在弧电流为10 A，入口总压为2.5 atm 时，氨 电弧加热发动机喷管扩张段长度变短对上游的流动状态影响较小，但对电弧加热发动机的工作性能有 较大影响；随着喷管长度变短，发动机的推力和比冲随之提高。计算获得的典型工况下发动机出口平 面上的轴向速度和温度的径向分布与文献报道的实验测量结果大体相符。

~(12)C~(6+)离子束诱导HeLa细胞DNA损伤效应

本文研究了HeLa细胞经过12C6+离子束辐照之后的DNA损伤效应,及辐照后p53激活的分子机制。运用中性单细胞电泳技术,检测了HeLa细胞经过4Gy 12C6+离子束辐照间隔0、3、6和12h之后DNA的损伤情况,及0.5、1、2和4Gy 12C6+离子束辐照后即时的DNA损伤情况。同时运用细胞生长实时监测仪监测了HeLa细胞在经过0、0.5和1Gy 12C6+离子束辐照之后的生长变化,并运用AO/EB双染检测了辐照细胞24h后的凋亡情况。另外,利用8mmol/L的咖啡因[抑制ATM(ataxia-telangiectasia,mutated)和ATR(ATM and Rad3-related kinase)]和20μmol/L的wortmannin[抑制ATM和DNA-PK(DNA-dependent protein kinase)]处理HeLa细胞后再进行1Gy 12C6+离子束辐照,通过westernblot检测p53的表达。结果显示,12C6+离子束辐照可造成HeLa细胞的DNA损伤,损伤随剂量升高而升高但随测定间隔时间降低,诱导HeLa细胞发生凋亡;而且辐照后p53表达升高。结果证明12C6+离子束辐照可造成HeLa细胞的DNA损伤并诱导损伤修复及凋亡等效应,损伤效应相关因子p53被激活,并且激活依赖于ATM。

电离辐射后不同杂合基因在肿瘤发生中的作用及分子机理

目的检验基因杂合导致的染色单体功能不全在肿瘤发生中的作用。方法将ATM杂合鼠与BRCA1杂合鼠杂交获得四种基因型的同胎小鼠或胚胎成纤维细胞(野生型、ATM单杂合型、BRCA1单杂合型和ATM/BRCA1双杂合型),经γ-射线照射后,通过形态特征识别转化细胞克隆、流式细胞法测定胸腺细胞亚群分布和成纤维细胞周期变化、细胞松弛素B阻断法分析微核形成、免疫荧光染色法统计γH2AX foci数。结果相同剂量的射线照射后,四种基因型细胞反应不同;野生型细胞转化率最低、凋亡水平最高。相反,ATM/BRCA1双杂合型细胞转化率最高、凋亡水平最低;两种单杂合型细胞的细胞转化率和凋亡水平居中。四种细胞的微核诱导都与剂量呈线性相关,但线性拟合得到的直线斜率不同,野生型细胞的斜率最小,单杂合型细胞次之,双杂合型细胞最大。四种基因型细胞的细胞周期在辐照后都呈现G_2期阻滞,但与野生型细胞相比,ATM单杂合细胞延迟逾越周期阻滞,BRCA1单杂合细胞则提前逾越,双杂合型细胞的周期变化曲线与野生型细胞一致。0.5Gyγ射线辐照在种细胞中诱导的γH2AX foci数一样,但0.2Gyγ射线辐照诱导的γH2AX foci数则不相同,野生型细胞中最多,两种单杂合型细胞次之,双杂合型细胞中最少。结论基因杂合与肿瘤发生存在相关性,其导致细胞在外源刺激条件下基因表达量不足,从而影响损伤识别、细胞凋亡、周期调控等,致使相对较多的损伤未经修复即传递给子细胞,最终导致细胞转化、肿瘤发生。

BRCA1 and its phosphorylation involved in caffeine-inhibitable event upstream of G2 checkpoint

Caffeine, which specifically inhibits ATM/ATR kinases, efficiently abrogates the ionizing radiation (IR)-induced G2 arrest and increases the sensitivity of various tumor cells to IR. Mechanisms for the effect of caffeine remain to be elucidated. As a target of ATM/ATR kinases, BRCA1 becomes activated and phosphorylated in response to IR. Thus, in this work, we investigated the possible role of BRCA1 in the effect of caffeine on G2 checkpoint and observed how BRCA1 phosphorylation was regulated in this process. For these purposes, the BRCA1 protein level and the phosphorylation states were analyzed by Western blotting by using an antibody against BRCA1 and phospho-specific antibodies against Ser-1423 and Ser-1524 residues in cells exposed to a combination of IR and caffeine. The results showed that caffeine down-regulated IR-induced BRCA1 expression and specifically abolished BRCA1 phosphorylation of Ser-1524, which was followed by an override of G2 arrest by caffeine. In addition, the ability of BRCA1 to transactivate p21 may be required for MCF-7 but not necessary for Hela response to caffeine. These data suggest that BRCA1 may be a potential target of caffeine. BRCA1 and its phosphorylation are most likely to be involved in the caffeine-inhibitable event upstream of G2 arrest.