Telomeres and chromosomal instability

Telomeres are distinctive structures, composed of a repetitive DNA sequence and associated proteins, which enable cells to distinguish chromosome ends from DNA double-strand breaks. Telomere alterations, caused by replication-mediated shortening, direct damage or defective telomere-associated proteins, usually generate chromosomal instability, which is observed in senescence and during the immortalization process. In cancer cells, this chromosome instability could be extended by their ability to repair chromosomes and terminate in break-fusion-bridge cycles. Dysfunctional telomeres can be healed by activation of telomerase or by the alternative mechanism of telomere lengthening. Activation of such telomere maintenance mechanisms may help to preserve the integrity of chromosomes even if they play a role in chromosomal instability. This review focuses on molecular processes involved in telomere maintenance and chromosomal instability associated with dysfunctional telomeres in mammalian cells.Received 24 July 2003; received after revision 5 September 2003; accepted 11 September 2003     

Mechanisms controlling germline cyst breakdown and primordial follicle formation

In fetal females, oogonia proliferate immediately after sex determination. The progress of mitosis in oogonia proceeds so rapidly that the incompletely divided cytoplasm of the sister cells forms cysts. The oogonia will then initiate meiosis and arrest at the diplotene stage of meiosis I, becoming oocytes. Within each germline cyst, oocytes with Balbiani bodies will survive after cyst breakdown (CBD). After CBD, each oocyte is enclosed by pre-granulosa cells to form a primordial follicle (PF). Notably, the PF pool formed perinatally will be the sole lifelong oocyte source of a female. Thus, elucidating the mechanisms of CBD and PF formation is not only meaningful for solving mysteries related to ovarian development but also contributes to the preservation of reproduction. However, the mechanisms that regulate these phenomena are largely unknown. This review summarizes the progress of cellular and molecular research on these processes in mice and humans.     

Non-B DNA structure-induced genetic instability and evolution

Repetitive DNA motifs are abundant in the genomes of various species and have the capacity to adopt non-canonical (i.e., non-B) DNA structures. Several non-B DNA structures, including cruciforms, slipped structures, triplexes, G-quadruplexes, and Z-DNA, have been shown to cause mutations, such as deletions, expansions, and translocations in both prokaryotes and eukaryotes. Their distributions in genomes are not random and often co-localize with sites of chromosomal breakage associated with genetic diseases. Current genome-wide sequence analyses suggest that the genomic instabilities induced by non-B DNA structure-forming sequences not only result in predisposition to disease, but also contribute to rapid evolutionary changes, particularly in genes associated with development and regulatory functions. In this review, we describe the occurrence of non-B DNA-forming sequences in various species, the classes of genes enriched in non-B DNA-forming sequences, and recent mechanistic studies on DNA structure-induced genomic instability to highlight their importance in genomes.     

Glutathione instability in stored blood

Zusammenfassung Das Sinken der Glutathionstabilität und der Pentosenbildung nach Inkubation mit Glucose und Glucose mit Methylenblau während der Blutlagerung wurde beobachtet. Die Glutathioninstabilität kann durch Präinkubation mit Adenosin normalisiert werden.     

Chromosome instability and deregulated proliferation: an unavoidable duo

The concept that aneuploidy is a characteristic of malignant cells has long been known; however, the idea that aneuploidy is an active contributor to tumorigenesis, as opposed to being an associated phenotype, is more recent in its evolution. At the same time, we are seeing the emergence of novel roles for tumor suppressor genes and oncogenes in genome stability. These include the adenomatous polyposis coli gene (APC), p53, the retinoblastoma susceptibility gene (RB1), and Ras. Originally, many of these genes were thought to be tumor suppressive or oncogenic solely because of their role in proliferative control. Because of the frequency with which they are disrupted in cancer, chromosome instability caused by their dysfunction may be more central to tumorigenesis than previously thought. Therefore, this review will highlight how the proper function of cell cycle regulatory genes contributes to the maintenance of genome stability, and how their mutation in cancer obligatorily connects proliferation and chromosome instability.     

Prediction and explanation of chemical mutation sites

Résumé En ce qui concerne I'ARN du VMT, les codons voisins y présentent des arrangements analogues. Il s'agit seulement des codons qui subissent une mutation sous l'action de l'acide nitreux, mutation qui conduit à une modification de la protéine de l'enveloppe. Cette observation suggère, que l'examen minutieux de la séquence d'un acide nucléique pourrait permettre de prédire les sites probables où aura lieu la mutation chimique et que les «hot spots» pour une mutation spontanée pourraient aussi avoir des codons voisins caractéristiques.     

Model instability in predictive exchange rate regressions

In this paper we aim to improve existing empirical exchange rate models by accounting for uncertainty with respect to the underlying structural representation. Within a flexible Bayesian framework, our modeling approach assumes that different regimes are characterized by commonly used structural exchange rate models, with transitions across regimes being driven by a Markov process. We assume a time-varying transition probability matrix with transition probabilities depending on a measure of the monetary policy stance of the central bank at home and in the USA. We apply this model to a set of eight exchange rates against the US dollar. In a forecasting exercise, we show that model evidence varies over time, and a model approach that takes this empirical evidence seriously yields more accurate density forecasts for most currency pairs considered.     

A possible correlation between reverse mutation and complementation

Résumé Les mutants présentant la complémentation intra-allélique sont probablement susceptibles aussi de mutation reversé vraie sous l'effet de l'acide nitreux.     

Protein profiling of genomic instability in endometrial cancer

DNA aneuploidy has been identified as a prognostic factor in the majority of epithelial malignancies. We aimed at identifying ploidy-associated protein expression in endometrial cancer of different prognostic subgroups. Comparison of gel electrophoresis-based protein expression patterns between normal endometrium (n?=?5), diploid (n?=?7), and aneuploid (n?=?7) endometrial carcinoma detected 121 ploidy-associated protein forms, 42 differentially expressed between normal endometrium and diploid endometrioid carcinomas, 37 between diploid and aneuploid endometrioid carcinomas, and 41 between diploid endometrioid and aneuploid uterine papillary serous cancer. Proteins were identified by mass spectrometry and evaluated by Ingenuity Pathway Analysis. Targets were confirmed by liquid chromatography/mass spectrometry. Mass spectrometry identified 41 distinct polypeptides and pathway analysis resulted in high-ranked networks with vimentin and Nf-κB as central nodes. These results identify ploidy-associated protein expression differences that overrule histopathology-associated expression differences and emphasize particular protein networks in genomic stability of endometrial cancer.     

程序数值误差的扰动检测与优化

很多用于关键领域的数值计算程序使用浮点数格式作为数据的内部表示,但由于浮点数在表示上存在误差,这类程序的正确性很难得到完全的保障.本文提出了一种自动的检测途径来帮助应用程序的开发人员获得他们所写代码的稳定性信息.它通过两种具体的扰动技术——数值扰动与算式扰动,来扰动底层的数值量和计算步骤,统计扰动下的运算差异,并最终评估数值计算代码的稳定性.数值扰动随机动态地改变程序数值的有效数字尾数,通过模拟误差的引入来观测程序的计算结果是否稳定;而算式扰动针对程序中算术表达式的计算过程,通过程序变换方法,将其转换成在实数域等价,但语法上不同的形式,然后以这些算式在浮点数下执行结果的差异来判断数值计算过程的稳定性.更进一步,本文使用了并行扰动算法和蒙特卡罗（Monte Carlo）方法来提高扰动技术的处理规模.当用户的硬件资源较丰富时,扰动技术将利用并行算法来提高运行效率;而当硬件资源不足时,蒙特卡罗方法也能在较短时间内得到一个可以接受的结果.我们对本文所提出的技术做了实现,并对文献中采用的一系列数值程序和GNU科学计算库（GSL）做了评估,评估结果显示,本文为数值计算稳定性的自动测试提供了一种实用技术.     

Defending the genome from the enemy within: mechanisms of retrotransposon suppression in the mouse germline

The viability of any species requires that the genome is kept stable as it is transmitted from generation to generation by the germ cells. One of the challenges to transgenerational genome stability is the potential mutagenic activity of transposable genetic elements, particularly retrotransposons. There are many different types of retrotransposon in mammalian genomes, and these target different points in germline development to amplify and integrate into new genomic locations. Germ cells, and their pluripotent developmental precursors, have evolved a variety of genome defence mechanisms that suppress retrotransposon activity and maintain genome stability across the generations. Here, we review recent advances in understanding how retrotransposon activity is suppressed in the mammalian germline, how genes involved in germline genome defence mechanisms are regulated, and the consequences of mutating these genome defence genes for the developing germline.     

Genomic instability in breast and ovarian cancers: translation into clinical predictive biomarkers

Breast and ovarian cancer are among the most common malignancies diagnosed in women worldwide. Together, they account for the majority of cancer-related deaths in women. These cancer types share a number of features, including their association with hereditary cancer syndromes caused by heterozygous germline mutations in BRCA1 or BRCA2. BRCA-associated breast and ovarian cancers are hallmarked by genomic instability and high sensitivity to DNA double-strand break (DSB) inducing agents due to loss of error-free DSB repair via homologous recombination (HR). Recently, poly(ADP-ribose) polymerase inhibitors, a new class of drugs that selectively target HR-deficient tumor cells, have been shown to be highly active in BRCA-associated breast and ovarian cancers. This finding has renewed interest in hallmarks of HR deficiency and the use of other DSB-inducing agents, such as platinum salts or bifunctional alkylators, in breast and ovarian cancer patients. In this review we discuss the similarities between breast and ovarian cancer, the hallmarks of genomic instability in BRCA-mutated and BRCA-like breast and ovarian cancers, and the efforts to search for predictive markers of HR deficiency in order to individualize therapy in breast and ovarian cancer.     

The dynamic and stochastic instability of betas: Implications for forecasting stock returns

The purpose of this paper is to simultaneously investigate several important issues that feature the dynamic and stochastic behavior of beta coefficients for individual stocks and affect the forecasting of stock returns. The issues include randomness, nonstantionarity, and shifts in the mean and variance parameters of the beta coefficient, and are addressed within the framework of variable-mean-response (VMR) random coefficients models in which the problem of heteroscedasticity is present. Estimation is done using a four-step generalized least squares method. The hypotheses concerning randomness and nonstationarity of betas are tested. The time paths, sizes, and marginal rates of mean shifts are determined. The issue of variance shift is examined on the basis of five special tests, called T*, B, S', G and W. Then the impacts of the dynamic and stochastic instability on the estimation of betas is tested by a nonparametric procedure. Finally, the VMR models' ability of forecasting stock returns is evaluated against the standard capital asset pricing model. The empirical findings shed new light on the continuing debate as to whether the beta coefficient is random and nonstationary and have important implications for modeling and forecasting the measurement of performance and the determination of stock returns.